CASE REPORTS

Patient 1

A 48-year-old man was referred for radiotherapy (RT) following

right and middle lobectomies for lung cancer. At operation a

9-cm mass invading the visceral pleura near the apex had been

removed and found to contain a centrally necrotic squamous

cell carcinoma. Lymph nodes within the lobectomy specimen

and a single mediastinal node contained no malignancy. The

bronchial resection margins were clear. Given the size of the

primary tumour and the extension of disease to the pleural

surface, the patient was considered to be at a high risk of local

recurrence and postoperative RT was indicated.

The patient received 50 Gy in 25 treatments to the

mediastinum and right chest using an anterior and posterior

field arrangement of 6-MV photon beams. A shielding block was

placed in the path of the posterior beam to limit the dose to the

spinal cord. A cord tolerance limit of 45 Gy was specified and

computer planning indicated that a dose of 43–45 Gy would be

received by the cord, with the shielding applied for eight of the

25 fractions. Port films were taken that demonstrated good

patient immobilization and accurate positioning of the shield.

The patient’s acute reactions were not unusually severe, but he

developed oesophagitis requiring minor treatment and a total

weight loss of 2.6 kg was noted during the course of the

treatment. His skin reaction was minimal. Shortly afterwards,

however, the patient developed oesophageal ulceration and

stenosis requiring multiple dilatations. One year after treatment

an oesophagoscopy and motility studies were normal but

dysphagia persisted. A CT scan suggested that asymptomatic

pulmonary fibrosis was also present, but not tumour recurrence.

The patient subsequently developed sensory loss and

weakness in the lower legs which extended proximally over the

next 5 months to the torso and affected his right forearm. An

MRI scan of the cervical and thoracic spinal cord demonstrated

increased T2-weighted signal intensity between levels C7 and

T8, consistent with radiation myelopathy (RM) and corres-

ponding to his RT fields. Rehabilitative therapy was initiated,

but over the forthcoming months his symptoms worsened with

loss of urinary and anal sphincter control, and increasing

spasticity of the legs.

He was referred for a neurosurgical opinion and it was

considered that in view of the continuing deterioration, a spinal

cord biopsy was warranted to exclude any other pathology. He

proceeded to laminectomy at the T2 level. At operation,

thrombosed arteries and veins were noted on the surface of the

spinal cord. A small incision was made in the midline and

necrotic material extruded through it under high pressure.

Case Report

Clinical application of in vitro radiohypersensitivitytestingDavid Christie,1 Martin Lavin2 and Leong Tan3

1East Coast Cancer Centre, Tugun, 2Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane and 3John Flynn

Medical Centre, Gold Coast, Queensland, Australia

SUMMARY

The cases of two patients who suffered severe late effects of radiotherapy are reported; each tested positive forelevated in vitro radiohypersensitivity (RHS) but negative for the ataxia–telangiectasia mutation. The first patientunderwent surgery and postoperative radiotherapy for lung cancer and subsequently developed fatal myelopathy.The second patient underwent triple-modality therapy for cervical cancer and suffered highly symptomatic pelvicfibrosis. The value of the testing was that it increased the confidence in the diagnosis of radiation effects and enabledsuitable treatment to proceed. An increasing role for clinical RHS testing is anticipated.

Key words: fibrosis; myelopathy; radiohypersensitivity; radiotherapy.

D Christie FRANZCR; M Lavin PhD; L Tan FRACS.

Correspondence: D Christie, East Coast Cancer Centre, Inland Drive, Tugun, Qld 4224, Australia. Email: dchristie@wesley.com.au

Submitted 4 January 1999; accepted 9 March 2000.

Australasian Radiology (2000) 44, 333–335

Postoperatively he developed a CSF leak, wound ulceration

and fever, all of which subsequently settled. Histological

analysis of the extruded material confirmed necrotic spinal

cord. Following the operation his legs became completely

paralysed, but he believed that the motor function of his arms

had improved.

Review of his RT records revealed no errors in calculation or

delivery of his treatment. The possibility of radiohypersensitivity

(RHS) was considered. Blood was sent for analysis with three

assays, including induced chromosomal aberrations (ICA), G2

cell cycle phase delay, and the ataxia–telangiectasia (AT)

mutation. The ICA study showed an unusually high rate of

aberrations per metaphase at 2.4 (controls: 0.8–1.0), but not as

high as an AT homozygote control (3.0). The G2 phase delay

demonstrated prolonged accumulation of cells in the G2 phase

although it was not as prolonged as that of an AT patient. The AT

mutation study was negative. The information was given to the

patient and genetic counselling was offered. He remained free

of recurrence of his lung cancer for 2 years following treatment,

but died of pneumonia most likely related to RM.

Patient 2A 37-year-old woman was referred for an opinion about

symptoms possibly related to previous treatment 18 months

earlier. She had undergone total abdominal hysterectomy,

bilateral salpingo-oophorectomy and dissection of pelvic lymph

nodes for cervix cancer. Thereafter she had received

chemotherapy and RT, consisting of three cycles of cisplatin

initially, followed by pelvic (50 Gy in 30 fractions) and para-

aortic (45 Gy in 30 fractions) RT given concurrently with weekly

cisplatin. During her combined adjuvant treatment she had

suffered nausea, vomiting, diarrhoea and pain.

Her symptoms persisted and 18 months later she had

generalized lower abdominal pain on defaecation, micturition

and intercourse. On examination moderately severe vaginal

shortening and stenosis, with generalized pelvic fibrosis, were

present, but no recurrence. Routine blood tests including

thyroid function tests showed no abnormality. A CT scan of the

abdomen and pelvis indicated some minor loss of tissue planes

in the pelvis. A barium follow-through was suggested and was

normal. At colonoscopy there were mild inflammatory changes

consistent with radiation colitis and proctitis. Because the

investigation findings were relatively mild, a cause for her

symptoms was considered to be unknown.

Blood was sent for RHS assessment and showed an

elevation of 2.7 times that of the normal population. A search for

the AT mutation was negative. Given the marked elevation in

RHS, the most likely cause for her symptoms was considered

to be radiation fibrosis. She was advised of the result and began

a course of hyperbaric oxygen therapy (HBO) with the aim

of improving her symptoms. That treatment relieved her

symptoms by approximately 50%.

DISCUSSIONThe present report describes two patients who suffered late

effects of a combined cancer treatment (including RT) and were

later shown to have RHS. The optimal method for determining

RHS is not yet known nor is it readily available for routine use in

testing for RHS before or after RT. In the aforementioned cases

and others1 the ICA assay has demonstrated its ability to

distinguish patients with RHS. The previous suspicion that such

cases would primarily consist of AT heterozygotes has not

proven to be correct.2 It is not known what proportion of RHS is

due to the AT mutation, but including the AT study in the analysis

would allow family members to be advised if they are also at risk

of RHS. Perhaps testing for RHS will eventually lead to the

screening of all individuals referred for radical RT to identify

those at risk of having an unusually severe reaction. This could

enable their RT to be tailored accordingly or avoided altogether.

Given the potential for fatal complications to occur (as in

case 1), conventional doses of radical RT should not be given in

the presence of RHS.

Late effects of combined cancer treatment can be difficult to

define and diagnose and are often incorrectly attributed to the

RT component because its late effects are so diverse. They can

be severely symptomatic or disabling, and the lack of a

convincing diagnosis agreed upon by the various specialists

contributing to the treatment can be dissatisfying and confusing

for the patient. Detailed assessment, including a search for

RHS, would seem to be worthwhile in helping to overcome

some of these problems. If RHS is demonstrated, a specific

diagnosis can be made with more certainty, and there may be

treatment available for it. Alternatively, the exclusion of RHS

might make other diagnoses more probable, such as post-

surgical effects.

Radiation myelopathy is a well-recognized,3,4 rare com-

plication of RT. It is even more rare for doses < 50 Gy in 25

fractions (at approximately 0.2%) and the reporting of such

cases has been encouraged.5 It seems likely that patients

suffering RM at doses lower than this have RHS, and this is

documented in at least one prior case.6 Unless there is testing

for RHS in such patients, the cause for RM might be attributed

to other factors such as high-dose chemotherapy.7 Case 1

reminds the clinician that there is a risk of RM even when the

spinal cord dose is kept within conventional tolerance limits,

and patients should be routinely warned about it. Patients who

suffer RM may have RHS and clinicians should be encouraged

to arrange testing for them.

A role for surgery in the management of RM is not yet

reported, nor are the findings at operation as reported here. In

the present case a therapeutic benefit from the procedure was

not clearly demonstrable, although it did at least serve to

confirm the presence of necrotic tissue consistent with RM.

Surgery might be avoided by performing RHS testing on

patients suffering RM. When a raised RHS level is associated

334 D CHRISTIE ET AL.

with typical MRI findings the diagnosis would be established.

Case 1 might also serve to remind clinicians of the need to

select lung cancer patients for postoperative RT carefully.

Further study into the value of RT in this setting is warranted. A

recent meta-analysis of the existing randomized trials indicated

that there was a significant survival disadvantage associated

with receiving it;8 but the meta-analysis included many patients

treated with higher-than-conventional doses, less precise

planning, cobalt equipment and with a relatively low initial risk of

local recurrence by virtue of having very early (T1N0) disease.

Although the treatment is now much more refined, a suitable

method of selecting patients who are at a high risk of local

recurrence has not yet been determined. In the meantime it

should be reserved for those with adverse prognostic features

such as involved margins or positive mediastinal nodes.

Regarding patient 2, her pelvic fibrosis was an uncommon

event and has not been associated with RHS so far. The clinical

and radiological features of the case were very non-specific,

and the aetiology of her symptoms could not have been

determined without the ICA result. Without it they could

otherwise have been attributed to the effects of her previous

surgery or an occult recurrence. The demonstration of RHS

enabled treatment aimed at relieving the late effects of

radiotherapy to be initiated. The use of HBO in this setting is

unproven but it has a reasonable track record in the treatment

of other late pelvic radiation effects9 and was thought to be

worthwhile. In order to justify the effort and expense of a course

of HBO therapy, a reasonable likelihood that the problems were

related to previous RT had to be determined and was provided

by the ICA result.

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