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Summary of Recommendations
Presentation and Initial Management
1. Patients presenting with a swelling in the scrotum
should be examined carefully and an attempt
made to distinguish between lumps arising from
the body of the testis and other intrascrotal
swellings. Grade C (p. S180)
2. Those patients suspected of harbouring a testi-
cular malignancy, ie a lump in the testis, doubtful
epididymo-orchitis, or orchitis not resolving
within two weeks, should be referred urgently
for urological assessment. Grade C. (p. S180)
3. Any patients suspected of having a testicular
malignancy should be seen urgently (within two
weeks) by a specialist. Grade C. (p. S180)
4. Education aimed at young men to inform them of
the disease and its curability should be supported.
Grade C (p. S180)
Primary Treatment
5. Preoperative investigations should include serum
LDH, AFP and HCG and a chest x-ray. Grade B
(p. S181)
6. Inguinal orchidectomy should be performed.
Grade C (p. S181)
7. All patients should be advised of the possibility
of receiving a prosthesis. Grade C (p. S181)
8. When appropriate, sperm storage should be
offered to men who may require chemotherapy,
radiotherapy or biopsy of the contralateral testis.
Grade C (p. S182)
9. Following conrmation of a germ cell tumour, all
patients should be referred to a specialist centre
for the management of testicular tumours andseen by an oncologist within 12 weeks. Grade B
(p. S182)
Management of the Contralateral Testis
10. A testicular biopsy should be considered in
patients at high risk of CIS and the subsequent
management of this condition should be in a
specialist oncology centre. Grade C (p. S183)
11. In view of the difculties in biopsy interpretation,
pathological review at a specialist centre is
recommended. Grade C (p. S183)
12. Contralateral testicular biopsy should only be
considered either before chemotherapy or any
secondary treatment or at least 2 years after
radiotherapy or chemotherapy have been com-
pleted. Grade C (p. S183)
13. Parafn sections should be stained routinely with
haematoxylin and eosin. Grade C (p. S183)
14. Comment should be made on the presence or
absence of CIS, the degree of spermatogenesis
and evidence of atrophy of seminiferous tubules.
Grade C (p. S183)
15. Immunocytochemical assessment of PlAP may
be helpful in a minority of cases. Grade C
(p. S183)
16. Patients with biopsy-proven carcinoma in situ of
the contralateral testis should be offered irradia-
tion of the testis (dose: 20 Gray in 10 fractions
over 2 weeks) to prevent progression to invasive
disease. Grade C (p. S184)
Pathology of Testicular Germ Cell Tumours17. The pathology should be reviewed by specialist
pathologists at the referral treatment centre.
Grade B (p. S186)
18. The presence or absence of blood or lymphatic
vascular invasion should be specied. Grade B
(p. S187)
Initial Investigations and Clinical Staging
19. Serial measurement of serum AFP and HCG is
essential for the follow up of patients with
teratoma. Grade B (p. S188)
20. Marker levels together with imaging techniques
should be used to allocate a prognostic group in
patients with metastatic disease. Grade B
(p. S189)
21. CT scanning of the thorax, abdomen and pelvis is
an essential part of the staging of all germ cell
cancers. Grade B (p. S189)
22. All CT scans should be reviewed by a radiologist
experienced in the interpretation of germ cell
tumour patients. Grade C (p. S189)
23. All staging should be completed and reviewed no
later than 3 weeks after diagnostic surgery. Grade
C (p. S190)
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Management of Stage I Seminoma
24. A policy of surveillance for patients with stage I
`pure' seminoma is not recommended routinely
but may be considered in rare instances where
radiation has previously been given or in patients
who are medically or mentally unable to tolerate
treatment. In such cases prolonged follow up is
necessary. Grade B (p. S191)
25. Adjuvant radiotherapy (dose: 30 Gray in 15
fractions) is currently recommended for stage I
seminoma in most cases. Grade B (p. S191)26. Stage I seminoma of the testis, where there are no
risk factors for pelvic nodal disease should,
following inguinal orchidectomy, should be
managed by prophylactic para-aortic node irra-
diation with parallel opposed elds, extending
from the disc space between dorsal verebrae 10
and 11 to the lower border of lumbar vertebra 5,
contralateral border at the transverse processes of
the lumbar vertebrae and ipsilateral border
through the renal pelvis. A dose of 30 Gray in
15 fractions is current standard practice. Grade A
(p. S191)
27. Stage I seminoma of the testis, where there are
risk factors for pelvic nodal disease following
inguinal orchidectomy, should be managed by
prophylactic paro-aortic node irradiation with
parallel opposed elds, extended to include
ipsilateral pelvic nodes. Grade B (p. S192)
Management of Stage I Teratoma
28. Patients with stage I teratoma or mixed semi-
noma/teratoma of the testis, particularly those
with no high risk features, should be managed by
surveillance following inguinal orchidectomy
Grade B (p. S192)29. Patients on surveillance should be seen in a
designated clinic following a strict protocol.
Grade C (p. S192)
30. CT scans of the thorax and abdomen should
routinely be performed as part of the follow up of
patients with germ cell tumours. Grade B
(p. S192)
31. A pelvic CT scan is only indicated where there
are known risk factors for pelvic disease. Grade B
(p. S193)
32. Adjuvant chemotherapy should be offered to
patients with stage I teratoma or mixed semi-noma/teratoma of testis following inguinal
orchidectomy if high risk features are present
(blood vessel and/or lymphatic invasion) or if the
patient is unable or unwilling to comply with a
policy of surveillance. Grade B (p. S193)
33. Two courses of BEP chemotherapy should be
given (etoposide dose 360mg/m2 per course)
Grade B (p. S193)
Management of Metastatic Seminoma
34. Radiation therapy to para-aortic and ipsilateral
pelvic lymph nodes (``dog leg'') is recommended
for the treatment of stage IIA metastatic
seminoma. Grade B (p. S194)
35. For stage IIB seminoma radiotherapy (dose: 30-
35 Gray over 15-17 fractions) or chemotherapy
are recommended as initial treatment. Grade B
(p. S194)
36. For patients with stage IIC and IID seminoma,
chemotherapy is the recommended initial treat-
ment. Grade B (p. S194)
37. Where combination chemotherapy is contraindi-
cated, radiotherapy for stage IIC disease may bean acceptable alternative. Grade C (p. S194)
38. Initial cisplatin-containing chemotherapy is re-
commended for advanced seminoma. Grade B
(p. S195)
39. Chemotherapy is recommended for patients with
stage III and IV disease and should consist of
cisplatin and etoposide. There is no evidence that
bleomycin adds to the efcacy of treatment.
Grade C (p. S195)
40. Carboplatin could be used as an alternative to
cisplatin in exceptional circumstances. Grade A
(p. S195)
Management of Metastatic Teratoma
41. Chemotherapy should only be given in a
specialist centre and overseen by a clinician
experienced in the management of germ cell
tumours. Grade B (p. S195)
42. Three cyles of BEP (etoposide dose 500 mg/m2
per course) is standard therapy for good
prognosis disease. Grade A (p. S196)
43. Under normal circumstances, weekly bleomycin
(30,000 IU) should be given to a total dose of
270,000 IU (equivalent to 270 mg/m2). Grade A
(p. S196)
44. The maximum dose of bleomycin should not
normally exceed 270,000 International Units (270
mg) in patients with good prognosis disease.
Grade B (p. S196)
45. For intermediate/poor prognosis patients no
treatment has been shown to be better than 4
cycles of BEP with etoposide at 500 mg/m2 per
course as standard therapy. Grade A (p. S196)
46. Patients with intermediate or poor prognosis
disease should be treated in specialist centres
and where possible should be entered into well-
designed multicentre studies to dene the besttreatment for this group of patients. Grade C
(p. S196)
47. Filgrastim or other growth factors are not
necessary as part of routine BEP chemotherapy.
Grade B (p. S197)
Treatment of Residual Masses After Chemotherapy
48. Patients with teratoma who have residual masses
(> 1 cm) after chemotherapy and whose markers
have normalised should be treated by complete
excision. Grade B (p. S198)
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49. Post chemotherapy surgery for metastatic terato-
ma should only be performed in a specialist
centre. Grade B (p. S198)
50. Further chemotherapy may be considered where
there has been incomplete excision and pathology
conrms viable germ cell cancer in the resected
specimen. Grade C (p. S198)
51. In patients with metastatic seminoma and residual
masses a policy of observation with CT scans
performed 6-monthly until complete remission or
disease stabilisation is recommended. Biopsyshould be considered in patients where large
residual masses persist but is recommended
where masses increase in size. Grade B (p. S199)
Treatment of Relapsed Disease
52. Patients with relapsed disease should be referred
to a specialist centre to be considered for entry
into well-designed clinical trials. Grade C
(p. S200)
53. Surgery should be considered the mainstay of
treatment for late relapse. Grade C (p. S200)
Central Nervous System (CNS) Metastases
54. Initial presentation with brain metastases or
sanctuary site CNS relapse should be treated
with curative intent. Patients with progressive
systemic and CNS disease following chemother-
apy generally have a poor prognosis. Grade C
(p. S201)55. Initial urgent resection of operable lesions should
be considered. Grade C (p. S201)
56. Radiotherapy has a role in the relapsed patient
with CNS disease. Grade C. (p. S201)
Nursing Care
57. Specialist nurse involvement is recommended at
all stages of management. Grade C (p. S202)
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Section 1: Scope of the Guideline Document
1.1 Scope
Testicular germ cell tumours are relatively rare,
comprising 1% of adult male cancers with a lifetime
risk of 1/450 in the United Kingdom. In 1992 there
were 1382 cases in England and Wales [1]. This is,
however, the most common cancer of young men and
the incidence is rising rapidly. As a result of thesefeatures of this condition it has a highly signicant
socio-economic impact. Fortunately major advances
have occurred in the management of this disease such
that anticipated cure rates exceed 90%.
Treatments for this disease are evolving rapidly and
vary from intensive `surveillance' for stage 1
teratoma (nonseminomatous germ cell tumours:
NSGCT) or radiotherapy for the early stages of
seminoma, to intensive chemotherapy followed by
complex surgery for advanced cases of teratoma.
The investigation and treatment of this disease can
therefore be costly in terms of human and economic
resources. The toxicity of therapy is signicant, with
treatment related deaths and long-term side effects
being well-documented. Potential effects on employ-
ment and fertility are of particular importance in this
age group.
1.2 Development
This guideline has been developed by the Scottish
Intercollegiate Guidelines Network (SIGN) Guideline
Development Group with the participation of The
Royal College of Radiologists' Clinical Oncology
Information Network (COIN) Testicular Cancer
Specialty Working Group (SWG) (see Appendix 1
for full membership of both groups)). The SIGN
group undertook a systematic literature review using
the Cochrane Library, Medline, Healthstar and the
Internet and drafted its guideline using evidence-
based literature and SIGN's methodology [2]. The
denitions of the types of evidence and the grading of
recommendations used in this guideline originate
from the US Agency for Health Care Policy and
Research [3].
A national open meeting was held in Scotland
involving a large number of health care professionals
from throughout Great Britain together with patient
representatives. At this meeting a draft document was
discussed. Feedback from this meeting was incorpo-
rated and the completed guideline was submitted to
SIGN before circulation to various health service
organisations. Comments were compiled and dis-
cussed by the group and the SIGN Editorial Board
reviewed the guideline prior to publication in
September 1998 [4].
The COIN Specialty Working Group rst met in
June 1997 and participated in the work of rening and
amending the SIGN guideline; the genesis of COIN is
described elsewhere [5,6]. SIGN agreed that COIN
could use its guideline as a source document for use
elsewhere in the UK. The COIN SWG met in
September 1998 and April 1999 to amend and
update the SIGN guideline before circulating it for
critical appraisal. It was circulated to all the Clinical
Oncology Home Fellows and Members of The RoyalCollege of Radiologists and to all the members of the
Association of Cancer Physicians in the UK. Each
individual received a structured appraisal form
requesting evidence-based comments. The Testicular
Cancer Working Group reviewed these comments and
appropriate changes were made. The recommenda-
tions made in this version represent the views of the
COIN group which acknowledges the work of the
SIGN Guideline Development Group. The current
guideline was nalised in January 2000; it was
approved by the Faculty Board for Clinical Oncology
on February 18 2000 and the Council of The RoyalCollege of Radiologists on March 17 2000.
1.3 Dissemination
This document will be disseminated to all Clinical
Oncology Fellows of The Royal College of Radi-
ologists in the journal Clinical Oncology and to all
Medical Oncologists; it is also planned to publish the
rst portfolio (addressing lung [7], prostate [8], breast
[9], colorectal and testicular cancer and generic
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aspects of radiotherapy [10] and chemotherapy) of
COIN Guidelines together as a single book. It will
also be available on the SIGN and RCR web sites
(www.sign.ac.uk and www.rcr.ac.uk) for download-
ing to local intranets.
1.4 Review
This document will be reviewed in 2001 with a view
to publishing a revision in 2002. Funding: the COINProject was supported by the National Health
Service Executive and the Central Health Outcomes
Development Unit. Con ict of interest: none
declared.
References
1. Ofce for National Statistics. Cancer Incidence (MD 197/1). London: ONS, 1998.
2. Scottish Intercollegiate Guidelines Network. An introduc-tion to SIGN methodology for the development of
evidence-based clinical guidelines (Publication 39).Edinburgh: SIGN, 1999.
3. US Department of Health Human Services. Agency forHealth Care Policy and Research. Acute Pain Manage-ment. Rockville (MD): The Agency; 1993. ClinicalPractice Guideline No.1. p. 107.
4. Scottish Intercollegiate Guidelines Network. Managementof adult testicular germ cell tumours (Publication 28).Edinburgh: SIGN, 1998.
5. Karp, SJ. Clinical Oncology Information Network: FromDrawing Board to Reality. Clin Oncol 1999;11:23
6. Karp, SJ. Guidance on the Creation of Evidence-LinkedGuidelines for COIN. Clinical Oncology 1999;11:28
32.7. COIN Lung Cancer Specialty Working Group. Guidelines
on the non-surgical management of lung cancer. ClinOncol 1999;11:S1S53.
8. COIN/BAUS Prostate Cancer Specialty Working Group.Guidelines on the non-surgical management of prostatecancer. Clin Oncol 1999;11:S55S88.
9. COIN Breast Cancer Specialty Working Group. Guide-lines on the non-surgical management of breast cancer.Clin Oncol 1999;11:S89S133.
10. COIN Radiotherapy Specialty Working Group. Guidelinesfor external beam radiotherapy. Clin Oncol 1999;11:S135S172.
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Section 2: Presentation and Initial Management
2.1 Presentation
General practitioners (GPs) will see a patient with a
testicular malignancy very infrequently. 8090% of
these patients present with an enlarged testicle or a
lump in the testicle and in 97% of patients a lump is
present on examination. It should be noted that a
decrease in testicular size may also occur. Pain andsymptoms suggesting inammation can cause confu-
sion but these features should not delay referral. Other
features which should heighten suspicion include a
dragging sensation, and a recent history of trauma.
Rare presentations include hydrocele and gynaeco-
mastia. Backache is present in 5% of patients but is a
very common and non-specic symptom [1]. A
history of testicular maldescent is present in 10% of
patients with testicular cancer. Recent reports have
not conrmed an association with vasectomy [2].
(Evidence level II)
Due to the rarity of a testicular malignancy and its
variable, complex and toxic treatment it is imperativethat the patient's GP and other community services be
well-informed and involved throughout treatment and
follow-up.
2.2 Referral
Patients with testicular tumours will most often
present with a testicular lump. Abnormal masses in
the epididymis are a common problem referred for
specialist assessment but these are unlikely to betesticular tumours. Testicular cancers can spread
rapidly and urgent referral of suspected cases is
indicated [3].
Recommendation 1 GRADE C
Patients presenting with a swelling in the scrotum
should be examined carefully and an attempt
made to distinguish between lumps arising from
the body of the testis and other intrascrotal
swellings. An ultrasound (performed within two
weeks) will be helpful in making this distinction.
Recommendation 2 GRADE C
Those patients suspected of harbouring a testi-
cular malignancy, ie a lump in the testis, doubtful
epididymo-orchitis or orchitis not resolving
within two weeks, should be referred urgently
for urological assessment.
Recommendation 3 GRADE C
Any patients suspected of having a testicular
malignancy should be seen urgently (within two
weeks) by a specialist.
2.3 Patient Awareness
There is evidence to suggest that delay in presentation
is more of a problem than delay in referral and this
has prompted some authors to suggest that a public
education campaign might be helpful [4].Though there is no evidence to recommend routine
testicular self-examination, men should be aware of
how their testicles feel. Knowledge of early signs and
symptoms of testicular cancer, i.e. a change in size or
shape of the testicle or a feeling of heaviness in the
scrotum, should be common knowledge in all men but
especially those with a history of testicular mal-
descent or family history of testicular cancer.
Recommendation 4 GRADE C
Education aimed at young men to inform them of
the disease and its curability should be supported.
References
1. Cantwell BMJ, Macdonald I, Campbell S. Millword MJ andRoberts JT. Back pain delaying diagnosis of metastatictesticular tumours (letter). Lancet 1989;2:739740.
2. Hewitt G, Logan CJ, Curry RC. Does vasectomy causetesticular cancer? Br J Urol 1993;71:607608.
3. Chilvers C, Saunders M, Bliss J, Nicholls J, Horwich A.inuence of delay on prognosis in testicular teratoma. Br JCancer 1989;59:126128.
4. Thornhill JA, Conroy RM, Kelly DG, Walsh A, Fennelly JJ,Fitzpatrick JM. Public awareness of testicular cancer andthe value of self-examination. Br Med J 1986;293:480481.
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Section 3: Primary Treatment
3.1 Preoperative Investigation
Blood should be taken for assay of the tumour
markers alpha fetoprotein (AFP), human chorionic
gonadotropin (HCG) and lactate dehydrogenase
(LDH) before operation. One or more serum markers
are raised in 75% of cases of teratoma and 35% of
cases of seminoma and measurement is necessary forstaging and follow up [1]. A chest x-ray should be
performed. Other staging investigations can be
deferred until after orchidectomy and should be
arranged in consultation with a specialist centre.
Recommendation 5 GRADE B
Preoperative investigations should include LDH,
AFP and HCG, and a chest x-ray.
Patients who are ill with high markers or widespread
metastases should be referred for immediate chemo-
therapy without having an orchidectomy. In suchcases, when examination or ultrasound scan demon-
strates that there is a testicular tumour, or gross
elevation of HCG and AFP are present, orchidectomy
should be delayed until after the treatment of
metastatic disease.
3.2 Primary Surgical Management
Inguinal Approach
The patient should be referred to a urologist. The
preferred surgical technique is orchidectomy throughan inguinal incision with division of the cord at the
internal inguinal ring. Where there is doubt about the
diagnosis, an inguinal approach should be used.
Recommendation 6 GRADE C
Inguinal orchidectomy should be performed.
Procedure: The testis should be delivered out through
the wound and the cord should be occluded using
non-crushing clamps. The testis is then separated
from the wound with towels and inspected. On the
rare occasions when the diagnosis is in doubt,
representative samples may be sent for frozen section,
if necessary bivalving the testis to inspect the testis
and obtain biopsies. In the event of malignancy not
being conrmed, the testis is reconstituted and
replaced in the scrotum. It must be explained
preoperatively that this procedure is being done to
exclude any cancer in a situation where there is a high
index of suspicion and that following such a bivalving
procedure in those situations where malignancy is not
conrmed and where the testis is replaced there may
be moderate to severe testicular damage.
Biopsy of the contralateral testis should be
considered in certain cases ( see Section 4).
Scrotal Exploration
From time to time a scrotal exploration is performed
for what is thought to be an inammatory non
malignant condition but cancer is found and it isnecessary to proceed to orchidectomy. In this
situation there is no need to perform secondary
wound excision and the postoperative management
should continue in exactly the same way as if the
operation had been performed through the conven-
tional inguinal approach [2].
Testicular Prostheses
There is evidence that loss of a testicle may result in
signicant psychological morbidity [3].
Recommendation 7 GRADE C
All patients should be advised of the possibility of
receiving a prosthesis.
For those who wish a prosthesis, written consent for
placement of a prosthesis should be obtained at the
time of consent for the orchidectomy. The prosthesis
is best and most easily placed at the time of the
primary orchidectomy. In view of the concerns about
silicon gel lled breast prostheses the newer `solid'
silicon prostheses should be used.
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3.3 Fertility Issues
A signicant proportion of men with testicular
tumours will have low sperm counts before orchi-
dectomy, which often worsens following removal of
the malignant testis [4]. In addition, both chemother-
apy and radiotherapy may result in infertility.
Consideration should therefore be given to under-
taking semen analysis and sperm storage.
Sperm storage should be undertaken in one of the
UK centres which have a storage licence from theHuman Fertilisation and Embryology Authority
(HFEA). It is illegal to store sperm samples
anywhere else. HFEA approved departments are
required to provide a counsellor familiar with current
legislation relating to genetic storage and the HFEA
consent form required for sperm storage. The
ideal timing of sperm storage will vary: not all
patients undergoing orchidectomy will require
further treatment. Where a biopsy of the contral-
ateral testis is being considered to exclude CIS, and
where the remaining testis is small, storage prior to
surgery (orchidectomy biopsy) should be con-sidered.
Recommendation 8 GRADE C
When appropriate, sperm storage should be
offered to men who may require chemotherapy,
radiotherapy or biopsy of contralateral testis.
3.4 Referral
There is evidence that treatment of testicular cancer in
a specialist centre is associated with improved results
[5,6].
Recommendation 9 GRADE B
Following conrmation of a germ cell tumour, all
patients should be referred to a specialist centre
for the management of testicular tumours and
seen by an oncologist within 1-2 weeks.
References
1. Rustin GJ, Vogelzang NJ, Sleiffer DT, Nisselbaum JN.Consensus statement on circulating tumour markers andstaging patients with germ cell tumours. Prog Clin Biol Res1990;357:277284.
2. Harding M, Paul J, Kaye SB. Does delayed diagnosis orscrotal incision affect outcome for men with non-seminomatous germ cell tumours? Br J Urol1995;76:491494.
3. Tinkler SD, Howard GC, Kerr GR. Sexual morbidityfollowing radiotherapy for germ cell tumours of the testis.
Radiother Oncol 1992;25:207212.4. Petersen PM, Skakebaek NE, Rrth M, Giwecman A.
Semen quality and reproductive hormones before and afterorchidectomy in men with testicular cancer. J Urol 1999161:822826.
5. Howard GCW, Clarke K, Elia MH et al. Scottish NationalAudit of current patterns of management for patients withtesticular and non-seminatomous germ cell cancers. Br JCancer. 1995;72:13031306.
6. Collette L, Sylvester RJ, Stenning SP et al. Does thetreating institution have an impact on the overall and failurefree survival of patients with `poor prognosis' metastaticnon-seminomatous germ cell tumours. J Natl Cancer Inst1999;91:839846.
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Section 4: Management of the Contralateral Testis
4.1 Carcinoma In Situ
All germ cell tumours with the exceptions of
spermatocytic seminoma arise from carcinoma in
situ (intratubular germ cell neoplasia) [1] which is
often demonstrable in the seminiferous tubules of the
testis surrounding the tumour. Approximately 5% of
men with testicular cancer have carcinoma in situ(CIS) of the opposite testicle [2]. Carcinoma in situ is
thought to progress to invasive GCT in 50100% of
cases and therapy should be considered [3]. Treatment
with systemic chemotherapy will reverse the histolo-
gical changes of CIS. Current evidence suggests,
however, that relapse occurs some years later with a
consequent risk of cancer [4]. Late postchemotherapy
biopsy should be considered in cases considered at
high risk.
A high incidence of carcinoma in situ (35%) is
found in young (530 years) patients where the
contralateral testis is small (5
16 ml) [5]. These patients constitute a high risk group in whom it is
appropriate to recommend biopsy at initial presenta-
tion. (Evidence level III)
Recommendation 10 GRADE C
A testicular biopsy should be considered in
patients at high risk of CIS and the subsequent
management of this condition should be in a
specialist oncology centre.
Recommendation 11 GRADE CIn view of the difculties in biopsy interpretation,
pathological review at a specialist centre is
recommended.
Recommendation 12 GRADE C
Contralateral testicular biopsy should only be
considered either before chemotherapy or any
secondary treatment or at least 2 years after
radiotherapy or chemotherapy have been com-
pleted.
4.2 Pathological Examination ofBiopsies from the ContralateralTestis
Suggested Procedure: A contralateral biopsy should
be 0.3-1.0cm in maximum dimension and should be
removed atraumatically without squeezing the tissueor handling it with forceps. Open biopsy is considered
the normal procedure but needle biopsy may be
adequate. The biopsy should be placed in Bouin's
xative for a minimum of 2 hours (smaller biopsies)
and a maximum of 24 hours. Further xation in
Bouin's uid results in poor histological sections.
Occasionally, the immunocytochemical assessment of
placental alkaline phosphatase (present in CIS cells)
is helpful in a biopsy showing equivocal morphology.
As demonstration of placental alkaline phosphatase
(PlAP) is more reliable on formalin than Bouin's
xed tissue, ideally two biopsies should be taken one
each for xation in Bouin's and formalin. In situations
where only one biopsy is taken, Bouin's xation takes
precedence.
Recommendation 13 GRADE C
Parafn sections should be stained routinely with
haematoxylin and eosin.
Recommendation 14 GRADE C
Comment should be made on the presence or
absence of CIS, the degree of spermatogenesis,
and evidence of atrophy of seminiferous tubules.
Recommendation 15 GRADE C
Immunocytochemical assessment of PlAP may be
helpful in a minority of cases.
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4.3 Management of CIS of theContralateral Testis
CIS is often associated with low sperm counts or
azoospermia and poor Leydig cell function, with
elevation of LH and reduction of testosterone levels
[6]. Testicular irradiation will permanently reverse
CIS but will cause permanent infertility and an
increased risk of hypogonadism. Patients with CIS
should be warned of the markedly increased risk ofsubsequent malignancy if no treatment is given.
Where relevant, sperm should be obtained for
banking. Patients may then be treated with irradiation,
orchidectomy (where the testis is hormonally non-
functional) or initial close observation if an attempt at
fathering a child is desired. Patients should be advised
of the risk of subsequent hypogonadism after
irradiation
Recommendation 16 GRADE C
Patients with biopsy-proven carcinoma in situ of
the contralateral testis should be offered irradia-
tion of the testis (dose: 20 Gray in 10 fractionsover 2 weeks) to prevent progression to invasive
disease.
Systemic chemotherapy is an inadequate treatment for
CIS as late relapse has been described [4].
References
1. Manivel JC, Reinberg Y, Niehans GA, Fraley E.Intratubular germ cell neoplasia in testicular teratomas
and epidermoid cysts:correlation with prognosis and possible biologic signicance. Cancer 1989;64:715720.
2. Dieckman KP and Loy V. Prevalence of contralateraltesticular intra-epithelial neoplasia in patients with testi-cular germ cell neoplasms. J Clin Oncol 1996;14:31263132.
3. Von der Maase H, Rrth M, Walbom-Jrgensen SW et al.Carcinoma in situ of contralateral testis in patients withtesticular germ cell cancer:study of 27 cases in 500 patients.Br Med J 1986;293:13981401.
4. Christensen TB, Daugaard G, Gertsen PF and Von derMaase H. Effect of chemotherapy on carcinoma in situ ofthe testis. Ann Oncol 1998;9:657660.
5. Harland SJ, Cook PA, Fossa SD et al. Intratubular germ cellneoplasia of the contralateral testis in testicular cancer:de-
ning a high risk group. J Urol 1998;160:13531357.6. Petersen PM, Giwercman A, Hansen SW et al. Impaired
testicular function in patients with carcinoma in situ of thetestis. J Clin Oncol 1999;17:173179.
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Section 5: Pathology of Testicular Germ Cell Tumours
5.1 Classication
Testicular germ cell tumours (GCTs) can be
subdivided into seminoma and teratoma (non-semi-
nomatous germ cell tumour (NSCGCT)); both must
always be considered as malignant neoplasms [1,2].
Combined tumours are not uncommon [3]. Semino-
mas consist of sheets and cords of relatively uniformcells which resemble primitive germ cells whereas
teratomas exhibit a wide variety of appearances
reecting the potential of the tumour stem cell to
differentiate along embryonic and extra-embryonic
lines analogous to the fertilised ovum. The main
classications in common use are those of the British
Testicular Tumour Panel and Registry (TTP&R) [1]
and the World Health Organisation (WHO) [2].
Pathology reports should include both the TTP&R
and the WHO terminologies (see Table 1).
Teratomas and seminomas have different clinical
outcomes and require different clinical management.
All teratomas including teratoma differentiated(mature teratoma), with the exception of epidermoid
cyst, are capable of metastasising [4] and must be
considered malignant.
Table 1. Comparison of British (TTP&R) and WHO Classica-tions
British WHO
Seminoma SeminomaSpermatocytic seminoma Spermatocytic seminomaTeratoma
teratoma differentiated malignant teratoma
intermediate (MTI) malignant teratomaundifferentiated (MTU)
yolk sac tumour malignant teratoma
trophoblastic
Non seminomatous germ cell tumour mature teratoma embryonal carcinoma with
teratoma (teratocarcinoma) embryonal carcinoma
yolk sac tumour choriocarcinoma
5.2 Pathological Examination ofOrchidectomy Specimens
After xation, samples should be taken from the
resection margin of the cord, middle cord, lower cord,
and from the interface between testis and rete testis.
Seminoma macroscopically is usually pale, uniform,
solid and well demarcated, although large areas of
yellow necrosis may be present. Teratoma is usually
irregular, friable, variegated and dark in colour with
multiple irregular foci of haemorrhage and necrosis.
Cystic areas are frequently present. Multiple blocks of
tumour should be taken (at least 1 block per cm of
maximum dimension of the tumour) including
samples of the main tumour and any satellite lesions.
Haemorrhagic foci are sampled because such areas
often contain trophoblastic tissue which has a higher
incidence of vascular spread. The periphery of the
tumour is more likely to contain viable tissue than the
centre which may be necrotic. The surrounding testis
should be sampled to detect the presence of
carcinoma in situ (CIS).
The orchidectomy specimen should be placed in an
adequate volume (at least 5:1) of formaldehyde
xative. The specimen should be bivalved through
the rete testis and epididymis either in theatre or assoon as it arrives in the pathology department in order
to allow proper xation. At least 1 block of tumour
should be taken for each cm of maximum tumour
dimension and blocks should be taken from the
surrounding testis, the rete testis and adjacent
epididymis mid portion of cord and the resection
margin of cord.
5.3 Histological Examination of
Testicular TumoursThe histology report should describe all the different
elements present together with an assessment of the
proportion of each, and should indicate if there is
involvement of tunica albuginea, rete testis or
spermatic cord. The nal report should give both
the TTP&R and WHO classications (see Table 1).
The incidence of relapse of clinical stage I
teratomas after orchidectomy is related to the
presence of blood or lymphatic (ie vascular) invasion
and a detailed examination should be made to detect
this [5].
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Recommendation 17 GRADE B
The pathology should be reviewed by a specialist
pathologist at the treatment centre.
Seminoma
Seminomas may be divided into classical and
anaplastic, though it is not clear that this distinction
is important. Spermatocytic seminoma is a different
non-germ cell tumour [24].Classical seminomas contain large polygonal cells
with clear cytoplasm and distinct cell boundaries.
There is little cellular pleomorphism and mitotic
gures are not frequent. There is usually a prominent
lymphocytic inltrate in the stroma and large areas of
necrosis may occur. The tumour is usually well
demarcated from the surrounding testis. Anaplastic
seminomas show greater cellular pleomorphism and
more mitotic gures. The lymphocytic inltrate is less
prominent and there is often a more inltrative
border. The clinical stage of the seminoma is more
important than the subdivision into anaplastic and
classical types. Seminomas may contain synctiotro-
phoblastic cells which secrete HCG, but seminomas
do not produce AFP. Seminomas usually stain for
PlAP but not for AFP or for cytokeratin.
Spermatocytic seminoma is a separate entity from
classical or anaplastic seminoma [24]. It consists of
solid sheets of cells resembling spermatocytes and
shows prominent cellular pleomorphism and mitiotic
activity. It does not have a lymphocytic inltrate in
the stroma and is not associated with CIS. it does not
stain for PlAP, HCG, AFP, cytokeratin or lymphocyte
markers. Spermatocytic seminoma does not metasta-
sise, and no further therapy is indicated afterorchidectomy.
Teratoma (Non-seminomatous GermCell Tumour (NSGCT))
Teratomas may occasionally consist entirely of well-
differentiated tissues and structures and are then
classied as teratoma differentiated. These are
malignant neoplasms when they arise in post pubertal
testes [4]. Malignant teratoma intermediate (MTI)
contains a mixture of differentiated structures and
undifferentiated malignant tissue in any proportion,
whereas MTU (malignant teratoma undifferentiated)
contains only undifferentiated malignant tissue.
Teratomas may also contain embryonic structures
such as yolk sac elements (yolk sac tumour) and
trophoblastic elements (malignant teratoma tropho-
blastic, or choriocarcinoma).
The WHO classication uses `teratoma' only if
differentiated structures are present, and a mature
teratoma is equivalent to TD in the British classica-
tion. Embryonal carcinoma is equivalent to MTU, and
embryonal carcinoma with teratoma is equivalent to
MTI. All the components which are recognised within
a teratoma should be mentioned in the pathology
report. Teratomas often stain for cytokeratin, AFP,
HCG and PlAP in a patchy distribution depending on
the components present within the tumour. Stains for
AFP and HCG should not be considered diagnostic of
yolk sac and trophoblastic differentiation, respec-
tively.
An epidermoid cyst of the testis is sometimes
considered to be a monodermal teratoma [7] but
should be treated as a benign condition not requiring
further therapy.
5.4 Pathological Tumour Staging
The pathology report should describe the extent of
local spread of the tumour so that the T category can
be assessed. The pathological staging of the tumour
(pT category) follows the 1997 UICC TNM
classication [8] (see Table 2).
Table 2. Pathological tumour staging categories
pT Primary tumour.
pTX Primary tumour cannot be assessed (if no radical
orchidectomy is performed TX is used).
pT0 No evidence of primary tumour (eg histological scar in
testis).
pTis Intratubular germ cell neoplasia (carcinoma in situ).
pT1 Tumour limited to testis and epidymis with no vascular/
lymphatic invasion; tumour may invade tunica albuginea
but not tunica vaginalis.
pT2 Tumour limited to testis and epididymis with vascular/
lymphatic invasion, or tumour extending through tunica
albuginea with involvement of tunica vaginalis.
pT3 Tumour invades spermatic cord with or without vascular/
lymphatic invasion.
pT4 Tumour invades scrotum with or without vascular/
lymphatic invasion.
5.5 Review of Pathology
Germ cell tumours of the testis are not common, and
many pathologists do not see a sufcient number of
cases to be fully competent in giving a comprehensive
report, which is essential for further clinical manage-
ment. The patient should be referred to a specialised
treatment centre where the pathology of the tumour
should be reviewed by a pathologist with a special
interest and experience in germ cell tumours [9].
5.6 The Pathology Report
The pathology report should include a comprehensive
macroscopic and microscopic description of the
orchidectomy specimen. The macroscopic description
should state if the specimen was received intact or
bivalved. The length of cord and the dimensions of
the testis and epididymis should be recorded. The
size, number and shape of any tumour masses should
be given together with a description of the appearance
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of the cut surface, the extent of replacement of the
testis, and macroscopic evidence of extension into
rete testis, epididymis, tunica vaginalis, vaginal sac or
spermatic cord. The number and site of blocks taken
for histology should be stated. The microscopic report
should describe all tumour components present giving
both the TTP&R (British) and WHO nomenclature. It
is important to comment on the presence or absence
of invasion of blood vessels or lymphatic vessels. The
condition of the residual testicular tissue should be
described paying particular attention to the presenceor absence of carcinoma in situ. The nal diagnosis
should be summarised at the end of the report giving
TTP&R and WHO terminology. The pathology report
should be issued without delay in order to facilitate
rapid decisions on future clinical management. If the
clinical and pathological diagnoses are at variance,
the pathologist should inform the clinician immedi-
ately by telephone. The pathology report should be
issued without delay in order to facilitate a rapid
decision on future clinical management, especially if
the clinical and pathological diagnoses are at
variance.
Recommendation 18 GRADE B
The presence or absence of blood or lymphatic
vascular invasion should be specied.
All types of tumour identied, together with an
assessment of their proportion, should be recorded in
the pathology report using primarily the British
(TTP&R) nomenclature with the equivalent WHO
nomenclature added in parenthesis. The extent of
tumour invasion should be specied with particular
reference to involvement of rete testis, tunica
albuginea, cord and resection margins. The pre-sence/absence of vascular invasion should be noted.
The UICC pathological stage (pT category) should be
given.
5.7 Pathology of Residual TumourMasses
After chemotherapy for metastatic malignant terato-
ma residual masses are common and should be
surgically excised and examined pathologically.
Persistent differentiated (mature) teratoma (TD)
has potential for continued growth and may be the site
of relapse or secondary (non-germ cell) malignancy.
Complete resection of residual masses should there-
fore be performed. The histological features of
resected residual masses are important in determining
further management. If only brosis, necrosis, and
completely resected TD are found, the patient is likely
to be cured without further treatment being required.
However, if residual masses after chemotherapy
contain undifferentiated (malignant) teratoma, or aspindle cell sarcomatous or other malignant tumour,
this indicates tumour resistance to drug treatment and
a lesser chance of cure [10]. Resected residual masses
should be adequately sampled in order to look for
residual viable tumour.
Particular mention should be made in the report of
the presence or absence of differentiated teratoma,
undifferentiated or malignant teratoma, or so-called
non-germ cell tumour (sarcomatous or other) ele-
ments. The adequacy of excision should be stated.
References
1. Pugh RC (editor). Pathology of the testis. Oxford:Blackwell Scientic. 1976.
2. Mosto FK, Sesterhenn I, Sobin LH. Histological typingof testis tumours. 2nd ed. Berlin: Springer-Verlag, 1998.
3. Thomas R, Dearnaley D, Nicholls J, Norman A. Ananalysis of surveillance for stage I combined teratoma/seminoma of the testis. Br J Cancer 1996;74:5962.
4. Simmonds PD, Lee AH, Theaker JM, Tung K, Smart CJ,Mead GM, Primary pure teratoma of the testis. J Urol1996;155:939942.
5. Klepp O, Olsson AM, Henrikson H et al. Prognosticfactors in clinical stage I nonseminotomous germ celltumours of the testis:Multivariate analysis of a prospective
multicentre study. J Clin Oncol 1990;8:509518.6. Skakkebaek NE, Berthelsen JG, Giwercman A, Mu ller J.Carcinoma-in-situ of the testis: possible origin fromgonocytes and precursor of all types of germ cell tumoursexcept spermatocytoma. Int J androl 1987;10:1928.
7. Reinberg Y, Manivel JC, Lerena J, Niehans G, Fraley EE.Epidermoid cyst (monodermal teratoma) of the testis. Br JUrol 1990;66:648651.
8. Sobin LH, Wittekind CH (editors). TNM classication ofmalignant tumours 5th edn. New York: Wiley, 1997.
9. Lee AHS, Mead GM, Theaker JM. The value of centralhistopathological review of testicular tumours beforetreatment. Br J Urol 1999;84:7578.
10. Stenning SP, Parkinson MP, Fisher C et al. Post-chemotherapy residual masses in germ cell tumour patients Cancer 1998 83:14091419.
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Section 6: Initial Investigations and Clinical Staging
6.1 Tumour Markers
AFP and HCG
The management of patients with germ cell cancer
has improved markedly since immunoassay techni-
ques of high sensitivity and adequate specicity have
allowed determination of serum levels of alpha-fetoprotein (AFP) and human chorionic gonadotro-
phin (HCG). These markers are good detectors of
residual malignant teratoma. However, neither marker
alone should be regarded as specic for germ cell
cancer as they may be raised with a variety of non-
germ cell tumour neoplasms. Mild elevations of AFP
can be seen after alcohol abuse, and, as a result of
chemotherapy [1], cannabis can similarly raise HCG.
However the combined accuracy and predictive value
of HCG and AFP is of a level that a decision to start,
continue, modify or resume treatment may be strongly
inuenced by the nding of rising serum levels ofeither marker.
About 70% of patients with teratoma will produce
elevated HCG and about 70% elevated AFP. One or
other value will be elevated in 75%. Serial monitoring
of AFP and HCG may enable the biological half life
to be calculated. In the absence of residual disease
after orchidectomy this is estimated as 24 hours for
the HCG and 4-6 days for AFP [2]. (Evidence level
IIb).
Recommendation 19 GRADE BSerum measurement of AFP and HCG is essential
for the follow up of patients with teratoma.
In patients with seminoma the markers are less useful:
whilst approximately 35% produce HCG, these are
often mild elevations and AFP is not produced by
pure seminoma. There are therefore no generally
applicable good serological markers for patients with
seminoma. As 25% of cases of teratoma are marker
negative it is important to measure both AFP and
HCG prior to orchidectomy. Owing to methodologi-
cal differences between laboratories, great care must
be taken in the interpretation of results as reference
ranges may vary.
LDH
Lactate dehydrogenase (LDH) is an excellent prog-
nostic indicator in patients with metastatic disease. It
is also often raised in metastatic seminoma. LDH is
not, however, sufciently specic for general applica-
tion in disease monitoring. Markedly elevated levels
may be of value in certain patients with advanced
disease who have normal AFP and HCG levels. Mild
increases in LDH during chemotherapy can be due to
hepatic insult or bone marrow recovery and reect the
lack of specicity of this marker.
PlAP
Placental alkaline phosphatase (PlAP) has been
studied, particularly in patients with seminoma butthe current evidence is that the relatively low
sensitivity (15-30%) and specicity seriously under-
mine its clinical value; its use is not recommended.
Good Practice in the Use of TumourMarkers
Serum markers (LDH, AFP and HCG) should be
performed prior to orchidectomy and within seven
days after surgery. If raised these should be monitored
weekly until they are within the reference range or
treatment starts.
6.2. Staging Systems
Once the diagnosis of a testicular germ cell tumour
has been made, staging investigations should be
performed to assess the extent of disease and to
allocate a prognostic group. In the past the most
commonly used staging system was the Royal
Marsden Hospital (RMH) system (see Table 3). For
teratoma and advanced metastatic seminoma this
classication has now been superseded by the
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Brain Scanning
Either MRI or CT scanning of the brain should be
performed where there are multiple (410) lung
metastases or an HCG 410,000 IU/l.
Other Staging Investigations
Other staging investigations such as bone scanning
may be indicated on an individual basis, particularly
in metastatic seminoma.
Recommendation 23 GRADE C
All staging should be completed and reviewed no
later than three weeks after diagnostic surgery.
References
1. Germa JR, Llanos M, Taberro JM & Mora J. Falseelevations of alpha-fetoprotein with liver dysfunction ingerm cell tumours. Cancer 1993;72:24912494.
2. Mead GM. Testis. In: Price P, Sikora K, editors. Treatmentof cancer. 3rd ed. London: Chapman & Hall, 1995.
3. International Germ Cell Collaborative Group. InternationalGerm Cell Consensus Classication: a prognostic factor- based staging system for metastatic germ cell cancers. JClin Oncol 1997;15:594603.
4. Loughrey GJ, Carrington BM , Anderson H et al. The value
of specialist oncological radiology review of cross sectionalimaging. Clin Radiol 1999;54:149154.
5. White PM, Howard GC, Best JJ, Wright AR. The role ofcomputed tomographic examination of the pelvis in themanagement of testicular germ cell tumours. Clin Radiol1997;52:124129.
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Stage I Seminoma with Risk of PelvicNode Disease
Where there has been previous inguino-scrotal
surgery, the eld should be extended to include the
ipsilateral pelvic nodes (``dog-leg''). This is also
suggested as standard radiotherapy in the manage-
ment of stage IIA or IIB pure seminoma of the testis,
i.e. with involved infra-diaphragmatic nodes of less
than 5 cm maximum size [2]. After dog-leg radio-
therapy to a dose of 30 Gray in 15 fractions for stage I
disease there is a 4% incidence of failure at distant
sites.
Recommendation 27 GRADE B
Stage I seminoma of the testis, where there are
risk factors for pelvic nodal disease following
inguinal orchidectomy, should be managed by
prophylactic para-aortic node irradiation with
parallel opposed elds extended to include
ipsilateral pelvic nodes.
In the case of orchidectomy via a scrotal incision, the
scrotum is only included in the radiotherapy elds if
there is felt to be a high risk of contamination. In
exceptional circumstances where radiotherapy is
contraindicated management is by surveillance or
carboplatin chemotherapy.
7.2 Management of Stage I
Teratoma and Mixed Seminoma/Teratoma
Surveillance
In patients with stage I teratoma or mixed seminoma/
teratoma (combined tumours of the testis) surveil-
lance has been used in order to avoid possible
treatment morbidity with adjuvant chemotherapy
and is feasible because of the high chance of cure
with chemotherapy on relapse. Studies of surveillance
show a consistent relapse rate of around 2530% [3].
The MRC surveillance study for stage I teratoma hasenabled subgroups of patients to be identied who
have a high risk of relapse on surveillance. The single
most important histological feature of high-risk
subgroups is blood vessel and/or lymphatic invasion,
with a recurrence risk of approximately 40% [4]. The
majority of patients (80%) relapse within the rst
year: 47% in abdominal nodes, 13% abdominal nodes
and lung, 17% lung and 23% marker rise only. Scrotal
interference prior to removal of the primary tumour is
not a contraindication to surveillance. ( Evidence level
IIa)
Recommendation 28 GRADE B
Patients with stage I teratoma or mixed semi-
noma/teratoma of the testis, particularly those
with no high risk features, should be managed by
surveillance following inguinal orchidectomy.
How often should Patients be followedup?
Surveillance is generally recommended for patients
without pathological risk features and who have no
social, psychological or geographic factors which
would preclude them from such a policy. The optimal
timing of a CT scan for patients on surveillance is not
known. Patients on surveillance are usually followed
up monthly for the rst year with clinical examination
and serum markers at every visit. At present chest
x-ray is performed at each visit and chest and
abdomen CT at three, six, nine and 12 months. A
current MRC randomised trial (TEO8) seeks to
determine the safest and most economical form of
follow up CT frequency. In the second year follow upshould be two-monthly with CT scans at 24 months.
Subsequent follow up should be three-monthly for the
third year, six-monthly to the fth year and annually
thereafter with clinical examination, serum markers
and chest x-ray at every visit. It is probably
reasonable to discharge the patient after 56 years.
Recommendation 29 GRADE C
Patients on surveillance should be seen in a
designated clinic following a strict protocol.
Which Body Parts should be imaged byCT on Surveillance?
All patients should have an initial CT scan of the
chest, abdomen and pelvis. Subsequently an abdom-
inal CT is performed in all cases. A chest CT is
generally performed at each visit, although there is no
rm evidence on whether this frequency of chest
scanning is necessary, or whether a CXR may sufce.
A pelvic CT may not be necessary in all cases.
Pelvic nodal disease is strongly associated with well
established risk factors, viz. previous scrotal/inguinal
surgery, invasive tumour (through tunica albuginea of
testis). If the presence of risk factors can be reliably
excluded from clinical information and the appear-
ance of a previous scan, pelvic CT can be omitted
from surveillance or reassessment [5]. Previous scans
should be available. (Evidence level III)
Recommendation 30 GRADE B
CT scans of the thorax and abdomen should
routinely be performed as part of the follow up of
patients with germ-cell tumours.
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Section 8: Management of Metastatic Disease
8.1 Management of MetastaticSeminoma
Stage II
The stage II category encompasses a wide range of
disease extent. Approximately 15% of patients fall
into this category and these are further subdividedinto A, B, C and D (Table 3) reecting the prognostic
signicance of bulk retroperitoneal disease.
Stage IIA
The data on the results of radiation therapy in the
management of IIA, i.e. nodal disease less than 2 cm
in maximum diameter, is scanty as these patients have
been included in reports of patients with tumour
masses less than 5 cm. In a recent report from Toronto
a 10% relapse was reported following radiotherapy
for stage IIA [1].
Recommendation 34 GRADE B
Radiation therapy to para-aortic and ipsilateral
pelvic lymph nodes (``dog leg'') is recommended
for the treatment of stage IIA metastatic semi-
noma.
Stage IIB
Patients with stage IIB seminoma have a lower
expectation of remaining relapse free with radio-
therapy alone. A recent study [1] reported a 12%
relapse for Stage IIB following dog leg or inverted Y
irradiation. Since it is now clear that metastatic
seminoma is as chemosensitive as teratoma, this
group of patients have increasingly been treated with
chemotherapy, although there have been no rando-
mised trials comparing chemotherapy and radio-
therapy. Progression-free survival rates range from
85% to 100%. Chemotherapy may be preferred as
initial therapy as it may prove more problematic to
deliver in patients who relapse after radiotherapy, but
radiotherapy should still be considered an effective
treatment for stage IIB disease.
Recommendation 35 GRADE B
For stage IIB seminoma radiotherapy (dose: 30
35 Gray over 1517 fractions) or chemotherapy
are recommended as initial treatment.
Stage IIC and IID
Three series in the literature have separated outpatients with larger masses (45 cm) and have shown
that this is an unfavourable group when treated with
initial irradiation therapy alone [24] with a high
relapse rate (435%). In addition, the irradiation
volume would, of necessity, be large and may include
renal or hepatic parenchyma, adding to toxicity. In
these patients, combination chemotherapy is recom-
mended. (Evidence level IIa)
Recommendation 36 GRADE B
For patients with stage IIC and IID seminoma,
chemotherapy is the recommended initial treat-ment.
Recommendation 37 GRADE C
Where combination chemotherapy is contra-
indicated, radiotherapy for stage IIC disease
may be an acceptable alternative.
Stage II, III and IV
Combination chemotherapy with cisplatin and etopo-
side is standard therapy for patients with bulky
metastatic seminoma or for patients relapsing after
radiotherapy [56]. Carboplatin has been assessed as
a possible alternative to cisplatin and etoposide but an
MRC randomised study of 130 patients with advanced
seminoma who received either single agent carbopla-
tin or etoposide and cisplatin was closed prematurely
because of data showing an inferior outcome for
carboplatin in combination in a trial in teratoma. It
was concluded that etoposide and cisplatin should
remain standard therapy and that carboplatin should
only be used in exceptional circumstances [6]. There
is no clear evidence that adding bleomycin to
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etoposide/cisplatin improves outcome. Bleomycin
toxicity may also be high in patients over 40 so is
usually omitted in treatment of seminoma. (Evidence
level Ib)
Recommendation 38 GRADE B
Initial cisplatin containing chemotherapy is
recommended for advanced seminoma.
Recommendation 39 GRADE CChemotherapy is recommended for patients with
Stage III and IV disease and should consist of
cisplatin and etoposide. There is no evidence that
bleomycin adds to the efcacy of treatment.
Recommendation 40 GRADE A
Carboplatin could be used as an alternative to
cisplatin in exceptional circumstances.
8.2 Management of MetastaticTeratoma
These cancers spread by by both lymphatic and blood
vessel channels. Prognosis relates not only to
anatomical extent of spread but also to the extent of
production of the tumour markers alpha-fetoprotein
(AFP), human chorionic gonadotrophin (HCG) and
lactate dehydrogenase (LDH) which may reect the
underlying biological aggressiveness of these cancers.
These features have been incorporated by the
International Germ Cell Consensus Classication
into the prognostic factor staging of good, inter-
mediate and poor diagnosis (Table 4) [7].
There is evidence that treatment of testicular cancer
in a specialist centre is associated with improved
results [8,9], particularly in patients with advanced
disease. (Evidence level III)
Recommendation 41 GRADE B
Chemotherapy should only be given in a
specialist centre and overseen by a clinician
experienced in the management of germ cell
tumours.
Management of Good Prognosis Disease
The important consideration in this group, with a
predicted cure rate of over 90%, is the reduction of
treatment-related toxicity. Standard treatment for
many years was four cycles of BEP chemotherapy.
One signicant advance would be the demonstration
that three rather than four courses of chemotherapy is
sufcient in this group. One US study comparing
three and four courses of BEP revealed equivalent
results of either treatment [10,11]. As elimination of
the nal course of therapy results in diminished
toxicity three courses of BEP may be the preferred
regimen for patients with good prognosis disease.
However, this study, though clearly important, was of
relatively small size and would not have been capable
of detecting a small but clinically signicant
difference in the two arms (up to 10%). Data from
an MRC/EORTC study (protocol TE20) for good
prognosis patients is now available on the issue of
three versus four cycles of BEP. This study is of
sufciently large size to ensure that any difference of
this magnitude would be detected and has shownequivalence between three and four courses of BEP
[12]. BEP 3 is now standard therapy for good
prognosis disease. In attempting to reduce the
incidence of treatment-related toxicity, investigations
have particularly concentrated on the problems
associated with cisplatin and bleomycin.
The side effects of cisplatin comprise a signicant
component of both the early and late toxicity of
treatment. These toxicities include renal impairment,
neuropathy, high tone hearing loss and additionally,
in the short term, severe gastrointestinal toxicity. The
amelioration of renal damage by the use of intensivehydration techniques is important although this adds
to the inpatient stay for continuous intravenous
infusion therapy. However, the renal damage of
cisplatin even with intensive hydration techniques
tends to cause loss of approximately 25% of the
patient's glomerular ltration capacity [13] and,
although this causes little immediate problem, there
is concern about an increased risk of hypertension in
later life.
Carboplatin causes little renal toxicity at conven-
tional dosage and does not cause neurotoxicity or
ototoxicity. It would therefore appear to be anattractive candidate as an alternative to cisplatin in
the management of these patients. A large MRC/
EORTC study compared BEP with bleomycin, etopo-
side and carboplatin (BEC). This was closed with
clear evidence that the carboplatin arm was inferior
[14]. A total of 589 patients were entered and a
signicantly worse one year failure-free survival rate
was noted for patients treated on the CEB arm (80%
vs. 90%). (Evidence level Ib)
A similar conclusion was reached in the USA in a
study of 265 patients treated with three courses of
either etoposide/cisplatin (EP) or etoposide/carbopla-
tin (EC). Relapse free survival was signicantly
inferior in the EC arm (p50.001) [5], and no further
trials involving carboplatin for metastatic disease
have been recommended.
Bleomycin treatment can cause a number of side
effects, including skin rashes and allergic reactions,
but pneumonitis is the most feared because of the
potential for fatal pulmonary toxicity in 23% of
patients [15]. Four studies have addressed this
problem, by means of randomised trials in which
bleomycin has been deleted in one arm, all in good
prognosis patients [1619]. (Evidence level Ib)
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Only one trial showing no difference has been
reported [16]. This study compared treatment with
VAB-6 with EP and was thus complicated by the use
of other drugs. An Australasian study [17]. which
compared PVB with PV (four cycles) showed a
signicant increase in tumour-related deaths in
patients treated with PV. A SECGC study which
compared BEP with EP (three cycles) was terminated
early because an interim analysis suggested less
favourable responses with EP [18]. Long term
follow up of an EORTC study comparing BEP withEP (four cycles) showed a signicant difference in
complete response rate in favour of BEP [19].
( Evidence level Ib and IIb)
Overall, the data indicates that weekly bleomycin
should continue to be part of standard chemotherapy.
The total dose of bleomycin should not exceed
270,000 International Units (IU) (i.e. 270 mg) in
patients with good prognosis disease. Where risks of
toxicity are increased (e.g. in patients with poor renal
function, previous mediastinal irradiation and older
patients) its omission may be appropriate [20]. In such
cases four cycles of EP (or BEP with bleomycin given
only on day two of each cycle [21]) are recom-
mended.
Recommendation 42 GRADE A
Three cycles of BEP (etoposide dose 500 mg/m2
per course) is standard therapy for good prognosis
teratoma.
Recommendation 43 GRADE A
Under normal circumstances, weekly bleomycin
(30,000 IU) should be given to a total dose of
270,000 Units (equivalent to 270 mg/m2
).
Recommendation 44 GRADE B
The maximum dose of bleomycin should not
normally exceed 270,000 IU in patients with good
prognosis disease.
Management of Patients withIntermediate and Poor PrognosisDisease
There is good evidence that patients with intermediate
and poor prognosis disease benet from specialist
centre treatment [9]. The dose of cisplatin in most
standard regimens has been 20 mg/m2 for ve days
combined with bleomycin and etoposide. Use of a
different cisplatin schedule (50 mg/m2 daily62) has
recently been compared with this standard regime in a
large randomised trial, the results of which are
awaited [12]. Increase in the intensity of cisplatin
treatment can be achieved by increasing the dose (e.g.
by a factor of two), or by giving cisplatin at shorter
intervals. Randomised trials however have proved
negative in both respects. In the USA, a randomised
trial in patients with poor risk germ cell tumours
showed no benets for double-dose cisplatin as part of
the BEP regimen [22]. (Evidence level Ib)
In 1990 the MRC/EORTC initiated a randomised
trial in intermediate and poor prognosis patients
comparing standard chemotherapy with six cycles of
BEP/EP against BOP/VIP (three cycles of bleomycin,
vincristine and cisplatin given every 10 days followed
by three cycles of etoposide, ifosfamide and cisplatin
given three weekly). The BOP/VIP schedule incorpo-rates rapid induction followed by potentially non-
cross resistant chemotherapy [23]. A total of 380
patients were randomised and analysis of the trial
suggests no advantage to the more intensive schedule.
This study also included a randomisation to receive
lgrastim (G-CSF). There was no evidence of any
advantage resulting from use of lgrastim in the BEP
arm of the study. This treatment should not be used
routinely [21].
In a further large randomised trial BEP was
compared with VIP, again with no improvement in
efcacy and increased toxicity [24]. Most centresrecommend 4 cycles of BEP as standard therapy
incorporating cisplatin (20 mg/m265) and etoposide
(100 mg/m265) with each course and bleomycin
given at a dose of 30,000 IU (30 mg) weekly to a dose
of 360,000 IU (360 mg). (Evidence level Ib)
High dosage chemotherapy with peripheral blood
stem cell or autologous bone marrow transplantation
has been used predominantly as salvage chemother-
apy, and this technique has been assessed in non-
randomised studies in certain centres earlier in the
disease where a particularly adverse prognosis can be
recognised. One study in Germany involving 141 patients with advanced disease has conrmed the
feasability and efcacy of repeated cyles of high dose
chemotherapy [61]. Randomised trials comparing this
approach with BEP as rst line treatment are now
ongoing. (Evidence level IIa)
In summary, at present there are no randomised
studies to indicate superiority for treatment other than
BEP but other approaches are being examined.
Recommendation 45 GRADE A
For intermediate/poor prognosis patients no
treatment has been shown to be better than fourcycles of BEP with etoposide at 500 mg/m2 per
course as standard therapy.
Recommendation 46 GRADE C
Patients with intermediate or poor prognosis
disease should be treated in specialist centres
and where possible should be entered into well-
designed multicentre studies to dene the best
treatment for this group of patients.
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Recommendation 47 GRADE B
Filgrastim or other growth factors are not
necessary as part of routine BEP chemotherapy.
References
1. Ward EP, Gospodarowicz M, Panzarella T et al. Manage-ment of stage II seminoma. J Clin Oncol 1998;16:716724.
2. Zagars GK. Seminoma with bulky abdominal disease. Int J
Radiat Oncol Biol Phys 1988;14:395397.3. Evensen JF, Fossa SD, Kjellevold K, Lien HH, Testicularseminoma: analysis of treatment and failure for stage IIdisease. Radiother Oncol 1985;4:5561.
4. Mason BR, Kearsley JH. Radiotherapy for stage 2testicular seminoma:the prognostic inuence of tumourbulk. J Clin Oncol 1988;6:18561862.
5. Bajorin DF, Sarosdy F, Pster DG et al. Randomised trialof etoposide and cisplatin versus etoposide and carboplatinin patients with good risk germ cell tumours: a multi-institutional study. J Clin Oncol 1993;11:598606.
6. Horwich A, Oliver RT, Fossa SD, Wilkinson P, Mead GM,Stenning S. A randomised MRC trial comparing singleagent carboplatin with the combination of etopside andcisplatin in patients with advanced metastatic seminoma.Proc ASCO 1996;15:Abstract 668.
7. International Germ Cell Collaborative Group. Interna-tional Germ Cell Consensus Classication: a prognosticfactor-based staging system for metastatic germ cellcancers. J Clin Oncol 1997;15:594603.
8. Howard GCW, Clarke K, Elia MH et al. Scottish NationalAudit of current patterns of management for patients withtesticular and non-seminatomous germ cell cancers. Br JCancer. 1995;72:13031306.
9. Collette L, Sylvester RJ, Stenning SP et al. Does thetreating institution have an impact on the overall andfalure free survival of patients with `poor prognosis'metastatic non-seminomatous germ cell tumours. J NatlCancer Inst 1999;91:839846.
10. Einhorn LH, Williams SD, Loehrer PG et al. Evaluation ofoptimal duration of chemotharapy in favourable-prognosisdisseminated germ cell tumours: a Southeastern CancerStudy Group protocol. J Clin Oncol 1989;7:387391.
11. Saxman SB, Finch D, Gonin R, Einhorn LH. Long-termfollow-up of a Phase III study of three versus four cylcesof bleomycin, etoposide and cisplatin in favourable prognosis germ cell tumours:the Indiana UniversityExperience. J Clin Oncol 1998;16:702706.
12. De Wit R, Roberts JT, Williamson P et al. Is 3 BEPequivalent to 3 BEP-EP in good prognosis germ cellcancer?: an EORTC/MRC Phase III study. Proc ASCO1999 18:Abstract 1187.
13. Hansen SW, Groth S, Daugaard G, Rossing N, Rorth M.Long term effects of renal function and blood pressure oftreatment with cisplatin, vinblastin and bleomycin inpatient with germ cell cancer. J Clin Oncol 1988;6:172831.
14. Horwich A, Sleijfer D, Fossa S, Kaye SB, Oliver RT,
Cullen MH et al. Randomised trial of bleomycin, etopsideand cisplatin compared with bleomycin, etoposide andcarboplatin in good-prognosis metastatic non-seminato-mous germ cell cancer: a multi-institutional MedicalResearch Council/ European Organization for Researchand Treatment of Cancer trial. J Clin Oncol1997;15:18441852.
15. Bajorin DF and Bosl GJ. Bleomycin in germ cell tumourtherapy:not all regimens are created equal. J Clin Oncol1997;15:17171719.
16. Bosl GJ, Geller NL, Bajorin D et al. A randomised trial ofetoposide + cisplatin versus vinblastine + bleomycin +cisplatin + cyclophosphamide + dactinomycin in patientswith good prognosis germ cell tumours. J Clin Oncol1988;6:12311238.
17. Levi JA, Raghavan D, Harvey V, Thompson D, SandemanT, Gill G et al. The importance of bleomycin incombination chemotherapy for good-prognosis germ cellcarcinoma. J Clin Oncol 1993;11:13001305.
18. Loehrer PJ, Johnson D, Elson P, Einhorn L, Trump D.Importance of bleomycin in favourable prognosis dis-seminated germ cell tumours: an ECOG trial. J Clin Oncol1995;13:470476.
19. de Wit R, Stoter G, Kaye SB et al. Importance of bleomycin in combination chemotherapy for good-prog-nosis testicular nonseminoma: a randomized study of theEuropean Organization for Research and treatment ofCancer Genitourinary Tract Cancer Cooperative Group. J
Clin Oncol 1997;15:18371843.20. Simpson AB, Paul J, Graham J, Kaye SD. Fatal bleomycin
pulmonary toxicity in the West of Scotland 19915: areview of patients with germ cell tumour. Br J Cancer1998;8:10611066.
21. Fossa SD, Kaye SB, Mead GM et al. Filgrastim duringcombination chemotherapy of patients with poor prognosismetastatic germ cell malignancy. J Clin Oncol1998;16:716724.
22. Nichols CR, Williams SD, Loehrer PJ, Greco FA,Crawford ED, Weetlaufer J et al. Randomised study ofcisplatin dose intensity in poor risk germ cell tumours: aSoutheastern Cancer Study Group and Southwest Oncol-ogy Group protocol. J Clin Oncol 1991;9:11631172.
23. Kaye SB, Mead GM, Fossa S, Cullen M, DeWit R,
Bodrogi I et al. Intensive induction-sequential chemo-therapy with BOP/VIP-B compared with treatment withBEP/EP for poor prognosis metastatic nonseminatomousgerm cell tumor: a randomised Medical Research Council/European Organisation for Research and Treatment ofCancer study. J Clin Oncol 1998;16:692701.
24. Nichols CR, Catalano PJ, Crawford D et al. Randomisedcomparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanceddisseminated germ cell tumours: an Eastern Co-operativeOncology Group, South West Oncology Group and Cancerand Leukemia Group B study. J Clin Oncol1998;16:12871293.
25. Boekmeyer C, Harstrick A, Metzer B et al. Sequential highdose VIP-chemotherapy plus PBSC support for advanced
germ cell cancer. Ann Oncol 1996;7(Suppl.):55.
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Section 9: Treatment of Residual Masses AfterChemotherapy
9.1 Surgery
Seminoma
Resection of post chemotherapy residual masses is
not routinely indicated for seminoma as complete
remission rates are high and as a viable tumour is
rarely found. Surgery is difcult and potentially
dangerous in these cases due to lack of clear tissue
planes.
Teratoma
Residual masses may remain after chemotherapy and
marker normalisation [13]. They may contain viable
tumour, differentiated teratoma or merely brosis/
necrosis. It should be made clear to patients at the
start of treatment that residual masses will have to be
removed surgically. The aim of surgery is completeexcision of the residual mass and associated abnormal
tissue post chemotherapy. Further clearance of the
retroperitoneal nodes or complete para-aortic lym-
phadenectomy can be performed but with an
increased risk of retrograde ejaculation. Patients
should receive preoperative counselling with parti-
cular regard to the possibility of retrograde ejacula-
tion and the extent of surgery (e.g. the possibility of a
nephrectomy being performed). Incomplete excision
is associated with poor prognosis. Series in which
several surgeons have operated sporadically have had
higher rates of incomplete resection than thosemanaged by a single surgeon working closely with
the oncology department. ( Evidence level III).
Whether this improves results is uncertain; it is
associated with an increased risk of retrograde
ejaculation.
Recommendation 48 GRADE B
Patients with teratoma who have residual masses
(41 cm) after chemotherapy and whose markers
have normalised should be treated by complete
excision.
If the testicular primary tumour has not been
removed, this should be done at the time of the
resection of residual masses as chemotherapy will
not reliably cure the primary tumour. (Evidence level
III)
Surgery for metastatic teratoma in the UK should
usually be performed in the specialist centres withexperience in this operation. In each, one surgeon,
working closely with the oncology department,
undertakes surgery for abdominal disease and co-
operates with a similarly specialised thoracic surgeon.
Coexisting abdominal and thoracic disease may be
best excised either at a single operation or by
sequential operations depending on the extent of
disease and condition of the patient. Anaesthesia and
postoperative care, especially where bleomycin
toxicity has occurred, present particular problems
with which anaesthetists and intensive therapy unit
staff caring for these patients must be familiar.
Recommendation 49 GRADE B
Post chemotherapy surgery for metastatic terato-
ma should only be performed in a specialist
centre.
Recommendation 50 GRADE C
Further chemotherapy should be considered
where there has been incomplete excision and
pathology conrms viable germ cell cancer in the
resected specimen.
9.2 Radiotherapy
Radiotherapy is almost never indicated for patients
with metastatic teratoma.
In patients with bulky stage II seminoma it has
been given to patients with residual masses following
chemotherapy. There is no data to conrm its value
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and a recent retrospective review of MRC data
indicates that there is no evidence to support its use
[4]. A policy of observation is therefore reasonable,
with biopsy considered in those patients in whom
large residual masses persist. (Evidence level III)
Recommendation 51 GRADE B
In patients with metastatic seminoma and residual
masses a policy of observation with CT scans
performed 6-monthly until complete remission ordisease stabilisation is recommended. Biopsy
should be considered in patients where large
residual masses persist but is recommended where
masses increase in size.
References
1. Einhorn LH, Williams SD, Mandelbaum I, Donohue JP.Surgical resection in disseminated testicular cancer follow-ing chemotherapeutic cytoreduction. Cancer 1981;48:904908.
2. Freiha FS, Shortcliffe LD, Rouse RV, Mark JB, HanniganFF Jr, Aston D et al. The extent of surgery afterchemotherapy for advanced germ cell tumours. J Urol1984;132:915917.
3. Hendry WF, A'Hern RP, Hetherington JW, Peckham MJ,Dearnaley DP, Horwich A. Para-aortic lymphadenectomy
after chemotherapy for metastatic non-seminomatous germcell tumours: prognostic value and therapeutic benet. Br JUrol 1993;71:208213.
4. Duschenne G, Stenning SP, Aass N et al. Radiotherapy afterchemotherapy for metastatic seminoma a diminishingrole. MRC Testicular Tumour Working Party. Eur J Cancer1997;33:829835.
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Section 10: Treatment of Relapsed Disease
Following achievement of complete remission for
metastatic testicular cancer relapse occurs in less than
10% of patients with good prognosis disease, but is
more likely in patients with more advanced disease.
Although patients failing to be cured with rst line
chemotherapy will be candidates for salvage therapy,
occasionally the radiological appearance of progres-
sive disease may mislead physicians to initiate
inappropriate salvage chemotherapy eg if the serum
markers are falling appropriately but progressive
pulmonary or abdominal disease is noted during
cisplatin chemotherapy clinicians should suspect the
growing teratoma syndrome [1]. Complete surgical
excision would be indicated.
Patients with rising markers usually require further
chemotherapy, except where relapse is localised and
has occurred late [2] when surgery may be more
appropriate. The standard salvage chemotherapy
regimen is VeIP (vinblastine, ifosfamide and cispla-
tin) [3]. Newer agents eg paclitaxel [4] and
gemcitabine [5] are active in a salvage setting, buttheir use has yet to be established. A further approach
is to increase the dose intensity; specically by
enhancing the doses of active drugs one may achieve
inproved therapaeutic results. High dose chemother-
apy with peripheral blood stem cell support can cure a
proportion of these patients [6].
Recommendation 52 GRADE C
Patients with relapsed disease should be referred
to a specialist centre to be considered for entry
into well-designed clinical trials.
The outlook may be better for patients whose relapse
occurs more than two years after initial therapy. In
these cases, surgery plays a major role and should,
where appropriate, be considered as the initial
strategy for treatment of later relapse [7]. In a few
of these patients relapse may comprise teratoma
differentiated only. In most, however, active germ
cell cancer (often producing AFP) will also be found.
Recommendation 53 GRADE CSurgery should be considered to be the mainstay
of treatment for late relapse.
References
1. Jefferey GM, Theaker JM, Lee AHS, Blaquiere RM, SmartCJ, Mead GM. The growing teratoma syndrome. Br J Urol1991;67:195202.
2. Gerl A, Clemm C, Schmeller N et al. Late relapse of germcell tumours after cisplatin-based chemotherapy. AnnOncol 1997;8:4147.
3. Loehrer PJ, Gonin R, Nichols CR et al. Vinblastine plusifosfamide plus cisplatin as initial salvage therapy inrecurrent germ cell tumour. J Clin Oncol 1998;16:25002504.
4. Motzer RJ, Bajorin DF, Schwartz LH, Hutter HS, Bosl GJ,Scher HI, et al. Phase II trial of paclitaxel shows antitumouractivity in patients with previously treated germ celltumours. J Clin Oncol 1994;12:22772283.
5. Einhorn LH, Stender MJ, Williams SD. Phase II trial ofgemcitobine in refractory germ cell tumour. J Clin Oncol1999;17;509511.
6. Beyer J, Kramar RA, Mandanas R et al. High dosechemotherapy as salvage treatment in germ cell tumours:a multivariate analysis of prognostic variables. J Clin Oncol1996;14:26382645.
7. Duschenne G, Stenning SP. Aass N et al. for the MRC
Tes