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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)

Clinical Oncology Clinical Oncology (2000)12:S175177# The Royal College of Radiologists


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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)

COIN Guidelines S177


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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.


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.


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.


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.


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].


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.


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].


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)


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.


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.


Parafn sections should be stained routinely with

haematoxylin and eosin.


Comment should be made on the presence or

absence of CIS, the degree of spermatogenesis,

and evidence of atrophy of seminiferous tubules.


Immunocytochemical assessment of PlAP may be

helpful in a minority of cases.



12/38

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


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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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.


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.


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.


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)


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.


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)


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].


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.


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)


For patients with stage IIC and IID seminoma,

chemotherapy is the recommended initial treat-ment.


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



23/38

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)


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)


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)



24/38

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.


Three cycles of BEP (etoposide dose 500 mg/m2

per course) is standard therapy for good prognosis

teratoma.


Under normal circumstances, weekly bleomycin

(30,000 IU) should be given to a total dose of

270,000 Units (equivalent to 270 mg/m2

).


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.


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.


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.



25/38


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.


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.


Post chemotherapy surgery for metastatic terato-

ma should only be performed in a specialist

centre.


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



27/38

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)


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].


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

test is guidelines 2000

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