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Radiation therapy in pituitary adenomasBergh, Alphonsus Cornelis Maria van den

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Radiation therapy in pituitary adenomas

Fons van den Bergh

Design: TiekstraMedia, Groningen

The thesis was financially supported by:

Stichting Onderwijs en Onderzoek Radiotherapie UMC Groningen

Integraal Kankercentrum Noord Oost

Groninger Endocrinologie Stichting

Endocrinologie UMCG

Astellas

AstraZeneca

Merck Serono

Pfizer

Sanofi-Aventis

Graduate School GUIDE

Wowww!

© 2008 A.C.M. van den Bergh, Groningen, The Netherlands

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or

transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise

without prior written permission of the author.

ISBN 978-90-367-3490-5


Proefschrift

ter verkrijging van het doctoraat in de Medische Wetenschappen

aan de Rijksuniversiteit Groningen

op gezag van de Rector Magnificus, dr. F. Zwarts,

in het openbaar te verdedigen op

woensdag 3 september 2008 om 13.15 uur

door

Alphonsus Cornelis Maria van den Bergh

geboren op 30 augustus 1960

te Halsteren

Promotores

Prof. dr. J.A. Langendijk

Prof. dr. B.H.R. Wolffenbuttel

Copromotores

Dr. R.P.F. Dullaart

Dr. J.W.R. Pott

Beoordelingscommissie

Prof. dr. J.J. Battermann

Prof. dr. A.R.M.M. Hermus

Prof. dr. J.J.A. Mooij

Contents

Chapter 1 7

Introduction

Chapter 2 29

Immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma:

beneficial effect on local control without additional negative impact on pituitary function

and life expectancy

Chapter 3 47

Radiotherapy is not associated with reduced quality of life and cognitive function in

patients treated for nonfunctioning pituitary adenoma

Chapter 4 65

Radiation optic neuropathy after external beam radiation therapy for acromegaly:

report of two cases

Chapter 5 73

review article

Radiation optic neuropathy after external beam radiation therapy for acromegaly

Chapter 6 91

Lack of radiation optic neuropathy in 72 patients treated for pituitary adenoma

Chapter 7 105

Tyrosine positron emission tomography and protein synthesis rate in pituitary adenoma:

different effects of surgery and radiation therapy

Chapter 8 117

Patient position verification with oblique radiation beams

Chapter 9 133

General discussion

Summary 141

Samenvatting 147

Publicationlist 155

Dankwoord 159

1 Introduction to


Chapter 1

8

Figure 1

Midsagittal view of the pituitary gland in relation to the bony structures

and the brain (adapted from Netter)

Figure 2

View on the caudal side of the brain, showing the pituitary gland

in relation to the optic structures and other cranial nerves (adapted from Netter).

Introduction

9

Introduction

A multidisciplinary approach is currently preferred in diagnosis and treatment deci-

sion-making in pituitary adenoma patients. In the multidisciplinary neuro-endocrine

meetings of the University Medical Center Groningen, the clinical benefits as opposed to

potential side effects of radiation therapy, as reported by other centres, were frequently

debated, resulting in suboptimal consistency in our approach to this patient category.

In order to increase our understanding of the clinical consequences of (post-operative)

radiation therapy as compared to no radiation therapy, it was decided to evaluate the

outcome of this treatment among pituitary adenoma patients treated in our institution

during the past decades. The single-centre cohort studies described in this thesis are

aimed to improve evidence-based decision-making in pituitary adenoma patients.

Pituitary Anatomy

The pituitary gland is a bean-shaped small organ, located in the sellar fossa, in the

centre of the skull base at the base of the brain. The word “pituitaria” is derived from

the Greek word “ptuo”, which means “spew” and the Latin word “ptuita” (mucus). The

normal size of the gland is approximately 10 mm in length, 5 to 10 mm in height and 10

to 15 mm in width (Figure 1 and Figure 2). The normal weight is 500-600 mg. This organ

plays a central role in hormone regulation; it integrates hormonal signals that control

adrenal, thyroid, reproductive, growth, and metabolic functions.

The pituitary gland is divided in the anterior and the posterior lobe, the so-called

adeno- and neurohypophysis. The anterior lobe contains 75 percent of the pituitary gland,

in which different hormones are produced. The most important are: growth hormone

(GH), prolactin (Pr), adrenocorticotrophic hormone (ACTH), thyrotropin (TSH), luteinising

hormone (LH) and follicle-stimulating hormone (FSH), produced by at least 5 different cell-

types. These different cell types are clustered and have their own position in the pituitary

gland; ACTH and TSH in the centre of the anterior pituitary lobe and PR and GH at both

lateral sides. The posterior lobe is a storage for anti-diuretic hormone (ADH) and oxytocin,

produced in the hypothalamus. The pituitary gland has a connection with the hypothala-

mus via the pituitary stalk and portal system. Neighbouring structures are the optic chi-

asm and optic nerves antero-superior, the sphenoid sinus antero-inferior, the cavernous

sinus and the cranial nerves III, IV, V and VI at both lateral sides and dorsal the clivus.

Pituitary adenomas

Pituitary adenomas originate only in the anterior lobe. In the vast majority of cases,

they are monoclonal and are characterised by complete disruption of the reticulin fi-

Chapter 1

10

bre network in contrast to pituitary hyperplasia1. These adenomas are benign lesions,

comprising 10-15% of all intracranial tumours2,3. Pituitary adenomas can be divided

in secreting and non-secreting tumours. Secreting tumours produce an excess of pi-

tuitary hormones with each its own syndrome: Pr (Prolactinoma), GH (Acromegaly,

gigantism), ACTH (Cushing’s disease), TSH (Thyrotrophinoma), and LH/FSH (Gonado-

trophinoma). Although almost all pituitary adenomas are classified as benign, many of

these lesions are locally invasive and cause major morbidity and mortality. The patho-

genetic mechanism in pituitary tumour genesis is complex and enigmatic4.

Incidence en prevalence

The incidence for all pituitary adenomas is estimated at 80 million persons per year.

An increase in the incidence is reported in the time period 1958-1991 in Sweden3. The

peak incidence occurs in the fourth to the sixth decade of life5. Incidence and prevalence

numbers for the Netherlands are not available.

In a systematic review, the prevalence of pituitary adenomas in the general popu-

lation has been estimated at 16.7% (14.4% in autopsy studies and 22.5% in radiologic

studies). The prevalence of macroadenomas (>1 cm) has been estimated at 0.16-0.2%6.

These figures contradict the conventional view of pituitary tumours as rare; pituitary

adenomas are in fact common in the general population.

Approximately 25% of all pituitary adenomas are clinically non-functioning/

non-secreting (NFA). The incidence is estimated at 10 per million persons per year. In

Belgium, the prevalence of clinically significant non-secreting pituitary adenomas was

138/1.000.000. The male to female ratio is estimated at: 3 : 28.

The incidence of prolactin producing pituitary adenomas (PR) is estimated at

6-10 per million persons per year and the prevalence at 60-100 per million9. A female

preponderance is observed of 20 to 1 in microadenomas; in macroadenomas female to

male ratio is equal.

The incidence of growth-hormone producing pituitary adenomas (GH) is esti-

mated at 4-6 per million persons per year and the prevalence at 40-60 per million9,10. The

incidence of ACTH producing pituitary adenomas (ACTH) is estimated at 2-3 per million

persons per year and the prevalence at 20-30 per million9.

TSH (Thyrotrophinoma) and LH/FSH (Gonadotrophinoma) are rare pituitary ade-

nomas9. Because of their rarity these tumours are not discussed in detail.

Clinical symptoms

NFAs, frequently macroadenomas, usually present with signs as a result of local mass

effect and extension outside the sella turcica. Symptoms are bitemporal hemianopsia,

decreased visual acuity, ophthalmoplegia and signs and symptoms as a consequence of

hormonal insufficiency. Loss of vision due to NFA is caused by compression of the optic

Introduction

11

system and results in visual field defects in 85% and in complete blindness in 2% of NFA-

patients8. Ophthalmoplegia is caused by invasion of the tumour in the cavernous sinus,

compressing the third, fourth and sixth cranial nerve.

Hypopituitarism due to pituitary adenoma is caused directly by destruction or

compression of normal pituitary tissue or indirectly due to compression of the pitu-

itary stalk or of the portal circulation with focal necrosis of normal pituitary tissue as

a result11. The prevalence of hypopituitarism is largely restricted to macroadenomas12.

Features of pituitary insufficiency include decreased libido and/or erectile dysfunction

in men, irregular menses or amenorrhea in premenopausal women, and fatigue (thyroid

hormone, cortisol, GH deficiency or deficiencies).

Secreting pituitary adenomas are in general smaller than NFA at the time of diag-

nosis, because their symptoms are based on excessive hormone production.

Prolactinoma with its hypersecretion of prolactin in women can result in irregu-

lar menses or amenorrhea, galactorrhea and loss of libido. In men, loss of libido and

impotence is observed.

With GH excess, leading to the syndrome of acromegaly, features develop insidi-

ously over decades, often resulting in a delay of 5 to 10 years in diagnosis after the esti-

mated onset of symptoms. Symptoms are enlargement of the acra (facial bones, hands

and feet), paresthesias, excessive sweating, arthropathy, headache, tiredness, and sleep

apnoea.

Cushing’s disease is caused by ACTH overproduction and characterized by weight

gain, centripetal fat distribution, fatigue, memory loss, irritability, depression, muscle

weakness, osteoporosis and purple striae.

Mortality

Overall mortality is reported to be higher in pituitary adenoma patients in comparison

with the normal population, primarily as a result of cardiovascular and cerebrovascular

disease3.

In a large cohort of mainly non-functioning pituitary adenomas of the Royal

Marsden Hospital, the overall age adjusted relative risk (RR) of death was 1.76 in com-

parison with the normal population13. The few deaths from progressive pituitary ade-

noma and from second brain tumours accounted for only a small excess mortality. An

increased mortality was reported due to cerebrovascular accidents. In the pituitary ade-

noma cohort of 334 patients, treated between 1962 and 1986, 128 deaths were observed

versus 80.9 expected (RR of death: 1.58 (95% CI: 1.32 - 1.9). Of these 128 deaths, 33 (26%)

were due to cerebrovascular deaths compared with 8.04 expected (RR 4.11: 95%CI: 2.84 -

5.75). Three of the 33 cerebrovascular deaths were due to subarachnoidal haemorrhage,

compared to 0.54 expected deaths (RR 5.51: 95%CI: 1.14 -16.09). Any relationship with

hypopituitarism, extent of surgery or radiation therapy could not be found.

Chapter 1

12

The Danish registry however reported no increased mortality due to cardiovascu-

lar and cerebrovascular disease. In this study, type of surgery and radiation therapy were

not identified as risk factors, while female sex was a risk factor8. Moreover, no increased

mortality due to malignant disease was reported in all kinds of pituitary adenoma8.

Other groups however, report an increased mortality in incompletely controlled

acromegaly patients in comparison with the general population due to cardiovascular

and malignant disease14,15.

Patients with untreated Cushing’s syndrome have excess mortality 16.

Treatment modalities

Active surveillance

An incidentaloma, most frequently a microadenoma (<1 cm), is diagnosed in about 10

percent of healthy persons on MRI, made for other reasons17,18.

Patients with an incidentaloma have a slightly increased risk of morbidity and

mortality, which implies a benefit of early diagnosis19. Therefore a conservative approach

with repeat scanning done at yearly intervals is suggested17.

Medication

Non-functioning pituitary adenomas in general do not respond to medical treatment20.

Patients with a prolactinoma have a treatment response of 95% on dopamine-agonists

and therefore medical treatment is the first choice.

Acromegalic patients respond in 65% of the cases on somatostatin analogues and

in more than 90% on Pegvisomant, a GH-receptor antagonist. Side-effects of somatosta-

tin analogues are diarrhea in 11%, flatulence in 8%, hair loss in 8%, episodically abdomi-

nal cramps in 3%, and gallbladder abnormalities in <10% of the patients. Pegvisomant is

expensive and in general does not result in tumour shrinkage21 and may even result in

tumour growth22.

In case of Cushing’s disease, medication is directed at decreasing adrenal steroid

secretion (e.g. ketoconazole, metyrapone, aminoglutethimide). These drugs frequently lose

effectiveness when the decrease in cortisol secretion results in enhanced ACTH secretion,

leading to escape from the competitive blockade on adrenal steroid biosynthesis. Long-

term ketoconazole is not recommended because of the risk of liver function impairment.

Mortality due to medication has not been reported.

Surgery

Surgery was first used by Horsley in 1889 but was refined by Cushing23. The treatment of

choice is either transsphenoidal or transcranial neurosurgical adenomectomy, aiming

at complete tumour removal or decompression of surrounding structures. The trans-

Introduction

13

sphenoidal approach usually allows for potential resection of a sellar tumour without

entering the subarachnoid space, thereby minimizing the risk of complications such as

cerebrospinal fluid leakage or meningitis. Complete surgical removal is often impossi-

ble, because of the invasive character of microadenomas and larger pituitary adenomas,

with infiltration of the neighbouring structures such as arachnoid membrane, dura,

sinus cavernosus and the skull base24,25.

The neurosurgeon’s conclusions on complete resection during operation is dif-

ferent from the conclusions on MRI26. This clarifies the statement of Turner et al. who

demonstrated that the surgeon’s assessment of complete surgical removal was unre-

lated to recurrence27. Specialization improves the outcome of pituitary surgery with less

morbidity and mortality28. Differences in results among centres for pituitary surgery

should be interpreted with caution even for those confined to comparable criteria of

remission28. Nowadays minimal invasive neurosurgery i.c. endoscope assisted trans-

sphenoidal microsurgery is applied29.

Non-functioning pituitary adenomas are most frequently macroadenomas at

diagnosis. In 90% of the cases, only a partial resection can be performed30.

Concerning prolactinoma, surgery is only rarely performed, in case of resistance

or intolerance to medication.

In regard to acromegaly, 75% of the tumours are macroadenomas, which often

extends laterally into the cavernous sinus or dorsally to the suprasellar region10. The

cure rate with surgery alone for intrasellar lesions is 59-95%21,28 and for larger tumours

26-68%21,28. Intraoperative GH-measurements and intraoperative MRI, can improve re-

sults31,32.

For Cushing’s disease, the immediate postoperative cure rate after first surgery

for microadenomas varies between 78-97% and for macroadenomas between 50-60%33.

After curative resection, the recurrence percentage is 5-25%34.

Although small series have shown, that neurosurgery can improve pituitary hy-

pofunction11,35-38, more often deterioration of the pituitary function will occur30. Other

specific side effects of surgery are leakage of cerebrospinal fluids, some degree of nasal

discomfort and transient diabetes insipidus or mild SIADH (syndrome of inappropriate

vasopressin secretion).

The mortality rate of neurosurgery is reported to vary between 0.26 and 3%39.

Radiation therapy

External beam radiation therapy for pituitary adenomas has been applied for more than

100 years and the first results were reported by Beclere and Gramegna, two French physi-

cians in 190940.

Because of a high operative mortality in the early 20th century, radiation therapy

was a primary method of treatment at that time. Surgery, however, was the only method

Chapter 1

14

to restore vision. Gradually, it was discovered that surgery followed by radiation therapy

was more effective than surgery alone41. In the sixties, there were differences in opi-

nion regarding the role of radiation therapy in NFA. Some investigators in the USA advo-

cated primary radiation therapy, but others recommended surgery followed by radiation

therapy, promoted also by the British and Scandinavian schools. Nowadays, because of

improved neurosurgical techniques, surgery is the treatment of choice in NFA with com-

pression. Primary radiation therapy is only applied if the patient refuses surgery or the

general condition of the patient does not allow neurosurgery.

Immobilisation of the head of the patient to apply more precisely the radiation

therapy to the tumour has been improved, starting with no immobilisation devices, fol-

lowed by tape and later on by immobilisation masks and stereotactic frames.

Outlining the tumour for target volume definition in radiation therapy has been

improved due to better imaging techniques. In the beginning, plain skull films, pneumo-

encephalography and later on cerebral angiography were used in outlining the tumour

with its suprasellar and parasellar extension. Since the availability of CT-scans in the

seventies this technique has been used for tumour outlining, followed by MRI 10 years

later. Nowadays, MRI is the preferred modality - if applicable and available - for primary

evaluation of the pituitary gland and outlining the tumour for radiation therapy co-

registered with the planning-CT scan42.

Radiation therapy treatment schedules

Between 1930 and 1945 the general approach was to use multiple courses of low-dose

radiation, repeated at intervals of 4 to 8 weeks. In general, a total of 3 to 5 courses were

applied, guided by patient’s visual response. Daily doses of 200 rads were used to a total

dose ranging from 2450 to 3000 rads per course.

Between 1945 and 1955, this policy changed into multiple courses of medium dose

radiation (i.e. total dose of 30-40% more per course) and repeated with shorter intervals.

From 1955 the multiple course approach was abandoned because it was more dele-

terious for the normal tissues, due to the total accumulated dose of the different courses

in a shorter overall treatment time. Since then, single-course high dose radiation therapy

has generally been applied, intended to deliver a radiation dose sufficiently high to achieve

permanent tumour control. The total dose increased in time from 2000 to 3000 rads in 2-3

weeks, to 3500 to 4500 rads in 4 to 5 weeks. Occasionally, the total dose exceeded 5000 rads

in 5-6 weeks, based on higher success rates (i.e. improved vision) with a higher dose.

In 1953 the International Commission on Radiological Units and Measurements

introduced the concept of absorbed dose and defined its unit, the rad. The rad was in

use until the introduction after 1960 by Le Systeme Internationale (SI) of the SI unit for

absorbed dose, called “Gray”, defined as J/kg. 100 rad is 1 J/kg is 1 Gray.

Introduction

15

In the sixties an initial slow build-up treatment with a small daily increment of

25 to 50 cGray for the first three to four days was applied in order to minimize any radia-

tion-induced edema in the optic chiasm. Nowadays, we have abandoned the incremen-

tal dose in the first treatment week and the most frequently used schedules are 23 to 25

fractions with a total dose of 45 to 50 Gray. Higher doses do not improve local control43.

Besides fractionation, the radiation source used also changed in time, based on

technical improvements. In the period 1930 to 1940 200 kV photons were used, followed

by 250 kV photons in the period 1940 to 1960. In 1955 the 25 MeV betatron came into use,

followed in 1962 by the cobalt 60 machine. In 1966 the introduction of the linear accele-

rator was started, generating 6MV photons, still in use nowadays.

The irradiation techniques evolved in time as well; the older two lateral opposed

field technique irradiated a large volume normal brain with an equivalent or even higher

dose of what was applied to the tumour with reports of brain necrosis as a result of that.

This technique was replaced by at least a three-field technique, consisting of 2 lateral

fields and one vertex field, or a plan with multiple fields with wedges, following a bi-

coronal 1100 arc, better targeting the high dose to the tumour and reducing the high dose

volume in the normal brain. Both coplanar techniques are still in use today44.

Since the availability of 3D radiation treatment planning systems in the nineties

of the previous century, non-coplanar radiation techniques became possible. It became

clear that for stereotactically guided conformal radiation therapy to volumes above 13

ml, four to six non-coplanar fixed fields are clearly superior to coplanar field arrange-

ments, whereas even techniques approaching dynamic conformal radiation therapy

such as a 30-field approach reveal no further sparing of normal brain tissue45. This tech-

nique has been introduced in the Radiation Oncology Department of the University

Medical Center Groningen in 2001.

Non-functioning pituitary adenoma

Most NFAs are incompletely resected, because they are inaccessible for complete resec-

tion for the neurosurgeon due to the critical structures in this area. In case of residual

disease, it has been reported that immediate postoperative radiation therapy results in

high local control rates of 90-95%13 and that an active surveillance policy results in a

high local recurrence rate (50-80%) within 10 to 15 years27. The reason to postpone ra-

diation therapy in case of residual disease is that in most series ultimate local control

rates with active surveillance policies, with salvage radiotherapy in case of regrowth, are

similar to immediate postoperative radiation therapy. In addition, it has been assumed

that delay of radiation therapy can prevent or delay hypopituitarism with its additional

sequelae. One should be aware of the fact that the pituitary function is already affected

in 50% of the cases immediately after first surgery54.

Chapter 1

16

Prolactinoma

For prolactinoma, reported cure rates after radiation therapy alone or in combination

with surgery vary between 25% and 93% respectively34,44. Radiation therapy in prolacti-

noma patients is currently only rarely applied.

GH-secreting pituitary adenoma

In acromegaly, radiation therapy can realize a reduction in GH excess of 30-50% in the

first year, followed by 10-15% in the years thereafter. Despite the development of potent

medical therapies and the improvement of neurosurgical techniques at least 10-20% of

patients will need any form of radiation therapy. In addition to decreasing GH excess,

radiation therapy has been shown to influence favourably the clinical consequences of

the reduction in soft tissue excess, visual symptoms, headache and glucose intolerance,

thereby confirming a favourable impact on the disease21.

ACTH-secreting pituitary adenoma

For Cushing’s disease reported cure rates after radiation therapy alone or in combina-

tion with surgery vary between 50% and 80% respectively34,44,46.

Mortality and radiation therapy

Increased mortality due to radiation therapy is a subject for debate. It was already men-

tioned that in a large cohort of mainly non-functioning pituitary adenomas the overall

age adjusted relative risk (RR) of death was 1.76 in comparison with the normal popula-

tion13. A possible risk factor, mentioned in this cohort for increased mortality, was radia-

tion therapy, but this factor showed no statistical significance.

The Danish registry however reported no increased mortality due to cardiovas-

cular and cerebrovascular disease. In this study surgery type and radiation therapy were

not identified as risk factors, while female sex was a risk factor8. Moreover, no increased

mortality due to malignant disease was reported in all kinds of pituitary adenoma8.

Side-effects of radiation therapy

Acute side-effects

Acute side-effects due to fractionated radiation therapy are mild to moderate erythema,

dry desquamation47,48, otitis externa47,49, otitis media47,49, tinnitus49, olfactory and gustatory

changes49,50, temporary localized epilation at the beam entrance and exit depending on the

Introduction

17

radiation dose47,50,51, headache49 and mild transient post radiation therapy somnolence52. In

general, all these side-effects are minor, well tolerated and self-limiting in most patients50.

Late side-effects

Late side-effects or toxicity of the normal tissues due to radiation therapy will - as a

general radiobiological rule – be smaller in fractionated radiation therapy. The risk of

radiation-induced complications is expected to be rare with modern equipment, mod-

ern techniques and current recommended doses of 45 to 50 Gray in 1.8 Gray fractions in

an overall treatment time of 5 weeks53.

Hypopituitarism

In the past, the normal pituitary gland has been thought to be relatively radioresistant,

tolerating doses up to 190 Gray without showing pathological damage. In time it became

clear that radiation therapy can induce hypopituitarism54. It is the most prevalent late

side effect as a result of direct damage to the pituitary and also secondary to hypotha-

lamic damage55, as is evidenced by appropriate pituitary responses to administration

of exogenous hypothalamic releasing hormones56-58. There is some evidence to suggest

that direct injury to hypothalamic neurones, rather than reduced cerebral blood flow, is

the major cause of progressive hypothalamic-pituitary dysfunction after fractionated

cranial irradiation. Direct damage to the cell nuclei in the hypothalamus may explain

the delayed onset of hormone deficiency, because these cells are dividing slowly and die

during mitosis years later before losing their function59. Radiation doses in excess of 50

Gray can have a direct effect upon pituitary function. However, at doses below 50 Gray,

hypopituitarism may initially be caused by hypothalamic dysfunction60.

Radiation-induced hypopituitarism depends, besides on the total dose, on fraction

size61. It increases in time for at least 10 years62. The severity, as measured by the number of

anterior pituitary hormone deficiencies, depends on the total dose. Higher radiation dose

given to the pituitary gland will result in a more rapid onset of hypopituitarism60. Among

patients who developed multiple hormone deficiencies, the most frequent order of loss of

anterior pituitary hormone function was GH, followed by LH/FSH, ACTH and then TSH.

Permanent radiation induced diabetes insipidus has not been reported 30,61. An

explanation for the difference in radiosensitivity between the anterior and posterior

pituitary lobe might be that the posterior lobe is only a storage place for hormones.

Pituitary function and pregnancy

In young adults with normal postoperative pituitary function and wish of future sib-

lings, some advocate not to give radiation therapy in order to avoid the possibility of

Chapter 1

18

radiation-induced hypopituitarism, even if there is an increased risk on tumour recur-

rence with all its consequences63. Infertility due to hypopituitarism in men and women

can be corrected with exogenous gonadotropins64,65.

Cerebrovascular disease (CVD)

A relationship between radiation therapy for pituitary adenoma and (as a consequence)

CVD has not been found66. Cerebral infarctions manifested at intervals of 3.2-14.6 years

after RT. Three out of seven patients with cerebral infarction had evidence of vascular

disease outside the treatment field. Only age was a negative prognostic factor.

Out of 331 patients of The Royal Marsden cohort, 64 developed CVD after primary

treatment of pituitary adenoma. In comparison with the normal population there was a

relative risk of 4.1 (95% CI: 3.6-4.7%). The actuarial incidence of CVD after primary treatment

of pituitary adenoma was 4% (95% CI: 2-7%) at 5 years, 11% (95% CI: 8-14%) at 10 years, and

21% (95% CI: 16-28%) at 20 years measured from the date of radiation therapy. In this cohort,

age, radiation therapy dose and extent of surgery were independent predictors for CVD.

Erfurth et al. stated that radiation therapy might act as a risk factor for CVD, but

not stronger than other risk factors for CVD in all types of pituitary patients67. Until this

moment it is not clear if applied radiation therapy is a risk factor in relation to CVD

afterwards.

Tumour induction

Tumour induction inside the brain

A cumulative risk of tumour induction inside the brain after surgery and radiation thera-

py of 1.3% (95%CI: 0.4-3.9%) to 2% (95%CI: 0.9-4.4%) over the first 10 years, and of 1.9%

(95%CI: 0.7-5%) to 2.4% (95% CI: 1.2-5%) over the first 20 years has been reported68,69. The

relative risk of a secondary brain tumour as compared to the incidence in the normal

population is 9.4. The median time to detection is 7 years for glioma, 9.7 years for sar-

coma and 13.8 years for meningioma.

However, no firm support for an increased incidence of a second brain tumour

is found by others in a cohort of 279 NFA patients treated between 1931 and 1988. Two

astrocytomas – 7 and 24 years after irradiation - and one meningioma – 19 years after

irradiation - were found (RR 2.7: 95%CI; 0.6-7.8) 70.

A genetic trait that predisposes to both pituitary tumours and brain tumours is

an alternative causal factor. To support this idea, there are reports of the co-occurrence

of meningioma and pituitary adenoma in non-irradiated patients71. Radiation-induced

meningiomas differ from “spontaneous meningiomas” in location, multiplicity and ag-

gressive biological behaviour72.

Introduction

19

There is no evidence that cranial irradiation per se is the causal factor. A cohort

study of non-irradiated pituitary tumour patients, who have the same initial malignan-

cy, is needed.

Tumour induction outside the brain

A relative risk for malignant tumours outside the brain of 3.91 is reported in patients

with NFA in comparison with the general population73. The absolute incidence in the

general population is estimated at 0.45%. In acromegalic patients the risk is not in-

creased in comparison with NFA patients73. However, no significant excess for cancer

outside the brain is seen by others in pituitary patients in comparison with the general

population69,74. The role of radiation therapy as risk factor is not yet clear and should be

balanced with the probably already increased risk without radiation therapy.

Brain necrosis

The overall incidence of brain necrosis has been estimated at 0.2%75. This incidence will

decline with modern equipment, such as stereotactic radiotherapy, and the currently

recommended doses.

Radiation Optic Neuropathy (RON)

A prevalence of 0.53% for Radiation Optic Neuropathy in NFA has been reported76. The

incidence will decline with modern radiation therapy equipment and current recom-

mended radiation therapy doses. An effective treatment for RON is not available76.

Permanent radiation induced damage of the cranial nerves III, IV, V and VI has not

been reported in series with modern radiation therapy equipment and currently recom-

mended radiation therapy doses.

Cognitive function

Patients with pituitary tumours may have impairment of both memory and executive

function. No correlation has been found with tumour size and type77. The decrease in

cognitive function seemed to be more pronounced among those treated with radiation

therapy and mainly affected the executive function78. No short-term memory loss have

been observed that is clearly attributed to radiation therapy50,79.

Research suggests that the pathogenesis of radiation induced neurocognitive

deficit may involve radiation induced injury to proliferating neuronal progenitor cells

in the subgranular zone of the hippocampus, which is a critical neurological centre for

learning and memory80.

Chapter 1

20

One should be aware that others reported no cognitive impairment due to ra-

diation therapy in GH-deficient pituitary adenoma patients, not receiving GH-replace-

ment81.

Quality of Life

Patients with a pituitary adenoma in general have impairment in both physical and

mental health measures compared with the normal population82. Patients with a non-

functioning adenoma however, have a greater impairment in measures of mental func-

tion than in physical function compared with the normal population and patients with

other pituitary adenomas82.

Page et al. reported impaired quality of life among patients with non-functio-

ning pituitary adenoma who were irradiated, in comparison with those who were not

irradiated. Patients were more depressed and emotionally affected. It remains unclear,

whether these differences are direct effects of radiation therapy or indirect effects due

to hormone abnormality or perception of disease severity83. The reasons why radiation

therapy was applied were not mentioned in this paper and the differences found can be

due to selection bias.

Nielsen et al. used the Short Form and Major depression inventory question-

naires8 to assess quality of life and depression among patients with non-functioning

pituitary adenomas. In transsphenoidally operated patients, mental health scores were

similar to the general population, while in patients that underwent craniotomy, mental

health and mental component scores were lower. Radiation therapy, pituitary status or

repeat surgery did not affect these quality of life dimensions. Age at first operation was

an independent risk factor for reduced physical functioning. There was no influence of

radiation therapy on depression.

Based on these results, it still remains unclear whether quality of life is nega-

tively affected by radiation therapy78.

Introduction

21

Aims of this thesis

The main objective of this thesis is to evaluate the results of radiation

therapy among patients with pituitary adenomas with regard to treatment

efficacy, side-effects and quality of life.

1

To determine the role of radiation therapy in residual non-functioning pitu-

itary adenoma in relation to local control, side effects and overall survival,

as reviewed in the literature and evaluated in our series. Chapter 2

2

To evaluate the influence of radiation therapy on cognitive function and

quality of life in patients with non-functioning pituitary adenoma.

Chapter 3

3

To establish the incidence of RON in acromegaly and its risk factors in the

literature. This side-effect has been evaluated in irradiated acromegalic

patients in the University Medical Center Groningen and is presented in a

complete updated review. Chapter 4-5

4

To establish the incidence of RON in non-functioning pituitary adenomas in

the literature in addition to our own series, presented in the first available

review published on this subject. Chapter 6

5

To investigate the diagnostic role of new-imaging techniques: how are Posi-

tron Emission Tomography (PET) imaging characteristics affected by surgery

and radiation therapy for pituitary adenoma. Chapter 7

6

Finally, we investigated whether the position of head and neck cancer

patients with conformal non-coplanar radiation techniques could be deter-

mined from portal images of oblique radiation beams. Chapter 8

Chapter 1

22

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46:401-406.

2 Immediate postoperative

radiotherapy in residual nonfunctioning

pituitary adenoma: beneficial effect

on local control without additional

negative impact on pituitary function

and life expectancy

Alfons C.M. van den Bergh, M.D.1; Gerrit van den Berg, M.D., Ph.D.2; Michiel A. Schoorl,

M.D.1; Wim J. Sluiter, Ph.D.2; Anton M. van der Vliet M.D.3; Eelco W. Hoving, M.D. Ph.D.4;

Ben G. Szabó M.D., Ph.D.1; Johannes A. Langendijk M.D., Ph.D.1;

Bruce H.R. Wolffenbuttel, M.D., Ph.D.2; Robin P.F. Dullaart, M.D., Ph.D.2

1 Departments of Radiation Oncology, 2 Endocrinology, 3 Radiology, 4 Neurosurgery,

University Medical Center Groningen, Groningen, the Netherlands.

International Journal of Radiation Oncology Biology Physics 2007; 67(3): 863-869

30

Chapter 2

Abstract

Purpose To demonstrate the benefit of immediate postoperative radiotherapy in

residual nonfunctioning pituitary adenoma (NFA) in perspective to the need for

hormonal substitution and life expectancy.

Methods and Materials Retrospective cohort analysis of 122 patients, operated

for NFA between 1979 and 1998. Recurrence was defined as regrowth on com-

puted tomography or magnetic resonance imaging. The occurrence of hormonal

deficiencies was defined as the starting date of hormonal substitution therapy.

Results Seventy-six patients had residual NFA after surgery and received im-

mediate postoperative radiotherapy (Group 1); three patients developed a recur-

rence, resulting in a 95% local control rate at 10 years. Twenty-eight patients had

residual NFA after surgery, but were followed by a wait-and-see policy (Group 2).

Sixteen developed a recurrence, resulting in a local control rate of 49% at 5 years

and 22% at 10 years (p<0.001 compared with Group 1). There were no differences

between Group 1 and 2 regarding the need for substitution with thyroid hormone,

glucocorticoids, and sex hormones before first surgery, directly after surgery and

at end of follow-up. There were no differences in hormone substitution free sur-

vival between Group 1 and Group 2 during the study period after first surgery. Life

expectancy was similar in Group 1 and 2, and their median life expectancy did

not differ from median life expectancy in the general population.

Conclusions Immediate postoperative radiotherapy provides a marked improve-

ment of local control among patients with residual NFA compared to surgery

alone, without an additional deleterious effect on pituitary function and life ex-

pectancy.

30

31

Immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma: beneficial effect on local control without

additional negative impact on pituitary function and life expectancy

Introduction

Pituitary adenomas are benign lesions comprising 10-15% of all intracranial tumours.

Approximately 25% of all pituitary adenomas are clinically nonfunctioning (NFA). An

incidence of 10 cases per million per year of NFAs is estimated1. Most patients present

with symptoms at middle age, because of slow growth and absence of symptoms of

hormonal hypersecretion2. This explains why NFAs are frequently macroadenomas with

extension outside the sellar region.

As NFAs usually present with signs resulting from local mass effect, such as

bitemporal hemianopsia, decreased visual acuity, and hypopituitarism, whereas pa-

tients quality of life may be impaired.

In contrast to other pituitary adenomas such as prolactinoma and growth hor-

mone secreting adenomas, NFAs in general do not respond well to medical treatment3.

Therefore, the treatment of choice is either transsphenoidal or transcranial surgery,

aiming at complete tumour removal or decompression of surrounding structures only.

Because of the invasive character of larger pituitary adenomas, with infiltration of the

neighbouring structures such as arachnoid membrane, dura, sinus cavernosus and the

skull base, complete surgical removal is frequently not achieved4.

Recent studies show a higher progression free survival rate for surgery plus ad-

juvant radiotherapy compared to surgery alone in patients with residual postoperative

NFA5,6.

More frequent anterior pituitary dysfunction7, radiation optic neuropathy8, cere-

brovascular disease9-13, and the induction of secondary tumors14,15 are proposed to be

adverse sequelae of radiotherapy.

This cohort study was initiated to evaluate the role of radiotherapy on local con-

trol in perspective to the need for hormonal substitution therapy, other potential side

effects, and life expectancy in patients with NFAs.

Methods and materials

Patients

Radiologic, neurosurgical, endocrinological and radiotherapy records of all patients

(N = 131) with a NFA who were operated upon at the University Medical Center Groningen

between 1979 and 1998 were reviewed. All patients had histologically and endocrinologi-

cally verified NFAs. Nine out of 131 patients were not included in this series because they

were lost to follow-up. The remaining 122 patients were included in the analysis.

The study population consisted of three distinctive groups:

Group 1 consisted of 76 patients (62%) with radiologic evidence of residual NFA, who re-

ceived immediate postoperative radiotherapy after the first operation. Twenty-six of these

32

Chapter 2

patients were operated transcranially (34%) and 50 by the transsphenoidal route (66%) (see

Table 1). The median time between surgery and the start of radiotherapy was 5.8 months;

it is just possible to decide on computed tomography (CT)/magnetic resonance imaging

(MRI), performed 3 to 4 months after operation, if there is residual pituitary adenoma, be-

cause mass effects due to operation have disappeared after that time period. The median

follow-up time between radiotherapy and last MRI was 93 (range, 14 - 248) months.

Group 2 consisted of 28 patients (23%) with radiologic residual NFA after neu-

rosurgery in which the consultant endocrinologist decided for a wait-and-see policy.

Twenty-one of these patients (75%) underwent a transsphenoidal procedure while in

7 patients (25%) a craniotomy was performed (see Table 1). The median follow-up time

between operation and last MRI was 71 (range, 3 - 206) months.

Group 3 consisted of 18 patients (15%; 12 after transsphenoidal surgery and 6 after

craniotomy) without radiologic evidence of residual NFA after surgery. Three patients in

this group received immediate postoperative radiotherapy.

Radiotherapy

All patients in Group 1 were treated with linear accelerators with 4-18 MV photons. A

two-field opposed lateral technique was used in 10 patients, a three-field technique in

25 patients, a five-field technique in 14 patients, a combination of these techniques in

25 patients, and a rotation technique in 2 patients. In the time period 1985 to 1990, the

radiation dose to the tumor was prescribed at the tumor encompassing isodose. From

1991 to 1998, it was prescribed at a central point in the tumor according to the recom-

mendations of the International Commission on Radiation Units and Measurements

(ICRU)16. Total radiation dose ranged from 45.0 to 55.8 Gray (Gy). The daily radiation frac-

tion size varied from 1.8 to 2.0 Gy. The median overall treatment time was 35 days (range,

30 - 42 days). The radiation fraction schemes used were 45 Gy in 25 daily fractions (n = 44;

58%), 50 Gy in 25 daily fractions (n = 19; 25%), 50.4 Gy in 28 daily fractions (n = 7; 9%), 46 Gy

in 23 daily fractions (n = 5; 7%), and 55.8 Gy in 31 daily fractions (n = 1; 1%). All radiation

treatment fields were applied daily, 5 times a week.

Progression and hormonal evaluation

Progression was defined as recurrence of completely resected or regrowth of residual

NFA on CT or MRI. The occurrence of hormonal deficiencies was defined as the starting

date of hormonal substitution therapy. Thyroid hormone and androgen deficiency were

diagnosed by subnormal serum FT4 and testosterone levels, respectively. In premeno-

pausal women, sex hormone deficiency was diagnosed by amenorrhea and low serum

estradiol levels. In women aged above 50 years, as an indication of postmenopausal sta-

tus, sex hormone deficiency was not classified. In women using estrogens/progestagens

for contraceptive reasons, sex hormone deficiency was also not classified. Glucocorti-

33



Table 1 Patient characteristics, treatment data, and anterior pituitary hormone substitutions in

Group 1 (immediate postoperative radiotherapy) and Group 2 (wait-and-see policy)

Group 1 (n = 76) Group 2 (n = 28) p-value

Age (years) 53 (17-75) 53 (12-79) 0.75

Sex: M/F 45/31 14/14 0.54

Preoperative hormonal substitutions

Thyroxin 21 of 76 (28%) 5 of 28 (18%) 0.51

Glucocorticoids 17 of 76 (22%) 4 of 28 (14%) 0.57

Sex hormones 7 of 61*(11%) 0 of 21*(0%) 0.29

Number of preoperative hormonal substitutions per patient

0: 45 (59%) 0: 21(75%)

0.431: 18 (24%) 1: 5 (18%)

2: 11 (14%) 2: 2 (7%)

3: 2 (3%) 3: 0

Surgery type: C/T 26/50 7/21 0.54

Hormonal substitutions directly after first surgery

Thyroxin 39 of 76 (51%) 16 of 28 (57%) 0.77


Sex hormones 28 of 61*(46%) 10 of 21 (48%) 0.91

Number of hormonal substitutions per patient directly after first surgery

0: 26 (34%) 0: 9 (33%)

0.811: 15 (20%) 1: 4 (14%)

2: 24 (32%) 2: 9 (32%)

3: 11 (14%) 3: 6 (21%)

Hormonal substitutions at end of FU

Thyroxin 60 of 76 (79%) 20 of 28 (71%) 0.51


Sexhormones 48 of 61*(79%) 15 of 21* (71%) 0.57

Number of hormonal substitutions per patient at end of FU

0: 7 (9%) 0: 6 (21%)

0.391: 11 (14%) 1: 3 (11%)

2: 21 (28%) 2: 6 (21%)

3: 37 (49%) 3: 13 (46%)

Abbreviations: M = male; F = female; C = craniotomy; T = transsphenoidal surgery; Ok = operation; Rt = radiotherapy; FU = follow-up; pts = patients.Age in median years (range).* In group 1, 15 of 31 women and in group 2, 7 of the 14 women were postmenopausal (age > 50 yrs) at time of first surgery; in these women sex hormone deficiency was not classified. None of the premenopausal women in each group used estrogens/progestagens for contraceptive reasons.

34

Chapter 2

coid deficiency was diagnosed by a low serum cortisol, by an insufficient serum corti-

sol response to insulin-induced hypoglycemia, or by an insufficient urinary tetrahydro

compound S excretion with cut-off criteria as described elsewhere17,18. Pituitary function

was checked at least twice annually. Growth hormone substitution was introduced in

our clinic in the mid-nineties; growth hormone deficiency was not taken into account in

the hormonal evaluation.

Cerebrovascular disease was defined as any transient or permanent cerebrovas-

cular disorder.

Statistical analysis

In univariate analysis, local control rate as well as hormone substitution free survival were

estimated using the Kaplan Meier method. To test the statistical significant differences

between survival curves, the log rank test was used. Data are given in median (range) or in

percentages. Frequencies of hormone deficiencies were compared in Chi-square analysis.

Life expectancy was studied after transformation of survival time to standar-

dized survival time (SST) to adjust for background mortality in the general population.

SST is the quotient of observed survival time and median life expectancy in the general

Dutch population matched for gender, age and year of operation. These life expectancies

were derived from the data provided by the Dutch authorities (www.cbs.nl). The analyti-

cal background of this method has been reported elsewhere19. A two-sided p-value <0.05

was considered to be significant.

Results

Local Control Rate

Group 1. In three out of 76 patients (4%), progression was observed after a median

interval of 23 (16, 23 and 104, respectively) months after surgery. Local control rate was 95%

at 5 as well as at 10 years (Fig. 1). Local recurrence or regrowth was always intra/parasellar.

Group 2. In 16 out of 28 patients (57%), progression developed after a median interval

of 30 (11-95) months. Local control rate was 49% and 22% at 5 and 10 years, respectively

(Fig. 1). This was significantly worse than the local control rate among patients in Group 1

(p = 0.001). Fourteen of these 16 patients received “salvage” radiotherapy after a median

interval of 38 months after the first neurosurgical procedure. Six patients received salvage

radiotherapy immediately after diagnosis of regrowth, 7 patients after a second operation

(4 craniotomy, 3 transsphenoidal procedure) and 1 patient after a third operation. All pa-

tients had residual NFA after repeated operation. The radiation fractio nation schedules used

were 45 Gy in 25 fractions (n = 13) and 50 Gy in 25 fractions (n = 1). Local control rate after

salvage radiotherapy at 5 and 10 years after first operation was 95%. In 2 patients, salvage

radiotherapy was not applied because of cerebral infarction in one and acute death shortly

after diagnosis of progression in the other.

35



Group 3. In 1 patient (6%) a recurrence developed 15 months after neurosurgery;

this patient was treated with radiotherapy.

Figure 1 Kaplan Meier plot showing local control of residual non-functioning pituitary adenoma in

Group 1 (after immediate postoperative radiotherapy), and in Group 2; (wait-and-see policy after first

operation); p = 0.001 by log-rank test.

Hormonal substitution free survival

Preoperatively, no significant differences in anterior pituitary hormonal substitution

were found between Group 1 and 2 (Table 1). Directly after first surgery, again, no differ-

ences were found regarding thyroid hormone-, glucocorticoid-, or sex hormone substi-

tution between Group 1 and 2 (Table 1). At the end of follow-up, the need for hormonal

substitution was also not different between the groups (Table 1). The number of hor-

mone deficiencies per patient at diagnosis, directly after first surgery and at the end of

follow-up was comparable between Group 1 and 2 (Table 1). As shown in Figure 2 - 4,

there were no differences in hormone substitution free survival with respect to thyroid

hormone, glucocorticoids, and sex hormones between the groups during the study pe-

riod after first surgery.

Before surgery one patient in Group 1 and none in Group 2 had antidiuretic

hormone deficiency. Postoperatively, an additional 6 patients in Group 1 and 2 patients

in Group 2 required permanent vasopressin treatment. These numbers did not change

until end of follow-up in either group (p = 0.97). Furthermore, the type of operation was

not associated with vasopressin-substitution (p = 0.99).

Years after first surgery

Local control

Cum

ulat

ive

prop

ortio

n

0

0,1

50 10 15 20 25

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

Group 2

Group 1

36

Chapter 2

Figure 2 Kaplan Meier plot showing thyroid hormone substitution free survival after first surgery in

Group 1 (immediate postoperative radiotherapy) and 2 (wait-and-see policy); p = 0.94 by log-rank test.


Glucocorticoid hormone substitution free survival

Cum

ulat

ive

inci

denc

e

0

0,1

50 10 15 20 25

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

Group 2 Group 1

Figure 3 Kaplan Meier plot showing glucocorticoid hormone substitution free survival after first surgery

in Group 1 (immediate postoperative radiotherapy) and 2 (wait-and-see policy) ; p = 0.22 by log-rank test.


Thyroid hormone substitution free survival

Cum

ulat

ive

inci

denc

e

0

0,1

50 10 15 20 25

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

Group 2

Group 1

37




Sex hormone substitution free survival

Cum

ulat

ive

inci

denc

e

0

0,1

50 10 15 20 25

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

Group 2

Group 1

Figure 4 Kaplan Meier plot showing sex hormone substitution free survival after first surgery in

Group 1 (immediate postoperative radiotherapy) and 2 (wait-and-see policy); p = 0.41 by log-rank test.

38

Chapter 2

Cerebrovascular disease

No statistically significant difference with regard to the incidence of cerebrovascular di-

sease was observed between Group 1 and 2 at diagnosis, after neurosurgery, and during

follow-up (p = 0.12). In Group 1, one out of 76 patients suffered cerebrovascular disease

before surgery and 13 patients between surgery and final follow-up. In Group 2, three out

of 28 patients suffered cerebrovascular disease before surgery and four patients between

first neurosurgery and final follow-up. Furthermore, no association was found between

the type of surgery and cerebrovascular disease (p = 0.61).

Epilepsy

No statistically significant difference was found in prevalence of epilepsy between Group

1 and 2 at diagnosis, after neurosurgery, and during follow-up (p = 0.19). In Group 1 one

out of 76 patients suffered epilepsy before surgery and 6 patients after neurosurgery un-

til end of follow-up. In Group 2, none of the 28 patients suffered epilepsy. No significant

association was found between the type of surgery and epilepsy (p = 0.47).

Tumor induction

In Group 1, 1 out of 76 patients was operated for a meningioma, localized right fronto-

parietal at a scar place, 14 years after a right-sided craniotomy and radiotherapy for a

NFA. Although p53 staining of the meningioma tissue was negative, a relationship with

radiotherapy cannot be excluded. In Group 2, 1 patient died due to a glioblastoma mul-

tiforme 1 year after surgery for NFA.

Overall survival and life expectancy

The overall survival was not different between Group 1 and 2 (Fig.5; p = 0.25). There was

no effect of type of surgery on overall survival. Median standardised survival time was

0.97 (95% CI, 0.56-1.39) in Group 1 and 2 combined (Fig. 6). There is no difference from the

expected value of 1.0 in the age and gender-matched general Dutch population.

39



Figure 5 Kaplan Meier plot showing overall survival in Group 1 (immediate postoperative

radiotherapy) in comparison with Group 2 (wait-and-see policy); p = 0.25 by log-rank test.

Figure 6 Observed cumulative death in our cohort (Group 1 and 2 combined; n = 104 patients) in

perspective to the expected cumulative death in the age and gender matched normal population in

The Netherlands; p = 0.25 by log-rank test


Overall survival

Cum

ulat

ive

prop

ortio

n

0

0,1

50 10 15 20 25

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

Group 2

Group 1

Standardized survival time

Mortality

Cum

ulat

ive

prop

ortio

n

0

0,1

0 0,5 1,0 1,5

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

Observed

Expected

40

Chapter 2

Discussion

In the present series of NFA patients, excellent local control (95% at 10 years) was

achieved when immediate postoperative radiotherapy was applied in case of residual

tumor. In comparison, local control was only 49% at 5 years and 22% at 10 years when

a wait-and-see policy was followed. Importantly, immediate postoperative radiotherapy

did not result in an additional need for conventional hormonal substitution treatment,

or in an excess of epilepsy, cerebrovascular disease, and intracerebral malignancy in

comparison to an expectant strategy. Furthermore, it is noteworthy that life expectancy

was similar in both groups, and did not differ from the general Dutch population. Our

survey thus suggests that immediate postoperative radiotherapy in case of residual NFA

can be applied safely.

Local control rate after immediate postoperative radiotherapy reported here

agrees with other studies, showing that 82% to 97% of patients remained free of tumor

regrowth after 10 years of follow-up5,6,20-22. Comparable with our data, a local control rate

of only 40% to 70% at 5 years and of 15% to 50% at 10 years was documented previously

when a wait-and-see policy was followed23-26. Importantly, despite protocolized follow-

up with serial MRIs, a symptomatic recurrence was observed in 4 of 34 prospectively

followed patients after a period of only 28 months27. In agreement, symptomatic recur-

rences were recently reported to be present in 6% to 21% of patients28. In the present

study, salvage radiotherapy in case of regrowth was deemed clinically necessary after a

median interval of 38 months after first surgery in 50% (14/28) of NFA patients; in 7 pa-

tients after a second and in 1 patient even after a third operation. A wait-and-see policy

can be expected to result in a higher frequency of MRI and an increased frequency of

re-operations, which likely results in emotional and social dysfunction29 as well as in

additional health care costs. One should, therefore, be aware of the possible risks of an

expectant policy in case of residual postoperative NFA.

A frequently used argument to postpone postoperative radiotherapy is the pos-

sible development of radiation-induced hypopituitarism7. This supposition is mainly

based on the results from a small series of 35 patients7. In that report, 50% of patients

had already pituitary hormonal deficiencies before radiotherapy, which increased to 75%

after this treatment.

Patient characteristics at diagnosis and directly after surgery were similar

in subjects with residual NFA who did and did not receive immediate postoperative

radio therapy in this series. It is of relevance, therefore, that our study clearly demon-

strates that there was no difference in the need for thyroid hormone, glucocorticoids,

sex-steroids, and vasopressin between the immediate postoperative radiotherapy group

and the wait-and-see group with salvage radiotherapy. This lack of negative impact of

immediate postoperative radiotherapy on pituitary function could not be attributed to

41



bias caused by differences in hormonal deficiencies before and shortly after surgery, or

in clinical characteristics between the groups. A potential shortcoming of our study is

that we did not evaluate the frequency of growth hormone replacement therapy in each

group. Such an analysis was not done because this treatment was introduced relatively

late in the time frame of our evaluation period. Moreover, it is very likely that many pa-

tients in each group already had growth hormone deficiency shortly after surgery, given

the high frequency of other hormonal deficiencies18,30.

Radiotherapy could result in other unwanted side effects. The possible nega-

tive effect of radiotherapy on the development of cerebrovascular disease is frequently

mentioned but still debated9,10,12,31. In the present series, the risk for cerebrovascular

di sease was not different between groups. The induction of intracranial malignancies

and menin giomas by radiotherapy is also debated14,15. In our cohort, no intracranial

malignancies and one meningioma was diagnosed in a total of 90 irradiated patients.

Another possible late side effect of radiation therapy is radiation optic neuropathy, but

we have already documented that this is a very rare complication, provided fractionated

radiotherapy is applied with a recommended total dose not exceeding 45 Gray in NFA

patients8.

In the present study, we did not evaluate the effect of radiotherapy on cognitive

function and on quality of life. Previous studies have shown diminished cognitive func-

tion and impaired quality of life in newly diagnosed patients with NFA compared to

healthy subjects32,33. A cross-sectional study demonstrated reduced cognition and some

impairment in quality of life in a mixed group of patients with non-functioning and

hormone secreting pituitary tumors who were treated with surgery and radiotherapy

compared to patients who were treated with surgery alone34. Such an effect was not

found in another report35. Furthermore, the contribution of postoperative radiotherapy

to a possible decline in mental performance and quality of life is not well understood,

because prospective data, which take the effects of both conventional pituitary hormone

substitution and growth hormone replacement into account, are currently not available.

Moreover, it can be expected that improvement in radiation treatment techniques will

result in significantly lower radiation doses to the cerebral parenchyma36, with an as-

sumed sparing effect on cognitive function.

Several studies have addressed the question whether there is increased mortality

in NFA patients, and to define the possible negative impact of radiotherapy on morta-

lity in this patient category31,37-39. The interpretation of these data is difficult, because of

inclusion of patients with hypopituitarism not due to NFA, the possible effect of (treated)

deficiencies of conventional anterior pituitary hormones and anti-diuretic hormone, as

well as the effect of growth hormone deficiency on mortality39. In the present series,

log-rank analysis demonstrated that survival did not differ between patients, who re-

ceived immediate post-operative radiotherapy and patients in whom a wait-and-see

42

Chapter 2

policy was followed. When all NFA patients were combined, life expectancy was similar

to that observed in the general age- and sex-matched population from the Netherlands.

In comparison, increased mortality has been observed in several31,37-39, but not in all sur-

veys40 comprising pituitary patients due to various causes. The largest series available so

far shows a modest excess in overall mortality in NFA patients, without a significant in-

dependent adverse impact of radiotherapy39. Several factors such as differences in time

frame of patient surveillance, with follow-up being starting as early as 1946 to 1958 in

some previous reports12 as well as the relatively low frequency of transcranial surgery

and the lack of additional negative impact of radiotherapy on conventional pituitary

hormone deficiencies in the present series, may explain part of the discrepancy.

In conclusion, immediate postoperative radiotherapy in case of residual NFA pro-

vides a marked long lasting improvement of local control among patients with residual

non-functioning pituitary adenoma compared to surgery alone, without an additional

deleterious effect on pituitary function and life expectancy. Therefore, results of this

study support to perform immediate postoperative radiotherapy in this patient category.

The present results also underscore that immediate postoperative radiotherapy is not

necessary in apparently complete resected NFA.

43



References

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perspective. Clin Oncol 1996;8:79-84

2. Nobels FE, Kwekkeboom DJ, Herder WW de, et al. Klinisch niet-functionerende

hypofyseadenomen; diagnostische mogelijkheden en therapeutische opties. [Clinically

non-functioning hypophyseal adenomas; Diagnostic possibilities and therapeutic options].

Ned Tijdschr Geneeskd 1992;136:1148-1152

3. Sassolas G, Trouillas J, Treluyer C, et al. Management of nonfunctioning pituitary adenomas.

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4. Rauhut F, Stuschke M, Sack H, Stolke D. Volume dependence of late effects after

radiotherapy of invasive pituitary adenomas. In: Wiegel T, Hinkelbein W, Brock M, Hoell

T, editors. Controversies in Neuro-oncology. Frontiers of radiation therapy and oncology. Basel:

Karger;1999. p. 315-317

5. Gittoes NJL, Bates AS, Tse W, et al. Radiotherapy for non-functioning pituitary tumours.

Clin Endocrinol 1998;48:331-337

6. Paek SH, Beverly Downes M, Bednarz G, et al. Integration of surgery with fractionated

stereotactic radiotherapy for treatment of nonfunctioning pituitary macroadenomas.

Int J Radiat Oncol Biol Phys 2005;61:795-808

7. Snyder PJ, Fowble BF, Schatz NJ, et al. Hypopituitarism following radiation therapy of

pituitary adenomas. Am J Med 1986;81:457-462

8. van den Bergh ACM , Schoorl MA, Dullaart RP, et al. Lack of radiation optic neuropathy in

72 patients treated for pituitary adenoma. J Neuroophthalmol 2004;24:200-205

9. Flickinger JC, Nelson PB, Taylor F, Robinson A. Incidence of cerebral infarction after

radiotherapy for pituitary adenoma. Cancer 1989;63:2404-2408

10. Brada M, Burchell L, Ashley S, Traish D. The incidence of cerebrovascular accidents in

patients with pituitary adenoma. Int J Radiat Oncol Biol Phys 1999;45:693-698

11. Brada M, Ashley S, Ford D, et al. Cerebrovascular mortality in patients with pituitary

adenoma. Clin Endocrinol 2002;57:713-717

12. Erfurth E, Bulow B, Svahn-Tapper G, et al. Risk factors for cerebrovascular deaths in patients

operated and irradiated for pituitary tumors. J Clin Endocrinol Metab 2002;87:4892-4899

13. Erfurth E, Hagmar L. Cerebrovascular disease in patients with pituitary tumors. Trends in

Endocrinol and Metab 2005;16:334-342

14. Erfurth E, Bulow B, Mikoczy Z, et al. Is there an increase in second brain tumours after

surgery and irradiation for a pituitary tumour? Clin Endocrinol 2001;55:613-616

15. Minniti G, Traish d, Ashley S, et al. Risk of second brain tumour after conservative surgery

and radiotherapy for pituitary adenoma: Update after further 10 years. J Clin Endocrinol

Metab 2004;90:800-804

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16. ICRU Prescribing, recording and reporting photon beam therapy. Report 50 1993, Bethesda,

MD, USA.

17. Tjeerdsma G, Sluiter WJ, Hew JM, et al. Hyperprolactinaemia is associated with a higher

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Eur J Endocr 1996;135:299-308

18. Dullaart RP, Pasterkamp SH, Beentjes JA, Sluiter WJ. Evaluation of adrenal function in

patients with hypothalamic and pituitary disorders; comparison of serum cortisol, urinary

free cortisol and the human-corticotrophin releasing hormone test with the insulin

tolerance test. Clin Endocrinol 1999;50:465-471.

19. Links TP, Tol KM van, Jager PL, et al. Life expectancy in differentiated thyroid cancer: A novel

approach to survival analysis. Endocr Relat Cancer 2005;12:273-280

20. Brada M, Rajan B, Traish D, et al. The long-term efficacy of conservative surgery and

radiotherapy in the control of pituitary adenomas. Clin Endocrinol 1993;38:571-578

21. Breen P, Flickinger JC, Kondziolka D, Martinez AJ.. Radiotherapy for nonfunctional pituitary

adenoma: Analysis of long-term tumor control. J Neurosurg 1998;89:933-938

22. Chun M, Masko B, Hetelekidis S. Radiotherapy in the treatment of pituitary adenomas.

Int J Radiat Oncol Biol Phys 1988;5:305-309

23. Sheline GE. Proceedings:Treatment of nonfunctioning chromophobe adenomas of the

pituitary. Am J Roentgenol Radium Ther Nucl Med 1974;120:553-561

24. Jaffrain-Rea ML, Derome P, Bataini JP, et al. Influence of radiotherapy on long-term relapse

in clinically non-secreting pituitary adenomas. A retrospective study (1970-1988). Eur J Med

1993;2:398-403

25. Park P, Chandler WF, Barkan AL, et al. The role of radiation therapy after surgical resection

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26. Woollons AS, Hunn MK, Rajapakse YR, et al. Non-functioning pituitary adenomas:

Indications for postoperative radiotherapy. Clin Endocrinol 2000;53:713-717

27. Soto-Ares G, Cortet-Rudelli C, Assaker R, et al. MRI protocol technique in the

optimal therapeutic strategy of non-functioning pituitary adenomas. Eur J Endocrinol

2002;146:179-186

28. Benveniste RJ, King WA, Walsh J, et al. Repeated transsphenoidal surgery to treat recurrent

or residual pituitary adenoma. J Neurosurg 2005;102:1004-1012

29. Andrewes DG, Kaye A, Murphy M, et al. Emotional and social dysfunction in patients

following surgical treatment for brain tumour. J Clin Neurosc 2003;10:428-433

30. Toogood AA, Beardwell CG, Shalet SM. The severity of growth hormone deficiency in

adults with pituitary disease is related to the degree of hypopituitarism. Clin Endocrinol

1994;41:511-516

31. Rosen T, Bengtsson B. Premature mortality due to cardiovascular disease in

hypopituitarism. Lancet 1990;336:285-288.

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32. Guinan EM, Lowy C, Stanhope N, et al. Cognitive effects of pituitary tumours and their

treatments: Two case studies and an investigation of 90 patients. J Neurol Neurosurg Psych

1998;65:870-876

33. Peace KA, Orme SM, Padayatty SJ, et al. Cognitive dysfunction in patients with pituitary

tumour who have been treated with transfrontal or transsphenoidal surgery or

medication. Clin Endocrinol 1998;49:391-396.

34. Noad R, Narayanan KR, Howlett T, et al. Evaluation of the effect of radiotherapy for pituitary

tumours on cognitive function and quality of life. Clin Oncol 2004;16:233-237

35. Wallymahmed ME, Foy P, MacFarlane IA. The quality of life of adults with growth hormone

deficiency: Comparison with diabetic patients and control subjects. Clin Endocrinol

1999;51:333-338

36. Perks JR, Jalali R, Cosgrove VP, et al. Optimization of stereotactically-guided conformal

treatment planning of sellar and parasellar tumors, based on normal brain dose volume

histograms. Int J Radiat Oncol Biol Phys 1999;45:507-513

37. Bulow B, Hagmar L, Mikoczy Z, Nordstrom CH, Erfurth EM. Increased cerebrovascular

mortality in patients with hypopituitarism. Clin Endocrinol 1997;46:75-81

38. Nilsson B, Gustavsson-Kadaka E, Bengtsson B, Jonsson B. Pituitary adenomas in Sweden

between 1958 and 1991: Incidence, survival and mortality. J Clin Endocrinol Metab

2000;85:1420-1425

39. Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality and

hypopituitarism. Lancet 2001;357:425-431

40. Bates AS, Bullivant B, Sheppard MC, Stewart PM. Life expectancy following surgery for

pituitary tumours. Clin Endocrinol 1999;50:315-319

3 Radiotherapy is not associated

with reduced quality of life and

cognitive function in patients treated for

nonfunctioning pituitary adenoma

André P. van Beek, M.D., Ph.D.1; Alphons C.M. van den Bergh, M.D.2;

Linda M. van den Berg, M.D.1; Gerrit van den Berg, M.D., Ph.D.1; Joost C. Keers, M.D.,

Ph.D.1; Johannes A. Langendijk, M.D., Ph.D.2; Bruce H.R. Wolffenbuttel, M.D., Ph.D.1

1 Departments of Endocrinology and 2 Radiation Oncology, University Medical Center

Groningen, University of Groningen, Groningen, The Netherlands.

International Journal of Radiation Oncology Biology Physics 2007; 68(4): 986-991

48

Chapter 3

Abstract

Purpose To assess the influence of different treatment modalities on long-term

health-related quality of life (HR-QoL) and cognitive problems among patients

who had been treated for nonfunctioning pituitary adenoma (NFA).

Methods and Materials Eighty-one patients (49 men and 32 women, aged 55

±10 years) with a minimal follow up period of 1 year after treatment for NFA

participated in this cross-sectional study. Sixty two patients were initially treated

by transsphenoidal surgery and 19 by craniotomy. Subsequently, 45 out of these

81 subjects (56%) received additional radiotherapy (RT) after surgery because of

a tumor remnant or regrowth. All subjects filled in standardized questionnaires

measuring HR-QoL, depression, fatigue and cognitive problems.

Results Patients who underwent additional RT more frequently underwent a

craniotomy and were younger at surgery, but not at entering this study. They also

used more hormonal substitution. Most HR-QoL domains showed a similar score

in patients who underwent RT, when compared with patients who did not receive

RT. However, vitality and physical functioning proved to be better in RT subjects,

and RT subjects also had better scores for depression, and physical and mental

fatigue (all p < 0.05). Some aspects of HR-QoL of patients who have been success-

fully treated for NFA are reduced compared with the normal population, but this

was much more pronounced in the group that did not receive RT. In multivariate

analysis, RT remained significantly associated with improved HR-QoL. No diffe-

rences in cognitive function scores were observed.

Conclusion Postoperative RT in patients with NFA is not associated with reduced

quality of life or cognition when compared with surgery alone.

49

Radiotherapy is not associated with reduced quality of life and cognitive function in patients treated for nonfunctioning pituitary adenoma

Introduction

Nonfunctioning pituitary adenomas (NFAs) are the most common tumors of the ante-

rior pituitary. Transsphenoidal surgery is the treatment of choice, but complete surgical

removal is frequently not achieved. Radiotherapy (RT) is often given as adjuvant treat-

ment in the postoperative period to patients with a tumor remnant or regrowth. Retro-

spective studies show that RT can effectively reduce the chance of tumor regrowth, as

reviewed by several investigators1-3. Current medical practice involves RT for large post-

operative tumor remnants and sequential MRI surveillance for smaller tumors followed

by RT in the presence of tumor expansion in many centers1,4. The restrictive use of post-

operative RT for NFAs is a consequence of absence of regrowth in a number of cases,

the excellent local control with radiation therapy when applied at time of recurrence,

and concerns related to possible long-term side effects5. The most important of these

complications is radiation-induced hypopituitarism and its associated excess morta-

lity6, although the role of RT per se on pituitary function remains disputed7. Radiation-

induced tumor formation and damage to the optic chiasm are also reported but are

considered rare under modern RT dosing schedules8-10. In addition, neuropsychological

changes after pituitary RT have been reported11-17. However, many studies on this sub-

ject are undersized, and results are potentially confounded by inhomogeneous group

composition and incomplete hormonal substitution. Further, type and date of surgery,

age, and duration of follow-up have usually not been taken properly into account to as-

sess the impact of modern RT.

With these considerations in mind, we sought to determine whether the use of

RT in the postoperative period has a significant effect on health-related quality of life

(HR-QoL) and cognitive function. We report data from a large and homogeneous cohort

of patients with NFAs.

Methods and Materials

Patients

Patients with histologically proven NFA were eligible for participation in this study if

they were between 20 and 70 years of age and if the interval between their last treat-

ment (RT or surgery) and the quality-of-life assessment was at least 12 months. Both

surgery and RT were performed in the University Medical Center Groningen, which is

a large tertiary referral centre for patients with pituitary pathology. To assure accuracy

and completeness of our data collection, patients were only recruited for participation if

they were still actively followed at our endocrine outpatient clinic. All patients included

in this study received surgery as primary treatment, in some cases followed by a second

surgical procedure if a large remnant accessible for surgery persisted. Radiotherapy was

50

Chapter 3

given postoperatively to patients with a remnant or after evidence of regrowth. Patients

with NFA were retrospectively identified by reviewing several different hospital data-

bases on surgery, radiotherapy, and diagnoses at the endocrine clinic. Thus, a total of 90

eligible patients could be identified who received primary surgical treatment for NFA in

our hospital between January 1963 and January 2005.

Questionnaires on quality of life and cognition, use of medication, presence of

co-morbidity, and social status were sent to all patients by mail. Use of medication and

presence of comorbidity was also confirmed by investigation of the medical charts.

Labora tory results from the last visit (i.e.,< 1 year earlier) to the outpatient clinic were

used. Written informed consent was obtained from all subjects.

Questionnaires

RAND 36. Health-related quality of life was measured with the RAND 36 (which is identi-

cal to the 36-item short form health survey [SF36]). This questionnaire contains 36 ques-

tions that record several dimensions of general well-being during the previous 4 weeks.

The items are formulated as statements or questions with Likert scale response options.

The 36 questions are organized into eight scales (physical functioning, physical pro-

blems, bodily pain, general health, vitality, social functioning, emotional problems, and

mental health) that are linearly converted to a scale of 0 to 100. The first three para-

meters measure physical health, the last three parameters measure mental health, and

the general health and vitality scales are sensitive to both physical and mental health

outcomes. Higher scores represent better quality of life18. Normative data by age are

available for the Dutch population19.

Multidimensional Fatigue Inventory-20. The Multidimensional Fatigue Inventory-20

(MFI-20) records fatigue and contains 20 statements, organized into five scales (general

fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue), with

a maximum score of 20 on each subscale20. Higher scores indicate a higher level of fa-

tigue or impairment. Dutch normative data were derived from Smets et al.21.

Hospital Anxiety and Depression Scale. The Hospital Anxiety and Depression Scale

(HADS) consists of 14 items pertaining to anxiety and depression22. Each item is scored

as a number, with a maximal score for each subscale (anxiety or depression) of 21. Higher

scores indicate more severe anxiety or depression. A score of 6 or higher on the depres-

sion scale or 7 or higher on the anxiety scale indicates clinical depression or anxiety.

Dutch normative data were derived from Spinhoven et al.23.

Cognitive Failures Questionnaire. The Cognitive failures Questionnaire is a measure

of everyday cognitive problems. This 25-item questionnaire measures failures in per-

ception, memory, and action in everyday life. The total score ranges 0-100, with higher

scores reflecting more cognitive problems24,25.

51


Laboratory assays

Plasma insulin-like growth factor-1 (IGF-1) was measured by radioimmunoassay after

acid-ethanol extraction (Nichols Institute of Diagnostics, San-Juan Capistrano, CA). Age-

adjusted Z scores of plasma IGF-1 were calculated using values obtained in healthy sub-

jects. Plasma cortisol was measured by radioimmunoassay (Elecsys 2010; Roche diagnos-

tics, Basel, Switzerland). An automatic immunoassay (Perkin Elmer Life Sciences, Gronin-

gen, The Netherlands) was used to determine free T4.


Differences were assessed with t tests (for continuous variables) or chi-square tests (for

cate goric variables). An α level of 0.05 was used for determining statistical significance.

When differences between groups reached statistical significance, the magnitude of the

effects was determined by Cohen’s d, a commonly used measure for effect size26. A value

of ± 0.5 was considered the medium effect size. Multiple linear regression was used to

determine associations between measures of quality of life, cognitive function, treatment

modalities, and demographic characteristics. Backward linear regression modeling was ap-

plied using a p value < 0.04 for entry and a p > 0.05 for removal of the selected variables.

Results

Ninety patients were eligible and were sent questionnaires on quality of life, mood, and

cognition. Eighty-one patients (49 men and 32 women, age 55 ±10 years) returned all ques-

tionnaires (response rate, 90%). Sixty-two had been operated by transsphenoidal route

and 19 by craniotomy. Fourteen patients had needed a second surgical intervention. Sub-

sequently, 46 of 81 subjects received additional RT after surgery because of a tumor rem-

nant or regrowth. Average time between surgery and RT was approximately 8 months.

Conventional external beam RT was administered in a daily dosage of 1.8 – 2.0 Gy, resul-

ting in a total dose of 45 – 50 Gy, using a two-field opposed lateral technique or a three-,

four- or five- field technique. All radiation treatment fields were applied daily, five times

per week, with an overall duration of 35 days. In the time period 1963-1990, the radiation

dose to the tumor was prescribed at the tumor encompassing isodose. From 1991 onward

it was prescribed at a central point in the tumor, according to the recommendations of the

International Commission on Radiation Units and Measurements.

Patient characteristics of those who received RT and those who did not are given in

Table 1 (next page). Patients who underwent RT more frequently had a craniotomy, were

younger at time of surgery, and their duration of follow-up was longer. They also used

more hormonal substitution, although this only reached statistical significance for the use

of thyroid hormone. Current age, social status, educational level, full-time/part-time em-

ployment, social security benefit, and comorbidity were all similar between both groups.

52

Chapter 3

Table 1 Patient characteristics

RT+ RT– P-value*

Number 45 36

Age (y)# 58 (32-70) 56 (34-70) NS

Sex (male/female) 26/19 23/13 NS

Primary treatment 0.004

Transsphenoidal surgery 29 33

Craniotomy 16 3

Age at primary treatment (y) 43 (13–67) 50 (16-67) 0.000

Duration of follow-up (y) 12 (1-43) 4 (1-30) 0.008

2nd surgical treatment 10 4 NS

Postoperative radiotherapy

Age at radiotherapy (y) 46 (14-68) -

Time between primary treatment and radiotherapy (y) 0.7 (0-31) -

Duration of follow-up after radiotherapy (y) 10 (1-26) -

Substitution of pituitary axis

Number of anterior pituitary hormones substituted: 0/1/2/3/4 2/10/10/14/9 6/10/8/6/6 NS

Thyroid hormone 31 (69%) 17 (47%) 0.049

Cortisol 32 (71%) 21 (58%) NS

Growth hormone 16 (36%) 9 (25%) NS

Sex hormones 29 (64%) 21 (58%) NS

Antidiuretic hormone 5 (11%) 3 (8%) NS

Data are given as median (ranges), absolute numbers and percentages.RT+: group with postoperative radiotherapy.RT–: group without postoperative radiotherapy.* : P-value by χ2-test, # the study included only patients in the age range 20 - 70.

Most HR-QoL domains showed a similar score in patients who underwent RT, when compared with

patients who did not receive RT (Table 2). However, physical functioning (effect Size [ES], 0.44), vitality

(ES, 0.47), mood (HADS - depression) (ES, 0.56), and physical and mental fatigue (MFI-20) (both ES, 0.54)

were reported to be significantly worse in patients who did not receive RT. No differences in cognitive

function scores were observed. In the group that did not receive RT, social functioning, vitality,

and gene ral health perception (three domains of RAND 36), fatigue, and depression scores were

significantly worse than in the reference population. In contrast, in patients who under went RT only

general health perception was less than in the reference population, whereas physical functioning,

pain (RAND 36) and anxiety (HADS) were even better.

53

Table 2 Health related quality of life and cognition in patients with or without radiotherapy.

RT+ RT– P-value Population reference

RT+ RT– P-value

mean ± SD mean Z-score ± SD*

RAND-36

Physical functioning 84±18 74±23 NS 82±23 0.31±0.80¶ –0.16±1.01 0.024

Social functioning 85±19 77±23 NS 87±21 –0.06±0.88 –0.40±1.08¶ NS

Role limitations due to physical problems 76±38 69±41 NS 79±36 –0.03±1.02 –0.19±1.07 NS

Role limitations due to emotional problems 88±30 78±37 NS 84±32 0.05±1.01 –0.24±1.17 NS

Mental health 79±14 72±20 NS 77±18 0.13±0.74 –0.28±1.10 NS

Vitality 66±17 56±25 0.042 67±20 –0.03±0.82 –0.51±1.18¶ 0.045

Pain 84±19 81±23 NS 80±26 0.27±0.76¶ 0.13±0.90 NS

General health perception 60±19 59±24 NS 73±23 –0.31±0,82¶ –0.39±1.05¶ NS

HADS

Anxiety 3.6±2.9 5.0±4.4 NS 4.7±3.6 –0.30±0.81¶ 0.08±1.22 NS

Depression 3.0±2.5 5.0±4.4 0.018 3.5±3.4 –0.16±0.73 0.43±1.30¶ 0.018

MFI-20

General fatigue 10.3±4.3 11.6±5.6 NS 9.9±5.2 0.08±0.82 0.33±1.08 NS

Physical fatigue 9.2±4.0 11.8±5.4 0.015 8.8±4.9 0.07±0.82 0.62±1.10¶ 0.015

Reduced activity 8.8±4.3 10.6±5.1 NS 8.7±4.6 0.03±0.93 0.42±1.10¶ NS

Reduced motivation 8.9±3.7 10.1±5.3 NS 8.2±4.0 0.18±0.94 0.46±1.31¶ NS

Mental fatigue 8.4±4.8 10.9±5.3 0.035 8.3±4.8 0.03±1.00 0.53±1.10¶ 0.035

CFQ

Memory 28±18 28±22 NS na

Distractibility 35±18 36±19 NS na

Blunders 30±16 29±20 NS na

(memory for) Names 46±23 51±24 NS na

* Z-scores for the RAND-36 are based on different age-groups. ¶ mean Z-score different from 0 (P < 0.05). na: not available


54

Chapter 3

Table 3 Multivariate analysis of RAND 36 Z- scores.

Phys

ical f

unct

ioni

ng

Soci

al fu

nctio

ning

Role

lim

itatio

ns d

ue to

phy

sica

l pro

blem

s

Role

lim

itatio

ns d

ue to

em

otio

nal p

robl

ems

Men

tal h

ealth

Vita

lity

Pain

Gene

ral h

ealth

per

cept

ion

Radiotherapy +0.56¶ +0.48*

Male patients +0.48*

Intact HPA axis +0.57¶ +0.53* +0.44*

IGF-1 Z score > –2 +0.47*

2nd operation +0.61* +0.56*

The model includes independent continuous variables (age, age at primary (surgical) treatment, duration of follow-up after primary treatment, IGF-1 Z-score and free T4 concentration) and dichotomous independent variables (sex (male versus female), radiotherapy (yes versus no), type of primary surgical operation (transsphenoidal versus craniotomy), substitution of individual pituitary axis (yes versus no), IGF-1 Z-score < –2 (yes versus no) and substitution of total number of anterior pituitary axis (n = 0,1,2,3 or 4)) HPA axis: Hypothalamic Pituitary Adrenal axis¶ P < 0.01, * P < 0.05 Note that the effect size is measured in standard deviation.

No differences in quality of life or cognitive functioning were observed related to

the current age, age at primary treatment, primary surgical operation route, or the second

surgical intervention. Hormonal substitution for loss of anterior pituitary function also

had no effect on HR-QoL.

Multivariate analysis independently identified that RT, sex, cortisol substitution

therapy, IGF-1 Z score < -2, and a second pituitary operation were independent determi-

nants of quality of life (RAND 36) (Table 3). Improved RAND scores were seen in patients

who received RT, in male patients, in patients with an intact corticotrophic axis, in pa-

tients with IGF Z score > -2, and in patients who underwent a second surgical procedure.

Effect sizes of these independent variables ranged from 0.4 to 0.6.

55

Discussion

We found no negative outcomes and even some limited positive effects in the percep-

tion of mental and physical health after RT in a large cohort of patients with NFA.

Health-related quality of life was measured in this study with the RAND 36 ques-

tionnaire, which has been shown to be a reliable and valid instrument with good in-

ternal consistency. Results were compared with age-adjusted normative data for the

Dutch population19. We found that social functioning, vitality, and general health per-

ception (three domains of RAND 36) were significantly lower in the group that did not

receive RT when compared with the reference population. In contrast, in patients who

underwent RT only general health perception was worse than in the age-matched con-

trol population, whereas physical functioning, pain (RAND 36), and anxiety (HADS) were

not adversely affected, and their score was even slightly better. The group of patients

that underwent RT reported significantly higher levels of vitality and less depressive

symptoms and physical and mental fatigue, with effect sizes ranging from 0.47 to 0.56,

indicating a clinically relevant medium size effect. This suggests that RT may be bene-

ficial to self-perceived health. Our results are in contrast to those found by Page et al.27.

They used the SF36 questionnaire, identical to the RAND 36, and reported that patients

treated with RT for nonfunctioning pituitary tumors were more depressed and anxious

than those who underwent mastoid surgery. However, this study group of patients with

NFA was smaller than ours, and only 18 patients had received RT after surgery. Further, it

is not clear from their report whether they properly corrected for age in each individual

patient. Noad et al.28 recently reported data on the effects of RT on cognitive function and

quality of life in patients with pituitary disease. Of the 71 patients who were assessed,

33 had nonfunctioning adenomas, 15 of whom underwent RT. It was concluded from

data of their entire group that patients who had received RT had no significant change

in the quality of life as measured by the physical and mental health composite of the

SF36. Recently, Dekkers et al.29 reported on the diminished quality of life in patients with

nonfunctioning pituitary macroadenomas. Although RT was very infrequently applied

in this study, a small subanalysis by means of linear regression revealed that RT was not

an independent predictor for reduced quality of life. Thus, results from smaller studies

on the effects of RT on quality of life are in accordance with our findings.

We extensively looked for a selection bias but did not find one. Age at sur-

gery and duration of follow-up are potential candidates. However, both in univariate

and multivariate analysis, RT remained a strong and independent predictor for quality

of life, and neither age at surgery nor duration of follow-up were of any importance.

Socioeconomic status and comorbidity also did not differ between groups. Further, RT

was given to patients with tumors that were larger or growing more aggressively. The

RT group even needed more hormone substitution therapy and more often underwent a


56

Chapter 3

craniotomy. Therefore, we believe that a selection bias toward a better quality of life for

patients who underwent RT is unlikely.

We found higher scores for depression in the group that did not receive RT. Scores

for anxiety were similar between both groups. Noad et al.28 also used the HADS and

found no treatment effect for RT. However, as mentioned earlier, their group size of NFA

patients was very small. A report from Peace et al.16 is in accordance with our findings.

They used the Beck Depression Inventory and the State-Trait Anxiety Inventory to assess

self-reported mood and found that RT exerted a mild protective effect on depression.

Several studies suggest that patients with pituitary tumors may continue to suf-

fer from cognitive impairment even after treatment of their disease11,15,17,30. McCord et

al.14 suggested that RT for pituitary tumors may be associated with cognitive impair-

ment. However, their assessment contained no formal, objective measures of cognitive

impairment and relied entirely on self-report. Grattan-Smith et al.30 performed neuro-

psychological testing in a group of patients with pituitary adenoma and reported memo-

ry and executive function impairments in these patients when compared with a control

group. In this study, no specific cause of the neuropsychological impairment was found,

and patients treated with RT performed equally when compared with those who did

not receive RT. Peace et al.15 found deficits primarily on test of executive function, but

they found them in response to surgery and not RT. Anterograde memory deficits were

found by Guinan et al.11 in patients with pituitary tumors. However, there was no nega-

tive treatment effect of pituitary RT. In accordance with the lack of evidence of reduced

cognitive performance associated with RT, we also found no indications of cognitive

impairment as a consequence of RT.

In conclusion, no negative outcomes and even some limited positive effects in

the perception of mental and physical health after RT were found in a large cohort of

patients with NFA. Our results are reassuring and raise no concern that RT applied after

surgery in the treatment of NFA leads to reduced quality of life or impaired cognition.

57


References

1. Boelaert K, Gittoes NJ. Radiotherapy for non-functioning pituitary adenomas. Eur J

Endocrinol 2001;144:569-575

2. Dekkers OM, Pereira AM, Roelfsema F, et al. Observation alone after transsphenoidal

surgery for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab

2006;91:1796-1801

3. Paek SH, Downes MB, Bednarz G, et al. Integration of surgery with fractionated stereotactic

radiotherapy for treatment of nonfunctioning pituitary macroadenomas. Int J Radiat Oncol

Biol Phys 2005;61:795-808

4. Gittoes NJ Radiotherapy for non-functioning pituitary tumors-when and under what

circumstances? Pituitary 2003;6:103-108

5. Park P, Chandler WF, Barkan AL, et al. The role of radiation therapy after surgical resection

of nonfunctional pituitary macroadenomas. Neurosurgery 2004;55:100-106

6. Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality

and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet

2001;357:425-431

7. van den Bergh AC, van den Berg G, Schoorl MA, et al. Immediate postoperative radiotherapy

in residual nonfunctioning pituitary adenoma: Beneficial effect on local control without

additional negative impact on pituitary function and life expectancy. Int J Radiat Oncol Biol

Phys 2007;67:863-869.

8. Erfurth EM, Bulow B, Mikoczy Z, et al. Is there an increase in second brain tumours after

surgery and irradiation for a pituitary tumour? Clin Endocrinol (Oxf) 2001;55:613-616

9. Gittoes NJ. Pituitary radiotherapy: Current controversies. Trends Endocrinol Metab

2005;16:407-413

10. van den Bergh AC, Schoorl MA, Dullaart RP, Lack of radiation optic neuropathy in

72 patients treated for pituitary adenoma. J Neuroophthalmol 2004;24:200-205

11. Guinan EM, Lowy C, Stanhope N, et al. Cognitive effects of pituitary tumours and their

treatments: Two case studies and an investigation of 90 patients. J Neurol Neurosurg

Psychiatry 1998;65:870-876

12. Baird A, Sullivan T, Zafar S, et al. Quality of life in patients with pituitary tumors: A

preliminary study. Qual Manag Health Care 2003;12:97-105

13. Johnson MD, Woodburn CJ, Vance ML. Quality of life in patients with a pituitary adenoma.

Pituitary 2003;6:81-87

14. McCord MW, Buatti JM, Fennell EM, et al. Radiotherapy for pituitary adenoma: Long-term

outcome and sequelae. Int J Radiat Oncol Biol Phys 1997;39:437-444

15. Peace KA, Orme SM, Padayatty SJ, et al. Cognitive dysfunction in patients with pituitary

tumour who have been treated with transfrontal or transsphenoidal surgery or

medication. Clin Endocrinol (Oxf) 1998;49:391-396

58

Chapter 3

16. Peace KA, Orme SM, Sebastian JP, et al. The effect of treatment variables on mood

and social adjustment in adult patients with pituitary disease. Clin Endocrinol (Oxf)

1997;46:445-450

17. Peace KA, Orme SM, Thompson AR, et al. Cognitive dysfunction in patients treated for

pituitary tumours. J Clin Exp Neuropsychol 1997;19:1-6.

18. Brazier JE, Harper R, Jones NM, et al. Validating the SF-36 health survey questionnaire: New

outcome measure for primary care. BMJ 1992;305:160-164

19. Van der Zee KI, Sanderman R. The measurement of the general health with the RAND-36, a

handbook. Groningen, The Netherlands: Rijks Universiteit Groningen, Noordelijk Centrum

voor Gezondsheidsvraagstukken; 1992.

20. Smets EM, Garssen B, Bonke B, et al. The Multidimensional Fatigue Inventory (MFI)

psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995;39:315-325

21. Smets EM, Visser MR, Willems-Groot AF, et al. Fatigue and radiotherapy: (B) experience in

patients 9 months following treatment. Br J Cancer 1998;78:907-912

22. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand

1983;67:361-370

23. Spinhoven P, Ormel J, Sloekers PP, et al. A validation study of the Hospital Anxiety and

Depression Scale (HADS) in different groups of Dutch subjects. Psychol Med 1997;27:363-370

24. Broadbent DE, Cooper PF, FitzGerald P, et al. The Cognitive Failures Questionnaire (CFQ) and

its correlates. Br J Clin Psychol 1982;21:1-16

25. Wallace JC, Kass SJ, Stanny CJ. The cognitive failures questionnaire revisited: Dimensions

and correlates. J Gen Psychol 2002;129:238-256

26. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Lawrence

Earlbaum Associates; 1998.

27. Page RC, Hammersley MS, Burke CW, et al.An account of the quality of life of patients after

treatment for non-functioning pituitary tumours. Clin Endocrinol (Oxf) 1997;46:401-406

28. Noad R, Narayanan KR, Howlett T, et al. Evaluation of the effect of radiotherapy for pituitary

tumours on cognitive function and quality of life. Clin Oncol (R Coll Radiol ) 2004;16:233-237.

29. Dekkers OM, van der Klaauw AA, Pereira AM, et al. Quality of life is decreased after

treatment for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 2006; 91:

3364-3369.

30. Grattan-Smith PJ, Morris JG, Shores EA, et al. Neuropsychological abnormalities in patients

with pituitary tumours. Acta Neurol Scand 1992;86:626-631.

59

Letter to the editor

Subjective ratings vs objective measurement of cognitive function: In Regard to van Beek et al. Int J Radiat Oncol Biol Phys 2007;68: 986-991

Martin Klein, Ph.D., 1 Jaap C. Reijneveld, M.D., Ph.D., 2, and Jan J.Heimans, M.D., Ph.D. 2

Department of 1 Medical Psychology , and 2 Department of Neurology, VU University Medical Center,

Amsterdam, the Netherlands.

To the Editor

We read with great interest the manuscript of van Beek et al.1 in which the authors re-

port on the impact of radiotherapy on long-term health-related quality of life (HRQOL)

and cognitive problems among patients treated for nonfunctioning pituitary adenoma

(NFA). Following treatment, HRQOL, depression, fatigue, and cognitive functioning of ir-

radiated and unirradiated patients was assessed using self-report questionnaires. Pa-

tients with or without RT attained comparable HRQOL scores in most domains and RT

was even significantly associated with improved HRQOL in a multivariate model. No

differences in cognitive function scores were observed.

Although we think that studies into the cognitive effects of treatment of these pa-

tients should be strongly encouraged, we would at the same time like to caution against

the use of self-report questionnaires as a means to measure cognitive functioning.

Numerous studies that focus on perceptions of cognitive functioning have con-

sistently found these self-reports to be unrelated to objective performance in distinct

patient groups, including those with cancer2, coronary artery bypass surgery3,4, multiple

sclerosis5,6, temporal lobe epilepsy surgery7, and HIV8. In cancer patients, and potentially

also in those with pituitary adenomas, cognitive complaints might more likely reflect

feelings of anxiety, depression and fatigue than a loss of cognitive abilities2. Considering

the elevated levels of depression and fatigue in the study of van Beek and colleagues,

this is most likely also the case in patients with NFA. We suggest these findings strongly

argue against relying on patient reports to assess cognitive function. Objective testing

remains the method of choice for assessing higher cognitive functions.


60

Chapter 3

References

1. van Beek AP, van den Bergh AC, van den Berg LM, et al. Radiotherapy is not associated

with reduced quality of life and cognitive function in patients treated for nonfunctioning

pituitary adenoma. Int J Radiat Oncol Biol Phys 2007;68:986-991.

2. Cull A, Hay C, Love SB, et al. What do cancer patients mean when they complain of

concentration and memory problems? Br J Cancer 1996;74:1674-1679.

3. Newman S, Klinger L, Venn G, et al. Subjective reports of cognition in relation to assessed

cognitive performance following coronary artery bypass surgery. J Psychosom Res

1989;33:227-233.

4. Khatri P, Babyak M, Clancy C, et al. Perception of cognitive function in older adults. Health

Psychol 1999;18:301-306.

5. Maor Y, Olmer L, Mozes B. The relation between objective and subjective impairment in

cognitive function among multiple sclerosis patients-the role of depression. Mult Scler

2001;7:131-135.

6. Middleton LS, Denney DR, Lynch SG, et al. The relationship between perceived and

objective cognitive functioning in multiple sclerosis. Arch Clin Neuropsychol 2006;21:487-494.

7. Sawrie SM, Martin RC, Kuzniecky R, et al. Subjective versus objective memory change after

temporal lobe epilepsy surgery. Neurology 1999;53:1511-1517.

8. van Gorp WG, Satz P, Hinkin C, et al. Metacognition in HIV-1 seropositive asymptomatic

individuals: self-ratings versus objective neuropsychological performance. Multicenter

AIDS Cohort Study (MACS). J Clin Exp Neuropsychol 1991;13:812-819.

61


To the Editor

We agree with Klein and colleagues that objective testing is very important in assess-

ment of cognitive functioning. They raise an important question with regard to the stra-

tegy of elucidating possible cognitive deterioration in patients receiving postoperative

radiotherapy to the pituitary gland.

Klein et al. state that numerous studies found discrepancies between self-re-

port measures of cognitive functioning and objective tests. This finding is likely subject

to publication bias. In addition, several studies mentioned by Klein are flawed by com-

paring global measures of self-report cognitive functioning with a single global objec-

tive neurocognitive score calculated as the mean of all the (standardized) scores1-3. This

is far from a balanced comparison. In fact, when analyzed in a proper way, Middleton

found that patients’ perceptions of their performance on specific tasks correlated with

their objective performance on those tasks2. Podewils and colleagues reported similar

results and concluded that individuals experiencing changes in cognitive function ap-

peared to have some awareness of their condition4.

Further, in a cross-sectional study design, patients with non-functioning pitui-

tary adenomas show differences in baseline characteristics, in treatment (type of sur-

gery, radiotherapy), and in outcome (presence of residual non-functioning adenoma,

hypopituitarism). In addition, this group receives multiple substitution therapy e.g.

growth hormone, hydrocortisone and thyroid hormone, with all the intrinsic imper-

fections of hormone replacement strategies in mimicking normal hormone secretion5.

Sometimes patients and doctors choose not to substitute sex steroid or growth hor-

mone deficiencies. Effects of endogenous hormone deficiencies and exogenous substi-

tution therapy may not be the same with respect to cognitive functioning. Moreover,

different surgical routes may damage different parts in the brain. And putative delete-

rious effects of radiotherapy will differ in time. Radiotherapy used to be given several

decades ago with two opposing lateral fields, potentially damaging the temporal lobes.

Modern radiotherapy evolved to use a multiple-field technique in order to spare more

normal surrounding tissue from the effects of ionizing radiation6,7. Thus, multiple fac-

tors are present that are likely to affect multiple different parts of the brain and there-

fore different cognitive domains. As a result, objective testing (even screening) in this

group is far from easy. Based on previous study reports, no obvious deficits in cognitive

functioning were expected. It is a logical next step and common practice to ask the

patient if they experience deficits in their own cognitive functioning. We chose the

Cognitive Failures Questionnaire and found no differences with regard to the applica-

tion of radiotherapy8. Further studies are warranted and should include interviewing

partners for cognitive problems in their spouses. Subsequently, formal testing can be

performed with special attention the reported problems in cognitive functioning. At-

62

Chapter 3

tention should be paid to the choice of these tests because many show a high inter-

rater variability and lack of validation.

Yours sincerely,

André P van Beek, Alphons C.M. van den Bergh, Linda M. van den Berg, Gerrit van den Berg,

Joost C. Keers, Johannes A. Langendijk,Bruce H.R. Wolffenbuttel.

References

1. Khatri P, Babyak M, Clancy C, et al. Perception of cognitive function in older adults. Health

Psychol 1999;18:301-306.

2. Middleton LS, Denney DR, Lynch SG, et al. The relationship between perceived and objective

cognitive functioning in multiple sclerosis. Arch Clin Neuropsychol 2006;21:487-494.

3. van Gorp WG, Satz P, Hinkin C, et al. Metacognition in HIV-1 seropositive asymptomatic

individuals: self-ratings versus objective neuropsychological performance. Multicenter

AIDS Cohort Study (MACS). J Clin Exp Neuropsychol 1991;13:812-819.

4. Podewils LJ, McLay RN, Rebok GW et al. Relationship of self-perceptions of memory

and worry to objective measures of memory and cognition in the general population.

Psychosomatics 2003; 44:461-70.

5. Romijn JA, Smit JW, Lamberts SW. Intrinsic imperfections of endocrine replacement

therapy. Eur J Endocrinol 2003;149:91-7.

6. Boelaert K, Gittoes NJ Radiotherapy for non-functioning pituitary adenomas. Eur J

Endocrinol 2001;144:569-575.

7. van den Bergh AC, van den Berg G, Schoorl MA et al. Immediate postoperative radiotherapy

in residual nonfunctioning pituitary adenoma: beneficial effect on local control without

additional negative impact on pituitary function and life expectancy. Int J Radiat Oncol Biol

Phys 2007;67:863-9.

8. van Beek AP, van den Bergh AC, van den Berg LM, et al. Radiotherapy is not associated

with reduced quality of life and cognitive function in patients treated for nonfunctioning

pituitary adenoma. Int J Radiat Oncol Biol Phys 2007;68:986-991.

4 Radiation optic neuropathy after

external beam radiation therapy for

acromegaly: report of two cases

Alfons C.M. van den Bergh1; Marjanke A. Hoving1; Thera P. Links3; Robin P.F. Dullaart3;

Adelita V. Ranchor5; Cees A. ter Weeme4; Alof A. Canrinus1; Ben G. Szabó1; Jan-Willem

R. Pott2

1 Department of Radiation Oncology, 2 Ophthalmology, 3 Endocrinology,

4 Neurosurgery, University Hospital Groningen and 5 Northern Centre for Healthcare

Research, University of Groningen, The Netherlands.

Radiotherapy and Oncology 2003; 68: 101-103

66

Chapter 4

Abstract

For diagnosing radiation optic neuropathy (RON) ophthalmological and imaging

data were evaluated from 63 acromegalic patients, irradiated between 1967 and

1998. Two patients developed RON: one patient in one optic nerve 10 years and

another patient in both optic nerves five months after radiation therapy. RON is

a rare complication after external beam radiation therapy for acromegaly, which

can occur after a considerable latency period.

67

Radiation optic neuropathy after external beam radiation therapy for acromegaly: report of two cases

Introduction

Acromegaly is an uncommon disease, mostly caused by a growth hormone (GH)- secre-

ting pituitary adenoma. Surgery, drug therapy with somatostatin analogs and external

beam radiation therapy are currently the available treatment options8. Postoperative

radiation therapy is performed to reduce the time span of medical treatment, to norma-

lize GH hypersecretion, and to prevent regrowth of residual tumour10.

In the past decades, scattered reports on radiation optic neuropathy (RON) have

appeared in the literature4. RON is usually defined as a sudden and profound irrever-

sible vision loss due to damage of the optic nerves or damage of the chiasm caused by

radiation therapy7. The aim of this retrospective study is to describe the occurrence of

RON in a cohort of patients treated with radiation therapy for a GH-secreting pituitary

adenoma.

Materials and Methods

During the period 1967-1998, 80 patients with acromegaly were diagnosed at the Uni-

versity Hospital Groningen, The Netherlands. The diagnosis of acromegaly was based on

the typical clinical features of acral enlargement and soft tissue swelling and was con-

firmed by appropriate laboratory tests. In all operated patients histological evaluation of

the specimen confirmed the presence of a GH-producing pituitary adenoma.

In 1999 and 2000, a retrospective investigation was performed. The ophthalmo-

logical, surgical and radiation therapy data were reviewed. The time period 1967-1998

was chosen because data before 1967 were frequently incomplete. To be included in the

present survey, time of follow-up had to be at least 18 months. The ophthalmological

data obtained before treatment were available in all but two patients and after radiation

therapy from all patients.

Of these 80 cases, 63 patients, who were treated with external beam radiation

therapy, were included in our survey. External radiation therapy was mostly performed

at the University Hospital Groningen (n = 56), but also in 2 other regional institutions

(n = 7), where equivalent radiation therapy schedules were applied.

Before 1977 the neurosurgical procedures were craniotomies only. Since 1978 the

transsphenoidal approach was the preferred method.

Visual acuity was measured with a Snellen acuity chart. A visual acuity less

than 0.8 was defined as impaired. Visual fields were obtained with Goldmann kinetic

perimetry. The visual field data (n = 1195) of all patients at diagnosis, after neurosur-

gery and/or radiation therapy were retrospectively reviewed by one neuro-ophthal-

mologist.

68

Chapter 4

We diagnosed RON using the criteria by Kline et al. and Parsons et al.7,9 :

• Irreversible visual loss with visual field defects, indicating optic nerve or chiasmal dys-

function.

• Absence of visual pathway compression due to recurrence or progression of tumour,

radiation-induced neoplasm, arachnoidal adhesions around the chiasm, radiation retino-

pathy or any other apparent ophthalmological disease.

• Absence of optic disc edema.

• Optic atrophy within 6 - 8 weeks after onset of symptoms.

Evaluation of RON was performed by review of visual field, visual acuity and fun-

doscopic examinations in combination with imaging of the sellar region.

The time span of follow-up was defined by the period between the first day of

radiation therapy and the last ophthalmologic examination.

Results and Discussion

Median age at the start of radiation therapy was 43 years (range 19-64 years). Twenty-

eight patients were males (44%) and 35 patients were females (56%). Fourteen patients

were treated with radiation therapy alone. Forty nine patients were treated with a com-

bination of radiation therapy and surgery of whom 40 patients had one, five patients

had two and one patient had three operations before radiation therapy. Two patients

underwent surgery after radiation therapy. One patient had radiation therapy in be-

tween two pituitary operations. Median follow-up time in the radiation therapy group

was 84 months (range 18 - 250 months).

Total radiation therapy dose ranged from 45 to 55.5 Gy (median dose 49.5 Gy).

Median overall treatment time was 36 days (range 31-54 days). The daily fraction size

varied from 1.8 to 2.1 Gy in 55 patients (median dose 1.8 Gy). In six patients the radia-

tion therapy course was initiated with gradually increasing doses between 1 Gy and 2 Gy

daily. From two patients only the total dose was known, but we assume that they were

treated with an increasing daily dose as just mentioned, which was standard between

1967 and 1974. The most common dose and fractionation scheme used was 45 Gy in 1.8

Gy daily fractions (n = 27; 43%), mainly performed in the time period 1985-1998. Fifty Gy

in 2 Gy daily fractions, mainly performed in the time period 1974-1984 was administered

to 20 patients (32%). Eleven patients received a total dose greater than 50 Gy; ten of them

had been irradiated before 1981. In all patients all radiation treatment fields were given

every treatment day.

In the time-period 1969-1978 the betatron with energy 18 MV HVD 17 mm PB was

used in 13 patients; a five- or seven-field technique was used with standard field sizes of

4 by 4 cm. Three patients were treated with a cobalt source, energy 1.25 MV HVD 11 mm

PB, a four-field technique was used twice and a combination of an opposed lateral field

69


technique followed by a three-field technique was used once. Treatment fields varied

between 4 and 5 cm in lateral or cranio-caudal dimension. From 1979 onwards patients

were treated on linear accelerators with 4MV photons (n = 2), 6 MV photons (n = 20),

8 MV photons (n = 24) and 10 MV photons (n = 1). A two-field opposed lateral technique

was used in seven patients, a three-field technique in 12 patients, a rotation technique

in one patient, a five-field technique in 11 patients, a six-field technique in one patient

and a combination of above mentioned techniques in 15 patients; most of the time a

combination of opposed lateral fields followed by a five-field (n = 11) or a three-field

technique (n = 3). In the time period 1979-1989 the treatment plan was normalised on

the encompassing isodose, afterwards according to ICRU11. Treatment-field dimensions

varied between 3 and 6 cm.

RON was diagnosed in two of the 63 irradiated patients (3.2%, 95% CI: 0.3 - 11.2%).

In one patient RON was unilateral (case 1) and in the other patient RON was bilateral

(case 2).

Case 1

A female, aged 52 years, underwent pituitary irradiation in 1969, with a total dose of 55.5

Gy given in 54 days, with an assumed daily dose 1 to 2 Gy, with 18 MV betatron pho-

tons and a seven-field technique for a GH-producing pituitary adenoma. At diagnosis

of acromegaly and within the first ten years after radiation therapy no visual deficits

were reported. In 1979 she suffered sudden visual loss in the left eye decreasing to light

perception only. On fundoscopy of the left eye, the optic nerve was atrophic. Goldmann

kinetic perimetry showed a central scotoma; the visual functions of the right eye were

normal. A CT-scan of the pituitary fossa showed a residual intrasellar pituitary mass

without suprasellar extension.

Subsequent CT-scans also did not reveal suprasellar mass; she declined to undergo

an MRI.

Case 2

The second patient, a 42 year old female, underwent a frontal craniotomy in 1968 be-

cause of a suprasellar pituitary adenoma. The optic nerves and the optic chiasm were

embedded in the tumour, but pre- and postoperatively the visual acuity of both eyes was

normal and there were no visual field defects. Six months later radiation therapy was

started, because of persistence of GH hypersecretion. The radiation schedule was 50 Gy

in 2 Gy daily fractions in 42 days. Eight megavolt photons and a three-field-technique

were used. Five months later, she complained about progressive visual loss, occurring

within a few weeks. At ophthalmological examination the visual acuity of the left eye

was 0.1 and was accompanied by a temporal hemianopsia. The visual acuity of the right

eye was 1.0 with an altitudinal visual field defect in the upper quadrant. On fundoscopy

70

Chapter 4

there was bilateral optic atrophy. The visual field defect of the left eye did not change,

but the visual acuity deteriorated gradually in a time span of 2 years to 1/60. The visual

field defects of the right eye worsened in 1983 and 1988. In this eye the visual acuity

changed to 0.7 in 1992 and 0.5 in 1995.

A pneumoencephalogram made in 1979 showed limited suprasellar extension of

the pituitary adenoma with the optic system well demarcated in the suprasellar air thus

excluding tumour recurrence. This finding strongly suggest that the visual deterioration

in the left eye was due to radiation treatment. We assume by reviewing of all ophthal-

mologic data and exclusion of other causes, that the gradually worsening of vision in the

right eye is also due to RON.

In the present series, two out of 63 irradiated patients (3.2%) developed RON. A

total radiation dose greater than 50 Gy and/or a radiation fraction size greater than 2

Gy are suggested to be risk factors for RON1,9. One of the presently reported cases had

a total radiation dose of 50 Gy and a radiation fraction size of 2 Gy. This would suggest

the presence of other risk factors, associated with the development of RON after radia-

tion therapy in GH-secreting pituitary adenoma. Apart from the probable risk attribu-

table to vascular compromise6,9, GH-secreting pituitary adenoma as such may confer an

increased risk for RON development as previously suggested1-3,5. In case 2 of the present

series the optic nerves and optic chiasm were embedded in the tumour, which may have

been contributed to the development of RON.

It is generally proposed, that most cases of RON occur within 18 months after

radiation therapy7. Case 1 of the present series well illustrates, that late development of

RON can occur, indicating that the clinician should remain alert of this complication,

even many years after radiation therapy.

RON is a rare complication after external beam radiation therapy for acromegaly,

which may occur after a considerable latency period.

71


References

1. Aristizabal S, Caldwell WL, Avila J. The relationship of time-dose fractionation factors to

complications in the treatment of pituitary tumors by irradiation. Int.J.Rad.Oncol.Biol.Phys.

1977;2:667-673.

2. Atkinson AB, Allen IV, Gordon DS, et al. Progressive visual failure in acromegaly following

external pituitary adenoma. Clin Endocrinol 1979;10:469-479.

3. Bloom B, Kramer S. Conventional Radiation Therapy in the Management of Acromegaly. In:

McL.Black P.et al., editors. Secretory Tumors of the Pituitary Gland, 1st ed. Progress in Endocrine

Research and Therapy, New York: Raven Press; 1984:179-190.

4. Forrest APM, Peebles Brown DA, Morris SR, Illingworth CFW. Pituitary radon implant for

advanced cancer. The Lancet 1956;270:399-401.

5. Hammer HM. Optic Chiasmal Radionecrosis. Trans.ophthal.Soc.U.K. 1983;103:208-211.

6. Jiang GL, Tucker SL, Guttenberger R, et al. Radiation-induced injury to the visual pathway.

Radiother.Oncol. 1994;30:17-25.

7. Kline LB, Kim JY, Ceballos R. Radiation optic neuropathy. Ophthalmology 1985;92:1118-1126.

8. Melmed S, Jackson I, Kleinberg D, Klibanski A. Current treatment guidelines for acromegaly.

J Clin Endocrinology and Metabolism 1998;83:2646-2652.

9. Parsons JT, Bova FJ, Fitzgerald CR, Mendenhall WM, Million RR. Radiation optic neuropathy

after megavoltage external-beam irradiation: analysis of time-dose factors. Int.J.Radiation

Oncology Biol.Phys. 1994;30:755-764.

10. Speirs CJ, Reed PI, Morrison R, Joplin GF. The effectiveness of external beam radiotherapy

for acromegaly is not affected by previous pituitary ablative treatments. Acta Endocrinol.

1990;122:559-565.

11. Wambersie, A. ICRU Report 62; prescribing, recording and reporting photon beam therapy

(Supplement to ICRU 50); 1999.

5 Radiation optic neuropathy

after external beam radiation therapy

for acromegaly

Alfons C.M. van den Bergh1, Robin P.F. Dullaart2, Marjanke A. Hoving1, Thera P. Links2,

Cees A. ter Weeme3, Ben G. Szabó1, Jan-Willem R. Pott4

1 Department of Radiation Oncology, 2 Endocrinology, 3 Neurosurgery,

4 Ophthalmology, University Hospital Groningen, The Netherlands.

Radiotherapy and Oncology 2003; 68: 95-100

Chapter 1

74

Chapter 5

75


Introduction

Acromegaly is an uncommon disease, mostly caused by a growth hormone (GH)- secre-

ting pituitary adenoma. Its incidence has been estimated at 2.8 - 6 cases per million and

its prevalence at 38 - 68 cases per million2,10,64.

A GH-secreting pituitary adenoma does not only lead to clinical signs and symp-

toms, like acral enlargement and soft tissue swelling, but may also be accompanied by

visual field defects and acuity loss caused by tumour compression on the optic nerves or

chiasm, often seen in combination with pituitary hormone insufficiencies.

Surgery, drug therapy with somatostatin analogs and external beam radiation

therapy are currently the available treatment options61. External beam radiation therapy

is available since the beginning of the 20th century12,35. It became clear, however, that

radiation therapy alone often results in insufficient biochemical control, which means a

decline but not a normalisation of GH hypersecretion3,4,24,29,56. Consequently, surgery be-

came the initial treatment of choice. According to some experts drug therapy may be the

first treatment of choice for selected patients61. Postoperative radiation therapy is per-

formed in many centres to reduce the postoperative time span of medical treatment, to

normalize remaining GH hypersecretion, and to prevent regrowth of residual tumour75.

Radiation Optic Neuropathy (RON) was for the first time reported by Forrest et

al. in 195630. They defined RON as a sudden and profound irreversible vision loss due to

damage of the optic nerves or damage of the chiasm caused by radiation therapy.

Kline et al. and Parsons et al. defined the following criteria for diagnosing RON49,65:

(a) irreversible visual loss with visual field defects, indicating optic nerve or chiasmal

dysfunction; (b) absence of visual pathway compression due to recurrence or progres-

sion of tumour, radiation-induced neoplasm, arachnoidal adhesions around the chiasm,

radiation retinopathy or any other apparent ophthalmological disease; (c) absence of

optic disc edema and (d) optic atrophy within 6 - 8 weeks after onset of symptoms.

In the past decades many reports on RON have appeared in the literature. The last

review of RON in acromegaly was published by Eastman et al. in 199225. The radiation dose

level for the occurrence of RON is not known. Moreover the dose-response relationship

for RON has not been firmly established due to the small numbers of events in most se-

ries46,65. It has been suggested that the maximal steepness of the sigmoid dose-response

curve for RON is between 50 and 60 Gy46,65. The occurrence of RON after doses as low as

45-50 Gy administered in fractions of 1.67 - 2 Gy seems to be a problem unique to patients

with pituitary tumours, and probably reflects pre-existing optic nerve and chiasm com-

pression and vascular compromise secondary to a mass effect or due to surgery46,65.

Some authors propose that the optic system in acromegalic patients might be

more sensitive to radiation damage compared to patients irradiated for non-functioning

pituitary adenomas5,6,13,39. This may be caused by vascular and hormonal changes in rela-

tion to acromegaly5, but this opinion is not uniformly accepted23,25.

76

Chapter 5

The purpose of this literature survey is to determine the incidence of RON in

acro megaly, and to establish risk factors associated with its occurrence

Literature search and data analysis

The literature review was done, using Medline between 1966 and June 2002 and Embase

between 1989 and 2002. Key words searched for were RON, acromegaly and radiotherapy

as well as pituitary adenoma and radiotherapy. All papers that included acromegalic pa-

tients were checked for vision loss due to radiation therapy. The references retrieved by

Medline and Embase were screened for other references, not found by using the above-

mentioned key words.

To estimate the incidence of RON in acromegaly we only included cohort series

of patients, in which RON was taken into consideration. In case of a cohort of all kind of

pituitary adenomas, it was only included in Table 1 in case of a known number of acro-

megalic patients, in which it was clear how many patients suffered RON. To evaluate risk

factors for RON development we included RON-patients from series in which radiation

treatment data were available, as well as individual case reports. This present survey

includes our own series of 63 patients of whom two developed RON11.

Incidence of RON

As shown in Table 1, 25 of 1845 patients developed RON, yielding an incidence of 1.36%

(95%CI: 0.94 - 1.89%). This figure is not significantly lower than that reported by Eastman

et al., who calculated an incidence of 2.2% (95%CI: 1.53 - 3.17%) (P = 0.10)25. The incidence

reported by Eastman et al. is likely to be overestimated, because they included single case

reports of RON in their review25. Although the incidence of RON is low, it is considered a

serious complication of radiation therapy. It is therefore of interest to identify the severity

of visual loss and the radiation treatment characteristics associated with its occurrence.

Table 1 Incidence of RON in reported series of acromegalic patients

Reference Number of patients

Total radiation dose (Gy)

Fraction size(Gy)

Number of RON cases

Treatment period

[73] 31 35-50 1.8 1 1942-1959

[34] 53 na na 1 1932-1960

[20] 22 na na 0 1938-1958

[50] 7 40-45 2.5 0 na

[27] 34 40 2 0 1940-1963

[33] 30 45 1.8 0 na

[56] 28 29.5-66 na 0 1946-1970

[45] 12 35-50 na 0 na

[51] 29 40-50 2 1 1957-1971

77


[47] 12 na na 0 na

[44] 10 35-37.5 2.2-2.35 0 na

[4] 10 55 2 0 na

[54] 25 16-80 na 0 1954-1975

[41] 6 45-50 2-2.5 0 1968-1973

[66] 19 44-76 2 0 1956-1972

[40] 18 40-60 na 1 1962

[5] 25 na na 1 1952-1971

[6] 23 42-45 na 4 1961-1975

[24] 47 40-56 2-3 1 na

[9] 102 na na 0 na

[17] 35 50 2 1 1967-1976

[8] 17 45-50 1.8-2 0 1971-1982

[16] 5 na na 0 1971-1979

[48] 28 30-46 2 0 1950-

[31] 33 50-55 na 0 1974-1983

[82] 27 50 na 0 1974-1982

[13] 40 45-50 1.8-2.2 5 1957-1982

[29] 46 37.5 2.5 0 1947-1983

[7] 11 40-50 na 0 1977-1984

[83] 25 50 1.8 0 1968-1982

[81] 80 na na 0 na

[70] 44 na na 1 1970-1984

[58] 17 44.5-62 2 1 1971-1982

[59] 27 36-48 1.92-3.6 1 1962-1987

[53] 41 40-50 1.6-2 0 1978-1988

[1] 12 31-70 na 1 1958-1987

[23] 25 24-53.44 1.67-2.5 0 1956-1988

[57] 46 35-40 2.33-2.66 0 1970-1988

[75] 33 40 2 0 1964-1978

[78] 15 44-55 1.8-2.5 0 1967-1985

[77] 56 50 1.8 0 1972-1986

[32] 22 45-50.4 1.8-2 0 1965-1989

[71] 29 45.7-56 1-2.5 0 1961-1986

[36] 11 50 2-2.2 0 1980-1985

[19] 10 40.5-50.4 1.8-2.5 0 1976-1991

[22] 54 48 na 0 1972-1983

[18] 19 45-50.4 1.8 0 1986-1991

[84] 19 40-45 1.8-2.25 0 1973-1992

[63] 10 45-59.4 1.8-2 0 1980-1991

[79] 52 40-52 1.8-2.5 1 1972-1986

[76] 28 45-50 1.8-2 0 N(1973-1995)

[68] 132 na na 1 1951-1996

[67] 32 47.4(45-54) 1.8(1.7-2) 0 1981-1999

[28] 67 53.6(40-75) 1.5-1.8 0 1969-1996

[37] 41 46-54 1.8-2.5 0 1948-1996

[21] 49 45.08±0.98 2 1 1960-2000

[11] 63 45-55.5 1.8-2.1 2 1967-1998

Total 1845 25na: not available

78

Chapter 5

Severity of visual loss and latency of RON occurrence

When reviewing reported cases of RON in acromegalic patients in whom total radiation

dose and fraction size are reported (Table 2) –using the abovementioned search method -

it appears that in 24 of 32 patients, in whom visual loss was specified, RON was bilateral

in 17 patients (71%) and unilateral in seven patients (29%). Visual acuity was less than

2/10 in 35 of 41 RON affected eyes.

It is generally proposed, that most cases of RON occur within 18 months after ra-

diation therapy49. However, Table 2 shows that in eight of 30 patients (27%), RON developed

more than 18 months after radiation therapy (median 12 months, range 5-120 months).

Thus late development of RON can occur, indicating that the clinician should remain alert

of this complication, even many years after radiation therapy.

RON in relation to radiation treatment characteristics

A radiation fraction size greater than 2 Gy and/or a total radiation dose greater than 50 Gy

are suggested to be risk factors for RON in general5,65. As shown in Table 2, it appears that

in 16 of 32 cases (50%) radiation fraction size was greater than 2 Gy and/or total radia-

tion dose was greater than 50 Gy. Information with respect to minimum and maximum

radiation doses according to ICRU 50/62 recommendations80 within the treated target

volume, that also encompass the optic system, was not available in most reports.

Other risk factors for RON development

Apart from the probable risk attributable to vascular compromise, GH-secreting pituitary

adenoma as such may confer an increased risk for RON development as previously sug-

gested5,6,13,39. Older age is another possible risk factor for RON65. In 27 of 32 cases, reviewed

in Table 2, age was reported. In this series median age was 53 years, which is approxi-

mately 10 years older than the age reported at diagnosis of acromegaly42, and than the

median age of the presented cohort11. However, in general there is a lack of data in pu b-

lished series with respect to age in those patients who did and who did not develop RON.

Therefore, it is not possible to draw definite conclusions about age as a risk factor for RON

development.

Remarkably, as shown in Table 2, 20 of 23 patients (87, 95%CI: 66 - 97%), in whom

gender was reported, were female, our two cases included (P<0.001 from an equal sex

distribution). Since the occurrence of acromegaly is not increased in females42 and it is

unlikely that females are treated with radiation therapy more frequently than males,

this would suggest that females are at an increased risk for the development of RON.

To our knowledge a female predisposition for RON has not been reported earlier.

79


Pathogenesis and treatment

RON is essentially defined as a diagnosis by exclusion49. Although the pathogenesis of

RON is unclear, its microscopic appearance would suggest an initial microvascular in-

jury that results in perivascular inflammation, hyalinization, and fibrosis of vessel walls

and also loss of endothelium and consequently infarction with reactive gliosis49. Using

MRI with gadolinium, enhancement of the retro-orbital optic nerves and chiasm usually

occurs, probably as a consequence of a disrupted blood brain barrier within the optic

nerves14,38. This may be used to differentiate RON from optic neuritis due to demyelina-

tion. Therefore, this diagnostic approach is currently proposed to improve the diagnosis

of RON14,38. A few months after the onset of RON the gadolinium enhancement of the

optic nerves on MRI disappears38.

Until now there is no effective treatment for RON69. The effect of high dose cor-

ticosteroids and of anticoagulants is unclear69. Hyperbaric oxygen therapy has also been

used to treat RON, but its efficacy is uncertain15,69.

80

Chapter 5

Table 2 RON in acromegalic patients, in whom total radiation dose and radiation fraction size are available

Ref Sex Age at RON (yrs)

OperationTotal dose (Gy)

Fraction size (Gy)

Treatment time(days)

Latencyof RON (months)

Visual status at diagnosis

Visual status due to RON

[72] M 46 No 50 2 36 6 N OD:FC OS:2/20

[72] F 60 No 50 2 34 8 N OD:FC

[5]* na na Na 50 2.5 35 15 N OD:Bl OS:Bl

[6]* F 58 Yes 42.4 2.83 22 14 N OD:HM OS:HM

[6]* F 51 No 43.8 3.13 19 13 N OD:reduced vision OS:Bl

[6]* M 53 Yes Yttrium-90 45.2 3 18 After external beam: 84 R OD:HM OS:Bl

[6]* F 63 No 42.4 2.83 22 10 R OD:Bl OS:Bl

[55] F 63 Yes 50 1.52 N 11 Na Visual loss not specified

[55] F 52 Yes 50 2 n 19 N Visual loss not specified

[17]* na na na 55 2.2 40 11 na Visual loss not specified

[39] F 64 No 42.5 2.8 21 8 N OD:Bl OS:Bl

[39] F 63 No 42.5 2.1 28 8 R OD:FC OS:FC

[39] F 50 No 42.5 2.8 21 9 N OD:Bl OS:Bl

[13]* na 51 na 46 2 31 18 N OD:Bl

[13]* F 51 N 45 1.96 31 12 R OD:LP

[13]* na 60 N 50 2 35 10 N OD:Visual loss not specified

[13]* na 51 na 50 2.17 38 12 N OS:Visual loss not specified

[13]* na 47 N 50 2 35 84 N OD:Bl OS:Bl

[59]* F 68 No 40 3.33 28 10 N OD:Bl OS:Bl

[59]* na na Yes 60 2 42 na na Visual loss not specified

[69] F 68 No 50 2 na 19 n OD:FC OS:2/10

[1]* F 50 No 40.42 1.55 35 36 N Visual loss not specified

[52] F 33 na 49.5 na 42 12 N Visual loss not specified

[38] F 65 Yes 45 1.8 na 24 N OD:VA2/7 OS:VA2/3

[62] F 61 No 45 1.8 35 8 N OD:Bl OS:Bl

[26] M 38 Yes 50 2.38 36 9 N OD:VA 0.3 OS:VA 0.1

[43] na na No 50 2.5 na na na Visual loss not specified

[74] F 54 Yes 56 2 38 16 N OD:LP OS:VA 0.4

[79]* na na na 42.5 1.93 na 60 na OS:Visual loss not specified

[21] F 53 Yes 46 2 N 9 na Visual loss not specified

[11] F 53 Yes 50 2 42 5 N OD:VA 0.5 OS:VA 1/60

[11] F 52 No 55.5 1-2 54 120 N OS:LP

na: not available; F: female; M: male; N: normal ;R: reduced; OS: oculus sinistra/ left eye; OD: oculus dextra/ right eye; VA: visual acuity; Bl: blind; LP: light perception; HM: hand movements: FC: fingercounting[ ]* these references are mentioned in Table 1 and Table 2, because an incidence was mentioned and in case of RON treatment characteristics were available.

81


Table 2 RON in acromegalic patients, in whom total radiation dose and radiation fraction size are available

Ref Sex Age at RON (yrs)

OperationTotal dose (Gy)

Fraction size (Gy)

Treatment time(days)

Latencyof RON (months)

Visual status at diagnosis


[72] M 46 No 50 2 36 6 N OD:FC OS:2/20

[72] F 60 No 50 2 34 8 N OD:FC

[5]* na na Na 50 2.5 35 15 N OD:Bl OS:Bl

[6]* F 58 Yes 42.4 2.83 22 14 N OD:HM OS:HM

[6]* F 51 No 43.8 3.13 19 13 N OD:reduced vision OS:Bl

[6]* M 53 Yes Yttrium-90 45.2 3 18 After external beam: 84 R OD:HM OS:Bl

[6]* F 63 No 42.4 2.83 22 10 R OD:Bl OS:Bl

[55] F 63 Yes 50 1.52 N 11 Na Visual loss not specified

[55] F 52 Yes 50 2 n 19 N Visual loss not specified

[17]* na na na 55 2.2 40 11 na Visual loss not specified

[39] F 64 No 42.5 2.8 21 8 N OD:Bl OS:Bl

[39] F 63 No 42.5 2.1 28 8 R OD:FC OS:FC

[39] F 50 No 42.5 2.8 21 9 N OD:Bl OS:Bl

[13]* na 51 na 46 2 31 18 N OD:Bl

[13]* F 51 N 45 1.96 31 12 R OD:LP

[13]* na 60 N 50 2 35 10 N OD:Visual loss not specified

[13]* na 51 na 50 2.17 38 12 N OS:Visual loss not specified

[13]* na 47 N 50 2 35 84 N OD:Bl OS:Bl

[59]* F 68 No 40 3.33 28 10 N OD:Bl OS:Bl

[59]* na na Yes 60 2 42 na na Visual loss not specified

[69] F 68 No 50 2 na 19 n OD:FC OS:2/10

[1]* F 50 No 40.42 1.55 35 36 N Visual loss not specified

[52] F 33 na 49.5 na 42 12 N Visual loss not specified

[38] F 65 Yes 45 1.8 na 24 N OD:VA2/7 OS:VA2/3

[62] F 61 No 45 1.8 35 8 N OD:Bl OS:Bl

[26] M 38 Yes 50 2.38 36 9 N OD:VA 0.3 OS:VA 0.1

[43] na na No 50 2.5 na na na Visual loss not specified

[74] F 54 Yes 56 2 38 16 N OD:LP OS:VA 0.4

[79]* na na na 42.5 1.93 na 60 na OS:Visual loss not specified

[21] F 53 Yes 46 2 N 9 na Visual loss not specified

[11] F 53 Yes 50 2 42 5 N OD:VA 0.5 OS:VA 1/60

[11] F 52 No 55.5 1-2 54 120 N OS:LP

na: not available; F: female; M: male; N: normal ;R: reduced; OS: oculus sinistra/ left eye; OD: oculus dextra/ right eye; VA: visual acuity; Bl: blind; LP: light perception; HM: hand movements: FC: fingercounting[ ]* these references are mentioned in Table 1 and Table 2, because an incidence was mentioned and in case of RON treatment characteristics were available.

82

Chapter 5

Conclusions

Our literature review suggests that RON occurs in 1.36% of patients with GH-secreting

pituitary adenoma, treated with external beam photon radiation therapy. Assuming that

in as much as 50% of reported cases, no risk factors related to radiation therapy were

present, would suggest that other risk factors, including vascular compromise and GH-

secreting pituitary adenoma itself, contribute to RON occurrence. RON may occur after a

considerable latency period. A female preponderance for developing RON is suggested.

The current dose-fractionation policy in our department is 45 Gy in 1.8 Gy frac-

tions for all pituitary adenomas if radiation therapy is indicated. To our opinion there

is no benefit in applying a higher total dose in pituitary adenoma radiation treatment,

because a dose-volume effect above 45 Gy is absent60. Taken into consideration that

in 50% of RON cases radiation treatment characteristics are likely to contribute to the

development of this complication, our treatment scheme could further decrease RON

development.

83


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6 Lack of radiation optic

neuropathy in 72 patients treated for

pituitary adenoma

Alfons C.M. van den Bergh, M.D.1; Michiel A. Schoorl, M.D.1; Robin P.F. Dullaart M.D.,

Ph.D.2; Anton M. van der Vliet, M.D.3; Ben G. Szabó, M.D., Ph.D.1; Cees A. ter Weeme,

M.D., Ph.D.4; Jan-Willem R. Pott, M.D., Ph.D.5

1 Department of Radiation Oncology, 2 Endocrinology, 3 Radiology, 4 Neurosurgery,

5 Ophthalmology, University Hospital Groningen, The Netherlands

Journal of Neuro-Ophthalmology 2004; 24(3): 200-205

92

Chapter 6

Abstract

The incidence of radiation optic neuropathy (RON) after external photon beam

radiation therapy for non-functioning pituitary adenoma (NFA) is not well stu-

died. Retrospective review was performed of ophthalmological and imaging data

in 72 patients with NFA treated between 1985 and 1998 with external beam radia-

tion therapy following surgery. Clinical follow-up after radiation therapy had to

be at least 18 months. RON was defined as a sudden and profound irreversible

visual loss affecting the optic nerve or chiasm. A review of previously published

cases of RON was then performed. In our cohort, no patient had RON. A total

of 11 adequately documented series reports of RON were found in the medical

literature on radiation-treated NFAs. The incidence of RON in NFA from these

series is 0.53% (95%CI, 0.26%-0.96%). An additional 14 single RON cases have been

reported, bringing the total of adequately documented RON cases to 25. RON is a

rare complication after external beam radiation therapy for NFA.

93


Introduction

Pituitary adenomas account for at least 12% of all intracranial neoplasms1. Their inci-

dence is estimated to be 20 to 30 per million2. Approximately 25% to 30% of patients with

pituitary adenomas do not have a classic hypersecretory syndrome such as acromegaly,

Cushing disease, or prolactinoma. Tumors that do not appear to secrete hormones are

called nonfunctioning adenomas (NFA)3. NFAs often present with signs of mass effect,

such as visual changes, and symptoms of pituitary insufficiency4.

Radiation therapy plays an important role in the treatment of NFAs. In the past,

radiation therapy alone was the treatment of choice unless there were large visual defi-

cits, in which case a craniotomy was performed to decompress the optic nerves and

chiasm. With improving microsurgical techniques, the preferred treatment became

neurosurgery followed by radiation therapy for extensive bulky lesions, histologically

invasive adenomas, or incomplete excision5. The routine use of post-operative radia-

tion therapy in case of residual tumor is controversial6-9; its use prevents regrowth of

residual tumor in most cases, but it may cause such side effects as radiation optic neu-

ropathy (RON)10,11. The incidence of RON after external beam radiation therapy for NFA

has not been well-documented. There is also debate as to whether patients with NFA

are less likely to have RON development after radiation therapy than those with growth

hormone-secreting or adrenocorticotropic hormone-secreting pituitary adenoma12-17.

The aim of this retrospective study was to discover the incidence of RON in a

cohort of irradiated patients with NFA. Also, a review of prior published series and indi-

vidual case reports is presented, from which an estimation of the incidence of RON in

irradiated NFA can be deduced.

Methods

In 2001, we conducted a retrospective investigation of the ophthalmological, neurosurgi-

cal, and radiation therapy records of 77 patients who had undergone surgery and exter-

nal beam radiation treatment of NFA from 1985 to 1998 at the University Hospital, Gro-

ningen, The Netherlands (n = 52) and four regional institutions with equivalent radiation

therapy protocols (n = 20).

The median age of our cohort at the start of radiation therapy was 52 years. The

sex distribution was 41 males (57%) and 31 females (43%). All 72 patients were treated

with a combination of surgery and radiation therapy. Sixty patients had one, ten patients

had two, and one patient had four operations before radiation therapy. One patient had

a second operation for tumor recurrence after operation and radiation therapy. Median

ophthalmological follow-up time after radiation therapy was 51 months (range, 19-171

months). Total radiation dose ranged from 45 to 55.8 Gy. The daily radiation fraction size

94

Chapter 6

varied from 1.8 to 2 Gy. Median overall treatment time was 35 days (range, 30-42 days).

The radiation fractionation schemes used were 45 Gy in 25 daily fractions (n = 49; 68%),

50 Gy in 25 daily fractions (n = 9; 13%), 50.4 Gy in 28 daily fractions (n = 7; 10%), 46 Gy

in 23 daily fractions (n = 6; 8%) and 55.8 Gy in 31 daily fractions (n = 1; 1%). All radiation

treatment fields were applied daily.

Patients were treated with linear accelerators with 4-MV photons (n = 5), 6-MV

photons (n = 45), 8-MV photons (n = 11), 10-MV photons (n = 5), and 16 to 18 MV photons

(n = 6). A two-field opposed lateral technique was used in 10 patients, a three-field tech-

nique in 30 patients, a five-field technique in 20 patients, and a combination of these

techniques in 22 patients. The most frequent combination was opposed lateral fields,

followed by a three-field (n = 13) or a five-field technique (n = 5). In the time period

1985 to 1990, the radiation dose to the tumor was prescribed at the tumor encompassing

isodose, and from 1991 to 1998 it was prescribed at a central point in the tumor accor-

ding to the recommendations of the International Commission on Radiation Units and

Measurements (ICRU)20.

Ophthalmological follow-up, defined as the period between the first day of irradiation

and the last ophthalmological examination, had to be at least 18 months. Five patients were

excluded because they were lost to follow-up before 18 months, reducing the cohort to 72.

Visual fields were obtained with Goldmann kinetic perimetry. The visual field

data of all patients at diagnosis, after neurosurgery, radiation therapy, and in follow-up

were reviewed by one neuro-ophthalmologist (J.-W.R.P.).

The diagnosis of RON was based on the criteria of Kline et al.18 and Parsons et

al.19 ; 1) irreversible visual loss with visual field defects of optic nerve or chiasmal origin;

2) absence of visual pathway compression caused by recurrence or progression of tu-

mor, radiation-induced neoplasm, arachnoidal adhesions around the chiasm, radiation

retinopathy, or other ophthalmologic disease; 3) absence of optic edema; 4) optic disc

pallor noted within six to eight weeks after onset of symptoms. The diagnosis of RON

was also based on review of visual fields, visual acuity, and fundoscopic examinations in

combination with brain imaging.

For our review of the published literature on RON, we performed a search of

Medline between 1966 and May 2003 and a search of Embase between 1989 and May

2003. Key words were radiation optic neuropathy, nonfunctioning pituitary adenoma,

and radiotherapy. All articles that included patients with NFA were checked for vision

loss caused by radiation therapy. The references retrieved by Medline and Embase were

screened for other references not found using the aforementioned key words.

To estimate the incidence of RON in NFA, we included only cohort series of pa-

tients in which RON was studied. In reports that included functioning and nonfunctio-

ning pituitary adenomas, we included only those in which the number of NFA and RON

cases were reported. To evaluate risk factors for RON, we included only those cases from

95


series and case reports in which radiation treatment data were available. Our calcula-

tions include our own series as well as previous reports. The 95% confidence interval

was calculated assuming a binomial distribution.

Results

In our cohort, no patient in the current study had RON diagnosed. One of 72 irradiated

patients had spiraling isopters on Goldmann perimetry without visual acuity loss as late

as 11 years after radiation therapy. Because of her unusual visual fields, Goldmann peri-

metry was repeated five times over a time period of 17 months with consistent spira-

ling. Fundoscopic examination of both eyes revealed normal optic discs. Gadolinium-

enhanced magnetic resonance imaging showed no pertinent abnormalities, such as high

signal in the optic nerves or chiasm21. Visual-evoked potentials showed no amplitude

reduction or latency increase with pattern stimulation. Two years later, the spiraling had

disappeared and visual acuity remained normal. Although she was initially considered to

have atypical RON22, this diagnosis was rejected when visual field defects normalized.

As shown in Table 1, we found 27 pertinent series of patients in whom the

develop ment of RON was considered. From these series, we calculated that 11 of 2,063

patients had RON, yielding an incidence of 0.53% (95% CI, 0.26%-0.96%). We found an

addi tional 14 RON single-case reports in the literature, making a total of 25 cases.

In 16 of these cases, visual acuity loss was reported (Table 2). It was bilateral

in nine patients (56%) and unilateral in seven patients (44%). Of the 25 eyes affected,

13 eyes (52%) had no light perception; two eyes (8%) had light perception; two eyes (8%)

had hand movements; four eyes (16%) had a visual acuity between 20/800 and 20/100,

and four eyes (16%) had a visual acuity better than 20/100.

In the 23 RON cases in which data were available, the peak latency between ra-

diation therapy and the development of RON was between 12 and 18 months18 (Table 2).

The median latency time was 11 months (range, 2-54 months). Four patients (16%) had a

latency period longer than 18 months.

In the 21 RON cases in which total radiation dose and radiation fraction size data

were available, 14 patients (67%) received a total dose of more than 50 Gy and/or a daily

fraction size more than 2 Gy. Of note, seven patients (33%) who had visual loss caused

by RON were treated with a supposedly safe daily radiation fraction size and total radia-

tion dose. Information was not available in most reports with respect to the ICRU 50/62

recom mended minimum (95% of the prescribed dose) and maximum radiation doses

(107% of the prescribed dose) to the optic system20.

In the 20 RON cases in which patient age or gender was reported, the median

patient age was 54 years (with 12 patients being older than 50 years), and 12 (60%) were

women (95%CI,36%-81%).

96

Chapter 6

Table 1 Incidence of radiation optic neuropathy (RON) in reported series of irradiated patients with

nonfunctioning pituitary adenomas.

Ref Number of patients

Total radiation dose (Gray)

Fraction size (Gray)

Number of RON cases

Treatment period

Colby, (1962)(27) 127 35 na 0 1938-1958

Emmanuel28 (1966) 57 40 2 0 1940-1960

Chang29 (1967) 291 24.5-30 2 0 1937-1964

Carlson30 (1971) 38 31.6-58.5 na 0 1955-1965

Arumugasamy31 (1971) 36 35-45 na 0 1942-1969

Hayes32 (1971) 71 45-50 2 0 1950-1967

Pistenma33 (1975) 62 44-70 na 0 1956-1972

Sheline34 (1975) 140 40-50 na 0 1933-1968

Kramer35 (1975) 143 45-46 2 0 1956-1972

Harris24 (1976) 35 42-59 2-2.5 4 1968-1973

Aristizabal12 (1977) 52 40-46 2-2.2 1 1952-1971

Erlichman36 (1979) 154 17.2-55 na 0 1958-1972

Symon37 (1979) 92 32.5-36 2.75-3 0 1968-1978

Ebersold38 (1986) 50 40-57 na 0 1975-1980

Vlahovitch39 (1988) 61 40-50 2-2.5 1 1968-1987

Flickinger40 (1989) 112 47.5-50 2 1 1964-1987

Tran41 (1991) 36 44-55 1.8-2.5 0 1967-1985

Grattan-Smith42 (1992) 17 na na 0 1980-1985

Salinger43 (1992) 29 45.7-56 1-2.5 0 1961-1986

Zaugg44 (1995) 35 40-45 1.8-2.25 0 1973-1992

Cornett45 (1996) 8 45-60 1.8-2.0 0 1988-1992

Grabenbauer 46 (1996) 50 46-63 1.9-2.25 2 1983-1990

Colao47 (1998) 59 45 1.8 1 1985-1996

Breen48 (1998) 120 37.6-65.6 1.5-2.5 1 1960-1991

Mitsumori49 (1998) 12 45 1.8 0 1989-1995

Sasaki50 (2000) 65 44-70 1.5-2 0 1969-1994

Isobe51 (2000) 39 48-60 2 0 1980-1995

Current series (2003) 72 45-55.8 1.8-2 0 1985-1998

Total 2063 11

na: not available

97


Table 2 Reported cases of radiation optic neuropathy (RON) in irradiated patients with

nonfunctioning pituitary adenomas in which radiation treatment characteristics are documented

Author(year of publication)

Gender Age at RON (yrs)

Surgery Total dose (Gy)

Fraction size(Gy)

Treatmenttime (days)

Latency of RON (months)


Crompton, 1961(52) F 56 Y 45 n.a. 28 12 n.a.

Harris24* 1976 F 41 N 45 2.25 32 6 OD: NLP; OS: 20/20

Harris24* 1976 M 62 Y 45 2.5 26 15 OD: NLP; OS: NLP

Harris24* 1976 M 66 N 45 2.5 26 6 OD: NLP; OS: NLP

Harris24* 1976 F 37 N 45 2.5 26 2 n.a.

Aristizabal12* 1977 n.a. n.a. n.a. 50 2 35 10 OD: NLP; OS: NLP

Martins53 1977 F 61 Y 67 2.25 37 33 OD: LP; OS: 20/20

Martins53 1977 F 44 Y 65.8 2.2 46 13 OD: NLP; OS: 20/30

Lorenzo54 1978 F 28 N 50 n.a. 35 14 n.a.

Fitzgerald22 1981 F 65 N 50 n.a. 42 13 OD: 20/20; OS: LP(helical isopters)

Fukamachi55 1982 F 49 Y 50 2 35 10 OD:20/400; OS:20/100

Hammer15 1983 F 52 Y 42.5 2.8 21 13; 25 OS: 20/200; OD: NLP

Kline18 1985 M 73 Y 50 2 38 12 OD: VA: 20/800;OS: 20/20

Kundra56 1990 M 40 Y 55 2.75 n.a. 6 n.a.

Kundra56 1990 M 46 Y 55 2.2 n.a. +6 n.a.

Zimmerman57 1990 M 64 Y 50.4 1.8 28 14 OD:HM; OS:20/25

Millar58 1991 F 56 Y 45 1.8 35 10 OD: NLP; OS: NLP

Guy21 1991 M 51 Y 53.4 2 NA 30 OD: 20/20; OS: 20/25

Hudgins59 1992 F 75 Y 54 1.8 NA 35 OD: N/A; OS: 20/20

Sallet60 1992 F 40 Y 30 n.a. n.a. 8 OD: 20/20; OS: NLP

Hughes61 1993 n.a. n.a. n.a. 50 2.5 n.a. n.a. n.a.

Hughes61 1993 n.a. n.a. n.a. 50 2.5 n.a. n.a. OD: 20/20; OS: 20/20, temporal field defect

McClellan62 1995 M 67 Y 45 1.8 36 3; 7 OD: HM; OS: NLP

Colao47* 1998 n.a. n.a. Y 45 1.8 35 12 n.a.

Breen48* 1998 n.a. n.a. n.a. 50 2 n.a. 54 n.a.

F: female; M: male; Surgery: Y: yes; N: no; OD: right eye; OS: left eye; VA: visual acuity; n.a.: data not available* These references are also included in Table 1, because patient and treatment characteristics were available.

98

Chapter 6

Discussion

Based on the review of our cohort of 72 cases and the published literature, RON is a rare

complication after external beam radiation therapy in patients with NFA. We found no

case of RON in our cohort. Our literature review found a total of 11 adequately docu-

mented cases of RON in series reports of radiation-treated NFA patients for an overall

incidence of 0.53%. This is significantly lower than the 1.36% incidence of RON in acro-

megalic patients23 (P = 0.01; odds ratio 2.56; 95% CI, 1.26-5.22). One possible determinant

contributing to the relatively increased incidence of RON in GH-secreting pituitary ade-

nomas compared to NFAs is the occurrence of more microvascular damage in associa-

tion with GH excess12.

An additional 14 RON cases emerged from single case reports. Reviewing the total

of 25 cases, we found that RON usually occurred between 12 and 18 months after radia-

tion treatment but could occur after a considerably longer latency period. Previous reports

do indicate that a total radiation dose greater than 50 Gy and/or a daily radiation fraction

size greater than 2 Gy are risk factors for developing RON19,24, although RON can occur at

lower doses14,19.

In as many as 33% of reported cases, we could identify no risk factors related to

radiation therapy. Older age has been touted as a possible risk factor for RON9,25, but our

series suggests that age is not a strong risk factor for developing RON in NFA, given the

median age of 52 years at the start of radiation therapy among our patients. Our review

also found no major gender predominance for the development of RON.

Based on these results, the current dose-fractionation policy in our department

is 45 Gy in 1.8 Gy fractions for all pituitary adenomas. According to McCollough et al.26,

there is no benefit in applying a higher total dose.

99


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7 Tyrosine positron emission

tomography and protein synthesis rate

in pituitary adenoma: different effects

of surgery and radiation therapy

Alfons C.M. van den Bergh, M.D.1; Jan Pruim, M.D., Ph.D.2; Thera P. Links, M.D., Ph.D.3;

Anton M. van der Vliet, M.D.4; Wim Sluiter, Ph.D.3; Bruce H.R. Wolffenbuttel, M.D.,

Ph.D.3; Johannes A. Langendijk, M.D., Ph.D.1; Eelco W. Hoving, M.D.,Ph.D.5;

Robin P.F. Dullaart, M.D., Ph.D.2

1 Department of Radiation Oncology, 2 Nuclear Medicine and Molecular Imaging,

3 Endocrinology, 4 Radiology University Medical Center Njmegen,

5 Neurosurgery, University Medical Center Groningen/University of Groningen,

Groningen, The Netherlands

Submitted to Radiotherapy and Oncology

106

Chapter 7

Abstract

Introduction Positron Emission Tomography (PET) using amino acid tracers is

able to establish biochemical tumour characterization in vivo. The use of PET in

the follow-up of non-functioning pituitary adenomas (NFA) and growth hormone

producing pituitary adenomas (GHA) after surgery and radiation treatment is not

yet clear.

Methods To determine the value of PET before and after transsphenoidal neu-

rosurgery in NFA and GHA, we investigated 12 patients with pituitary adenoma

(9 NFA and 3 GHA) before and 4 months after surgery with magnetic resonance

imaging (MRI) and tyrosine PET (TYR-PET). Three years after radiation therapy

TYR-PET was used to document residual activity in 6 of these patients (4 NFA-

and 2 GHA). Tumour size was quantified by computerized MRI measurements. In

TYR-PET, tumour activity was assessed by computerized measurements of the

hot spot and by determination of protein synthesis rate (PSR).

Results In response to surgery, MRI showed a median tumour volume reduc-

tion of 58% (P < 0.01). TYR-PET demonstrated 62% volume reduction (P < 0.02),

but no change in PSR (P > 0.30). After radiation therapy the MRI-volumes of the

residual pituitary adenomas did not change but the volume of the hot spot on

TYR-PET-imaging was reduced by 58% (P = 0.02), and PSR decreased in 5 of 6 pa-

tients (P = 0.12)

Conclusion Amino acid PET tumour activity is reduced parallel with MRI volume

changes after surgery. The decrease in TYR-PET activity after radiation therapy,

despite unaltered MRI tumour volume, supports the concept that it is possible to

follow biological tumour activity with this technique. The diagnostic merit of this

tracer technique, predicting pituitary adenoma regrowth, needs to be validated

in a large prospective study.

107

Tyrosine positron emission tomography and protein synthesis rate in pituitary adenoma: different effects of surgery and radiation therapy

Introduction

In view of the high recurrence rate in case of residual pituitary adenoma after surgery

alone the accurate evaluation of post-operative residual pituitary adenoma by ima ging

techniques is essential1,2. The detection of residual pituitary adenoma after surgery by

magnetic resonance imaging (MRI) and/or computed tomography (CT) is frequently

hampered by postoperative tissue remodelling3,4. It is particularly difficult to distinguish

residual vital adenoma tissue from operative changes in sellar structures, and to dis-

criminate between vital and non vital tissue after radiation therapy. Moreover, it is ob-

vious that the diagnostic yield of hormonal assessment is mostly restricted to those

tumours which abnormally secrete anterior pituitary hormones, like growth hormone,

adrenocorticotropic hormone and prolactin. Therefore an additional imaging technique

is necessary which enables to document the biological behaviour of the tumour.

Pituitary adenomas are characterized by a high amino acid metabolism5-8. Con-

sequently, positron emission tomography (PET) with radio labeled amino acids may be

a suitable method for accurate detection of the activity of these tumours in response to

medical and surgical treatment and radiation therapy. Accordingly, it has been shown

in prolactinoma and growth hormone producing pituitary adenoma (GHA)9, that amino

acid metabolism changes in response to medical treatment5, but treatment responses

after surgery and radiation therapy in NFA and GHA have not been reported so far.

L-[1-11C]-tyrosine is suitable for calculation of protein synthesis rates, since this

tracer has a small pool of free tyrosine in plasma and tissue and a rapid high incorpora-

tion into protein, which is not hampered by the blood brain barrier. This allows not only

visualization but also quantification of the protein synthesis rate (PSR), which is higher in

metabolically active and proliferating pituitary adenoma than in normal brain tissue5,10,11.

We hypothesized that after surgical tumour reduction TYR-PET tumour volume

would decrease parallel with MRI tumour volume changes, without affecting PSR. In view

to the efficacy of radiation therapy to prevent re-growth of residual pituitary ade noma1,

we expected that this treatment would, in contrast, affect biological tumour acti vity, as

determined by TYR-PET tumour volume and/or PSR. The present study was therefore

initiated to demonstrate the feasibility of pituitary TYR-PET imaging and measure ment

of protein synthesis rate after neurosurgical intervention and in response to radiation

therapy.

Patients and methods

Patient characteristics

The study was approved by the medical ethics committee of the University Medical Cen-

ter Groningen, and all participants provided informed consent. In all patients, hormonal

108

Chapter 7

evaluation was carried out to determine hormonal deficiencies using pre-specified cut

off values for hormonal deficiencies12. Before entry in the study, they had received re-

placement therapy with thyroid hormone and glucocorticoids if necessary. In case of

suspected acromegaly, growth hormone excess was established by an elevated level

of growth hormone during a glucose tolerance test and an elevated level of insulin-

like growth hormone-1 in plasma. None of the patients was considered to have prolac-

tinoma or Cushing’s disease. In all patients transsphenoidal surgery was carried out and

the pituitary tumour classified as NFA or GHA on histopathological grounds (9 NFA and

3 GHA). In 6 of these patients (4NFA and 2 GHA) MRI and PET-images were performed

3 years after radiation therapy.

PET acquisition and imaging analysis

TYR-production

TYR was produced via a modified microwave induced Bücherer-Strecker synthesis. The

radiochemical purity was over 99%. A mean dose of 300MBq (range 55-375MBq) of TYR

was injected intravenously. The procedures were protocolized to assure a maximum

pharmaceutical quality. Radiochemical and chemical purity were verified by high per-

formance liquid chromatography.

Blood sampling

All quantitative PET sessions included placement of a catheter in the radial artery for

sampling blood radioactivity. During the sessions, blood samples were taken at 0.25,

0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.25, 2.75, 3.75, 4.75, 7.50, 12.50, 17.50, 25.00, 35.00, 45.00

minutes after injection.

Camera

PET sessions were performed with an ECAT 951/31 camera (Siemens/CTI, Knoxville,

USA). A transmission scan of 20 minutes to correct for attenuation was obtained imme-

diately before the emission scan. The spatial resolution of the camera was 5 mm. in the

center of the field of view. TYR was administered as a one minute bolus via a MEDRAD

MCT Plus infusion pump. Axial images with a slice thickness of 3mm. were made of the

head and neck area. A region of interest (ROI) was drawn around the hot spot in the sella

turcica by hand on the relevant planes and the volume of the ROI and the PSR in the ROI

were calculated.

All PET-measurements were determined twice, immediate after imaging and at

the time of completion of this study, with no discrepancies in measured volumes and

PSR between the first and second measurements.

109


MRI acquisition and imaging analysis

Tumour size on MRI (1.5T Siemens; slice thickness of 3 mm) was quantified by com-

puterized measurements on coronal T1-weighted (TR/TE 650-800/20) contrast-enhanced

images and a restricted field of view (20 × 20 cm), after identification of the tumor boun-

daries by one neuro-radiologist (AMvdV). The major criteria used for pituitary adenoma

detection on MRI were or no enhancement or delayed contrast enhancement after injec-

tion of gadolinium. MRI-images and PET-images were evaluated separately, each inves-

tigator being blinded for the results of the other technique.


Data are given in medians (ranges). Data before and after intervention were compared

using the paired Wilcoxon test. Relationships between variables were determined by

Spearman’s rank correlation analysis. A two-sided P-value < 0.05 was considered signifi-

cant.

Results

We studied 12 patients with pituitary macroadenomas (9 patients with NFA and 3 with

GHA) who were evaluated before transsphenoidal surgery and 4 months after. Before

and shortly after neurosurgery all GHA patients had biochemical evidence of growth

hormone hypersecretion, but they were not treated with somatostatin analogues, pegvi-

somant or dopamine-agonists. This group included 9 men and 3 women with a median

age of 46 (range 25 - 68 years). As determined by MRI, tumour volume decreased by 58%

(median) from 4.85 (1.4-13.9) cm3 to 2.6 (0-12.2) cm3 postoperatively (P < 0.01). Using TYR-

PET, metabolic tumour volume decreased by 62% from 5.05 (1.1-8.0) to 2.05 (0-6.6) cm3

(P < 0.02). Figure 1 demonstrates TYR-PET imaging results pre- (A) and postoperatively (B)

in a representative NFA patient. The tumour volume as determined by TYR-PET was not

significantly different from its volume by MRI, both pre- or postoperatively (combined-

data set, n = 24, P> 0.30). The relationship between MRI tumour volume and TYR-PET

tumour volume also did not differ either between the pre- and postoperative situation.

In the combined data-set, these measures of tumour volume were positively correlated

( r = 0.58, P < 0.01). PSR was 35.3 (28.4-63.8) mmol/ml/min pre-operatively, and remained

unchanged after transsphenoidal surgery (33.4 (0-62.4) mmol/ml/min, P > 0.30; median

change –3.3%).

110

Chapter 7

Figure 1 A representative axial PET-image of one NFA patient before (A) and 4 months after surgery

before radiation therapy (B) and 3 yrs after radiation therapy (C)

To determine the effect of radiation therapy on pituitary TYR-PET characteris-

tics, we studied 6 patients before and approximately 3 years after this treatment. This

group comprised 4 patients with NFA and 2 patients with GHA, who also participated

in the neurosurgical intervention protocol. In these patients the pituitary tumour was

not completely removed by surgery or active acromegaly had persisted after this treat-

ment. Fractionated radiation therapy was applied with 1.8 Gray daily dose to a total of

45 Gray in 5 weeks, using a three to five field technique, and was given 6 months after

transsphenoidal surgery. This group included 5 men and 1 women with a median age of

48 (range 37- 60) years. In these patients, tumour volume by MRI was very similar before

(1.95 (1-4.9) cm3) and after radiation therapy 1.95 (1-4.9) cm3, P = 1.0; median change 0%).

In contrast, TYR-PET tumour volume decreased by 58% from 2.05 (1-3.7) to 1.0 (0-1.9) cm3

(P = 0.02) (Figure 2), whereas PSR decreased in 5 patients (total group: 67% change from

33.4 (2.6-40.8) to 13.2 (0-46.2) mmol/ml/min, P=0.12) (Figure 3). Figure 1 demonstrates

TYR-PET imaging results before radiation therapy (B) and 3 years after radiation therapy

(C) in a representative NFA patient.

A B C

111


3 years after RTPostoperative0

4

2

Figure 2 PET-volumes (cm3) of the pituitary adenomas 4 months after surgery before radiation

therapy and 3 years after radiation therapy. Medians, interquartile ranges and 5% and 95% ranges are

shown in the boxplots.

0

20

40

3 years after RTPostoperative

Figure 3 PSR values (mmol/ml/min) of the pituitary adenomas 4 months after surgery, but before

radiation therapy and 3 years after radiation therapy. Medians, interquartile ranges and 5% and 95%

ranges are shown in the boxplots.

112

Chapter 7

Discussion

This study has demonstrated that in all untreated NFA and GHA patients tested abnor-

mal TYR-PET uptake is present and PSR can be determined. Our findings therefore sug-

gest, that PET imaging using amino acid as tracer is a feasible technique to document

amino acid metabolism in these tumours in vivo. The volume of the TYR-PET uptake de-

creased parallel with the MRI tumour volume reduction after transsphenoidal surgery.

In response to radiation therapy however, the volume of the TYR-PET uptake decreased

but the MRI tumour volume did not show any change. These findings support the con-

cept that this technique bears clinical potential to detect changes in biological activity

of these tumours.

Several amino acid tracers, including 11L-C-Methionine have been used so far to

detect biological activity of pituitary adenoma. In this study, we used L-[1-11C]-Tyrosine

as tracer, because Tyrosine has a higher incorporation into proteins and a lower amount

of metabolites than methionine in brain and tumour tissue11, and this tracer is not in-

corporated to a relevant extent in normal pituitary tissue and in brain tissue, as docu-

mented in PET-imaging studies of glioma patients13,14. Furthermore, in animal models a

radiation dose-dependent reduction of tracer uptake has been reported, which corre-

lated with the changes in tumour volume15. In the present study, its incorporation in

NFA and GHA was found to be sufficient for imaging. Thus, all NFA and GHA were well

visualized because the high ratio of uptake in the adenoma compared to the surroun-

ding structures.

MRI is considered to be the imaging modality of choice for the diagnosis and

follow-up of pituitary disorders, because of its adequate soft tissue contrast4. In our

study, there was considerable agreement between TYR-PET and MRI tumour volumes,

and tumour volume measured by MRI was not significantly different compared to its

TYR-PET volume. It seems that heterogeneity of tracer uptake within adenoma or its

remnant was not large enough to result in measurable differences in tumour volume

between these imaging techniques. Indeed, in agreement with our hypothesis that

radiation therapy would affect TYR-PET uptake and/or PSR, we observed that TYR-PET

but not MRI tumour volume decreased after radiation therapy, which can be expected to

diminish protein metabolism in remaining tumour tissue6. TYR-PET imaging may there-

fore provide a clinically relevant imaging technique which is complementary to MRI. In

particular, the presence of residual pituitary adenoma after surgery has therapeutic con-

sequences1, and our study raises the possibility that abnormal amino acid PET imaging

and metabolism in pituitary adenoma after neurosurgical intervention could be helpful

to target additional therapy. However, we could not perform fusion of MRI with TYR-PET

scanning with the presently used imaging modalities, and it was not possible to docu-

ment abnormalities in pituitary anatomy precisely with TYR-PET imaging. Finally, our

113


report should be regarded as a proof of concept study. A limitation is its small sample

size, which precludes to determine the value of PET in NFA compared to hormone secre-

ting tumours, such as GHA, ACTH-producing adenomas and prolactinomas.

In conclusion, the present preliminary study results suggest that TYR-PET may

yield complementary information regarding biological tumour activity in NFA and GHA.

The diagnostic value of this tracer technique to predict pituitary adenoma behaviour

needs to be validated in a larger long-term study.

114

Chapter 7

Reference List

1. Bergh van den ACM, Berg van den G, Schoorl MA et al. Immediate postoperative

radiotherapy in residual nonfunctioning pituitary adenoma; beneficial effect on local

control without additional negative impact on pituitary function and life expectancy.

Int J Rad Oncol Biol Phys 2007; 67(3): 863-869.

2. Gittoes NJL. Radiotherapy for non-functioning pituitary tumors-when and under what

circumstances? Pituitary 2003; 6:103-108.

3. Rodriguez O, Mateor B, Pedraja R et al. Postoperative follow-up of pituitary adenomas after

trans-sphenoidal resection: MRI and clinical correlation. Neuroradiology 1996; 38:747-754.

4. Parrott J, Mullins ME. Postoperative imaging of the pituitary gland. Top Magn Reson

Imaging 2005; 16:317-323.

5. Bergström M, Muhr C, Lundberg PO et al. PET as a tool in the clinical evaluation of pituitary

adenomas. J Nucl Med 1991; 32(4):610-615.

6. Daemen BJG, Zwertbroek R, Elsinga PH et al. PET studies with L-[1-11C]tyrosine, L-[methyl-

11C]methionine and 18F-fluorodeoxyglucose in prolactinomas in relation to bromociptine

treatment. Eur J Nucl Med 1991; 18:453-460.

7. Bergström M, Muhr C, Jossan S et al. Differentiation of pituitary adenoma and meningioma:

visualization with positron emission tomography and [11C]-L-Deprenyl. Neurosurgery 1992;

30(6):855-861.

8. Tang BNT, Levivier M, Heureux M et al. 11C-methionine PET for the diagnosis and

management of recurrent pituitary adenomas. Eur J Nucl Med Mol Imaging 2006; 33(2):169-178.

9. Muhr C. Positron emission tomography in acromegaly and other pituitary adenoma

patients. Neuroendocrinology 2006; 83:205-210.

10. Ishiwata K, Vaalburg W, Elsinga PH et al. Metabolic Studies with L-[1-14C]Tyrosine for the

Investigation of a Linetic model to Measure Protein Synthesis Rates with PET. J Nucl Med

1988; 29:524-529.

11. Vaalburg W, Coenen HH, Crouzel C et al. Amino Acids for the Measurement of Protein

Synthesis In Vivo by PET. Nucl Med Biol 1992; 19(2):227-237.

12. Dullaart RP, Pasterkamp SH, Beentjes JA et al. Evaluation of adrenal function in patients

with hypothalamic and pituitary disorders; comparison of serum cortisol, urinary free

cortisol and the human-corticotrophin releasing hormone test with the insulin tolerance

test. Clin Endocrinol 1999; 50(4):465-471.

13. Heesters MAAM, Go KG, Kamman RL et al. 11C-tyrosine position emission tomography and

1H magnetic resonance spectroscopy of the response of brain gliomas to radiotherapy.

Neuroradiology 1998; 40:103-108.

14. Willemsen ATM, Waarde van A, Paans AMJ et al. In vivo protein synthesis rate

determination in primary or recurrent brain tumors using L-[1-11C]-Tyrosine and PET. J Nucl

Med 1995; 36:411-419.

115


15. Daemen BJG, Elsinga PH, Paans AMJ et al. Radiation-Induced Inhibition of Tumor Growth as

Monitored by PET Using L-[1-11C]Tyrosine and Fluorine-18-Fluorodeoxyglucose. J Nucl Med

1992; 33(3):373-379.

8 Patient position verification

with oblique radiation beams

Nanna M. Sijtsema, Alfons C.M. van den Bergh, Fred R. Burlage,

Henk P. Bijl, Johannes A. Langendijk, Harm Meertens

Department of Radiation Oncology, University Medical Center Groningen/University

of Groningen, Groningen, The Netherlands

Radiotherapy and Oncology 2007; 85(1): 126-131

118

Chapter 8

Abstract

Purpose In this study we investigated whether the position of head and neck

cancer patients during radiotherapy could be determined from portal images of

oblique radiation beams. Currently applied additional anterior posterior (AP) and

lateral verification beams could then be abandoned.

Method The patient position was determined from portal images of the oblique

radiation beams and compared with that determined from AP and lateral verifi-

cation beams. Seven hundred and fifty-one portal images of 18 different patients

were analyzed.

Results The set-up errors of patients that were treated with oblique gantry an-

gles could be determined with the same accuracy from the oblique beams as

from the AP and lateral verification beams in the ventrodorsal and craniocau-

dal direction. An additional AP beam was necessary to obtain the same accuracy

in the lateral direction, because the used beam directions were relatively close

to lateral. The position verification of patients treated with both oblique gantry

angles and isocentric table rotations was more accurate if AP and lateral verifica-

tion beams were used.

Conclusions For patients treated with an irradiation technique with oblique

gantry angles (and no isocentric table rotations) position verification can be per-

formed by using these oblique radiation beams.

119


Introduction

In radiotherapy of head and neck cancer patients portal imaging to achieve accurate po-

sitioning is of major importance. Van Herk et al.3 and Stroom et al.8 studied the relation-

ship between set-up variations and target margins. They concluded that the margin be-

tween clinical target volume (CTV) and planning target volume (PTV) can be decreased

most effectively by decreasing the standard deviation of the overall systematic error.

This overall systematic error is predominantly determined by the difference

in patient position between planning CT and linear accelerator (Linac) and can be

decreased by using an off-line verification protocol. In our department we use the

Shrinking Action Level (SAL) verification protocol by Bel et al.1. In the SAL protocol

the patient position at the Linac is only corrected if the average set-up error exceeds

a certain action level. The action level decreases with the number of measurements N

according to the relation: αN = α0/√N, where α0 is the initial action level, αN the action

level after N measurements and N ≤ Nmax. After Nmax fractions, the second stage of the

protocol starts in which only once a week portal images are collected and the action

level stays equal to αNmax.

The set-up error has to be determined in a coordinate system that corresponds

to the patient/couch directions: ventrodorsal/height, craniocaudal/longitudinal and

late ral to be able to correct the patient position by means of table movements at the

Linac. For patients that are treated with an irradiation technique that contains at least

one lateral and one anterior posterior (or a posterior anterior) beam the set-up errors

can be determined from the portal images of these treatment beams.

At our department there are two groups of patients treated with techniques

with oblique beams only. The first group includes patients with double-sided lymph

node metastases from squamous cell head and neck cancer, that are treated with a

technique designed to spare the spinal cord. This technique is based on the technique

described by Fogliata et al.5 and will be discussed in more detail in the Materials and

methods section. The main radiation beams have oblique gantry angles. In all other

beams the spinal cord is blocked out and therefore, no vertebrae can be recognized on

the portal images of these beams, which make these beams unsuitable for position veri-

fication. This technique is referred to as ‘Bellinzona technique’.

The second group includes patients with pituitary adenomas that are treated

with a technique in which the four radiation beams form a tetrahedron shape. In this

technique, referred to as ‘Tetrahedron technique’, all radiation beams have oblique gantry

angles and two beams also have a table rotation. For the position verification of these two

patient groups additional anterior posterior (AP) and lateral verification beams are used.

We have calculated that the verification beams result in an extra dose to the

spinal cord of about 1.0 Gy for the Bellinzona technique when the SAL verification pro-

120

Chapter 8

tocol is used and in case one position correction is necessary (14 fractions with two

verification beams of 4 MU). Because both patient groups are treated with advanced

techniques in order to spare the normal tissue as much as possible, it was considered

inappropriate to add a dose of about 1 Gy to a relative large area, just for verification.

However, set-up errors can result in much larger dose effects, especially in the Bellinzo-

na technique with a high dose gradient close to the spinal cord in ventrodorsal direction.

Therefore, the main purpose of this study was to investigate the use of portal images of

the oblique radiation beams of the Bellinzona and the Tetrahedron technique for verifi-

cation as well. In case of a comparable accuracy, the anterior posterior and lateral portal

images can then be abandoned.

Materials and Methods

Bellinzona technique

In the Bellinzona technique two oblique radiation beams are used covering the spinal

cord: a right anterior oblique (RAO; gantry angle ≈ 290°) and a left anterior oblique beam

(LAO; gantry angle ≈ 70°). In the other main beams the spinal cord is blocked out. In

addition, several small beams are used to obtain a homogeneous dose distribution. All

beams have a common isocenter. Only the right and left anterior oblique beams can be

used for verification, because the other beams hardly contain any bony structures.

The patients were treated in supine position and immobilized with a five-point

thermoplastic head mask (Efficast, Orfit Industries, Belgium). A SAL correction protocol

was used with Nmax = 4 and α = 5 mm. The deviation of patient position on the Linac

with respect to the planning CT was determined by comparison of portal images of an

anterior posterior (AP) and a lateral verification beam of 4 MU and 10 × 15 cm2 (15 cm in

the craniocaudal direction) with the corresponding Digitally Reconstructed Radiographs

(DRRs)1.

Furthermore, portal images of the right and left anterior oblique radiation beams

that are used for treatment were made and compared with the corresponding DRRs. The

deviation in the patient coordinates determined from the oblique radiation beams was

compared with that determined from the orthogonal verification images of the verifica-

tion beams.

1 Actually the deviations of both the portal image and the DRR with respect to the simulator

film were determined, from which the deviation of the portal image with respect to the DRR was

calculated. This procedure was used because the image quality of the simulator film was much better

than that of the DRR.

121


Tetrahedron technique

In the Tetrahedron technique, four radiation beams are used with equidistant angles

of 109°. No opposing beams are used, which results in a steeper dose gradient between

high and low dose regions. All beams have a common isocenter. Normally, the beams

are oriented as described in Table 1. The gantry angle of beam 1 is chosen such that the

beam does not hit the eyes. The angles of all other beams follow from the first beam.

The patients were treated in supine position with the head in slight hyperextension

and immobilized with a three-point thermoplastic head mask (Efficast, Orfit Industries,

Belgium). A SAL correction protocol was used with Nmax = 4 and α = 4.7 mm. The devia-

tion of patient position on the Linac with respect to the planning CT was determined by

comparison of portal images of an AP and a lateral verification beam of 4 MU and 10x10

cm2 with the corresponding DRRs1. Furthermore, portal images were made of the radia-

tion beams 2 - 4 shown in Table 1. The craniocaudal from ventral beam (nr. 1 in Table 1)

cannot be used for verification because the imager has to be removed from the gantry

to be able to setup this irradiation geometry. The deviation in the patient coordinates

determined from the oblique beams was compared with that determined from the AP

and lateral images.

The 6 MV photon beam of an Elekta Sli Linac (Elekta AB, Stockholm, Sweden)

was used for all irradiations. The portal images were collected with the Elekta camera

based iView system. The deviation of the portal images and DRRs with respect to simu-

lator films was determined with a software package called myView, which was devel-

oped at the radiotherapy department of University Medical Center Leiden.

Nr. Field direction Purpose Typicalgantry angle[°]

Table rotation[°]

Typicalfield size[cm2]

Typicalnumberof MU

1 Craniocaudal from ventral Irradiation 55 90 5 × 5 50

2a Craniocaudal from dorsal Irradiation 164 90 5 × 5 50

3b Caudocranial from left Irradiation 79 –34 5 × 5 50

4b Caudocranial from right Irradiation 281 34 5 × 5 50

5b Anterior posterior Verification 0 0 10 × 10 4

6b Lateral Verification 90 0 10 × 10 4

a Field used for portal imaging if there was no danger of collision of imager with patient.b Field used for portal imaging

Table 1 Summary of the most important beams used for irradiation and verification in the

Tetrahedron technique.

122

Chapter 8

Analysis of portal images of oblique radiation beams

In this study 751 portal images of 18 different patients were analyzed. The analysis of

each portal image gives a projection of the 3D set-up deviation in the plane of the imager.

The set-up deviation of the patient in all three patient directions: lateral, ventrodorsal

and craniocaudal can be determined from at least two portal images of beams with

diffe rent gantry angles by means of a coordinate transformation as described by Siddon7.

The accuracy of the calculated set-up deviation in the patient directions depends on the

difference in gantry angles. In theory it should be possible to determine the set-up devia-

tion from portal images of oblique beams with the same accuracy as from AP and lateral

beams if the difference in gantry angle is 90 degrees. In the appendix A a more detailed

description of the analysis is given.

Results

Validation of the method

First, the method used for analysis of portal images of oblique beams was validated. For

this purpose, a metal sphere was irradiated with the Tetrahedron technique and portal

images were collected from both the oblique beams and the AP and lateral verification

beams. The sphere was moved by introducing a table displacement. Portal images were

collected for eight different sphere positions with an accurately known displacement

with respect to the reference position (determined from the table position readout with a

precision of 0.1 mm). The average difference between the displacements determined from

the orthogonal portal images and the actual displacement was 0.4 mm (1SD = 0.5 mm) in

the lateral , –0.3 mm (1SD = 0.7 mm) in the ventrodorsal and 0.1 mm (1SD = 0.4 mm) in the

craniocaudal direction. For the portal images from oblique beams de average difference

was 0.1 mm (1SD = 0.2 mm) in the lateral, 0.0 mm (1SD = 0.7 mm) in the ventrodorsal and

0.2 mm (1SD = 0.3 mm) in the craniocaudal direction.

Bellinzona technique

In Fig. 1, the lateral (a), ventrodorsal (b) and craniocaudal (c) set-up errors of nine pa-

tients treated with the Bellinzona technique are shown. On average portal images were

collected from 10 irradiation fractions for each patient, which resulted in 93 sets of por-

tal images from the AP and lateral verification beams and the left and right anterior

oblique radiation beams. The set-up errors determined from the left and right anterior

oblique beams were plotted as a function of those determined from the AP and lateral

verification beams (circles). The lateral set-up errors showed a wide spread around the

correspondence line. However, the set-up errors in the ventrodorsal and the craniocau-

dal direction showed a good correlation between the results from the oblique and the

orthogonal beams. An overview of the Pearson correlation coefficients and the mean

123


difference between the set-up errors from the oblique and orthogonal beams is given in

the upper part of Table 2. Se

t-up

erro

r fro

m o

bliq

ue fi

elds

[mm

]

Set-up error from verification fields [mm]

Oblique fieldsOblique and AP fields

8

6

4

2

0

–2

–4

–6

–8–8 –6 –4 –2 0 2 4 6 8

8

6

4

2

0

–2

–4

–6

–8–8 –6 –4 –2 0 2 4 6 8

8

6

4

2

0

–2

–4

–6

–8–8 –6 –4 –2 0 2 4 6 8

a b c

Figure 1 Set-up errors in the lateral, height and craniocaudal direction of patients treated with

the Bellinzona technique. Set-up errors determined from oblique radiation beams are plotted as a

function of those determined from orthogonal verification beams.

Lateral Ventrodorsal Craniocaudal

LAO and RAO fields versus verification fields

Pearson correlation* 0.50 0.85 0.54

Mean difference set-up error –1.2 mm –0.0 mm –0.5 mm

1 SD difference set-up error 2.0 mm 1.3 mm 1.3 mm

LAO and RAO + AP fields versus verification fields


Mean difference set-up error –0.3 mm 0.0 mm –0.2 mm


*Sigma 2-tailed < 0.001

Table 2 Comparison of set-up errors determined from the left anterior oblique (LAO) and right

anterior oblique (RAO) irradiation fields and the verification fields of patients treated with the

Bellinzona technique.

The gantry angles of the left and right anterior beams for the Bellinzona technique

were about 70° and 290° for most patients. Therefore, it can be expected that the inaccuracy

in the lateral set-up error determined from these oblique beams will be relatively large.

Therefore, we investigated the effect of adding an AP verification beam to the left and right

anterior oblique beams. The resulting set-up errors are represented by plus signs in Fig. 1.

124

Chapter 8

The addition of the AP beam had a large effect on the spread of the scatter plot for the lateral

set-up error. In the ventrodorsal direction there was no influence at all and in the craniocau-

dal direction there was little influence. An overview of the Pearson correlation coefficient

and the mean difference between the set-up errors from the combination of the oblique ir-

radiation plus the AP beam and the verification beams is given in the lower part of Table 2.

Tetrahedron technique

Portal images of nine patients treated with the Tetrahedron technique were analyzed.

The radiation beams 2, 3 and 4 from Table 1 were imaged if possible. For two patients it

was not possible to collect the radiation beam nr. 2 because of the danger of collision of

the imager with the patient. In addition, an AP and one lateral verification beam were

imaged. This resulted in 71 sets of portal images from two oblique and the verification

beams and 51 sets of portal images from three oblique and the verification beams. In

Fig. 2 the scatter plots of the set-up errors determined from the oblique beams versus

those determined from the verification beams are given for the lateral (a), the ventrodor-

sal (b) and the craniocaudal (c) direction. The results calculated from two oblique radia-

tion beams are indicated with circles and those from three oblique radiation beams with

plus signs. An overview of the Pearson correlation coefficients and the mean diffe rences

between the set-up errors determined from the oblique radiation beams and the verifi-

cation beams is given in Table 3. The results show a statistically significant correlation

between the set-up errors determined from the oblique and the AP and lateral verifica-

tion beams. However, the correlation coefficient is only 0.4-0.5 for two oblique beams

and 0.5-0.7 for three oblique beams.

125


Set-u

p er

ror f

rom

obl

ique

fiel

ds [m

m]

Set-up error from verification fields [mm]

Two oblique fieldsThree oblique fields

8

6

4

2

0

–2

–4

–6

–8–8 –6 –4 –2 0 2 4 6 8

8

6

4

2

0

–2

–4

–6

–8–8 –6 –4 –2 0 2 4 6 8

8

6

4

2

0

–2

–4

–6

–8–8 –6 –4 –2 0 2 4 6 8

a b c

Figure 2 Set-up error in the lateral, height and craniocaudal direction of patients treated with the

Tetrahedron technique. Set-up errors determined from oblique radiation beams are plotted as a

function of those determined from orthogonal verification beams.

Lateral Ventrodorsal Craniocaudal

Two oblique fields versus verification fields


Mean difference set-up error 0.7 mm 0.3 mm –0.6 mm


Three oblique fields versus verification fields


Mean difference set-up error 0.9 mm –0.1 mm –0.5 mm


* Sigma 2-tailed < 0.001

Table 3 Comparison of set-up errors determined from the oblique fields and the verification fields of

patients treated with the Tetrahedron technique.

126

Chapter 8

Discussion

The phantom measurements point out that the displacement could be determined from

the oblique radiation beams of the Tetrahedron technique with the same accuracy as

from the orthogonal verification beams. The differences between measured displace-

ment and set-up displacement can completely be attributed to the accuracy of the table

movement (0.1 mm precision), gantry rotation (1°) and the image resolution (0.4 mm per

pixel).

However, this result only holds for phantoms and not for real patients. In the case

of patient images the situation becomes much more complex. First, the interpretation of

the images is more difficult. The contrast of the bony structures in the portal images is

low and the images of the verification beams of only 4 MU are relatively noisy. Secondly,

the head and neck region of a patient is not a rigid body. Therefore, also rotations and de-

formation can occur. In the portal images rotations can not always be distinguished from

translations which lead to errors in the determination of the set-up error.

The problem with the interpretation of patient data is that the real set-up error

is not known. It is current practice to determine the patient set-up error from portal

ima ges of an AP and a lateral verification beam. Therefore, we have compared the set-up

errors from the oblique radiation beams with those determined from the AP and lateral

beams. However, one should bear in mind that also the set-up error determined from

the AP and lateral beams contains measurement errors.

Bel et al. have investigated whether a wedged pair of oblique beams could be

used for the position verification of patients with parotid gland or tonsillar tumors2.

They concluded that it was not possible to obtain consistent translational set-up devia-

tions using bony structures, due to patient rotations.

The results of the patients treated with the Bellinzona technique show a good

agreement between the set-up errors determined from the oblique radiation beams and

from the orthogonal verification beams in the ventrodorsal and craniocaudal direction

(Table 2). The inaccuracies in the set-up errors can be explained by the inaccuracies in

the gantry angle (1°), in the review process of the portal images and in the calculation of

the set-up errors from the oblique fields. The inter- and intraobserver variability in the

review of patient images is about 1 mm (1 SD) in our institute (data not shown). There-

fore, we assumed an accuracy of 1.0 mm (1 SD) in the set-up errors determined from the

AP and lateral portal images. We assume a normal distribution of the set-up errors. This

indicates an accuracy of 1.7 mm (1 SD) in the set-up errors determined from the oblique

radiation beams in the lateral and 0.8 mm (1 SD) in the ventrodorsal and craniocaudal

directions.

The accuracy of the calculation of the set-up errors from the oblique fields de-

pends on both de difference in gantry angle between the oblique fields6 and the distance

127


to the isocenter of the bony structures used in the image analysis4. Based on the results

of Kolkman-Deurloo et al. it can be expected that the maximum deviations in the calcu-

lation for the Bellinzona technique (with a difference in gantry angle of about 40 °) will

be twice that of a calculation with a difference in gantry angle of 90°.

The difference between the oblique radiation and the verification beams has de-

creased in the lateral and in the craniocaudal direction by adding an AP verification

beam to the oblique beams (Table 2). The difference in the ventrodorsal direction was

not influenced by the addition of the AP beam. In this situation the AP verification beam

is used in the determination of the set-up errors in both situations. Hence, the measure-

ments are not independent anymore and a quantitative interpretation of these data is

not possible. However, we assume that the lateral set-up error can be obtained with the

same accuracy from the combination of the AP and oblique beams as from the AP and

lateral beams. The accuracy of the set-up error in the ventrodorsal and craniocaudal

direction determined from the combination of the oblique and AP beams is about 1 mm.

Because the information content of the portal images (contrast, amount of bony struc-

tures, beam of view) of the oblique and orthogonal beams is comparable, this result is in

agreement with what one would expect.

For the Tetrahedron technique with two oblique beams the accuracy in the set-up

errors from the oblique beams will be 1.4 mm (1 SD) in the lateral and the craniocaudal

direction and 0.7 mm in the ventrodorsal direction. If three oblique beams are used the

accuracies (1 SD) are 1.2 mm in the lateral, 0.8 mm in the craniocaudal direction and

0.5 mm in the ventrodorsal direction. The accuracy in the ventrodorsal direction is much

better than 1.0 mm. Only relatively small set-up errors were found in the ventrodorsal

direction. However, the difference in set-up errors does not depend on the magnitude

of the set-up error. Therefore, the most probable explanation is that the accuracy in the

review process in the ventrodorsal direction is better than 1.0 mm (1 SD).

It is expected that the accuracy in the review of the radiation beams is less than

that of the verification beams because the beam size and therefore the field of view is

smaller and as a result less bony structures can be recognized and the interpretation

of the images is harder. The results for the lateral and craniocaudal set-up errors are in

agreement with this assumption. Especially if only two radiation beams are used the

accuracy in the set-up errors determined from these radiation beams is less than that

of the verification beams. In the ventrodorsal direction the accuracy of both methods

seems to be comparable.

128

Chapter 8

Conclusions

For the Bellinzona technique patient set-up errors can be determined with the same ac-

curacy from the two oblique radiation beams combined with an AP verification beam as

from an AP and a lateral verification beam. Furthermore, both a right and a left oblique

beam are used instead of one lateral beam, which gives a better result in case of patient

rotations around the length axis.

For the patients treated with the Tetrahedron technique using an AP and lateral

verification beam gives the most accurate results for position verification and is there-

fore recommended.

129


Appendix A

The set-up deviation as determined from portal image i is defined as Rmv,i = (ui,vi,wi),

where ui and vi lie in the plane of the imager and wi is perpendicular to the plane of the

imager. Therefore, only ui and vi can be determined from the portal image. In the patient

coordinate system (x,y,z) the positive x-direction corresponds to the left, the positive y

to the dorsal and the positive z tot the cranial direction. The set-up deviation in the pa-

tient coordinate system R = (x,y,z) is related to Rmv,i by an isocentric table rotation φi and

a gantry rotation φi:

(1)

−

−

=

i

i

i

ii

ii

ii

ii

w

v

u

z

y

x

010

)cos(0)sin(

)sin(0)cos(

)cos(0)sin(

010

)sin(0)cos(

θθ

θθ

φφ

φφ

for a patient in supine position with the head in the direction of the gantry. Eq. 1 can be

solved for ≥ 2 portal images with different gantry angles θi and θj. We have implemented

the matrix transformation in an Microsoft Excel spreadsheet for n portal images and

used the Microsoft Excel Solver (Microsoft Corporation, Redmond, WA) to find the solu-

tions for wi that minimize the function Cn(w):

(2)( ) [ 22

1,

2 )()()()()()( jjiijjii

n

jijjiin wzwzwywywxwxwC −+−+−= ∑

=

[ ]]]

The iteration process was performed with a convergence of 0.001 and a maximum of

100 iterations

130

Chapter 8

References

1. Bel A, van Herk M, Bartelink H, et al., A verification procedure to improve patient set-up

accuracy using portal images. Radiother Oncol 1993;29:253-260.

2. Bel A, Keus R, Vijlbrief RE, et al., Set-up deviations in wedged pair irradiation of parotid

gland and tonsillar tumors, measured with an electronic portal imaging device. Radiother

Oncol 1995;37:153-159.

3. van Herk M, Remeijer P, Rasch C, et al., The probability of correct target dosage: dose-

population histograms for deriving treatment margins in radiotherapy. Int J Radiat Oncol

Biol Phys 2000;47:1121-1135.

4. Fencil LE and Metz CE. Propagation and reduction of error in three-dimensional structure

determined from biplane views of unknown orientation. Med Phys 1990;17:951-961.

5. Fogliata A, Cozzi L, Bieri S, et al., Critical appraisal of a conformal head and neck cancer

irradiation avoiding electron beams and field matching. Int J Radiat Oncol Biol Phys

1999;45:1331-1338.

6. Kolkman-Deurloo I-KK, Visser AG, Idzes MHM, Levendag PC. Reconstruction accuracy of a

dedicated localiser for filmless planning in intra-operative brachytherapy. Radiother Oncol

1997;44:73-81.

7. Siddon, RL. Solution to treatment planning problems using coordinate transformations.

Med Phys 1981;8:766-774.

8. Stroom JC, Boer HCJ de, Huizenga H, et al., Inclusion of geometrical uncertainties in

radiotherapy treatment planning by means of coverage probability. Int J Radiat Oncol Biol

Phys 1999;43:905-919.

9 General discussion

134

Chapter 9

135

General discussion

General discussion

This thesis is based on the results of a number of studies focussing on the role of ra-

diation therapy in pituitary adenomas. An important finding of our series of non-func-

tioning pituitary adenomas (NFA) is that immediate postoperative radiation therapy

in case of residual disease strongly reduces the likelihood of re-growth. Health-related

quality of life in treated NFA patients was found to be similar to that of the normal

population, and the results of our study suggest that radiation therapy does not ad-

versely affect health status. Life expectancy in both irradiated and non-irradiated

NFA-patients with well-substituted hypopituitarism is comparable with the general

population. Just in a very small proportion of patients with residual non-functioning

pituitary adenoma, immediate postoperative radiation therapy may be regarded as

over-treatment. There are, however, currently no predictive factors available, which

could reliably select patients for either immediate postoperative radiation therapy or

an active surveillance policy.

The possible induction of radiation-induced side effects is often used to delay

or reject radiation therapy in NFA. However, in our series, this policy can not be con-

firmed as the incidence of possible treatment-related side effects after immediate post-

operative radiation therapy were similar to that observed in case of an active surveil-

lance policy in residual NFA. These results indicate that the possible treatment-related

side effects, such as pituitary insufficiency induced by radiation therapy, are counter-

balanced by hypopituitarism resulting from tumour re-growth and/or repeated surgical

procedures. The consequences of an active surveillance policy, including frequent MRI-

imaging, the risk of a second or even multiple operations and finally radiation therapy,

should therefore not be underestimated. The possible (psychological) consequences of

the uncertainties for the patient and his or her family in case of such a policy should

also be taken into consideration.

It should be emphasised that patients included in this thesis were treated be-

tween 1970 and 2000 with relatively conventional radiation delivery techniques such as

3D-conformal radiation therapy. Since then, technological developments in radiation

oncology have rapidly evolved. Currently, more advanced radiation techniques such as

intensity modulated radiation therapy and stereotactic radiation therapy are clinically

available and enable radiation oncologists to achieve a steeper dose gradient from the

target volume to normal tissues, and thus, theoretically, to a further increase in the

therapeutic ratio.

It is important that patients are well informed about the arguments in favour of

and against radiation therapy and other possible treatment modalities. Therefore, an in-

formative visit to a radiation oncologist, with expertise in the field of pituitary adenoma,

should be part of the standard procedure.

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Chapter 9

As presented in this thesis, radiation optic neuropathy (RON) after conventio-

nally fractionated radiation therapy in patients with acromegaly and non-functioning

pituitary adenoma is a rarely occurring side-effect. It still remains unclear whether RON

is more frequently occurring among patients with acromegaly than among those with

non-functioning pituitary adenoma. Acromegaly with its endocrine syndrome is accom-

panied by damage to the blood vessels, and as a consequence, these patients are as-

sumed to be more susceptible for radiation damage. Another explanation can be that the

reported doses, received by the optic nerves and optic chiasm, are an underestimation of

the really applied dose to the optic system due to limitations of the different radiation

therapy calculation methods used over time. The pituitary in the sella turcica is sur-

rounded by air cavities. In acromegaly generally these cavities are enlarged. Depending

on the radiation treatment technique used, the different radiation beams pass more or

less air cavity-length to reach the pituitary fossa. In air the radiation beam is less attenua-

ted in comparison with normal tissue. The calculation methods in the past were not

accurate enough to implement the attenuation factor for air. As a consequence the dose

in the optic system will then be higher than assumed and reported. This might result

in a small rise in occurrence of RON in acromegaly in comparison with non-functioning

pituitary adenoma patients. On the other hand, in acromegaly the osseous structures

are also more prominent in comparison with patients with NFA, which may also have

an impact on dose distribution. The reported dose-response curves for radiation optic

neuropathy are worthwhile, but should be interpreted with keeping these remarks in

mind.

The basal pathophysiological mechanism of RON remains to be clarified. In

addition, it still remains unclear why the optic chiasm/optic nerves are more suscep-

tible for radiation damage in comparison with the other cranial nerves. Basic research is

needed to understand the responsible mechanism, enabling the clinician to prevent and

treat this very rare but serious side effect after radiation therapy. Fortunately, it is to be

expected that the use of currently available advanced radiation therapy techniques will

further diminish this very rare side effect.

Nowadays, position verification is considered standard in case of radiation

therapy for all curative indications, including pituitary adenoma. With the introduction

of three-dimensional-conformal and intensity modulated radiation therapy, non-copla-

nar radiation beam techniques are easier to apply in comparison with the past. The

verification procedures for these techniques are discussed in one of the chapters and

although complicated, resulted in adequate reproducibility.

The first step in radiation therapy for these patients is the production of a per-

fect immobilisation device system. Second, the use of high quality CT-scans in treat-

ment position and co-registration with high quality MRI- and PET scans are essential in

order to define the target volume as accurate as possible. Improved set up accuracy and

137

General discussion

advanced verification procedures during treatment will enable smaller margins from

clinical target volume to planning target volume to account for the different uncertain-

ties. Improving target volume definition methods will result in smaller radiation volumes

and, theoretically less side effects. The availability of radiation dose calculation systems,

that take into account the tissue inhomogeneities and provide information closer to the

actual radiation dose distribution in both the target volume and the surrounding normal

tissues, are essential.

Radiosurgery is a radiation technique that is increasingly used for small pi-

tuitary adenomas, which are located more than 3 mm from the optical system. Some

assume that the fall-off effect on hypersecretion is more rapid in comparison with con-

ventionally fractionated radiotherapy and that sparing the normal pituitary function

with radiosurgery is superior to conventional techniques. Until now these assumptions

have not been confirmed by adequate data1,2. The assumed benefit of radiosurgery is

mainly based on selection bias, because only smaller adenomas are suitable and se-

lected for radiosurgery. In case radiosurgery can be safely applied, however, it should be

considered, as the number of visits to the radiation therapy department can be reduced

considerably, which is more convenient for the patient. Fractionated stereotactic radia-

tion therapy is a suitable technique for larger tumours.

Further improvement of the therapeutic ratio can be expected from particle

therapy3. The beam properties of proton or heavy ions radiosurgery or stereotactic radia-

tion therapy will result in lower doses to the non-target tissues in and outside the brain,

which is superior to the currently used photons. The better dose conformity that can be

obtained with particles will also allow for hypofractionation, particularly in the case of

larger tumours, which might also be interesting in terms of cost-effectiveness.

Radiation therapy is a so-called tertiary medical specialty. This means practi-

cally, that the decision to refer patients with pituitary adenomas to the radiation oncolo-

gist is generally taken by endocrinologists and neurosurgeons. Thus far, this decision

has been dependent to a large extent on their personal opinion about the role of radia-

tion therapy. This thesis contributes to an evidence-based approach of radiation therapy

of patients with pituitary adenomas. In our centre, the pro’s and con’s of neurosurgery,

radiation therapy and medical treatments are discussed in a multidisciplinary team in

which all relevant medical disciplines involved do participate. Such a multidisciplinary

approach, using clear guidelines for every patient with a pituitary adenoma should be-

come standard in order to improve the quality of outcome for the patients. Given the

relative low incidence of this disease, the wide range of possible treatment modalities

and the required expertise, this approach will also enable to initiate translational and

clinical research projects.

138

Chapter 9

References

1. Sheehan JP, Niranjan A, Sheehan JM et al. Stereotactic radiosurgery for pituitary adenomas;

an intermediate review of its safety, efficacy, and role in the neurosurgical treatment

armamentarium. J Neurosurg 2005; 102:678-691.

2. Brada M, Ajithkumar TV, Minniti G. Radiosurgery for pituitary adenomas. Clin Endocrinol

2004; 61:531-543.

3. Chen CC, Chapman P, Petit J, Loeffler JS. Proton radiosurgery in neurosurgery. Neurosurg

Focus 2007; 23(6):1-5.

141

Summary

Summary

Chapter 1 general introduction This chapter includes a description of the ana-

tomy of the pituitary gland, the prevalence and the various treatment modalities

of pituitary adenoma, as well as the side-effects of treatment.

The pituitary gland plays a central role in hormone production and hormone

regulation in the human body. Pituitary adenomas account for at least 12% of all

intracranial neoplasms with an incidence of 20 to 30 per million per year. Almost

all pituitary adenomas are benign tumours. Approximately 25% to 30% of the pi-

tuitary adenomas do not result in hormonal overproduction and these adenomas

are generally referred to as non-functioning pituitary adenomas (NFA). In the

absence of hormonal excess patients present with symptoms due to mass effect

of the NFA such as compression of the optic apparatus, resulting in loss of vision.

Furthermore, pituitary hormone secretion may be impaired. Age at diagnosis is

generally between 40 and 50 years.

Hypersecretory pituitary adenomas account for 70% to 75% of the pituitary ade-

nomas.

These tumours may produce the following hormones in excess:

• growth hormone (GH); GH hypersecretion manifests as acromegaly in adults and

gigantism in adolescents, and results in growth of many anatomical structures

of the human body.

• adrenocorticotrophic hormone (ACTH); ACTH excess manifests as Cushing’s di-

sease.

• prolactin (Prl); Prl excess results in galactorrhoea in women and reduced fertility

in men and women.

In general, patients with hypersecretory adenomas present at a younger age in

comparison with patients with NFA and these adenomas are usually smaller.

Neurosurgery is in most cases the treatment of choice for NFA, GH- and ACTH-

secreting adenoma in order to decompress the neighbouring anatomical struc-

tures of the pituitary adenoma and/or to reduce hypersecretion of hormones.

In case of prolactinoma and residual disease after neurosurgery among patients

with a GH- and ACTH-secreting adenoma, treatment with hormone-suppressing

medication relieves symptoms and adverse metabolic consequences.

Radiation therapy, in most cases applied postoperatively, results in long-term local

control and improvement of hormonal hypersecretion.

Possible side-effects of radiation therapy are used as argument to postpone or

reject radiation therapy in residual pituitary adenomas. These side-effects are dis-

cussed and are placed in perspective to the adverse consequences of local exten-

142

Summary

sion of the pituitary adenomas itself, the neurosurgical procedures and the effects

of sustained medication. In addition, the use of more advanced and emerging

radiation delivery techniques will further reduce the probability of radiation-

induced side-effects.

The purpose of the study, presented in Chapter 2, was to demonstrate the benefit

of immediate postoperative radiation therapy in residual non-functioning pitui-

tary adenoma in perspective to the need for hormonal substitution and life expec-

tancy. A retrospective cohort analysis was performed of 104 patients with residual

NFA after surgery, operated in the time period 1979-1998 at the University Medical

Center Groningen. Recurrence was defined as regrowth on computed tomography

or magnetic resonance imaging. The occurrence of hormonal deficiencies was de-

fined as the initiation of hormonal substitution therapy.

Seventy-six patients with residual NFA received immediate postoperative radia-

tion therapy. In these patients local control was 95% after 10 years. Twenty-eight

patients with residual NFA after surgery were followed with a wait-and-see

po licy. In this group, local control was achieved in 49% of the patients after 5 years

and in 22% after 10 years. Thus, the difference in local control in favour of imme-

diate postoperative radiation therapy amounted to 46% and to 73% after 5 and

10 years, respectively. The majority of the patients in the wait-and-see policy

group in whom a local recurrence developed received salvage radiation therapy,

most frequently after re-operation. The median time interval between first sur-

gery and radiation therapy was 38 months. Immediate postoperative radiation

therapy and salvage radiation therapy at recurrence were similar in regard to

technique, daily (1.8-2 Gray) and total dose (45-50 Gray) applied.

At present it is often assumed that immediate postoperative radiation therapy in

case of residual pituitary adenoma adversely affects the development of hypopi-

tuitarism as compared with a wait-and-see policy. The results from our retrospec-

tive study suggest that this assumption may need modification: preoperatively,

directly after first surgery and at the end of follow-up no differences in favour of

the patients with a wait-and-see policy were found regarding the need for thyroid-,

glucocorticoid- and sex-hormone substitution. Also the number of hormone defi-

ciencies per patient over time was not different between the two groups.

From our analysis it is likely that the supposed increased frequency of pituitary

insufficiency attributable due to the immediate postoperative radiation therapy

is counterbalanced by a high local recurrence rate, which necessitates re-opera-

tion as well as radiation therapy in the majority of patients. Moreover, overall sur-

vival in patients with residual NFA was found to be similar in the wait-and-see

policy group compared to those patients who received immediate postoperative

143

Summary

radiation therapy. Also in both groups of patients, life expectancy did not differ

from that in the general population. Our results, therefore, do not support the

opinion that it is advantageous to postpone radiation therapy in case of residual

non-functioning pituitary adenoma. However, it is also noteworthy that our study

demonstrated that in 15 patients with a completely resected non-functioning pi-

tuitary adenoma, local control rate after 10 years was as high as 95% with surgery

alone. Therefore, routine use of postoperative radiation therapy is not justified for

all pituitary adenomas.

The purpose of the cross-sectional study in a large cohort of patients with non-

functioning pituitary adenomas, presented in Chapter 3, was to determine

whether the use of radiation therapy in the postoperative period has a significant

effect on health-related quality of life (HRQoL) and cognitive function. Ninety

NFA-patients, treated with surgery in the time period 1963-2005 at the University

Medical Center Groningen, were eligible. Questionnaires on quality of life, mood,

cognition, use of medication, presence of co-morbidity, and social status were

sent to all patients by mail. Eighty-one patients (49 men and 32 women, median

age 55 years) returned all questionnaires, yielding a response rate of 90%. Forty-

six of them received radiation therapy after neurosurgery because of residual

disease or re-growth. Average time between neurosurgery and radiation therapy

was 8 months. The radiation schedule applied was a total dose of 45 to 50 Gray

in a daily dosage of 1.8 – 2 Gray. Those patients who received radiation treatment

did more frequently have a craniotomy, were younger at the time of surgery, and

their duration of follow-up was longer. Furthermore, thyroid hormone substitu-

tion was more frequently necessary.

The HRQoL-questionnaires were equally scored by patients who received radia-

tion therapy and those who did not. Some domains of the questionnaires were

better scored by patients, who received radiation therapy. No differences in

cogni tive function scores were observed between irradiated and non-irradiated

patients. In comparison with the reference population, social functioning, vita-

lity, general health perception, fatigue and depression scores were worse in the

group of patients without radiation therapy. In patients who did undergo radia-

tion therapy only, general health perception was less than in the reference Dutch

population, whereas physical functioning, pain and anxiety seemed even better.

In conclusion, no negative outcomes and even some limited positive effects in

the perception of mental and physical health after radiation therapy were found

in our cohort of patients with NFA. Our results are reassuring and do not suggest

that radiation therapy applied after surgery in the treatment of NFA leads to re-

duced HRQoL or impaired cognition.

144

Summary

The aim of our retrospective analysis in Chapter 4 was to describe the occur-

rence of radiation optic neuropathy (RON) in our cohort of patients treated with

radiation therapy for a GH-secreting pituitary adenoma. RON is usually defined

as a sudden and profound irreversible visual loss due to damage of the optic

nerves or damage of the chiasm caused by radiation therapy. During the time pe-

riod 1967-1998 63 patients with acromegaly were treated with external beam ra-

diation therapy in our region. All visual field, visual acuity, fundoscopic examina-

tions and imaging data from these patients were evaluated for diagnosing RON.

Median follow-up time in this cohort was 84 months (range 18-250 months) be-

tween the first day of radiation therapy and last ophthalmological examination.

The median total dose applied was 49.5 Gray and the median daily dose applied

was 1.8 Gray. Two patients developed RON; one patient in one optic nerve 10 years

after radiation therapy with visual acuity decreased to light perception only and

another patient in both optic nerves 5 months after radiation therapy with vision

loss to 1/60 in the left eye and 0.5 in the right eye. Most cases of RON occur within

18 months, but this series show, that late development can occur. RON is a rare

but serious complication after external beam radiation therapy for acromegaly.

A clinician should be aware of this, also after a considerable latency time.

The purpose of the literature review in Chapter 5 was to determine the incidence

of RON in acromegaly, and to establish risk factors associated with its occurrence.

In the time period 1966-2002, 57 published series could be retrieved from Medline

and Embase, in which the occurrence of RON after fractionated radiation therapy

in acromegalic patients was reported. In this series RON developed in 25 out of

1845 patients yielding an incidence of 1.36%. Based on RON cases in these series

and 12 case reports, information on total radiation dose and radiation fraction

size was available in 32 patients who developed RON. RON was bilateral in 71%

and unilateral in 29% of these patients. Visual acuity was reduced to less than

2/10 in 35 of 41 RON affected eyes. It is generally postulated that most cases of

RON occur within 18 months after radiation therapy. In this review 27% of pa-

tients with RON developed this complication more than 18 months after radia-

tion therapy with a range to 120 months. A radiation fractionation size greater

than 2 Gray and/or a total radiation dose greater than 50 Gray are suggested to

be risk factors for RON in general. In this review 50% of the patients with RON

were treated with an assumed safe radiation therapy schedule. This suggests

that other risk factors, including vascular compromise and GH-secreting pitui-

tary adenoma itself contribute to RON occurrence. It was not possible to draw

definite conclusions about age as a possible risk factor for RON development as

suggested by others. Seventy-eight percent of the patients, in whom gender was

145

Summary

reported, were female. Since the occurrence of acromegaly is not increased in

females and it is unlikely that females are treated more frequently with radiation

therapy than males, this would suggest that females are at an increased risk for

the development of RON.

RON is essentially considered as a diagnosis by exclusion. Using MRI with gado-

lineum, enhancement of the retro-orbital optic nerves and chiasm usually occurs

probably as a consequence of a disrupted blood brain barrier within the optic

nerves. This diagnostic approach is currently proposed to improve the diagnosis

of RON. Until now there is no effective treatment for RON.

With the current dose-fractionation policy in our department - 45 Gray in 1.8 Gray

fractions are assumed “safe”- and with the introduction of advanced and emer-

ging radiation delivery techniques, it is expected that these implementations will

probably further decrease this serious side-effect of radiation therapy.

In Chapter 6, the first aim was to assess the development of RON in our cohort

of patients with non-functioning pituitary adenomas, who received radiation

therapy in the time period 1985 - 1998. Ophthalmological and imaging data of

72 patients with a minimum follow-up of 18 months after radiation therapy were

retrospectively checked. The median follow-up was 51 months. The total radia-

tion dose applied varied between 45 and 55.8 Gray with a daily dose varying from

1.8 to 2 Gray. No RON was diagnosed in these 72 patients. One of the 72 patients

had spiralling isopters on Goldman perimetry without visual acuity loss 11 years

after radiation therapy. This patient was initially considered as atypical RON, but

the visual fields ultimately normalized and the diagnosis was rejected.

The second aim of this study was to determine the incidence of RON in reported

series of non-functioning pituitary adenomas in relation to risk factors, based

on a literature review. We performed a literature search, using Medline and Em-

base, regarding the time period 1966 – 2003. Twenty seven series were found and

our series was added. In 11 of 2063 irradiated NFA patients, RON was diagnosed,

yielding a percentage of 0.53. Additional 14 case reports on RON in NFA could be

retrieved. RON was bilateral in 56% and unilateral in 44% of reported patients.

Only 16% of affected eyes had a residual visual acuity due to RON of more than

2/10, 52% of the affected eyes had no light perception anymore. The median time

between radiation therapy and the development of RON was 11 months. Sixteen

percent of patients had a latency time of more than 18 months with a maximum

of 54 months. Thirty-three percent of patients with RON were irradiated with an

assumed safe radiation schedule, as reported in Chapter 5. Older age has been

considered as a possible risk factor, but our series suggest that age is not a strong

risk factor for developing RON in NFA. No major gender predominance was found.

146

Summary

Based on our series and the literature review RON should be regarded as a very

rare complication after external beam radiation therapy for non-functioning pi-

tuitary adenoma, especially when using up-to-date radiation schedules.

The results of a study on the role of Tyrosine-PET (TYR-PET) for pituitary adenoma

imaging after surgery and radiation therapy were reported in Chapter 7. TYR-PET

is able to visualize protein synthesis in tissues. TYR-PET imaging was compared

with magnetic resonance imaging (MRI), which is currently the standard imaging

modality in pituitary adenomas. In 9 NFA-patients and 3 GHA-patients TYR-PET

and MRI images were compared pre- and postoperatively. The results showed

that tumour volume reduction of the pituitary adenoma after surgery was similar

when determined by both imaging modalities. In six of these patients (4 NFA- and

2 GHA –patients) TYR-PET was used to document residual activity three years af-

ter completion of radiation therapy. In these patients the MRI-volumes remained

unchanged in contrast to TYR-PET imaging, that revealed a median reduction of

50%. Likewise, there was also a trend towards reduced protein synthesis in the

residual pituitary adenoma 3 years after completion of radiation therapy. These

preliminary results support the concept that it is possible with TYR-PET imaging

to follow biological tumour activity of pituitary adenoma, and suggest that this

imaging technique may yield additional information compared to MRI.

Chapter 8 contains a description of the radiation techniques used at the department

of Radiation Oncology of the University Medical Center Groningen, with emphasis

on whether the position in head and neck cancer patients and pituitary adenoma

patients during radiation therapy could be determined from portal images of the

oblique radiation beams. Currently applied additional anterior posterior (AP) and

lateral verification beams could then be abandoned. Seven hundred and fifty-one

portal images from 18 different patients were analyzed, of which 9 were pituitary

adenoma patients. These patients were irradiated with the tetrahydron technique,

in which 4 radiation beams are used with equidistant angles of 109 degrees with

the isocenter located in the pituitary fossa. The results showed that the position in

pituitary adenoma patients treated with the tetrahedron technique could not be

reliably verified using portal images of the oblique radiation beams themselves, but

that additional AP and lateral verification beams are required for verification and

correction of the position of the treatment fields.

Chapter 9 contains the general discussion, in which new and emerging develop-

ments in radiation therapy are described. The need for a multidisciplinary ap-

proach in the diagnosis and treatment of pituitary adenomas is emphasized.

147

Samenvatting

Samenvatting

Radiotherapie bij het hypofyseadenoom

Hoofdstuk 1 algemene inleiding Dit hoofdstuk bevat een beschrijving van de

anatomie van de hypofyse en van de frequentie van vóórkomen van het hypofy-

seadenoom met zijn verschillende behandelingsmogelijkheden.

De hypofyse speelt een centrale rol in de hormoonproduktie en hormoonregu-

latie van het menselijk lichaam. Minstens 12 procent van alle nieuwvormingen

in het hoofd zijn hypofyseadenomen. Bijna alle hypofyseadenomen zijn goed-

aardig. De incidentie van deze aandoening bedraagt 20 tot 30 per miljoen per

jaar. Bij benadering hebben 25% tot 30% van de hypofyseadenomen geen klinisch

relevante hormoonproductie en worden geclassificeerd als niet-hormoon pro-

ducerend (NFA). Patiënten presenteren zich met symptomen die het gevolg zijn

van massawerking door het hypofyseadenoom, leidend tot compressie van de

oogzenuwen, het optische kruis en/of de hypofyse. Dit resulteert in afname van

het gezichtsvermogen en hypofysefunctieverlies. De leeftijd van de patiënt bij

diagnose varïeert over het algemeen van 40 tot 50 jaar.

Hypofyseadenomen met hormoon overproductie nemen 70% tot 75% van het to-

taal voor hun rekening.

Deze tumoren kunnen de volgende hormonen overmatig aanmaken:

• Groeihormoon (GH); GH hypersecretie manifesteert zich als acromegalie bij vol-

wassenen en gigantisme bij adolescenten en leidt tot overmatige groei van ver-

schillende lichaamsstructuren.

• Adrenocorticotroop hormoon (ACTH) of wel het bijnierschors stimulerend hor-

moon; overmatige ACTH productie veroorzaakt de ziekte van Cushing.

• Prolactine (Prl); overmatige Prl productie resulteert in melkuitvloed uit de tepels

bij vrouwen en afgenomen vruchtbaarheid bij zowel mannen als vrouwen.

Over het algemeen presenteren patiënten met hormoonproducerende hypofyse-

tumoren zich op jongere leeftijd dan patiënten met niet-hormoon producerende

hypofysetumoren. De tumorvolumina van de hormoonproducerende hypofyse-

tumoren zijn over het algemeen kleiner dan die van de niet-hormoonproduce-

rende hypofysetumoren.

Bij de meeste patiënten met een NFA, GH- of ACTH-producerende hypofyseade-

noom wordt eerst tot neurochirurgie overgegaan met als doel om de druk van het

hypofyseadenoom op de omliggende anatomische structuren weg te nemen en/

of de overmatige hormoonproductie te doen verminderen.

148

Samenvatting

In het geval van een prolactinoom en bij restziekte na neurochirurgie bij patiënten

met een GH- en ACTH-producerend hypofyseadenoom doet hormoon onderdruk-

kende medicatie de symptomen en de negatieve metabole gevolgen afnemen.

Radiotherapie wordt meestal postoperatief gegeven en resulteert in langdurige

locale controle en afname van de overmatige hormoonproductie.

Mogelijk te verwachten bijwerkingen van de radiotherapie worden als argument

aangegrepen om radiotherapie uit te stellen of om er van af te zien. Deze bijwer-

kingen worden besproken en afgezet tegen de negatieve gevolgen van tumorgroei

zelf, de noodzaak van neurochirurgisch ingrijpen en de gevolgen van de hormoon

onderdrukkende medicatie. Bovendien zal het gebruik van meer geavanceerde

bestralingstechnieken waarschijnlijk de kans op bijwerkingen van de radiothera-

pie nog verder doen afnemen.

Het doel van het onderzoek, gepresenteerd in Hoofdstuk 2, was om het voor-

deel van het direct toepassen van postoperatieve radiotherapie bij rest NFA in

perspectief te plaatsen tot de behoefte aan hormoonsubstitutie en de levens-

verwachting van de patiënt. Een retrospectieve cohort analyse werd uitgevoerd

bij 104 patiënten met een rest NFA na chirurgie, geopereerd in de tijdsperiode

1979-1998 in het Universitair Medisch Centrum Groningen. Een recidief werd

gedefinieerd als groei van het hypofyseadenoom, vastgesteld door middel van

computertomografische- of magnetische resonantie beeldvorming. Het optreden

van hormoon functieverlies werd gedefinieerd als het moment, vanaf wanneer

hormoonsubstitutie werd gestart.

Zesenzeventig patiënten met rest NFA ondergingen direct postoperatief radiothe-

rapie. In deze patientengroep bedroeg de locale controle 95% na 10 jaar. Achten-

twintig patiënten met rest NFA na chirurgie werden expectatief vervolgd. In deze

groep werd een locale controle van 49% na 5 jaar en 22% na 10 jaar bereikt. Het

verschil in locale controle in het voordeel van direct postoperatieve radiotherapie

bedroeg derhalve respectievelijk 46% na 5 jaar en 73% na 10 jaar. De meerderheid

van de patiënten in de expectatieve groep, bij wie een lokaal recidief ontstond,

ondergingen uitgestelde “salvage” radiotherapie, meestal vaak voorafgegaan door

heroperatie. Het mediane tijdsinterval tussen de eerste operatie en de uitgestelde

“salvage” radiotherapie bedroeg 38 maanden. De direct postoperatief gegeven en

de uitgestelde “salvage” radiotherapie waren gelijkwaardig voor wat betreft bestra-

lingstechniek, dagdosis (1.8-2 Gray) en totale dosis (45-50 Gray) straling.

In het algemeen wordt verondersteld dat het direct toepassen van postoperatieve

radiotherapie bij rest NFA leidt tot een meer en sneller hypofysefunctieverlies dan

bij een expectatief beleid. De resultaten van dit retrospectief onderzoek suggere-

ren, dat deze veronderstelling aanpassing behoeft: preoperatief, direct na de eer-

149

Samenvatting

ste operatie en aan het eind van de follow-up werden geen verschillen gezien ten

voordele van de patiënten, bij wie een expectatief beleid werd gevoerd voor wat be-

treft de behoefte aan schildklierhormoon, bijnierschorshormoon en geslachtshor-

moonsubstitutie. Ook het aantal hormoonassen per patiënt, waarvoor hormoon-

substitutie nodig was, bleek niet verschillend te zijn tussen de twee groepen.

Uit onze analyse wordt het aannemelijk, dat de veronderstelde toegenomen fre-

quentie van hormoonfunctieverlies van de hypofyse tengevolge van direct ge-

geven postoperatieve bestraling in balans wordt gehouden door het hormoon-

functieverlies als gevolg van een hoog lokaal recidief percentage, die heroperatie

als ook uitgestelde “salvage” radiotherapie behoeft. Bovendien bleek dat de ab-

solute overleving van de patiënten met een rest NFA gelijk was in beide patiën-

tengroepen. De levensverwachting in beide groepen patiënten week niet af van

de levensverwachting in de algemene Nederlandse bevolking. Onze resultaten

ondersteunen daarom niet het standpunt dat het voordeel biedt de radiotherapie

uit te stellen bij rest NFA.

Echter, het is ook vermeldenswaardig, dat onze studie bij 15 patiënten met een

compleet gereseceerde NFA laat zien, dat de locale controle na 10 jaar 95% be-

draagt met neurochirurgie alléén. Hieruit kunnen we afleiden, dat het routine-

matig direct toepassen van postoperatieve radiotherapie bij alle NFA patiënten

niet gerechtvaardigd is.

Het doel van de cross-sectionele studie in een cohort van patiënten met een

niet-functionerend hypofyse adenoom, gepresenteerd in Hoofdstuk 3, was om

te bepalen of het gebruik van radiotherapie in de postoperatieve periode een sig-

nificant effect heeft op gezondheidgerelateerde kwaliteit van leven (HRQoL) en

cognitief functioneren. Negentig NFA patiënten, behandeld met chirurgie in de

tijdsperiode 1963-2005 in het Universitair Medisch Centrum Groningen, werden

bestudeerd. Vragenlijsten over kwaliteit van leven, stemming, cognitief func-

tioneren, gebruik van medicijnen, aanwezigheid van co-morbiditeit en sociale

status werden per post naar alle patiënten verzonden. Eénentachtig patiënten

(49 mannen en 32 vrouwen, mediane leeftijd 55 jaar) retourneerden alle vragen-

lijsten, resulterend in een responspercentage van 90. Zesenveertig van hen had-

den radiotherapie na neurochirurgie gekregen, omdat er rest NFA of hergroei van

het NFA was. De gemiddelde tijd tussen neurochirurgie en radiotherapie bedroeg

8 maanden. Het radiotherapie schema, dat werd toegepast, bestond uit een totale

dosis van 45 tot 50 Gray met een dagdosis van 1.8 tot 2 Gray. Deze met radio-

therapie behandelde patiënten hadden vaker een craniotomie ondergaan, waren

jonger op het moment van chirurgie en hun follow-up duur was langer. Tevens

was schildklierhormoon-substitutie vaker nodig.

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Samenvatting

De HRQoL-vragenlijsten werden gelijkwaardig gescoord door patiënten die radio-

therapie kregen, en degenen die geen radiotherapie kregen. Sommige onderdelen

van de vragenlijsten werden beter gescoord door patiënten die radiotherapie had-

den gekregen. Geen verschillen in cognitieve functie scores werden waargenomen

tussen bestraalde en niet-bestraalde patiënten. In vergelijking met de referentie

populatie waren sociaal functioneren, vitaliteit, algemene gezondheidsperceptie,

vermoeidheid en depressie scores slechter in de groep patiënten die géén radiothe-

rapie had gekregen. Bij patiënten die radiotherapie hadden gekregen, was alleen

algemene gezondheidsperceptie slechter dan die van de referentie Nederlandse

bevolking, waarbij lichamelijk functioneren, pijn en angst zelfs beter scoorden.

Concluderend zijn er geen negatieve uitkomsten, maar zelfs beperkte positieve

effecten bij de beleving van mentale en lichamelijke gezondheid na radiothe-

rapie in ons cohort patiënten met NFA. Onze resultaten zijn geruststellend en

suggereren, dat radiotherapie na chirurgie niet leidt tot afgenomen kwaliteit van

leven of verslechterde cognitie.

Het doel van onze retrospectieve analyse in Hoofdstuk 4 was het optreden van

radiatie opticus neuropathie (RON) te beschrijven in ons cohort van patiënten

behandeld met radiotherapie voor een GH-producerend hypofyseadenoom.

RON wordt gedefinïeerd als een plotseling en ernstig onomkeerbaar verlies van

gezichtsvermogen ten gevolge van schade aan de oogzenuwen of het optische

chiasma, veroorzaakt door de radiotherapie. Gedurende de tijdsperiode 1967-1998

werden in onze regio 63 patiënten met acromegalie behandeld met uitwendige

radiotherapie. Alle gezichtsveldonderzoeken, gezichtsscherptes, fundoscopi-

sche onderzoeken en diagnostische beeldvorming gegevens van deze patiënten

werden geëvalueerd om de diagnose RON te stellen. De mediane follow-up duur

in dit cohort bedroeg 84 maanden (spreiding 18-250 maanden), bepaald vanaf de

eerste bestralingsdag tot het laatste oogheelkundig onderzoek. De gegeven mediane

totale bestralingsdosis bedroeg 49.5 Gray en de mediane dagdosis bedroeg 1.8 Gray.

Twee patiënten kregen RON; één patiënt in één oogzenuw 10 jaar na radiothera-

pie met gezichtsscherpteverlies tot slechts alleen lichtwaarneming en de andere

patiënt in beide oogzenuwen 5 maanden na radiotherapie met gezichtsscherpte

verlies tot 1/60 in het linkeroog en 0.5 in het rechteroog. De meeste gevallen van

RON treden op binnen 18 maanden, maar deze serie laat zien dat in sommi-

ge gevallen RON in een veel later stadium kan optreden. RON is een zeldzame,

maar ernstige complicatie na uitwendige bestraling voor acromegalie, waar een

medicus bedacht op moet zijn, ook na een aanzienlijke latentie periode.

Het doel van het literatuuroverzicht in Hoofdstuk 5 was om inzicht te krijgen

in de incidentie van RON in acromegalie en om risicofactoren te bepalen, die

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Samenvatting

in verband te brengen zijn met het optreden van RON. Er konden 57 artikelen

in de tijdsperiode 1966-2002 via Medline en Embase gevonden worden, waar-

in het optreden van RON na gefractioneerde radiotherapie bij acromegalie-

patiënten was beschreven. Gebaseerd op deze artikelen ontwikkelden 25 van

de 1845 patiënten RON, wat een percentage van 1.36 betekent. Gebaseerd op

de RON casus in deze artikelen en 12 case reports, bleek er informatie aan-

gaande totale dosis en dagdosis beschikbaar van 32 patiënten, die RON ont-

wikkelden. RON trad beiderzijds bij 71% en eenzijdig bij 29% van de patiën-

ten op. Gezichtsscherpte bleek afgenomen tot minder dan 2/10 in 35 van de

41 aangedane ogen. Het wordt over het algemeen aangenomen dat RON bij

het merendeel optreedt binnen 18 maanden na de gegeven radiotherapie. In

dit overzicht ontwikkelden 27% van de patiënten deze aandoening meer dan

18 maanden na de radiotherapie met een maximum van 120 maanden. Een

dagdosis groter dan 2 Gray en/of een totale dosis groter dan 50 Gray worden in

het algemeen aangeduid als risicofactoren voor RON. In dit overzicht werden

50% van de patiënten met RON behandeld met een verondersteld veilig radio-

therapie fractioneringschema. Dit suggereert dat andere risicofactoren, zoals

slechte bloedvaten en het GH-producerend hypofyseadenoom op zich, bijdra-

gen aan het optreden van RON. Het was niet mogelijk tot harde conclusies te

komen aangaande leeftijd als mogelijke risicofactor voor het ontwikkelen van

RON, zoals eerder gesuggereerd door andere onderzoekers. Zevenen tachtig

procent van de patiënten, van wie het geslacht vermeld was, waren vrouw.

Omdat het optreden van acromegalie niet verhoogd is bij vrouwen, en het niet

waarschijnlijk is dat vrouwen vaker met radiotherapie behandeld worden dan

mannen, suggereert deze bevinding dat vrouwen een verhoogd risico hebben

om RON te ontwikkelen.

RON is in essentie een diagnose per exclusionem. MRI-onderzoek met gadolineum

kan aankleuring van de retro-orbitale oogzenuw en het optische chiasma aan-

tonen, welke het gevolg is van een onderbroken bloed-hersen barrière in de oog-

zenuwen. Deze diagnostische toepassing wordt tegenwoordig aanbevolen om de

diagnose RON beter te kunnen bepalen. Tot op dit moment is er geen effectieve

behandeling voor RON.

Met het huidige dosis-fractioneringschema in ons instituut - 45 Gray in 1.8 Gray

fracties -, en met de introductie van geavanceerde bestralingstechnieken, ligt het

in de verwachting dat deze implementaties verder zullen leiden tot een lagere

kans op deze ernstige bijwerking van de radiotherapie.

In Hoofdstuk 6 was de eerste doelstelling van ons onderzoek het optreden van

RON te bepalen in ons cohort patiënten met een niet-functionerend hypofyse-

152

Samenvatting

adenoom, die radiotherapie ondergingen in de tijdsperiode 1985 - 1998. De oog-

heelkundige en beeldvormende diagnostiekgegevens van 72 patiënten, die een

minimale follow-up van 18 maanden na radiotherapie hadden, werden retro-

spectief gecontroleerd. De mediane follow-up bedroeg 51 maanden. De totale

geappliceerde radiotherapie dosis varieerde tussen de 45 en 55.8 Gray met een

dagdosis van 1.8 tot 2 Gray. Er werd geen RON vastgesteld bij deze groep van

72 patiënten. Eén van de 72 patiënten had spiraliserende isopters bij Goldman

gezichtsveldonderzoek zonder gezichtsscherpte verlies 11 jaar na radiotherapie.

Deze patiënt werd aanvankelijk beschouwd als een atypische RON-casus, maar

de gezichtsvelden normaliseerden uiteindelijk en de diagnose werd verworpen.

De tweede doelstelling was door literatuuronderzoek de incidentie van RON in

relatie tot risicofactoren te bepalen in artikelen over niet-functionerende hypofyse-

adenomen. Gebruikmakend van Medline en Embase over de tijdsperiode 1966–2003

werden 27 artikelen gevonden met NFA series, en onze serie werd hieraan toege-

voegd. Bij 11 van de 2063 bestraalde NFA patiënten werd RON gediagnosticeerd,

leidend tot een percentage van 0.53. Hiernaast konden 14 case reports over RON

bij NFA worden gevonden. RON was dubbelzijdig bij 56% en eenzijdig bij 44% van

de patiënten. Slechts 16% van de aangedane ogen had een resterende gezichts-

scherpte van meer dan 2/10, 52% van de aangedane ogen had geen lichtperceptie

meer. De mediane tijdsduur tussen radiotherapie en het optreden van RON was

11 maanden. Zestien procent van de patiënten had een latentietijd van meer dan

18 maanden met een maximum van 54 maanden. Drieëndertig procent van de

patiënten was bestraald met een aangenomen veilig radiotherapie fractionering-

schema, zoals vermeld in Hoofdstuk 5. Hogere leeftijd wordt beschouwd als een

mogelijke risicofactor, maar ons overzicht suggereert dat leeftijd niet een duide-

lijke risicofactor is voor het ontwikkelen van RON in NFA. Er werd geen duidelijke

geslachtspredispositie gevonden. Gebaseerd op ons cohort en het literatuurover-

zicht dient RON beschouwd te worden als een zeldzame complicatie na uitwendige

bestraling van het niet-functionerend hypofyseadenoom, in het bijzonder wanneer

hedendaags vigerende radiotherapieschema’s gebruikt worden.

In Hoofdstuk 7, werd de rol van Tyrosine-PET (TYR-PET) als beeldvorming-

modaliteit voor het hypofyseadenoom na chirurgie en radiotherapie bestudeerd.

TYR-PET is in staat eiwit synthese in weefsels te visualiseren. TYR-PET – opnames

werden vergeleken met magnetische resonantie opnames (MRI), welke op dit mo-

ment de standaard beeldvormingmodaliteit is voor hypofyseadenomen. Bij 9 NFA

patiënten en 3 GHA patiënten werden TYR-PET- en MRI-opnames pre- en posto-

peratief met elkaar vergeleken. De resultaten lieten zien dat de volume reductie

van het hypofyseadenoom na chirurgie met beide beeldvormingmodaliteiten het-

153

Samenvatting

zelfde was. In zes van deze patiënten (4 NFA en 2 GHA patiënten) werd TYR-PET

gebruikt om restactiviteit van de ziekte vast te leggen 3 jaar na het beëindigen van

de radiotherapie. In deze patiënten bleven de MRI volumes ongewijzigd, maar de

TYR-PET opnames als contrast toonden een mediane afname van 50%. Eveneens

was er een trend naar afgenomen eiwitsynthese in het restadenoom 3 jaar na het

beëindigen van de radiotherapie. Deze resultaten ondersteunen het concept dat

het mogelijk is met TYR-PET beeldvorming de biologische tumoractiviteit van het

hypofyse adenoom te vervolgen, en het geeft aan dat deze beeldvormingtechniek

aanvullende informatie kan bieden naast MRI.

Hoofdstuk 8 bevat een beschrijving van de bestralingstechnieken, die gebruikt

worden op de afdeling radiotherapie van het Universitair Medisch Centrum

Groningen bij een gedefinïeerde patiënten groep met een hoofdhalstumor en bij

patiënten met een hypofyseadenoom; de vraagstelling van het hierin beschreven

onderzoek is of de positie van het tumorgebied in relatie tot de bestralingsvelden

bij deze patiëntengroepen gedurende de uitwendige bestralingsperiode gecontro-

leerd kan worden door de verificatiefoto’s van de schuin ingeschoten bestralings-

bundels zelf. Het gangbare gebruik van de extra toegevoegde voorachterwaartse en

zijwaartse verificatiebundels zou dan beëindigd kunnen worden. Zevenhonderd

en één en vijftig verificatiefoto’s van 18 verschillende patiënten werden geanaly-

seerd, van wie er 9 hypofyse adenoom patiënten waren. Deze patiënten werden

bestraald met de tetraëdertechniek, waarbij gebruik wordt gemaakt van 4 bestra-

lingsbundels met gelijke hoeken van 109 graden ten opzichte van elkaar, waarbij

het draaipunt ter plaatse van de hypofyse geplaatst is.

De resultaten laten zien, dat de positie van de hypofyseadenoom patiënten be-

handeld met de tetraëdertechniek niet accuraat geverifieerd kunnen worden,

indien verificatiefoto’s opnames van de (schuin ingeschoten) bestralingsvelden

zelf worden gebruikt, maar dat verificatiefoto’s vanuit andere richtingen (voor-

achterwaarts en zijwaarts) nodig zijn voor verificatie en correctie van de positie

van de bestralingsvelden.

Hoofdstuk 9 bevat de algemene discussie, waarin de nieuwe en opkomende ont-

wikkelingen in de radiotherapie zijn beschreven. De noodzaak van multidiscipli-

naire samenwerking bij het stellen van de diagnose en de behandeling van het

hypofyseadenoom wordt onderstreept.

Chapter 1

154

155

Publicationlist

Publicationlist

Apart from the papers, as described in chapters 2 to 8, several other papers were authored

or co-authored:

• E.J. Duiverman, J. Clément, K.P. van de Woestijne, H.J. Neijens, A.C.M. van den Bergh,

K.F. Kerrebijn. Forced Oscillation Technique; reference values for resistance and reactance

over a frequency spectrum of 2 - 26 Hz in healthy children aged 2,3 - 12,5 years. Bull. Euro.

Physiopathol. Respir, 21: 171-178,1985.

• M.A. Moerland, A.C.M. van den Bergh, R. Bhagwandien, W.M. Jansen, C.J.G. Bakker,

J.J.W. Lagendijk, J.J. Battermann. The influence of respiration induced motion of the kidneys

on the accuracy of radiotherapy treatment planning, a magnetic resonance imaging study,

Radiotherapy & Oncology, 30: 150-154,1994.

• K.W. Schuit, D.T. Sleijfer, W.J. Meijler, R. Otter, J. Schakenraad, Fons C.M. van den Bergh,

B. Meyboom-de Jong. Prevalence and severity of symptoms and functional status of

patients with disseminated cancer visiting outpatient department for follow -up. J. Pain.

Symptom-Manage, 16 (5): 290-297,1998.

• F. van den Bergh, H. Meertens, L. Moonen, B. van Bunningen, A. Blom.The use of a

transverse CT image for the estimation of the dose given to the rectum in intracavitary

brachytherapy for carcinoma of the cervix. Radiotherapy and Oncology, 47: 85-90,1998.

• P.L. Jager, H.J.A. Mensink, A.C.M. van den Bergh en D.A. Piers. Een injectie met

strontium-89: een eenvoudige behandeling voor patiënten met pijnlijke botmetastasen bij

hormonaal uitbehandeld prostaatcarcinoom. Klinische lessen. Ned. Tijdschr. Geneeskd., 8 mei;

I43 (19): 969-973,1999.

• K.I. van der Zee, B.P. Buunk, R. Sanderman, G. Botke and F. van den Bergh. The Big Five

and Identification-Contrast Processes in Social Comparison in Adjustment to Cancer

Treatment. Eur. J. Pers., 13: 283-306,1999.

• K. van der Zee, B. Buunk, R. Sanderman, G. Botke, F. van den Bergh. Social comparison and

coping with cancer treatment. Personality and Individual Differences, 28: 17-34,2000.

156

Publicationlist

• C. L. Creutzberg, W. L.J. van Putten, P.C.M. Koper, M.L.M. Lybeert, J.J. Jobsen, C.C. Wárlám-

Rodenhuis, K.A.J. de Winter, L.C.H.W. Lutgens, A.C.M. van den Bergh, E. van de

Steen-Banasik, H. Beerman, M. van Lent. Surgery and postoperative radiation therapy

versus surgery alone for patients with stage I endometrial carcinoma. The Lancet, 355:

1404-1412,2000.

• C. L. Creutzberg, W.L.J. van Putten, P.C. Koper, M.L.M. Lybeert, J.J. Jobsen, C.C. Wárlám-

Rodenhuis, K.A.J. de Winter, L.C.H.W. Lutgens, A.C.M. van den Bergh, E. van de Steen-

Banasik, H. Beerman, M. van Lent. The morbidity of treatment for patients with stage 1

endometrial cancer: results from a randomized trial. Int. J. Radiation Oncology Biol. Phys. 51,

no 5, pp. 1246-1255,2001.

• H.E. Stiegelis, M. Hagedoorn, R.Sanderman, K. van der Zee, B. Buunk, A.C. van den Bergh.

Cognitive Adaptation: A comparison of cancer patients and healthy references. Br-J-Health-

Psych., Vol 8(3): 303-318, Sep 2003.

• F.T.C. Bennenbroek, B.P. Buunk, H. E. Stiegelis, M. Hagedoorn, R. Sanderman, A. C.M. van

den Bergh, G. Botke. Audiotaped social comparison information for cancer patients

undergoing radiotherapy: differential effects of procedural, emotional and coping

information. Psychooncology, 12(6): 567-79, Sep 2003.

• C.l. Creutzberg, W.L.J. van Putten, P.C. Koper, M.L.M. Lybeert, J.J. Jobsen, C.C. Wárlám-

Rodenhuis, K.A.J. de Winter, L.C.H.W. Lutgens, A.C.M. van den Bergh, E. van der Steen-

Banasik, H. Beerman, M. van Lent. Survival after relapse in patients with endometrial

cancer: results from a randomized trial. Gynecol-Oncol., 89(2): 201-9, May 2003.

• Bennenbroek, F.T.C., Buunk, B.P., Stiegelis, H.E., Hagedoorn, M., Sanderman, R., van den

Bergh, A.C.M. & Botke, G. Audiotaped social comparison information for cancer patients

undergoing radiotherapy: Differential effects of procedural, emotional and coping

information. Psycho-Oncology, 12(6): 567-79, Sep 2003.

• C.L. Creutzberg, W.L.J. van Putten, C.C. Wárlám-Rodenhuis, A.C.M. van den Bergh, K.A.J. de

Winter, P.C.M. Koper, M.L.M. Lybeert, A. Slot, L.C. Lutgens, M.C. Stenfert Kroese, H. Beerman,

M. van Lent. Outcome of high-risk stage IC, grade 3, compared with stage I endometrial

carcinoma patients: the Postoperative Radiation Therapy in Endometrial Carcinoma Trial.

J.Clin.Oncol., 22(7): 1234-41, Apr 1 2004.

157

Publicationlist

• H.E. Stiegelis, M. Hagedoorn, R. Sanderman, F. Bennenbroek, B. Buunk, A.C.M. van

den Bergh, G. Botke, A.V. Ranchor. The impact of an informational self-management

intervention on the association between control and illness uncertainty before and

psychological distress after radiotherapy. Psychooncology, 13(4): 248-59, Apr 2004.

• E. Wiegman, A. van den Bergh. Diagnose in beeld; een vrouw met witte irisvlekken.

Nederlands Tijdschrift voor Geneeskunde, 149(51), 17 december 2005.

• Poortmans P, Bossi A, Vandeputte K, Bosset M, Miralbell R, Maingon P, Boehmer

D, Budiharto T, Symon Z, van den Bergh AC, Scrase C, Van Poppel H, Bolla M; EORTC

Radiation Oncology Group Guidelines for target volume definition in post-operative

radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group.

Radiother Oncol., 84(2):121-7, Aug 2007.

• Roenhorst AW, van den Bergh AC, van Putten JW, Smit EF. Iris metastasis in small-cell lung

carcinoma. J Thorac Oncol., 2(12):1128-9, Dec 2007.

• van der Laan HP, van den Bergh A, Schilstra C, Vlasman R, Meertens H, Langendijk JA.

Grading-system-dependent volume effects for late radiation-induced rectal toxicity after

curative radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys.,15;70(4):1138-45,

Mar 2008.

• M. Bolla, Th.M. de Reijke, G. van Tienhoven, A.C.M. van den Bergh, J. Oddens,

P.M.P. Poortmans, E. Gez, P. Kil, A. Akdas, G. Soete, O. Kariakine, E.M. van der Steen-Banasik,

E. Musat, L.A.J.M. Collette, for the EORTC Radiation Oncology Group and Genito-Urinary

Tract Cancer Group. Long term or short term androgen suppression combined with

irradiation in locally advanced prostate cancer. Will be submitted Jul 2008.

159

Dankwoord

Dankwoord

Een proefschrift tot stand brengen doe je met veel mensen samen. Onderstaande perso-

nen wil ik graag in het bijzonder danken zonder anderen tekort te willen doen!

Onder leiding van Prof.dr. B.G. Szabó, hoofd van de afdeling Radiotherapie Universitair

Medisch Centrum Groningen tot 2003, en Prof.dr. C.A ter Weeme, neurochirurg Universi-

tair Medisch Centrum Groningen werd een aanvang genomen met dit proefschrift in de

midjaren negentig. Het was in het begin samen zoeken naar hoe het onderzoek vorm te

geven. De oorspronkelijke initiator was Dr.Th.P. Links, endocrinoloog UMCG.

Prof. dr. B.G.Szabó, beste Ben, ik dank je voor de impulsen, die je aan dit onderzoek gege-

ven hebt. Het heeft wat jaren gevergd, maar het proefschrift ligt er nu. Met de komst van

Prof.dr. J.A. Langendijk in 2005 was jij bereid de rol van eerste promotor aan hem over te

dragen. Fijn dat jij een actieve rol speelt 3 september.

Prof. dr. C.A. ter Weeme, Cees, ook dank voor jouw inbreng in de totstandkoming van dit

proefschrift. Goed waren de gesprekken in de tijd dat het tegenzat. Na jouw overlijden

heeft Marijke, jouw echtgenote, altijd geïnteresseerd de voortgang van het onderzoek

gevolgd, Marijke dank daarvoor!

Dr. Th.P. Links, beste Thera, door jou ben ik aangespoord te starten met het voor ons lig-

gende onderzoek. Het is een bijzondere weg gebleken met veel verrassingen en leermo-

menten.

Dr. R.P.F. Dullaart, eerste co-promotor, is de bruggenbouwer tussen de eerste en tweede

promotiecommissie geweest. Beste Robin, zonder jou had dit proefschrift er niet gelegen!

Jouw niet-aflatende stimulans, trouw, vriendschap en altijd opbouwende kritiek is een

voorbeeld voor velen. Een avond samen achter een stuk tekst leverde elke keer een nog

betere versie op en veel gezelligheid. Het was een bijzondere periode voor ons beiden.

Prof. dr. J.A. Langendijk, beste Hans, dank voor jouw steun dit project tot een goed einde

te brengen. Jij kwam naar Groningen als afdelingshoofd midden in mijn onderzoek en

werd mijn eerste promotor. Jouw goede aanvullingen en duidelijke sturing hebben mede

voor dit eindresultaat zorg gedragen.

Jouw vertrouwen in en waardering voor het hypofyseonderzoek in Groningen wordt be-

vestigd door het feit dat Margriet Sattler haar wetenschappelijke stage mag besteden

aan het verder onderbouwen van de rol van radiotherapie bij het hypofyseadenoom.

160

Dankwoord

Prof. dr. B.H.R. Wolffenbuttel, beste Bruce, na jouw komst uit Maastricht naar Groningen als

hoofd van de afdeling Endocrinologie was jij graag bereid mijn nieuwe tweede promotor

te worden. Jouw oordeel was dat er onderzoek moest plaatsvinden naar kwaliteit van

leven en cognitief functioneren bij patiënten met een hypofyseadenoom. Dit diende ook

onderdeel uit te maken van het proefschrift. Mede door de komst naar het UMCG van

Dr. A.P van Beek, endocrinoloog, kon dit snel verwezenlijkt worden.

Dr. J.W.R. Pott, tweede co-promotor, beste Jan-Willem, samen hebben we veel geleerd van

al het retrospectieve oogheelkundewerk op zoek naar Radiatie Opticus Neuropathie. Het

was een bijzondere speurtocht. In de tussentijd probeerden wij als verdedigende types

op het hockeyveld het doelpuntsaldo aan onze kant zo laag mogelijk te houden, en ook

van de derde helft genoten we.

Prof. dr. J.J. Battermann, radiotherapeut-oncoloog, Prof.dr. A.R.M.M. Hermus, endocrinoloog

en Prof.dr.J.J.A. Mooij, neurochirurg wil ik graag bedanken voor hun bereidheid plaats te

nemen in de beoordelingscommissie van dit proefschrift.

Dat mijn opleider Jan Battermann ook in dit deel van mijn vorming participeert stel ik

op prijs.

Dr. G. van den Berg, beste Gerrit, voorzitter van de multidisciplinaire hypofysewerk-

groep in het UMCG. Onder jouw leiding is deze bespreking uitgegroeid tot wat hij

nu is in een prettige opbouwende omgeving, waar kwaliteit voorop staat en waar

iedereen graag komt. Dank voor al je werk achter de schermen samen met Mariska

Groeneveld en Inge Pop ter ondersteuning van het voor ons liggende en nog volgende

onderzoek.

Dr. W.J. Sluiter, beste Wim, de gedegen statistiek in dit proefschrift is aan jou toe te schrij-

ven. Jouw deur stond en staat altijd voor mij open en ik hoop dat dit nog lang zo blijft.

Jouw vertrouwen in dit onderzoek in al die jaren en jouw genuanceerde opvattingen en

vertrouwen in mijn vak waardeer ik zeer.

Dr. H. Meertens, beste Harm, jouw komst naar Groningen betekende het voortzetten van

een prettige samenwerking, die ontstaan is in het AVL/NKI tijdens mijn wetenschappe-

lijke stage. Met veel hulp van anderen hebben we de megavolt imaging een prominente

plaats binnen onze afdeling kunnen geven. Ons oorspronkelijke idee over positieverifi-

catie bij non-coplanaire bestralingstechnieken hebben we kunnen uitwerken en publi-

ceren samen met Dr. N.M. Sijtsema.

Dr. N.M. Sijtsema, beste Marianna, dank voor jouw doorzettingsvermogen in dit project!

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Dankwoord

Dr. J. Pruim, beste Jan, het PET-stuk heeft nogal op zich laten wachten, maar het eindre-

sultaat is er mede door jou. PET-onderzoek bij hypofysetumoren is tot op heden beperkt

en dient verder uitgezocht te worden.

Drs. A. van der Vliet, beste Ton, in de tijd dat je nog in het UMCG werkte, hebben we veel

MRI-foto’s van hypofysepatiënten samen beoordeeld. Jouw spontaniteit en behulpzaam-

heid werkten voor mij stimulerend.

UMCG-hypofysewerkgroep-leden: vanaf mijn toetreden tot deze groep in 1994 heb ik mij

bij jullie thuis gevoeld en veel van jullie geleerd over neuroradiologie, neurochirurgie,

neuro-ophthalmologie en neuro-endocrinologie.

Veel dank aan de administratie Radiotherapie, Oogheelkunde, Endocrinologie, Neuro-

chirurgie, Pathologie, Radiodiagnostiek, archiefmedewerkers, huisartsen, oogartsen,

internisten en radiotherapeuten voor het verstrekken van informatie. Met jullie steun

hebben we een complete database op kunnen zetten, die steeds verder uitgebouwd zal

worden.

Alle collega’s en medewerkers van de afdeling Radiotherapie UMCG en Martini Zieken-

huis, die het mij mogelijk gemaakt hebben dit proefschrift af te ronden, wil ik bedanken.

Het waarnemen van mijn klinische taken bij een periode van “schrijfvrij” is maar één

aspect van mijn waardering voor jullie.

G. Wortmann-Even, beste Gerda, niet alleen dank voor je ondersteuning bij het organi-

satiewerk van de promotie, maar ook van de EORTC-meeting. Je behulpzaamheid en

attentheid zijn jouw kenmerken.

Drs. B.E. Straatman-Cortsen, secretaresse radiotherapie Martini Ziekenhuis, beste Bente,

niet alleen dank voor jouw ondersteuning bij het afronden van dit proefschrift met alle

letters en komma’s en onze gezamenlijke bezoeken aan Tiekstramedia. Het is prettig

samen werken met je door je toewijding en accuratesse.

Dr. Marjanke Hoving, Chris Trompert en Michiel Schoorl: jullie hebben als medisch student je

wetenschappelijke stage gewijd aan de rol van radiotherapie bij het hypofyseadenoom.

Jullie begeleiden heeft mij veel plezier gegeven. Marjanke, jij was me voor en hebt je

proefschrift in mei dit jaar mogen verdedigen.

Dr. A.P. van Beek, endocrinoloog, beste André, jouw nieuwe inbreng in het hypofyseonder-

zoek is niet alleen voor mij stimulerend en leerzaam!

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Dankwoord

Alle patiënten met een hypofysetumor, die ik heb mogen spreken en behandelen en die

bereid waren in het onderzoek te participeren, wil ik dank zeggen. Nog steeds leer ik

veel van jullie.

Parallel aan het hypofyse-onderzoek liep in onze regio de participatie in drie EORTC-

prostaatkanker trials, waarvan ik locaal coördinator ben. Het succesvol opstarten en

het actief inbrengen van patiënten in deze trials met zijn kwaliteitscontroles is geen

sinecure.

Hierbij bedank ik de participerende patiënten en hun families, de verwijzende urologen,

de ondersteunende specialismen en huisartsen in de regio, collega-radiotherapeuten en

arts-assistenten, fysische staf, radiotherapeutisch laboranten en patiëntenserviceme-

dewerkers.

Dank aan het IKN datamanagement en aan het datamanagement van onze afdeling,

met name Petra Vos, die sinds het begin er onafgebroken bij betrokken is.

Dear friends of the EORTC-ROG group, to collaborate in an international network is for

me stimulating and makes our profession with all the goals more interesting than it

already is.

Paranimfen Dr. Rikus Knegtering en Dr. René Tio, ik liet jullie wachten op de datum, maar

het stond reeds vast dat jullie mijn paranimfen zouden zijn. Onze gezinnen hebben op

allerlei manieren raakvlakken met elkaar, wat veel vriendschap geeft. Met veel plezier

trekken we samen op. Mede door jullie achtergrond als psychiater en cardioloog kan ik

met een gerust hart naar de promotie uitkijken.

Vrienden in en buiten Groningen. Dank voor jullie warme belangstelling in al die jaren

voor ons gezin met al zijn onderwerpen, waaronder dit proefschrift, voor jullie gezellig-

heid en vertrouwen.

Pa, het verschijnen van dit proefschrift en de promotie zou jij graag meegemaakt hebben.

Samen met Ma heb jij mij gestimuleerd geneeskunde te studeren. Op ondersteuning van

jullie kant - niet alleen tijdens mijn studie en specialisatie- heb ik altijd kunnen rekenen.

Ma, gelukkig kun jij deze bijzondere dag wel met ons allen in goede gezondheid mee-

maken.

Mijn schoonvader kan jammer genoeg eveneens deze dag niet meer meemaken. Mijn

schoonmoeder ondanks haar hoge leeftijd wel, al heeft ze er wel eens aan getwijfeld of

het zo mocht zijn. Al die jaren hebben jullie mij met veel belangstelling gevolgd.

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Dankwoord

Peter, mijn broer en Angelien, de zus van mijn vrouw met hun partners Caroline en

Rien en hun kinderen Ingrid met partner Simon, Hans met partner Judith en Sanne en

Floor betekenen veel voor ons. Deze hechte familieband is voor mij en ons gezin GOUD

waard.

Het thuisfront is en blijft het centrale punt bij voor- en tegenspoed. Lieve Nienke en

Niels, Joris en Gijs, jullie zorgen voor genoeg afleiding met jullie belevenissen en discus-

sies!

Lieve Margo, bijna 30 jaar met jou samen, je bent attent, gastvrij en je weet het altijd

gezellig te maken. Jij hebt in alle omstandigheden mij ondersteund en gestimuleerd het

proefschrift af te maken.

Nu is Het boek af, nieuwe uitdagingen dienen zich al weer aan!

Fons van den Bergh

3 september 2008

Fons van den Bergh is op 30 augustus 1960 te Halsteren geboren. Het diploma gymnasium alpha werd in 1978 aan het Gymnasium Juvenaat Heilig Hart te Bergen op Zoom behaald. Aansluitend werd een applicatiecursus natuur en scheikunde aan de Geneeskunde Faculteit te Nijmegen gevolgd.In 1979 startte de artsenopleiding aan de Medische Faculteit van de Erasmus Universiteit te Rotterdam; de eed werd afgelegd op 16 mei 1986. De militaire dienstplicht werd hierna in de functie van sociaal-medisch arts uitgeoefend. In 1987 werd begonnen als arts-assistent Radiotherapie niet in opleiding in de Dr. Daniel den Hoed kliniek (Hoofd Prof. dr. B. van der Werf-Messing). De specialisatie tot radiotherapeut-oncoloog vond plaats in het Universitair Medisch Centrum Utrecht (Hoofd/opleider Prof. dr. J.J. Battermann) in de periode 1988-1993. Tijdens deze periode werd de wetenschappelijke stage gewijd aan conformatie radiotherapie op de afdeling radiotherapie van de Universiteit van Michigan, Ann Arbor, Verenigde Staten, en van het Nederlands Kanker Instituut te Amsterdam (begeleider Dr. H. Meertens, klinisch fysicus).Sinds 1993 is Fons verbonden als radiotherapeut-oncoloog aan het Universitair Medisch Centrum Groningen (UMCG) en sinds 2002 tevens aan het Martini ziekenhuis te Groningen. Hij is lid van de hypofysewerkgroep in het UMCG en uro-oncologisch consulent voor Het Integraal Kankercentrum Noord Oost.Hij heeft zitting in de Landelijke Werkgroep Urologische Tumoren en is betrokken bij de landelijke richtlijn Prostaat en Zaadbalkanker.Sinds 2006 is hij mede-organisator van het nationale radiotherapeutendebat over borst- en prostaatkanker.In de Radiation Oncology Group(ROG) van de European Organisation for Research and Treatment of Cancer (www.EORTC.eu) is hij sinds 1996 actief betrokken bij het prostaatkanker onderzoek. In 2006 leidde dit tot het gastheerschap voor de EORTC-ROG Meeting te Groningen. Op dit moment is hij lid van de Steering Committee in de hoedanigheid van voorzitter van de membershipcommittee en inkomend voorzitter van de Genito-Urinary working party. Hij is gehuwd met Margo van Willegen. Samen hebben ze drie kinderen: Nienke, Joris en Gijs.

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