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124
Management of adult testicular
germ cell tumours
A national clinical guideline
March 2011
KEY TO EVIDENCE STATEMENTS AND GRADES OF RECOMMENDATIONS
LEVELS OF EVIDENCE
1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias
1+
Well conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias
1-
Meta-analyses, systematic reviews, or RCTs with a high risk of bias
High quality systematic reviews of case control or cohort studies
2++ High
quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the
relationship is causal
2+
Well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the
relationship is causal
2-
Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal
3
Non-analytic studies, eg case reports, case series
4
Expert opinion
GRADES OF RECOMMENDATION
Note: The grade of recommendation relates to the strength of the evidence on which the recommendation is based. It does not
reflect the clinical importance of the recommendation.
A
B
t least one meta-analysis, systematic review, or RCT rated as 1++,
A
and directly applicable to the target population; or
body of evidence consisting principally of studies rated as 1+,
A
directly applicable to the target population, and demonstrating overall consistency of results
A body of evidence including studies rated as 2++,
d
irectly applicable to the target population, and demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 1++ or 1+
C
A body of evidence including studies rated as 2+,
directly applicable to the target population and demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 2++
D
Evidence level 3 or 4; or
Extrapolated evidence from studies rated as 2+
GOOD PRACTICE POINTS

Recommended best practice based on the clinical experience of the guideline development group
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fulltext/50/index.html). More information on accreditation can be viewed at
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Scottish Intercollegiate Guidelines Network
Management of adult testicular germ cell tumours
A national clinical guideline
March 2011
Management of Adult Testicular Germ Cell Tumours
ISBN 978 1 905813 71 1
Published March 2011
Citation text
Scottish Intercollegiate Guidelines Network (SIGN). Management of Adult Testicular Germ Cell
Tumours. Edinburgh: SIGN; 2011. (SIGN publication no. 124). [March 2011]. Available from URL:
http://www.sign.ac.uk
SIGN consents to the photocopying of this guideline for the
purpose of implementation in NHSScotland
Scottish Intercollegiate Guidelines Network
Elliott House, 8 -10 Hillside Crescent
Edinburgh EH7 5EA
www.sign.ac.uk
CONTENTS
Contents
1Introduction................................................................................................................. 1
1.1Background................................................................................................................... 1
1.2
Remit of the guideline................................................................................................... 1
1.3
Updating the evidence.................................................................................................. 1
1.4
Statement of intent........................................................................................................ 2
2
Key recommendations.................................................................................................. 4
2.1
Tumour markers............................................................................................................ 4
2.2
Primary management.................................................................................................... 4
2.3
Management of stage I disease...................................................................................... 4
2.4
Management of metastatic disease................................................................................ 4
2.5
Treatment of relapsed disease....................................................................................... 4
2.6
Late toxicity.................................................................................................................. 5
3
Presentation and referral.............................................................................................. 6
3.1Presentation.................................................................................................................. 6
3.2Referral......................................................................................................................... 6
4Tumour markers........................................................................................................... 7
4.1
AFP and HCG............................................................................................................... 7
4.2LDH.............................................................................................................................. 7
5
Primary management................................................................................................... 8
5.1
Preoperative investigation............................................................................................. 8
5.2
Primary surgical management....................................................................................... 8
5.3
Fertility issues............................................................................................................... 8
5.4
Specialist nursing care................................................................................................... 9
6
Management of the contralateral testis........................................................................ 11
6.1 Diagnosis of carcinoma in situ...................................................................................... 11
6.2
Management of carcinoma in situ................................................................................. 11
7Clinical staging............................................................................................................. 12
7.1
Staging systems............................................................................................................. 12
7.2
Radiological staging...................................................................................................... 13
7.3
Other staging investigations.......................................................................................... 14
8
Management of stage I disease..................................................................................... 15
8.1
Management of stage I seminoma................................................................................. 15
8.2
Management of stage I NSGCT and mixed seminoma/NSGCT...................................... 18
Management of Adult Testicular Germ Cell Tumours
9
Management of metastatic disease............................................................................... 20
9.1
Management of metastatic seminoma............................................................................ 20
9.2
Management of metastatic non-seminomatous germ cell tumours................................. 21
10
Management of residual masses after chemotherapy................................................... 24
10.1
Radiological imaging for residual mass.......................................................................... 24
10.2Surgery.......................................................................................................................... 24
10.3Radiotherapy................................................................................................................. 25
11Treatment of relapsed disease...................................................................................... 26
12Late toxicity.................................................................................................................. 30
12.1Epidemiology................................................................................................................ 30
12.2
Cardiovascular late effects............................................................................................. 30
12.3
Second malignancies..................................................................................................... 32
13
Post-treatment follow up.............................................................................................. 35
13.1
Follow-up strategies for stage I seminoma..................................................................... 35
13.2
Follow-up strategies for stage I NSGCT.......................................................................... 37
13.3
Follow-up strategy for metastatic seminoma.................................................................. 37
13.4
Follow-up strategy for metastatic NSGCT...................................................................... 38
14
Provision of information............................................................................................... 39
14.1
Information and communication................................................................................... 39
14.2
Checklist for provision of information........................................................................... 39
14.3
Psychosexual issues...................................................................................................... 41
14.4
Sources of further information....................................................................................... 42
15Implementing the guideline.......................................................................................... 45
15.1
Auditing current practice............................................................................................... 45
15.2
Resource implications of key recommendations ........................................................... 45
16The evidence base........................................................................................................ 46
16.1
Systematic literature review........................................................................................... 46
16.2
Recommendations for research..................................................................................... 46
16.3
Review and updating.................................................................................................... 46
17Development of the guideline...................................................................................... 47
17.1Introduction.................................................................................................................. 47
17.2
The guideline development group................................................................................. 47
17.3
Consultation and peer review........................................................................................ 48
Abbreviations............................................................................................................................... 50
Annexes ..................................................................................................................................... 52
References................................................................................................................................... 59
1 INTRODUCTION
1Introduction
1.1background
Testicular germ cell tumours are relatively rare. In 2008, 203 new cases were diagnosed in
Scotland with a crude incidence of 8.1 cases per 100,000 of the male population, making it
the 15th most common cancer in men in Scotland.1
It takes on a greater significance than numbers alone might suggest as it is one of the few
curable solid cancers even when it has metastasised, with a crude overall five-year survival
rate in Scotland of 95.8%.1 Although the cure rate is high, the toxicity of therapy is significant
with treatment-related deaths and long term effects being documented. Potential effects on
employment and fertility are of particular importance in the affected age group.
Testicular germ cell tumours can be subdivided into seminoma and non-seminomatous germ
cell tumours (NSGCTs) both of which must always be considered as malignant neoplasms.
Seminomas consist of sheets and cords of relatively uniform cells which resemble primitive
germ cells whereas NSGCTs exhibit a wide variety of appearances reflecting the potential of
the tumour stem cell to differentiate along embryonic and extra-embryonic lines analogous to
the fertilised ovum.
NSGCTs and seminomas have different clinical outcomes2 and require different clinical
management, although in some instances it may be difficult to distinguish between poorly
differentiated seminomas and NSGCTs.3
1.2REMIT of the guideline
1.2.1overall objectives
This guideline provides recommendations based on current evidence for best practice in the
management of testicular cancer. It excludes the management of germ cell testicular tumours
in children, germ cell tumours in women and extragonadal tumours.
1.2.2target users of the guideline
This guideline will be of particular interest to patients, oncologists, urologists, radiologists,
clinical nurse specialists, general practitioners, pathologists, and all healthcare professionals
involved in the management of men with testicular germ cell tumours.
1.3
updating the evidence
Since the publication of the first SIGN guideline on adult testicular germ cell tumours (SIGN 28)
in 1998 treatments for testicular disease have evolved rapidly and some of the recommendations
from SIGN 28 are now out of date. This guideline updates SIGN 28 to reflect the most recent
evidence on testicular germ cell tumours.
Where no new evidence was identified to support an update, text and recommendations are
reproduced from SIGN 28. The original supporting evidence was not re-appraised by the
current guideline development group. The key questions used to develop this guideline can
be found in Annex 1.
The sections have been re-sequenced to follow the patient pathway. Throughout the guideline
the pathology classification has been changed to incorporate the World Health Organisation
(WHO) classification in addition to the British Testicular Tumour Panel and Registry (BTTP&R)
classification to reflect current practice.
1
Management of Adult Testicular Germ Cell Tumours
1.3.1
Summary of updates to the guideline
1
Introduction
Minor update
2
Key recommendations
New
3
Presentation and referral
Minor update
4
Tumour markers
Minor update
5
Primary management
Minor update
6
Management of the contralateral testis
Minor update
7
Clinical staging
Minor update
8
Management of stage I disease
Completely revised
9
Management of metastatic disease
Section 9.2.1 revised
10
Treatment of residual masses after chemotherapy
Updated
11
Treatment of relapsed disease
Updated
12
Late toxicity
New
13
Post-treatment follow up
Minor update
14
Provision of information
New
15
Implementing the guideline
Revised
16
The evidence base
Minor update
Annex 1 Key questions addressed in this update
New
Annex 2 Pathology of testicular germ cell tumours
Minor update
Annex 3 CNS metastases in germ cell tumours
New
1.4Statement of intent
This guideline is not intended to be construed or to serve as a standard of care. Standards
of care are determined on the basis of all clinical data available for an individual case and
are subject to change as scientific knowledge and technology advance and patterns of care
evolve. Adherence to guideline recommendations will not ensure a successful outcome in
every case, nor should they be construed as including all proper methods of care or excluding
other acceptable methods of care aimed at the same results. The ultimate judgement must be
made by the appropriate healthcare professional(s) responsible for clinical decisions regarding
a particular clinical procedure or treatment plan. This judgement should only be arrived at
following discussion of the options with the patient, covering the diagnostic and treatment
choices available. It is advised, however, that significant departures from the national guideline
or any local guidelines derived from it should be fully documented in the patient’s case notes
at the time the relevant decision is taken.
1.4.1
Prescribing of licensed medicines outwith their marketing authorisation
Recommendations within this guideline are based on the best clinical evidence. Some
recommendations may be for medicines prescribed outwith the marketing authorisation (product
licence). This is known as ‘off label’ use. It is not unusual for medicines to be prescribed outwith
their product licence and this can be necessary for a variety of reasons.
Generally the unlicensed use of medicines becomes necessary if the clinical need cannot be met
by licensed medicines; such use should be supported by appropriate evidence and experience.4
Medicines may be prescribed outwith their product licence in the following circumstances:
ƒƒ for an indication not specified within the marketing authorisation
ƒƒ for administration via a different route
ƒƒ for administration of a different dose.
2
1 INTRODUCTION
“Prescribing medicines outside the recommendations of their marketing authorisation alters
(and probably increases) the prescribers’ professional responsibility and potential liability. The
prescriber should be able to justify and feel competent in using such medicines.”4
Any practitioner following a SIGN recommendation and prescribing a licensed medicine
outwith the product licence needs to be aware that they are responsible for this decision, and
in the event of adverse outcomes, may be required to justify the actions that they have taken.
Prior to prescribing, the licensing status of a medication should be checked in the current
version of the British National Formulary (BNF).4
1.4.2additional advice to nhsscotland from NHS quality improvement
scotland and the scottish medicines consortium
NHS QIS processes multiple technology appraisals (MTAs) for NHSScotland that have been
produced by the National Institute for Health and Clinical Excellence (NICE) in England and
Wales.
The Scottish Medicines Consortium (SMC) provides advice to NHS Boards and their Area Drug
and Therapeutics Committees about the status of all newly licensed medicines and any major
new indications for established products.
No relevant SMC advice or NICE MTAs were identified.
3
Management of Adult Testicular Germ Cell Tumours
2
Key recommendations
The following recommendations were highlighted by the guideline development group as
the key clinical recommendations that should be prioritised for implementation. The grade of
recommendation relates to the strength of the supporting evidence on which the evidence is
based. It does not reflect the clinical importance of the recommendation.
2.1TUMour Markers
;;
S erum markers should be checked pre-orchidectomy, 24 hours after orchidectomy and
weekly thereafter until normal.
2.2primary management
;;
linical specialist nurse involvement is recommended as early as possible in the
C
management of patients with testicular germ cell tumours.
2.3management of stage I disease
SEMINOMA
A
In patients with stage I seminoma who are to receive adjuvant 'dog-leg' or para-aortic
strip radiotherapy, a dose of 20 Gy in ten fractions over two weeks should be prescribed
to the International Commission on Radiation Units (ICRU) reference point.
C
The potential risk of second malignant neoplasms should be outlined to patients where
adjuvant radiotherapy is being considered.
NON-SEMINOMATOUS GERM CELL TUMOURS
;;
Patients on surveillance should be seen in a designated clinic following a strict protocol.
B
In low-risk patients under surveillance CT scanning at three and 12 months postorchidectomy is recommended.
2.4management of metastatic disease
A
Patients with a good prognosis metastatic non-seminomatous germ cell tumour should
receive three cycles of BEP chemotherapy in either a 3-day or 5-day schedule.
2.5
treatment of relapsed disease
D
The International Prognostic Factors Study Group’s model should be applied to
guide prognostic information for patients who relapse after first line platinum based
chemotherapy.
4
2 KEY RECOMMENDATIONS
2.6
late toxicity
C
Survivors of testicular cancer should be advised not to smoke.
;;
ncologists should advise survivors of testicular cancer and their GPs of the increased
O
risk of cardiovascular disease.
;;
atients should remain vigilant of any unusual or alert symptoms, particularly relating to
P
the gastrointestinal, respiratory or urinary tract, and report these promptly to their GPs.
;;
here should be increased awareness of the risk of haematological malignancies especially
T
after chemotherapy and solid malignancies in or near the fields of radiotherapy. There
should be a low threshold for further investigation and appropriate referral to secondary
care if any alert symptoms are reported.
5
Management of Adult Testicular Germ Cell Tumours
3
Presentation and referral
3.1Presentation
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.5,6 In Scotland, there is recent evidence that patients are presenting with earlier stage
disease than previously reported.7
Most general practitioners (GPs) will see a patient with a testicular malignancy only very
infrequently, if ever. Most of these patients present with an enlarged testicle or a painless, solid,
unilateral mass in the scrotum (lump). A decrease in testicular size may also occur. Scrotal pain
is present in around 20% of patients with tumours at presentation and up to 27% of patients
with testicular cancer may have local pain. Another feature which should heighten suspicion is
a dragging sensation in the scrotum. Rare presentations include hydrocoele and gynaecomastia,
which appears in around 7% of cases. Backache is present in about 10% of patients but is a
very common and non-specific symptom.8 Reports have not confirmed an association with
vasectomy.9 A small proportion of patients present following local trauma to the testes, however,
it is not thought that the trauma causes the cancer, but rather that it brings an existing tumour
to the attention of the patient and physician.
;;
ue to the rarity of testicular malignancy and its variable, complex and potentially toxic
D
treatments, it is imperative that the patient’s general practitioner and other community
services are well informed and involved throughout treatment and follow up.
3.2Referral
Patients with testicular tumours will most often present with a testicular lump. Abnormal masses
in the epididymis are a common problem referred for specialist urology assessment but these
are unlikely to be testicular tumours and do not represent such an urgent problem. Increasing
tumour bulk is associated with advancing stage of disease and correspondingly the need for
increasingly toxic therapy and consequently poorer outcomes. It is therefore essential to refer
for investigation urgently (within two weeks).

ƒƒ P
atients 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.
ƒƒ An ultrasound, if available at this stage, should be performed to make a distinction.
DThose patients suspected of harbouring a testicular malignancy, ie a lump in the testis,
doubtful epididymo-orchitis or orchitis not resolving within two to three weeks, should
be referred urgently for urological assessment.
6
3
4
4 TUMOUR MARKERS
4Tumour markers
4.1AFP AND HCG
Management of patients with NSGCTs has improved markedly since immunoassay techniques
of high sensitivity and adequate specificity have allowed determination of serum concentrations
of alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG). These markers are good
detectors of residual NSGCT after orchidectomy. However, neither marker should be regarded
as specific for NSGCT and may be raised with a variety of non-germ cell tumour neoplasms.
Mild elevations of AFP can be seen after alcohol abuse, and 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 influenced by the
finding of rising serum concentrations of either marker.
About 50% of patients with NSGCTs will produce elevated HCG and about 60% elevated AFP.
Owing to overlap in positivity the combined sensitivity varies from 60-75%. 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 HCG and 4-6 days for AFP.10
;;
2+
S erum markers should be checked pre-orchidectomy, 24 hours after orchidectomy and
weekly thereafter until normal.
C
Measurement of serum AFP and HCG is essential in the follow up of patients with
non-seminomatous germ cell tumours.
In patients with seminoma the markers are less useful: whilst 15-40% 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 25-45% of NSGCTs
are marker negative it is important to measure both prior to surgery. Owing to methodological
differences between laboratories, great care must be taken in the interpretation of results as
reference ranges may vary.
4.2LDH
Other than as a prognostic indicator in patients with NSGCTs, lactate dehydrogenase (LDH) is
not sufficiently specific for general application in disease monitoring. Mild increases in LDH
during chemotherapy can be due to hepatic insult and reflect the lack of specificity of this marker.
7
Management of Adult Testicular Germ Cell Tumours
5
Primary management
Primary orchidectomy is the treatment of choice for most testicular tumours. It is intended
that this section on primary treatment should be practicable in any district general hospital in
Scotland with surgical facilities, which should include the availability of testicular prostheses.
5.1
Preoperative investigation
One or more markers are raised in 75% of cases of NSGCT and measurement is necessary for
staging and follow up.11 Blood should be taken for assay of the tumour markers AFP, HCG and
LDH before operation (see section 4).
3
Bilateral testicular ultrasound can confirm evidence of disease and measure testicular volume.12
Chest X-ray may show evidence of metastases.13 Other staging investigations can be deferred until
after the primary orchidectomy and should be arranged in consultation with a specialist centre.
3
D
Preoperative investigations should include assay of AFP, HCG, and LDH, bilateral
testicular ultrasound, and a chest X-ray.
;;
5.2
atients with metastases where the diagnosis is not in doubt, on account of high markers
P
and the presence of a testicular mass, may be referred for immediate chemotherapy. In
such cases, when examination or ultrasound scan demonstrates that there is a testicular
tumour, delayed orchidectomy should be performed, either at the time of excision of
residual masses or following chemotherapy, for those patients who are not undergoing
additional surgery.
Primary surgical management
5.2.1inguinal approach
The preferred surgical technique is orchidectomy through an inguinal incision with division of
the cord at the internal inguinal ring.14 Where there is doubt about the diagnosis, an inguinal
approach should be used.
D
3
Where possible an inguinal orchidectomy should be performed.
On the rare occasions when the diagnosis is in doubt, representative samples may be sent for
frozen section. In this situation it is often best to bivalve the testis to be sure not to miss an
abnormal area.
Biopsy of the contralateral testis should be considered in certain cases (see section 6).
5.2.2
TESTICULAR PROSTHESES
There is evidence that loss of a testicle may result in significant psychological morbidity.15
D
A testicular prosthesis should be offered to all patients.
Patients should be offered a testicular prosthesis with careful discussion about the pros and
cons of prosthesis. If possible, the discussion should happen as much in advance as possible so
that the patient has enough time to reflect upon his decision and make an informed choice.16-18
5.3
4
fertility issues
A significant proportion, possibly up to 50%, of men with testicular tumours will have low
sperm counts. In addition, both chemotherapy and radiotherapy may result in infertility.19
Consideration should therefore be given to undertaking semen analysis and sperm storage.
DWhen appropriate, sperm storage should be offered to men who may require
chemotherapy or radiotherapy.
8
3
4
5 PRIMARY MANAGEMENT
Sperm storage should be undertaken in one of the Scottish centres which have a storage licence
from the Human Fertilisation and Embryology Authority (HFEA). It is illegal to store sperm
samples anywhere else. Centres in Scotland licensed by the HFEA are:
ƒƒ
ƒƒ
ƒƒ
ƒƒ
ƒƒ
Aberdeen Maternity Hospital
Edinburgh Royal Infirmary
Glasgow Royal Infirmary
Monklands Hospital, Airdrie
Ninewells Hospital, Dundee
Departments managing these patients require a counsellor familiar with HFEA consent procedures
for sperm storage. The ideal timing of sperm storage will vary; not all patients undergoing
orchidectomy will require further treatment. Where a biopsy of an atrophic contralateral testis
is being considered to exclude carcinoma in situ (CIS), storage prior to surgery is desirable.
5.4
specialist NURSING CARE
As there is opportunity for an excellent prognosis from this tumour type the nursing care given
has an essential part to play in reflecting a good treatment outcome. Problems for the patient
are complex and can lead to psychological morbidity.
;;
5.4.1
Clinical specialist nurse involvement is recommended as early as possible in the
management of patients with testicular germ cell tumours.
EXPERIENCE AND TRAINING
Referral to a specialist centre has been shown to be associated with improved outcome in patients
with testicular cancer.20 It is likely that this is due to the input of the entire multidisciplinary team.
Therefore nurses in specialist centres should receive training in all aspects of the management
of these patients. Nurses who are well trained, have been taught good listening skills, and have
access to continuing educational opportunities and support, can influence a good outcome.
5.4.2
;;
ostregistration education in cancer nursing skills is essential and should be available
P
to all nursing staff to enable provision of more effective care for patients. ;;
S tandards of nursing care specific to the recommended treatments and which cover all
aspects of cancer nursing practice should be devised, implemented and audited.
PSYCHOSOCIAL SUPPORT
Despite an excellent prognosis there are high levels of morbidity in patients with testicular
cancer.21 Psychological morbidity can occur at any stage throughout the illness perhaps as a
result of treatment, unemployment or concerns over fertility issues. Nurses should have the
ability to recognise anxiety and depression, as early referral to a clinical psychologist, can
significantly reduce patients’ emotional distress and enhance adaptation processes.22 However
routine adjuvant psychological therapy is not necessary.23
;;
urses involved in the care of patients with testicular cancer should have appropriate
N
listening/counselling skills and access to training in the assessment of emotional distress.
;;
urses have a key role in supplying information about fertility issues and should have
N
specific training in this field.
9
Management of Adult Testicular Germ Cell Tumours
5.4.3
LIAISON WITH SUPPORT SERVICES
In addition to coping with a diagnosis of a life threatening disease, patients and their families
must often make significant adjustments to their lifestyle, financial status and overall life plan.
Nurses are in an ideal position to access support and advice from other networks and by earlier
recognition of potential problems could perhaps reduce stress.
;;
5.4.4
orking within a previously agreed multiprofessional care plan, nurses should focus
W
activity on patient- and family-centred care. A named nurse should be available to provide
support and information on the availability of additional services of support networks.
Referral TO ONCOLoGY
There is evidence that treatment of testicular cancer in a specialist centre is associated with
improved results.20
;;
Management should be discussed by an appropriate multidisciplinary team.
DFollowing confirmation of a germ cell tumour, all patients should be referred to a
specialist centre for the management of testicular tumours.
10
3
6 MANAGEMENT OF THE CONTRALATERAL TESTIS
6
Management of the contralateral testis
6.1 DIAGNOSIS OF carcinoma in situ
All germ cell tumours with the exception of spermatocytic seminoma arise from carcinoma
in situ (intratubular germ cell neoplasia)24,25 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.26 Carcinoma in situ is thought to progress
to invasive germ cell tumours in 50-100% of cases and therapy should be considered.27
Carcinoma in situ in the contralateral testis is more common in the subgroup of patients who
have a small (<12 ml) contralateral testis and where the diagnosis of a testicular cancer is made
at or less than the age of 30 years. The risk of CIS is 34% in such patients, which represents a
high risk group, and biopsy should be considered.28 Normally this would be done at the time
of orchidectomy at a specialist centre.29
3
4
D
Patients with a testicular cancer who are 30 years old or less and have a small (<12
ml) contralateral testis should be considered for biopsy of the contralateral testis to
diagnose CIS. If CIS is identified subsequent management should be in a specialist
centre.
6.2
;;
In view of the difficulties in interpretation, pathological review at a specialist centre is
recommended. ;;
ontralateral testicular biopsy should, where possible, be performed after all sperm
C
samples have been obtained for storage and before chemotherapy or any secondary
treatment.
MANAGEMENT OF carcinoma in situ
No evidence was identified to indicate a single treatment pathway for managing patients
with CIS. Irradiation of a testis containing CIS has been shown to eradicate early abnormal
changes and prevent the progression to invasive disease.30 Where radiotherapy is to be given
a standard dose is 20 Gy given in ten daily fractions over two weeks. A number of different
doses and fractionations have been tried but an optimal dose has yet to be defined.31,32 Leydig
cell function is maintained in a proportion of patients but about 40% of patients will require
hormone replacement therapy.32
3
Although the risk of progression to invasive cancer in people with untreated CIS is high, another
option would be to monitor the testis and treat if an invasive cancer develops. A further option for
infertile patients who already require testosterone replacement is a prophylactic orchidectomy.
All of these options should be discussed with the patient.
DPatients with biopsy-proven CIS of the contralateral testis should have the options of
surveillance, prophylactic orchidectomy and adjuvant radiotherapy discussed with
them. Where radiotherapy is given, a dose of 20 Gy in 10 fractions over two weeks is
adequate to eradicate CIS and testosterone replacement may not be necessary.
Systemic chemotherapy is an inadequate treatment for CIS as late relapse has been described.33,34
11
Management of Adult Testicular Germ Cell Tumours
7Clinical staging
7.1STAGING 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 make an assessment of the prognostic group
the patient is in. In the past the most commonly used staging system was the Royal Marsden
Hospital (RMH) system (see Table 1).
For metastatic germ cell tumours this classification has now largely been superseded by the
International Germ Cell Consensus Classification (IGCCC) prognostic grouping (see Table 2).35
However, the RMH Stage II subgrouping of para-aortic nodes by size may still be of value in
the staging of seminoma. The use of tumour markers is discussed in section 4 and imaging
techniques for staging are discussed in section 7.2.
D
Marker concentrations should be used along with imaging techniques to allocate a
prognostic group.
;;
ll patients should be staged and allocated a prognostic group according to the IGCCC
A
classification.
Table 1: RMH staging
I
IM
II
IIA
IIB
IIC
IID*
No evidence of disease outside the testis
As above but with persistently raised tumour markers
Infradiaphragmatic nodal involvement
Maximum diameter <2 cm
Maximum diameter 2-5 cm
Maximum diameter >5-10 cm
Maximum diameter >10 cm
III
Supra- and infradiaphragmatic node involvement
Abdominal nodes A, B, C, as above
Mediastinal nodes M+
Neck nodes N+
IV
Extralymphatic metastases
Abdominal nodes A, B, C, as above
Mediastinal or neck nodes as for stage III
Lungs:
¾ L1 <3 metastases
¾ L2 Multiple metastases <2 cm maximum diameter
¾ L3 Multiple metastases >2 cm in diameter
Liver involvement H+
Other sites specified
* The Stage IID category was formulated at the 1989 Seminoma Consensus Conference.36
12
7 CLINICAL STAGING
Table 2: IGCCC prognostic grouping
NSGCT
SEMINOMA
GOOD PROGNOSIS with all of:
Testis/retroperitoneal primary
Any primary site
No non-pulmonary visceral metastases
No non-pulmonary visceral metastases
AFP<1,000 ng/ml
Normal AFP
HCG<5,000 IU/L
Any HCG
LDH<1.5 upper limit of normal
Any LDH
[56% of NSGCTs]
[5-year survival 92%]
[90% of seminomas]
[5-year survival 86%]
INTERMEDIATE PROGNOSIS with all of:
Testis/retroperitoneal primary
Any primary site
No non-pulmonary visceral metastases
Non-pulmonary visceral metastases
AFP ≥1,000 and ≤10,000 ng/ml or
Normal AFP
HCG ≥5000 and ≤50,000 IU/L or
Any HCG
LDH ≥1.5 normal ≤10 normal
Any LDH
[28% of NSGCTs]
[5-year survival 80%]
[10% of seminomas]
[5-year survival 73%]
POOR PROGNOSIS with any of:
Mediastinal primary or non-pulmonary No patients classified as poor prognosis
visceral metastases
AFP>10,000 ng/ml or
HCG>50,000 IU/L or
LDH>10 normal
[16% of NSGCTs]
[5-year survival 48%]
7.2RADIOLOGICAL STAGING
All patients require formal staging with contrast-enhanced computed tomography (CECT) of the
chest, abdomen and pelvis to help with formulating a management plan.37 Ideally, the CECT
scan should not be performed before a histological diagnosis has been made as histology will
aid in the interpretation of the scan and a small proportion of patients will have benign disease.
After orchidectomy, scanning should be avoided in the immediate postoperative period as
patients may not be able to cooperate fully due to discomfort. Intercurrent infection and reactive
changes related to surgery may also cause difficulties with interpretation. However, the staging
scan should be regarded as urgent and should be carried out within three weeks of surgery.
4
D
CECT scanning of the thorax, abdomen and pelvis is an essential part of the staging of
all germ cell tumours.
;;
eticulous and reproducible technique is important for accuracy and comparability
M
between examinations.
13
Management of Adult Testicular Germ Cell Tumours
It should be borne in mind that CECT is a high radiation-dose examination and every effort
should be made to avoid unnecessary scanning, and to use the lowest-dose technique where
practicable.
It may not be practicable for all scans to be performed at the cancer centre. In these circumstances
scans should be reviewed by a radiologist with appropriate expertise.
;;
ll CECT scans should be reviewed at a meeting of the uro-oncology multidisciplinary
A
team by a radiologist experienced in their interpretation in patients with germ cell tumours.
;;
It is helpful to the radiologist to have the following clinical and pathological details:
ƒƒ Side of primary
Spread to nodal groups follows a predictable course according to the side of the
lesion.
ƒƒ Histology (if available)
Tumour type and any adverse histological features.
ƒƒ M
arker status and current marker levels
Helpful in interpreting equivocal lesions.
ƒƒ Risk factors for pelvic nodal disease
Although a pelvic scan should be done for initial staging it may be omitted in
subsequent scans in the absence of known risk factors (previous inguino-scrotal
surgery, previous retroperitoneal surgery or irradiation, tumour invasion through
the tunica vaginalis, and the presence of para-aortic nodal disease).38
;;
Any previous imaging should be available to the radiologist.
7.3OTHER STAGING INVESTIGATIONS
7.3.1
MAGNETIC RESONANCE IMAGING
Magnetic resonance imaging (MRI) is equivalent to CT for detection of pelvic or abdominal
nodes, and involves no ionising radiation.37 However, MRI is less sensitive for the detection of
pulmonary metastases and examination times are longer than CT.39 The utility of MRI for routine
staging and follow up is also limited by lack of availability. Magnetic resonance imaging remains
the modality of choice for suspected bone marrow or central nervous system involvement and
generally may be useful for problem solving in difficult cases.
;;
7.3.2
agnetic resonance imaging may be helpful when CT scanning is inconclusive, is
M
contraindicated because of allergy to contrast media, or where there is concern about
radiation dose.
BRAIN SCANNING
Either MRI or CT scanning of the brain should be considered where there are multiple lung
metastases and/or HCG >10,000 IU/L.
7.3.3
OTHER INVESTIGATIONS
Other staging investigations such as cerebrospinal fluid tumour markers and bone scanning
may be indicated on an individual basis.
;;
14
ll staging should be completed and reviewed at a meeting of the uro-oncology
A
multidisciplinary team no later than three weeks after surgery, although immediate
postoperative scans may be misleading.
8 MANAGEMENT OF STAGE I DISEASE
8
Management of stage I disease
Stage I disease is defined as no known residual disease following orchidectomy, with no
evidence of metastatic disease on clinical examination, a normal CT scan of chest, abdomen
and pelvis and normal postoperative tumour markers. Ninety per cent of seminomas and 57%
of NSGCTs, will present as stage I disease.7
8.1
MANAGEMENT OF STAGE I SEMINOMA
There are a number of options for patients with stage I pure seminoma following orchidectomy.
These include active surveillance, adjuvant radiotherapy and adjuvant carboplatin chemotherapy.
No randomised studies have been identified that compare all three management strategies
directly. The data regarding efficacy and toxicity (in particular the risk of second malignancies
and cardiovascular toxicity) for each option are described in this section.
One systematic review assessing relapse with time for each of the stage I management strategies
identified a 17% relapse rate for patients on surveillance and <5% relapse rates for patients
following adjuvant treatments (radiotherapy or chemotherapy).40 The annual rate of relapse falls
below 1% at four years for surveillance patients, and at two to three years for patients receiving
either adjuvant radiotherapy or adjuvant carboplatin.
2++
C
Patients with stage I seminoma should have the advantages and disadvantages of
the various post-orchidectomy management options discussed with them, including
surveillance, single-dose adjuvant carboplatin and adjuvant radiotherapy.
;;
atients in whom compliance for follow up is likely to be poor may be advised to pursue
P
adjuvant therapy over surveillance.
Spermatocytic seminoma is pathologically different to classical seminoma and no further
treatment is indicated following orchidectomy.
8.1.1
Active SURVEILLANCE
An analysis of studies with median follow up ranging from 30 to 145 months showed that
active surveillance for patients with stage I seminoma results in a relapse rate of 17% and a
cause-specific survival of 99.7%. Approximately 2% of patients with stage I seminoma on active
surveillance will relapse after two years, accounting for 9% of all relapses.41
2++
In the largest study addressing the issue of risk factors for seminoma recurrence on surveillance,
statistically significant prognostic factors for relapse on multivariate analysis include primary
tumour size >4 cm and rete testis invasion.42
2++
The risk of second malignancy in patients treated with orchidectomy alone for testicular germ
cell tumours (seminoma and NSGCT) is not increased in comparison with an age and periodmatched population. It is not clear what imaging follow up these patients underwent, and
therefore their exposure to ionising radiation from CT scanning is unknown.43
2+
In the two studies that separated patients receiving radiotherapy from those undergoing
orchidectomy alone (in seminoma and NSGCT) no statistically significant increased risk of
cardiovascular disease (CVD) was seen in the surgery alone group.43,44
2+
B
In patients with stage I seminoma post-orchidectomy, active surveillance may be
considered as a management option.
15
Management of Adult Testicular Germ Cell Tumours
8.1.2
ADJUVANT RADIOTHERAPY
In an RCT of 478 post-orchidectomy patients with stage I seminoma who had undergone no
prior inguinoscrotal surgery, adjuvant radiotherapy to a dose of 30 Gy in 15 fractions solely
to the para-aortic nodes resulted in equivalent three year relapse-free survival rates (96%) and
three year overall survival rates (99.3%) when compared to para-aortic strip and ipsilateral pelvic
node (‘dog-leg’) radiotherapy. Pelvic relapse-free survival was 1.8% lower in the para-aortic
radiotherapy alone arm of the study compared with the 'dog-leg' arm. Para-aortic radiotherapy
is associated with less acute toxicity (leucopenia, diarrhoea and reduction in sperm counts).45
1+
A
In patients with stage I seminoma who have undergone no previous inguinoscrotal
surgery and who are to receive adjuvant radiotherapy following orchidectomy, the
volume should be limited to the para-aortic nodal strip.
;;
If para-aortic nodal irradiation is used, CT scanning of the pelvis may be considered
during follow up.
DIn patients with stage I seminoma who have undergone previous inguinoscrotal surgery
and who are to receive adjuvant radiotherapy following orchidectomy, the para-aortic
nodal strip volume should be extended to include the ipsilateral pelvic nodes (‘dog-leg
radiotherapy’).
A randomised trial of 625 patients concluded that in post-orchidectomy patients with stage I
seminoma, a radiotherapy dose of 20 Gy in ten fractions is equivalent to 30 Gy in 15 fractions
to the para-aortic strip or to ‘dog-leg’ fields in terms of two year relapse-free survival (97% (95%
confidence interval (CI) 94.4% to 98.4%) v 97.7% (95% CI 94.4% to 98.4%)) and results in less
acute toxicity (leucopenia and moderate-severe lethargy). A significantly greater proportion of
patients are unable to return to work at four weeks following radiotherapy with 30 Gy compared
with 20 Gy (46% v 28%).46
A
In patients with stage I seminoma who are to receive adjuvant ‘dog-leg’ or para-aortic
strip radiotherapy, a dose of 20 Gy in ten fractions over two weeks should be prescribed
to the International Commission on Radiation Units (ICRU) reference point.
One systematic review of over 6,900 patients with testicular cancer showed that the risk of
second malignant neoplasms (excluding contralateral germ cell tumours) was increased by a
factor of between two and three in those who had received radiotherapy, although many patients
would have been treated to larger volume and greater dose than is current practice.47 The risk
of malignancy in organs which lay at least partly within the radiotherapy portals increased by
a factor of between three and seven. A number of more recent and large retrospective cohort
studies show consistent findings of an excess of second malignancies (non-germ cell tumour)
with a latency of approximately 10-15 years before the excess risk is apparent.48-50
16
1++
2-
In a cohort of more than 2,000 testicular cancer survivors, a statistically significant association
between radiation dose and second malignancy risk was reported, with patients treated with
26-35 Gy and 40-50 Gy para-aortic strip or ‘dog-leg’ radiotherapy having a hazard ratio of 2.3
(95% CI 1.5 to 3.6) and 3.2 (95% CI 2.1 to 5.1) respectively, when compared with patients
undergoing orchidectomy alone (p value for trend <0.001).43
2+
The standardised incidence ratio (SIR) for the development of a second malignant neoplasm
following radiotherapy for testicular cancer decreases with increasing age at diagnosis (p value
for trend <0.001). Thus, the SIR for patients aged under 30 at diagnosis who receive adjuvant
radiotherapy is 3.9 (95% CI 2.9 to 5.3), compared with 1.3 (95% CI 1.0 to 1.7) in those aged
50 or over at diagnosis.43,48
2+
8 MANAGEMENT OF STAGE I DISEASE
In patients with seminoma undergoing adjuvant radiotherapy to the mediastinum, the SIR for
cardiovascular disease (myocardial infarction (MI) and/or angina) is significantly increased
at 2.48 (95% CI 1.77 to 3.37),44 and the standardised mortality ratio for cardiac-specific
mortality is increased.51 One study showed that the relative risk of a cardiovascular event was
2.4 (95% CI 1.04 to 5.45) in patients with testicular cancer undergoing radiotherapy (but not
chemotherapy) post-orchidectomy compared with those on surveillance (absolute risk reduction
5.85%),52 but a proportion of these patients received treatment to the mediastinum as well
as the infradiaphragmatic nodes. When the patients who received mediastinal radiotherapy
were excluded from the dataset, an increased risk of CVD persisted in the remaining irradiated
patients.52 In another study that separated infradiaphragmatic radiotherapy (RT) from infra- and
supradiaphragmatic RT in patients with seminoma, no statistically significant increased risk of
CVD was noted in patients receiving only infradiaphragmatic RT.44
In one study with a median of 13.3 years follow up after treatment with radiotherapy for stage I
and II seminoma excess mortality was seen in patients with greater than 15 years follow up, with
a standardised mortality ratio (SMR) of 1.85 (95% CI 1.42 to 2.38).51 However, such patients
were likely to have been irradiated to a larger field size and to a greater radiation dose than
current patients with stage I seminoma.
2+
2+
C
The potential risk of second malignant neoplasms should be outlined to patients where
adjuvant radiotherapy is being considered.
8.1.3
ADJUVANT chemotherapy
In post-orchidectomy patients with stage I seminoma the Medical Research Council (MRC) TE19
study found that, with a median follow up of four years, single-dose carboplatin (AUC7) results in
two- and three-year relapse-free survival equivalent to adjuvant radiotherapy.53 Patients receiving
carboplatin experience significantly less dyspepsia and lethargy but more thrombocytopenia
than patients receiving radiotherapy. Patients receiving radiotherapy are less likely to be able
to return to work by four weeks post-treatment than patients treated with adjuvant carboplatin
(62% v 81%, p<0.0001).
The dose and scheduling of carboplatin is important. At a dose of 400 mg/m2, two cycles of
carboplatin result in a trend to lower relapse rates than a single cycle.54 At a dose of AUC 7
(based on ethylene diamine tetra-acetic acid (EDTA) clearance), the dose of carboplatin is 1015% greater than that calculated for a single dose of 400 mg/m2.
;;
1++
1+
In patients receiving a single dose of adjuvant carboplatin, the dose should be AUC7
(ie that dose required to achieve an area under the concentration time curve of 7 mg/ml
per minute) based on EDTA clearance.
A risk adapted strategy (using the risk factors of tumour size (>4 cm) and presence or absence
of rete testis invasion) is feasible and can spare >30% of patients from adjuvant therapy. In
one study of such a strategy,55 patients with low-risk stage I seminoma (tumour <4 cm and
no rete testis invasion) underwent surveillance and patients with high-risk features underwent
adjuvant carboplatin. The study showed a 6% relapse rate in the low-risk surveillance group,
and a 3.3% relapse rate in the high-risk carboplatin-treated group. The five year disease-free
survival was 93.4% for surveillance and 96.2% for the carboplatin group. Five-year overall
survival was not compromised and 100% of patients in both groups survived.
Early follow up in a trial of adjuvant carboplatin suggested a reduction in the risk of developing
contralateral germ cell tumours,53 however, longer term outcomes from a cohort study yields
conflicting results,56 raising the possibility that carboplatin may delay rather than prevent
contralateral tumours.
2+
1++
2-
17
Management of Adult Testicular Germ Cell Tumours
One small cohort study of 199 patients with stage I seminoma treated with adjuvant carboplatin
showed no excess risk of second non-germ cell malignancy when compared to an age- and
period-matched population, although median follow up was nine years with only a small
percentage of patients being followed up for longer than 15 years.56 The same study showed
no increase in SMR for cardiovascular mortality. The incidence of non-fatal cardiovascular
disease was not analysed in this study. No excess overall mortality was seen compared to the
reference population.
2-
AIn post-orchidectomy patients with stage I seminoma, adjuvant carboplatin
chemotherapy may be considered as a management option.
Follow up treatment in patients with stage I seminoma is covered in section 13.1.
8.2
MANAGEMENT OF STAGE I NSGCT AND MIXED SEMINOMA/NSGCT
8.2.1SURVEILLANCE
In patients with stage I NSGCT or mixed seminoma/NSGCT of the testis surveillance is desirable
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 30%.57 The MRC surveillance
study for stage I NSGCT has enabled identification of subgroups of patients who have a high
risk of relapse on surveillance.25,58 The single most important histological feature of high-risk
subgroups is blood vessel and/or lymphatic invasion, with a recurrence risk of approximately
40% in the presence of testicular vein or lymphatic tumour invasion.2,25,58 A similar conclusion
was reached in a European Organisation for Research and Treatment of Cancer (EORTC) study
of surveillance for stage I NSGCT.59
2+
Although the mean age at presentation is older for patients with combined tumours than for
those with NSGCT, the pattern of relapse is identical.36 The majority of patients (80%) relapse
within the first year; 47% in abdominal nodes, 13% abdominal nodes and lung, 17% lung and
23% marker rise only.60 Scrotal interference prior to removal of the primary tumour is not a
contraindication to surveillance.
CPatients with stage I NSGCT or mixed seminoma/NSGCT of the testis with no high-risk
features should be managed by surveillance following inguinal orchidectomy.
Surveillance is generally only recommended for patients without pathological risk features for
relapse and who have no social, psychological or geographic factors which would preclude
them from such a strategy. Patients on surveillance are followed up monthly for the first year
with clinical examination and serum markers at every visit. A recent study found that a CT scan
performed at three and 12 months is adequate for most patients.61
Based on relapse rates and clinical experience the guideline development group has provided
a suggested surveillance protocol (see section 13).
;;
Patients on surveillance should be seen in a designated clinic following a strict protocol.
B
In low-risk patients under surveillance, CT scanning at three and 12 months postorchidectomy is recommended.
An abdominal CT should be performed in all patients under surveillance. Practice regarding
chest CT and X-ray varies, due to a lack of evidence on whether chest scanning at each clinic
visit is necessary, or whether scanning could be limited to at-risk groups.
18
1+
8 MANAGEMENT OF STAGE I DISEASE
A pelvic CT may not be necessary in all patients. Pelvic nodal disease is strongly associated with
well established risk factors, namely, previous scrotal/inguinal surgery, previous retroperitoneal
surgery/irradiation, invasive tumour (through tunica albuginea of testis), bulky abdominal
nodes. If presence of risk factors can be reliably excluded using clinical information and the
appearance of a previous scan, pelvic CT can be omitted from surveillance or reassessment.38
Previous scans should be available.
3
D
A pelvic CT scan is only indicated where there are known risk factors for pelvic disease.
8.2.2
ADJUVANT CHEMOTHERAPY
Patients with stage I NSGCT or combined tumour and high-risk features should be offered
two courses of standard adjuvant bleomycin, etoposide and cisplatin (BEP) ie two courses of
cisplatin 50 mg/m2 on days 1-2 per three weekly cycle, bleomycin 30 IU on days 2, 8 and 15
per three weekly cycle and etoposide 120 mg/m2 on days 1, 2 and 3 per three weekly cycle.62
It is important to recognise that adjuvant chemotherapy should only be given to patients with
(high-risk) stage I NSGCT once the tumour markers have reached normal levels. If markers are
elevated but still falling it is possible that they would begin to rise, in which case two courses
of chemotherapy may be inadequate. Such patients should, therefore, have weekly tumour
marker estimations until the trend has become apparent.
3
Patients with low-risk stage I NSGCT or combined tumours, who are unable or unwilling to
follow a policy of surveillance, may be treated with two courses of BEP chemotherapy.
;;
isks and benefits of adjuvant chemotherapy and surveillance, in particular risk of relapse,
R
should be discussed with patients to agree an appropriate management strategy.
D
Two courses of adjuvant BEP chemotherapy should be offered to patients with stage
I NSGCT or mixed seminoma/NSGCT of the 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.
Patients with rising markers postoperatively (stage IM) should be considered to have metastatic
disease and should be treated accordingly (see section 9.2).
19
Management of Adult Testicular Germ Cell Tumours
9
Management of metastatic disease
9.1
Management of metastatic seminoma
9.1.1
STAGE II SEMINOMA
The RMH stage II category encompasses a wide range of disease extent (see Table 1).
Approximately 15% of patients fall into this category,63 and these are further subdivided into
A, B, C and D reflecting the prognostic significance of bulk retroperitoneal disease.
No systematic reviews or RCTs are available comparing treatments for stage II seminoma. Only
observational primary studies were identified, of which only one was a comparative study (with
an historical control group).63 Two non-systematic reviews were also identified.64,65 9.1.2
STAGE IIa and IIB seminoma
Results after treatment with both chemotherapy and radiotherapy are good, particularly in stage
IIA disease.49,66 There are no data to support the use of one treatment over another.
3
The adverse effect profile is different for chemotherapy and radiotherapy and the optimal
treatment for an individual patient will depend on clinical judgement and patient preference.
One study, comparing 33 patients with IIA/B seminoma treated with carboplatin and radiotherapy
to 80 historical controls treated with radiotherapy alone, found a trend towards better relapsefree survival in favour of combination therapy (97% v 81%).63 The treatment effect was more
pronounced for patients with stage IIB tumours (overall survival 100% v 94%, relapse-free
survival 100% v 73%).
2-
D
Sequential chemotherapy and radiotherapy can be considered as an alternative to
radiotherapy alone in stage IIB.
;;
9.1.3
In stage IIA seminoma both chemotherapy and radiotherapy treatment options should
be considered and discussed with the patient. The optimal treatment for an individual
patient will depend on clinical judgement and patient preference.
STAGE IIC AND IID SEMINOMA
Three series in the literature separate out patients with larger masses and show that this is an
unfavourable group when treated with initial irradiation therapy alone.67-69 In the three series,
a total of 49 patients received primary irradiation with either infra-diaphragmatic or infra- and
supra-diaphragmatic radiotherapy. Seventeen patients (35%) relapsed following this treatment.
In addition, the irradiation volume would, of necessity, be large and include renal or hepatic
parenchyma, adding to toxicity.
Scheduling of chemotherapy in patients with stage IIC or IID seminoma is similar to that for
patients with good prognosis NSGCT which is described in section 9.2.1.
C
For patients with stage IIC or IID seminoma, chemotherapy is the recommended initial
treatment.
C
Scheduling of chemotherapy is similar to that used for NSGCTs, although the risks of
bleomycin pulmonary toxicity may be higher in this generally older age group and
bleomycin omission should be considered.
;;
20
Where chemotherapy is contraindicated, radiotherapy may be an acceptable alternative.
2+
9 MANAGEMENT OF METASTATIC DISEASE
9.1.4
Stage III AND IV SEMINOMA
Collected data on radiation therapy for stages III and IV disease show a survival of 36%
(136/375).70 As treatment with radiation therapy involves at least infra- and supra-diaphragmatic
fields to cover sites of known disease, and due to the risk of relapse and need for salvage
chemotherapy, initial systemic therapy is preferable. The use of initial radiation therapy in
stage III and IV disease has been supplanted by the use of cisplatin-based chemotherapy.71-73
CPatients with stage III and IV seminoma should be treated with cisplatin-based
chemotherapy.
Carboplatin has been assessed as a possible alternate to cisplatin, but an MRC randomised
study of 130 patients who received either carboplatin or etoposide and cisplatin was closed
prematurely due to poor accrual. Data showed an inferior disease-free survival for carboplatin in
a parallel trial in NSGCT. It was concluded that etoposide and cisplatin should remain standard
therapy and that carboplatin should only be used in exceptional circumstances.74
2+
1+
BIn patients with stage III and IV seminoma carboplatin should only be used as an
alternative to cisplatin in exceptional circumstances.
9.2
MANAGEMENT OF METASTATIC Non-Seminomatous Germ Cell Tumours
These cancers spread 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 AFP,
HCG and LDH which may reflect the underlying biological aggressiveness of these cancers.
These features have been incorporated by the International Germ Cell Consensus Classification
into the prognostic factor based staging of good, intermediate, and poor prognosis (see Table 2).35
Patients with no radiological abnormalities but rising markers are labelled stage IM and should
be treated as having metastatic disease. Current issues in the treatment of these patients include
the need for:
ƒƒ the reduction of treatment-related toxicity (for the good prognosis group, with a predicted
cure rate of over 90%),
ƒƒ an increase in efficacy of chemotherapy in the other groups.
9.2.1management 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,35 for example by reducing the number of cycles of chemotherapy
from four to three.
BEP refers to the 3-weekly regimen using bleomycin 30 mg on days 1 or 2, 8 and 15, and
etoposide 500 mg/m2 and cisplatin 100mg/m2 during week 1.
3-day BEP involves delivery of cisplatin over days 1 and 2 and etoposide over days 1-3.
5-day BEP involves delivery of cisplatin and etoposide over days 1-5.
S ystematic reviews have shown three cycles of BEP to have equal efficacy to four cycles in
terms of relapse-free survival, disease-free survival and progression-free survival. Three cycles
of BEP are also associated with less toxicity and better quality of life than four cycles. There
was no difference in efficacy between 3-day BEP and 5-day BEP.75,76
1++
APatients with a good prognosis metastatic non-seminomatous germ cell tumour should
receive three cycles of BEP chemotherapy in either a 3-day or 5-day schedule.
Other attempts to reduce the incidence of treatment-related toxicity have particularly
concentrated on the problems associated with cisplatin, etoposide and bleomycin.
21
Management of Adult Testicular Germ Cell Tumours
Cisplatin and carboplatin
The side effects of cisplatin comprise a significant component of both the early and late toxicity
of the BEP regimen. 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 intensive hydration 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 18% of
the patient’s glomerular filtration capacity and, although this causes little immediate problem,
for successfully treated patients who reach their fifth and sixth decades of life there may be a
considerable burden, especially an increased risk of hypertension.77
Carboplatin causes little renal toxicity at conventional dosage and does not cause significant
neurotoxicity or ototoxicity.78 As a result it is an attractive candidate as an alternative to cisplatin
in the management of patients with good prognosis disease. Trials comparing carboplatin with
cisplatin in this group of patients have been undertaken to assess if efficacy can be maintained
with a reduction in toxicity. These trials found that substitution of cisplatin with carboplatin results
in either no difference or inferior response rates, relapse-free survival and overall survival.75,76
1++
4
AIn patients with good prognosis metastatic non-seminomatous germ cell tumours
carboplatin should only be given in circumstances in which cisplatin is contraindicated.
Etoposide
Reducing the etoposide dose below 500 mg/m2 per cycle results in inferior progression-free
survival and overall survival.75,76
1++
Bleomycin
Bleomycin treatment can cause a number of side effects, including skin rashes and allergic
reactions, but pneumonitis is the most serious because of the potential for fatal pulmonary toxicity
in 1% of patients.79 Patients with impaired renal function are at increased risk of developing
pneumonitis, especially in those aged >40 years, with stage IV disease or with cumulative
bleomycin dose greater than 300 mg.79
2+
F our cycles of etoposide and cisplatin (EP) was equivalent to three cycles of BEP in terms of
favourable response rates (although the relevant study was underpowered to show a difference
in event-free or overall survival).75, 80 Four cycles of EP result in greater neutropenia but less skin
toxicity and less neuropathy than three cycles of BEP.75,80
educing the bleomycin dose results in inferior progression-free survival and overall survival
R
than conventional dosing, except where four cycles of EP are used.75,76
APatients with good prognosis metastatic non-seminomatous germ cell tumour and in
whom bleomycin is contraindicated should receive four cycles of EP chemotherapy
(with 500 mg/m2 etoposide and 100 mg/m2 cisplatin per cycle).
Randomised trials have demonstrated no significant improvement in relapse rate following
maintenance therapy, but report that the associated toxicity was greater.76
1++
here is evidence that treatment of testicular cancer in a specialist centre is associated with
T
improved results.20
3
DChemotherapy should only be given in a specialist centre and overseen by a clinician
experienced in the management of germ cell tumours.
22
9 MANAGEMENT OF METASTATIC DISEASE
9.2.2
MANAGEMENT OF PATIENTS WITH INTERMEDIATE AND POOR PROGNOSIS Nonseminomatous germ cell TUMOURS
In this group, with a predicted cure rate of 50-80%, the main challenge is to increase the efficacy
of chemotherapy. A number of approaches are under evaluation including dose escalation of
cisplatin, alternating regimens and reduction of inter-cycle interval-accelerated chemotherapy.81
Improvement of therapeutic results in those patients with aggressive disease can conceivably
be achieved by adding new drugs to the current regimens or by increasing the efficacy of the
drugs already in use. In vitro experiments and early clinical trials have shown that a dose effect
relationship exists for the action of cisplatin on germ cell tumours.82,83
The dose of cisplatin in most standard regimens has been 20 mg/m2 for five days combined
with bleomycin and vinblastine or etoposide. Increase in the intensity of cisplatin treatment
can be achieved by increasing the dose, (eg 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 benefits for doubledose cisplatin as part of the BEP regimen.84
The MRC/EORTC randomised trial (n=380) compared 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 every three weeks).
The BOP/VIP schedule incorporated rapid induction followed by potentially non-cross resistant
chemotherapy but found no advantage to the more intensive schedule.81,85
1+
The use of alternating regimens has also been addressed in other studies. The rationale for
alternating administration of different chemotherapy combinations is based on the theoretical
consideration that a given tumour mass contains cell populations which are sensitive to one
combination but resistant to the other and vice versa. Drug combinations in sequence have
been explored in non-randomised studies of cisplatin, vincristine, methotrexate, bleomycin/
actinomycin D, cyclophosphamide, etoposide (POMB/ACE) chemotherapy.86 One hundred and
six out of 193 fully evaluable patients had large volume metastatic disease and their overall
survival was almost 80%.
High-dose chemotherapy with peripheral blood stem cell or autologous bone marrow
transplantation has been used predominantly as salvage chemotherapy, 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 involving 141 patients with
advanced disease confirmed the feasibility and efficacy of repeated cycles of high-dose
chemotherapy.87
2+
Randomised trials of this approach as both salvage and first line treatment are now ongoing
but currently the role of high-dose chemotherapy remains unclear.88
In summary, at present there are no randomised studies to indicate superiority for treatment
other than BEP but other approaches are being examined.
D
Patients with adverse prognostic factors should be treated in specialist centres. Where
possible, patients should be entered into well designed multicentre studies to define
the optimal treatment for this group.
B
Outwith the trial setting standard initial chemotherapy for patients with intermediate
and poor-risk germ cell tumours is four courses of 5-day BEP.
23
Management of Adult Testicular Germ Cell Tumours
10 Management of residual masses after
chemotherapy
10.1
radiological imaging for residual mass
Residual masses are commonly seen following chemotherapy at a site of previous disease and
are often considerably smaller than at initial diagnosis. Testicular tumours tend to spread initially
via lymphatic spread to abdominal nodes (para-aortic and inter-aortocaval) and hence, this is
the most common site for a residual mass.
CT scanning is the most commonly used radiological investigation for assessment of residual
masses due to availability, ease of examination and reproducibility. CT is currently only able
to identify a residual mass by virtue of its size and is unable to discriminate active tumour from
treated fibrotic tissue. Using ionising radiation, there is a significant radiation dose.
MRI scanning is rarely used to assess residual masses due to significantly longer scanning times
and the inability to scan the lungs as part of a testicular tumour follow-up protocol. However,
it is as accurate as CT in identification of a residual mass but is currently unable to discriminate
active tumour from treated fibrotic tissue.39 A significant advantage of MRI scanning is the
absence of a radiation dose and it therefore should be considered if serial scans are required
over a short period of time.
PET (positron emission tomography) imaging using 2-[18F] fluoro-2-deoxy-D-glucose (FDG) is
a diagnostic technique that allows the visualisation of tumour cells with a higher than normal
metabolic rate when compared with tissue cells. PET/CT scanning with FDG combines the
functional imaging of PET scanning with the anatomical imaging of CT and can distinguish
residual viable tumour from fibrotic tissue. Care must be exercised with NSGCT masses as
differentiated teratoma may not show uptake on FDG-PET scanning.89 It is, however, more
accurate in seminoma masses where a negative result correlates closely with the absence of
active disease.90
A study of FDG-PET for detection and therapy control of metastatic germ cell tumour, concluded
that PET scanning should not be performed earlier than two weeks after completion of therapy.91
;;
In patients with a residual mass post-chemotherapy, FDG-PET/CT is not routinely
recommended, however may be used as a problem solving tool.
;;
F DG-PET/CT scans should not take place less than two weeks after chemotherapy due
to false positives secondary to inflammatory responses.
3
2+
10.2SURGERY
10.2.1SEMINOMA
Resection of seminoma is difficult and potentially dangerous due to lack of clear tissue planes
and tumour infiltration beyond resection margins, and is limited to exceptional cases where
the mass is well circumscribed and looks as though it can be resected completely.
;;
Surgery is not routinely indicated for patients with seminoma who have residual masses.
10.2.2NSGCT
Residual masses may remain after chemotherapy and marker normalisation.92 They may contain
viable embryonal carcinoma/yolk sac tumour/choriocarcinoma, differentiated teratoma, fibrosis/
necrosis or show transformation into non-germ cell malignancy. It should be made clear to
patients at the start of treatment that residual masses may have to be removed surgically. There
is a subgroup of patients with residual masses where immediate surgery may not be necessary
and careful monitoring is adequate. These are patients where the mass is ≤2 cm and is not
24
3
10 MANAGEMENT OF RESIDUAL MASSES AFTER CHEMOTHERAPY
cystic.93 The aim of surgery is complete excision of the residual mass and associated abnormal
tissue. Further clearance of the retroperitoneal nodes or complete para-aortic lymphadenectomy
can be performed but with an increased risk of retrograde ejaculation.94 Patients should receive
preoperative counselling with particular regard to the possibility of retrograde ejaculation and
the possible extent of surgery (eg the possibility of a nephrectomy being performed).
3
D
Patients with NSGCT who have residual masses after chemotherapy and whose markers
have normalised should be treated by complete excision.
If the 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.95
3
D
If the primary testicular tumour has not already been removed, an orchidectomy should
be performed at the same time as retroperitoneal lymph node dissection.
Incomplete excision is associated with poor prognosis.95 Series in which several surgeons have
operated sporadically have had higher rates of incomplete resection96 than those managed by
a single surgeon.92
2+
Surgery for metastatic NSGCTs in Scotland should be performed in a specialist centre with
experience in this operation. Surgeons should work closely with the oncology department
undertaking surgery for abdominal disease and cooperating with similarly specialised thoracic
surgeons. Thoracic surgery involves excision of mediastinal and pulmonary masses. 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 lung toxicity has occurred, present particular
problems with which anaesthetists and intensive therapy unit staff caring for these patients
must be familiar.
;;
S urgery for metastatic NSGCTs should be performed in a specialist centre with experience
in the operative management of these patients.
The role of chemotherapy or radiotherapy after surgery is unclear and is not necessary in all
patients even when there is viable tumour in the resected specimen. Some predictors for relapse
have been identified and include incomplete resection, greater than 10% of tissue being viable
tumour, the amount of embryonal carcinoma and the proliferation index. There is no clear
survival benefit in offering immediate chemotherapy post resection but in patients at high risk
of recurrence this should be considered.97,98
For selected patients whose response to chemotherapy is inadequate, and markers plateau
or rise, consideration may be given to interventional surgery.99 In this group, patients with
completely resectable tumour and elevated AFP alone have the highest chance of benefit
from post chemotherapy retroperitoneal lymph node dissection (RPLND) and surgery must be
planned in close cooperation between surgeon and oncologist.100 Chemotherapy may need to
be restarted immediately after initial recovery from surgery. Laparoscopic post chemotherapy
RPLND is feasible in expert hands but remains experimental.101
10.3RADIOTHERAPY
In patients with bulky stage II seminoma, radiotherapy has been given frequently to patients
with residual masses following chemotherapy. There are no data to confirm its value and a
retrospective review of MRC data indicates that there is no evidence to support its use.102
3
D
Patients with seminoma who have residual masses following chemotherapy can
generally be managed by a policy of observation rather than radiotherapy.
25
Management of Adult Testicular Germ Cell Tumours
11Treatment of relapsed disease
Following achievement of complete remission with chemotherapy for metastatic testicular
cancer, relapse is very unlikely. It occurs in less than 10% of patients with good prognosis
disease, but is more likely in patients with more advanced disease.75
There are two broad approaches which may be adopted to manage patients with relapsed
disease; standard-dose salvage or high-dose chemotherapy (HDCT). There is little evidence
from RCTs comparing these strategies. Within each strategy there are different approaches and
patient characteristics. They are usually reported in single institution or small multicentre studies
making comparison and conclusion hard to achieve. This highlights the need to apply prognostic
factors to this heterogeneous patient population to offer the most appropriate salvage therapy.
Although patients failing to be cured with first line chemotherapy will be candidates for salvage
therapy, occasionally the radiological appearance of progressive disease may mislead physicians
to initiate inappropriate salvage chemotherapy, for example, if the serum markers are falling
appropriately but progressive pulmonary disease is noted during cisplatin chemotherapy one
might suspect pseudo-progression from either bleomycin lung disease or enlarging differentiated
teratoma. Complete surgical excision of differentiated teratoma remains the treatment of choice.
Compared to early relapse, those relapsing more than two years from initial treatment have
better survival outcomes especially if the disease is unifocal and can be completely surgically
resected.103
;;
Surgery should be considered the mainstay of treatment for late relapse where feasible.
The small number of patients presenting with relapsed disease necessitates a specialist centre
approach. There is evidence that the outcomes for salvage therapies are worse in units who
see less than 20 first line metastatic patients per year.104,105
3
D
Patients with testicular germ cell cancer who relapse after first line cisplatin based
chemotherapy should be managed in specialised centres.
Patients with rising markers found to have more than one site of disease will require further
salvage chemotherapy. This includes patients who after first line chemotherapy have nonresectable and radiologically progressive disease.
This is a small, heterogeneous group of patients and some studies have used criteria to predict
survival outcomes. These scoring criteria are based on cohort studies which lack external
validation. An analysis of 1,984 patients relapsing after standard first line chemotherapy identified
a number of prognostic factors that can be combined in a model (see Table 3) to estimate two
year progression-free and overall survival (see Table 4).106
26
3
11 TREATMENT OF RELAPSED DISEASE
Table 3: International Prognostic Factors Study Group Prognostic Score
SCORE POINTS
Parameter
0
1
2
3
Primary site
Gonadal
Extragonadal
-
Mediastinal
nonseminoma
Prior response
complete
remission/
partial
remission,
negative
markers
partial
progressive remission,
disease
positive
markers /stable
disease
Progression-free
interval, months
>3
≤3
-
AFP salvage
Normal
≤1,000
>1,000
HCG salvage
≤1,000
>1,000
-
-
liver, bone, brain
metastases
No
Yes
-
-
-
ƒƒ Regroup score sum into categories: (0)=0; (1 or 2)=1; (3 or 4)=2; (5 or more)=3
ƒƒ Add histology score points: pure seminoma=-1; non-seminoma or mixed tumours=0
ƒƒ Final prognostic score (-1=very low risk; 0=low risk; 1=intermediate risk; 2=high risk;
3=very high risk)
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. The International Prognostic Factors Study Group: J Clin Oncol Vol. 28(33), 2010:4906-4911.
Table 4: Survival rates according to prognostic categories
Prognostic
category
(n=564)
Score No. of %
patients
Very low
-1
76
13.0 1
Low
0
132
22.6 2.17
Intermediate
1
219
High
2
Very high
3
No classification
Hazard
ratio
2-year
progressionfree survival
(%)
3-year
overall
survival
(%)
75.1
77.0
1.32 to 3.58
51.0
65.6
37.4 3.20
2.00 to 5.11
40.1
58.3
122
20.9 4.85
2.98 to 7.89
25.9
27.1
36
6.1
6.70 to 20.45 5.6
11.70
95% CI
6.1
69
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.
The International Prognostic Factors Study Group: J Clin Oncol Vol. 28(33), 2010:4906-4911.
D
The International Prognostic Factors Study Group’s model should be applied to
guide prognostic information for patients who relapse after first line platinum based
chemotherapy.
27
Management of Adult Testicular Germ Cell Tumours
The use of platinum in first line treatment is essential. The sensitivity to platinum, which is
indicated by response to subsequent salvage therapies with either high- dose or standard-dose
regimens, helps predict outcome. Thus, platinum chemotherapy is a crucial component of any
salvage regimen offered with a potential of cure.
The Beyer criteria have been used to predict the likely benefit from high-dose chemotherapy
and should only be used to score patients prior to consideration of high-dose treatment (see
Tables 5 and 6).107
3
Table 5: Beyer prognostic groupings
Criteria
Score
Progressive disease before HDCT
1
Mediastinal primary tumour
1
Refractory disease (stable disease, but with evidence of tumour progression 1
within four weeks of the last chemotherapy) before HDCT
Absolute refractory disease (failing to achieve stable disease) before HDCT
2
HCG >1,000 IU/L before HDCT
2
Table 6: Beyer Risk Score
Prognostic groups
Failure-free survival (%)
Overall survival (%)
1 year
2 year
1 year
2 year
Good (score 0)
56
52
73
61
Intermediate
(score 1 or 2)
28
27
50
34
Poor (>2)
5
5
19
8
C
Due to the low survival predicted for the Beyer poor prognosis group (score >2) such
patients should not be subjected to high-dose chemotherapy. Those with intermediate
and good Beyer prognostic score (0 to 2) may be considered for high-dose chemotherapy.
There are few randomised controlled trials of patients with relapsed disease as the numbers
of patients remain small. The only RCT comparing a cycle of high-dose chemotherapy to
conventional chemotherapy did not show a significant benefit in terms of event-free and overall
survival for high-dose chemotherapy.108
1-
This is in contrast to smaller phase II trials and a large matched pair analysis.109-111,112 The former
suggested an increase of 29-90% in disease-free rates with high-dose strategies compared to
standard approaches, at a minimum of two years follow up. The latter suggested an improvement
in overall survival of 9 -11% and event-free survival of 6-12%.112
2++
3
High-dose chemotherapy cannot be recommended as routine treatment for relapsed germ cell
tumours although it may still remain a treatment option, in selected cases, using the prognostic
models described above.
One RCT which compared a single cycle of high-dose chemotherapy to two consecutive
cycles showed the survival benefit was similar for both groups but that sequential high-dose
chemotherapy was better tolerated with a lower death rate due to toxicity in the sequential
treatment arm.113
28
1-
11 TREATMENT OF RELAPSED DISEASE
Due to the many different regimens used for high-dose chemotherapy in each study, and the
lack of direct comparisons, it is difficult to recommend an optimal regimen, however, two cycles
of high-dose carboplatin and etoposide may be better tolerated than one cycle with more than
two chemotherapy agents.
B
High-dose chemotherapy is not routinely recommended as salvage therapy for germ
cell cancer patients who relapse after standard platinum based chemotherapy.
At time of relapse most patients retain platinum sensitivity and standard-dose salvage regimens
should be cisplatin- and ifosphamide-based. Response rates are generally around 50% with
long term disease-free survival rates of 20-30%. The largest body of evidence for standard-dose
salvage therapy is for the paclitaxel-based, TIP (paclitaxel, ifosphamide and cisplatin)114 or
vinblatin-based, VIP (etoposide, ifosphamide and cisplatin).115 Increasingly, TIP is being used
but there is no randomised comparison in terms of efficacy or toxicity of these two regimens.
The doses used in TIP have been reported to lead to better outcomes in terms of response rates
and survival,114 although patients in this study had good prognostic features compared to other
series. Furthermore, some patients may have had suboptimal first line therapy accounting for
some of the apparent improved results compared to other TIP regimens.116
3
In patients who relapse after standard-dose salvage therapy only high-dose chemotherapy
offers a chance of cure.110 For others, further lines of treatment are generally considered to be
palliative. The choice of third line therapy will be heavily dependent on the patient’s bone
marrow reserve, performance status and resolution of toxicity from prior regimens. There are
a number of single agent and combination regimens, containing gemcitabine, oxaliplatin,
paclitaxel and epirubicin, none of which have been subject to comparative studies.117-120 These
regimens lead to a low overall response rate of 18-24% with short duration of response (median
4.5 to 17 months) and significant haematological toxicity.
2+
3
The only independent predictor of response to third-line therapy was a long progression-free
interval following high-dose therapy.121 The most active regimen in this area is single agent
oral etoposide which has the advantage of outpatient administration.121
3
There is a need for further evidence of effective treatment strategies in this patient group.
;;
he aim of treatment following progression after high-dose chemotherapy or where
T
high-dose chemotherapy is not considered beneficial should be for palliation. Careful
consideration should be given to benefit/risk ratios of standard cytotoxics in this setting
due to heavy prior treatment.
;;
ecruitment to clinical trials is strongly recommended in patients with relapsed disease,
R
where appropriate.
29
Management of Adult Testicular Germ Cell Tumours
12Late toxicity
12.1Epidemiology
Germ cell tumours occur in relatively young patients representing the commonest cancer in
teenage and young adults in Scotland. As survival and incidence rates continue to increase
more young men will live longer with potential toxicities of their therapy.122,123
There are well documented short, medium and long term effects of treatment such as
neurotoxicity, nephrotoxicity, pulmonary toxicity and androgen deficiency.75 There is also an
emerging body of evidence of very late toxicity occurring well beyond the time most people
are discharged. The most serious of these late effects, with the largest volume of evidence,
pertains to the risk of second cancers and cardiovascular (CV) events. These have been studied
in the LATENT (Late Adverse Treatment Effects in Netherlands Testis Cancer patients) study
which showed a cumulative incidence of either major late effect of 17.6% by 20 years after
diagnosis, accounting for an absolute excess risk for second malignancy and CV disease of 32
and 15 cases per 10,000 person-years, respectively.43 There have been major changes in the
management of testicular cancer which will affect emerging late toxicity patterns.124 However,
there remains an unmet information need for patients and their GPs regarding long term effects.
Many of the studies of commonly applied therapies have short follow up with little late toxicity
reporting and no reporting of very late toxicity.125,53,62
12.1.1
OVERALL MORTALITY
One large population based study of almost 39,000 patients looking at non-cancer deaths
showed a raised SMR of 1.06 (95% CI 1.02 to 1.17) from several pooled cancer registries.126
This equates to an absolute excess number of deaths of 3.7 per 10,000 person years. The SMRs
were generally higher from NSGCTs compared to seminomas. It is notable that when SMRs were
analysed according to era of treatment no decline was seen despite the introduction of more
modern therapies. Mortality for those diagnosed before age of 35 was significantly elevated
regardless of treatment.
2+
12.2CARDIOVASCULAR LATE EFFECTS
12.2.1
CARDIOVASCULAR MORTALITY
A Norwegian registry of 3,378 patients showed a marginally increased SMR of 1.2 (95% CI
1.0 to 1.5), for all CV disease in germ cell patients although the SMR for myocardial infarction
was not statistically raised.127
2+
Mortality from hypertension related disorders is significantly raised in germ cell cancer patients,
SMR=1.39 (95% CI 1.01 to 1.89); for those treated aged less than 35 years the SMR for CV
disease was 1.23 (95% CI 1.09 to 1.39).126
12.2.2
CARDIOVASCULAR INCIDENCE
The LATENT study43 of 2,707 patients had a median follow up of 17.6 years and showed, 20
years post-diagnosis, a cumulative excess incidence for either serious late effect of 4% for those
treated with chemotherapy and 1.5% for those receiving sub-diaphragmatic radiotherapy. This
increased to >10% for those treated with extended field radiotherapy or combined modality
treatments.
In a large study a twofold or greater age-adjusted relative risk of developing CV disease that was
not explained by increases in cardiac risk factors was observed for all treatment modalities. The
estimated event rate at 10 years was 1.4% for patients managed with surveillance compared to
7.2% for patients treated with radiotherapy, 3.4% for those treated with chemotherapy and 4.1%
for those treated with both modalities.52 In a smaller cohort study of patients with metastatic
testicular cancer, which had a longer median follow up of 14 years, the CV disease event rate
was sevenfold that of stage I patients.128
30
2+
2+
12 LATE TOXICITY
12.2.3
A study comparing CV disease incidence in 2,512 five-year survivors of testicular cancer,
found that SIR for MI specifically was elevated for survivors of NSGCT aged less than 45 years
(2.06, 95% CI 1.15 to 3.41) and for those aged 45-54 (1.86, 95% CI 1.2 to 2.74).44 However,
beyond the age of 55, SIR rate for MI was not elevated above that of age-matched controls. A
similar trend for the SIR for MI in seminoma to decrease with increasing follow-up time was
documented in this study.
2+
The latency of cardiac events is around 5-8 years52 but up to 16 years post-treatment.128
2+
CARDIOVASCULAR RISK
One study showed that 97% of patients treated with chemotherapy had at least one CV risk
factor (hypertension, hypercholesterolaemia, a smoking history, or a positive family history for
CV events), with all risk factors being statistically significantly more frequent in those treated
with chemotherapy compared to stage I controls.128 There are, however, inconsistencies in the
evidence with regard to individual CV risk factors. For example, in an underpowered study
investigators were unable to demonstrate any adverse effect of cisplatin-based chemotherapy
on lipid profiles,129 whilst others have documented significant increases in lipids compared
to national estimates.130 In a further study, a significant difference was noted in low density
lipoprotein (LDL)-cholesterol or the use of lipid lowering drugs in a cohort of testis cancer
patients treated with chemotherapy (mostly BEP) compared to controls.131
A large case control study (n=1,289) of blood pressure found, at median follow up of 11 years,
an age-adjusted increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP)
compared with stage I patients, with an odds ratio for hypertension of 1.24 (95% CI 0.88 to
1.75) for radiotherapy patients, 1.62 (95% CI 1.14 to 2.32) for patients treated with <850 mg
of cisplatin and 2.37 (95% CI 1.4 to 4.01) for patients treated with >850 mg of cisplatin.132
However, in a smaller study, with shorter median follow up of seven years, no significant
differences were noted in hypertension rates.131
12.2.4
2+
3
2+
Obesity is seen more frequently in those treated with the highest doses of cisplatin compared to
controls and those treated with other therapies (age-adjusted odds ratio 2.4, 95% CI 1.3 to 4.4).132
2++
The LATENT study showed that the increased risk due to smoking, which in itself is an
independent predictor of CV disease in this patient group, was significantly greater (hazard ratio
1.8, 95% CI 1.3 to 2.4). In multivariate analysis for CV disease, including peripheral vascular
disease, chemotherapy was associated with a hazard ratio of 1.7 (95% CI 1.2 to 2.4).43
2+
The largest study of CV risk factors suggests clustering of these factors in testis cancer patients,
especially in those treated with a cumulative dose of cisplatin >850 mg (age-adjusted odds
ratio for metabolic syndrome 2.8, 95% CI 1.6 to 4.7). In this study a smoking history of ≥20
pack-years was an independent predictor of the presence of the metabolic syndrome.133
2++
Individual management strategies
Three single-centre studies, in which patients with stage II A/B seminoma represented up to
37% of the total series, reported late radiotherapy toxicity.51,134,135 The use of extended field
radiotherapy and outdated techniques, in terms of dose and fractionation schedules, are
associated with an increased CV risk, although this is difficult to quantify from these studies due
to small numbers, extent of radiotherapy field and different reporting of the CV risk. The largest
study of 477 patients (although only 17% had stage II seminoma) showed a SMR of 1.6 (95%
CI 1.21 to 2.24).51 The SMR was higher for those treated below the age of 40 years and with
mediastinal radiotherapy. When analysis is restricted to stage II patients SMR is non-statistically
elevated (SMR 1.54, 95% CI 0.62 to 3.19).
2+
3
Two cohort studies examined the late effects following adjuvant chemotherapy for stage I high
risk NSGCT, with BEP over two cycles, but neither study commented on adverse CV effects.62,136
31
Management of Adult Testicular Germ Cell Tumours
For metastatic disease, the documented increase in CV risk is more marked with regimens that
may be considered outdated systemic therapy for germ cell cancer, such as cisplatin, vinblastine
and bleomycin (PVB) and less prominent for MI specifically with BEP,44 though follow up of
this group is relatively short (12.2 years). There is limited evidence demonstrating a lack of
heterogeneity of effect with carboplatin- versus cisplatin-based therapies and regimens with or
without bleomycin.44,52 Studies that have analysed the increased risk by era of treatment have
generally not shown a decline in excess morbidity with more recent therapies.44,127
2-
Assessing risk
Combined modality chemotherapy and radiotherapy for germ cell cancer is associated with
an increased SIR for MI (2.06, 95% CI 1.17 to 3.35) and CV disease overall 2.78 (95% CI 1.09
to 7.07).52
2+
There is little evidence to support the use of standard CV risk factor screening tools in patients
with testicular cancer, such as the Framingham index. However, in a Scandinavian study over
50% of testicular cancer survivors fell into an intermediate or high risk group on the Systematic
Coronary Risk Evaluation (SCORE) model for estimating risk of fatal CV event within 10 years.
Those patients treated with a cumulative cisplatin dose of >850 mg have an odds ratio (relative
to surgically treated patients) of 3.4 (95% CI 1.3 to 8.7).137
3
;;
ncologists should advise survivors of testicular cancer and their GPs of the increased
O
risk of cardiovascular disease.
;;
Ps should reinforce advice to survivors of testicular cancer on prevention of
G
cardiovascular disease as outlined in SIGN 97.
C
Survivors of testicular cancer should be advised not to smoke.
12.3SECOND MALIGNANCIES
One systematic review suggested an approximately twofold higher risk of second malignancy
for chemotherapy and radiation alone and a threefold risk for combined modality treatment in
survivors of testicular cancer compared with the general population.75 Various solid cancers
and leukaemias are seen with significantly increased frequency following therapy for testicular
cancer.75 The survival rates for these second cancers are similar to those seen in patients with
no prior cancer history.138
2++
3
No studies investigating the information which should be given to patients regarding potential
second cancers (excluding new germ cell primaries) resulting from cancer treatment were
identified. The most useful evidence was derived from large registry based observational
studies. Evidence was considered only from studies analysing outcomes from standard treatment
approaches.
12.3.1
SECOND NON-GERM CELL CANCER MORTALITY
Deaths due to cancers of stomach, lung and pancreas had significantly elevated SMRs. As yet
there does not appear to be a reduction in second malignancy related mortality despite the
introduction of newer management strategies.127
32
2+
12 LATE TOXICITY
12.3.2
SECOND NON-GERM CELL CANCER INCIDENCE
The increased risk of second malignant neoplasm (SMN) after treatment for a germ cell tumour
appears to be around twofold (SMR 2.0, 95% CI 1.7 to 2.4), representing an absolute excess
risk of 14.1 cases per 10,000 person-years of follow up for a Norwegian population.127
2+
In pooled cancer registry data of 29,511 survivors of testicular cancer, including Scottish, second
non-germ cell cancers were reported with increased SIRs from sex-, age- and population-adjusted
controls, (SIR 1.65, 95% CI 1.57 to 1.73).139 There are similar SIRs from individual national
studies including 1.7-fold, (95% CI 1.5 to 1.9), representing an absolute excess of 32.3 cases
per 10,000 person years of follow up for a Dutch population.43 Amongst an English population
living more than 20 years after a diagnosis of testicular cancer, the SIR of second cancers for
seminoma patients was 2.18 (95% CI 1.79 to 2.64) and 1.97 for NSGCT patients (95% CI 1.4
to 2.69).140
2+
2-
SIRs of >2 are reported for solid cancers including gastrointestinal cancers (stomach, pancreas,
bile duct, small bowel, colorectal), lung cancer, urinary tract (bladder, kidney, prostate),
melanoma and non-melanaomatous skin cancer, thyroid cancer and soft tissue sarcoma.43, 139,140
22+
The SIR for haematological malignancies (excluding chronic lymphocytic leukaemia) ranges
from 1.6, (95% CI 0.6 to 3.5)43 to 2.6 (95% CI 2.1 to 3.2)141 leading to an excess cumulative risk
of 0.23% by 30 years after treatment for testicular cancer. However, SIRs can be considerably
higher (approximately sixfold) for NSGCT139 in the early years of follow up.140 The risk appears
to be higher after treatment with chemotherapy alone compared to radiotherapy alone.141 Risk
appears to be increased with the more recent introduction of etoposide to regimes containing
cisplatin139 and appears to be dose-related for both chemotherapy and radiotherapy.142
2-
12.3.3LATENCY OF SECOND NON-GERM CELL CANCER
12.3.4
There is evidence of a latency effect for both leukaemias and for solid tumours which appears
to be longer for the latter. There is a trend to increasing SIR with various common solid cancers
with increasing follow-up time, particularly for seminomas, with evidence that the risk continues
after 20 years.139,140
2-
For leukaemia, median latency is around five years.139, 142 The risk was found to decline sharply
after the first five years following initial treatment, but remained significantly elevated beyond
15 years of follow up, the risk being higher for chemotherapy compared to radiotherapy.141
Further evidence suggests an early increase in risk of leukaemia with an increased excess in
the first 10 years following treatment for both seminoma and NSGCT amongst UK patients.140
2-
The median latency for solid second malignancies after radiotherapy for stage IIA/B appears to
be in the range of eight134 to 15 years,49 usually within or at the edge of the radiotherapy field.
2-
RISK FACTORS FOR SECOND NON-GERM CELL CANCER
Radiotherapy
In a multivariate analysis of potential risk factors for second malignancies hazard ratios of
2.6 (95% CI 1.7 to 4.0) for subdiaphragmatic radiotherapy and 3.6 (95% CI 2.1 to 6.0) for
subdiaphragmatic and mediastinal radiotherapy were found.43
3
In six single-centre studies49-51,134,135,143 of up to 453 patients, the use of extended field radiotherapy
(using generally outdated techniques in terms of dose and fractionation schedules) was associated
with an increased non-germ cell second malignancy rate, with a relative risk up to fourfold. The
risk appears higher if patients are treated at a younger age,43 but may not be apparent until after
many years. No increase was noted until after 15 years of follow up in some series.51
2-
33
Management of Adult Testicular Germ Cell Tumours
Chemotherapy
There is an increased risk for second malignancy after combination chemotherapy (either BEP
or PVB), (SIR 2.1, 95% CI 1.4 to 3.1).43 The risk of second malignancy after cisplatin-containing
regimens was associated with a hazard ratio of 2.1-fold compared to patients treated with
surgery alone.43 The SIRs for individual tumour types were significantly raised for carcinoma
of the bladder and melanoma.43 Two studies looking at stage I NSGCT and adjuvant BEP did
not comment on second malignancy but both had only short median follow-up times of four
years and 9.4 years respectively.62,136
2+
3
Surgery
There appears to be no significant increase in risk for those treated by orchidectomy alone,
compared with age- and period-matched population controls.43
2+
Smoking
There is evidence that smoking can increase the risk of SMN, hazard ratio 1.6 (95% CI 1.3 to
2.4), however, increased risks persisted for all treatments after adjustment for smoking.43
2+
Age
There is evidence to suggest decreasing relative risk of second malignancies with increasing
age at diagnosis. The excess relative risk of leukaemia after seminoma decreased strongly with
increasing age.141
;;
ncologists should advise patients and their GPs of the increased risk of non-germ cell
O
second malignancies. It should be noted that the risks are greatest for those treated before
age 30 years. Increased risks continue beyond 15 years following treatment.
;;
eneral health advice should be reinforced, particularly avoidance of smoking, and
G
patients should be encouraged to maintain a healthy diet and level of physical activity
in order to reduce cancer risk (see also section 2 of SIGN 67: Management of Colorectal
Cancer).
;;
atients should remain vigilant of any unusual or alert symptoms, particularly relating to
P
the gastrointestinal, respiratory or urinary tract, and report these promptly to their GPs.
;;
here should be increased awareness of the risk of haematological malignancies especially
T
after chemotherapy and solid malignancies in or near the fields of radiotherapy. There
should be a low threshold for further investigation and appropriate referral to secondary
care if any alert symptoms are reported. Annual urinalysis for haematuria may be
considered.
There is no evidence to suggest that organ-specific surveillance for second malignancy is
recommended, in view of the level of increased risk compared to that of the general population
and the wide range of potential malignancies. The risks of surveillance procedures that may be
invasive or involve cumulative exposure to radiation and the effectiveness of current procedures
to detect early stage malignancy must be taken into account. For example, in the case of a family
history of colorectal cancer, the risk must be assessed as being greater than fivefold that of the
age-matched population before surveillance is recommended.144 This situation may change
significantly in the future, with the development of more effective surveillance strategies.
34
2-
13 POST-TREATMENT FOLLOW UP
13 Post-treatment follow up
The rationale for follow up is to:
ƒƒ
ƒƒ
ƒƒ
ƒƒ
detect relapse at a stage where therapy has the best chance of being effective
monitor and treat treatment-related toxicity
detect metachronous cancers in particular contralateral testicular cancers
offer support and counselling with particular reference to issues such as employment and
fertility.
Suggested follow up regimens are illustrated in tables 7 to 10 below.
The optimum timing of imaging in the follow up of patients is not clear but is being investigated.
13.1FOLLOW-UP STRATEGIES FOR STAGE I SEMINOMA
One well conducted systematic review assessed the rates of relapse with time for each of
the stage I management strategies.40 The crude relapse rates (17% for surveillance, <5% for
adjuvant strategies) are consistent with other studies (median follow up ranged from 28 to 208
months). The data regarding relapse for each of the management strategies are itemised in the
following sections.
13.1.1Surveillance
In approximately 92% of patients with stage I seminoma who relapse on surveillance, the site
of first detected relapse is in the infradiaphragmatic nodes (primarily the para-aortic nodes).
The annual hazard rate for relapse on surveillance exceeds 5% for two years after diagnosis,
lies between 1% and 5% during years 3 and 4, and falls below 1% thereafter.40
13.1.2
13.1.3
2++
Adjuvant radiotherapy
In approximately 78% of patients with stage I seminoma who relapse following 'dog-leg'
radiotherapy, the site of first detected relapse is in the chest or palpable lymph node areas (neck,
supraclavicular fossa or inguinal regions). The annual hazard rate for relapse following 'dogleg' radiotherapy lies between 1% and 5% from years 1 to 3, and falls below 1% thereafter.40
2++
In approximately 59% of patients with stage I seminoma who relapse following para-aortic
nodal radiotherapy, the site of first detected relapse is in the infradiaphragmatic (mostly pelvic)
nodes. The annual hazard rate for relapse following para-aortic radiotherapy lies between 1%
and 5% from years 1 to 3, and falls below 1% thereafter.40
2++
Adjuvant carboplatin
In approximately 85% of patients with stage I seminoma who relapse following a single dose
of carboplatin, the site of first detected relapse is in the infradiaphragmatic nodes (primarily
the para-aortic nodes), with half of the rest being detected in the chest. The annual hazard rate
for relapse following carboplatin lies between 1% and 5% during years 1 to 3, and falls below
1% thereafter.40
2++
BPatients who undergo surveillance or adjuvant therapy for stage I seminoma should
be followed up according to protocols which take into account the likely site and
timing of first relapse to define the frequency of clinic visits, blood tests and radiology
investigations. This should include cross-sectional imaging of the abdomen in patients
under surveillance and after adjuvant carboplatin, and chest imaging in all patients.
Cross-sectional imaging of the pelvis may also be indicated in selected patients (eg after
para-aortic radiotherapy alone, or where the risk of pelvic nodal disease is considered
to be elevated).
35
Management of Adult Testicular Germ Cell Tumours
An example follow-up schedule is described in Table 7. This schedule takes into account the
likely timing and site of relapse for each postorchidectomy strategy. Cross-sectional imaging
with CT is recommended in patients undergoing surveillance as well as following para-aortic
radiotherapy and adjuvant carboplatin, however, studies are ongoing (such as the MRC Trial
of imaging and schedule in seminoma testis (TRISST) study) on this topic.
Table 7: Suggested follow-up protocol for stage I seminoma post-treatment
STRATEGY
Surveillance
Adjuvant
para-aortic
nodal RT
Adjuvant
'dog-leg' RT
Adjuvant
carboplatin
Year 1
Year 2
Year 3
Year 4
Year 5
Years 6-10
3-monthly
clinic
visit*
3-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
annual
clinic visit
6-monthly
CT of
abdomen§
6-monthly
CT of
abdomen§
annual
CT of
abdomen§
annual
CT of
abdomen§
3-monthly
clinic
visit*
3-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
discharge
from clinic
annual CT
of pelvis
annual CT
of pelvis
annual CT
of pelvis
3-monthly
clinic
visit*
3-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
3-monthly
clinic
visit*
3-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
annual
CT of
abdomen§
annual
CT of
abdomen§
annual
CT of
abdomen§
discharge
from clinic
annual
clinic visit
* each clinic visit involves an assessment of symptoms, clinical examination, chest X-ray and
tumour markers (AFP and HCG); LDH has not been shown to be helpful in the follow up in
patients with germ cell tumours (see section 4.2)
§ may include CT of pelvis as well (if prior inguinoscrotal surgery)
36
13 POST-TREATMENT FOLLOW UP
13.2FOLLOW-UP strategies FOR STAGE I NSGCT
Table 8: Suggested follow-up protocol for stage I post orchidectomy low-risk NSGCT
STRATEGY
Year 1
Year 2
Year 3
Surveillance
monthly
clinic
visit*
2-monthly
clinic visit*
3-monthly 4-monthly 6-monthly annual
clinic
clinic
clinic
clinic visit
visit*
visit*
visit*
CT scan of
abdomen
at 3
and 12
months§
Consider
stopping in
uncomplicated
cases
Adjuvant
monthly
chemotherapy clinic
visit* for
6 months,
then
2-monthly
for 6
months
3-monthly
clinic visit*
Year 4
Year 5
Years 6-10
6-monthly 6-monthly 6-monthly annual
clinic
clinic
clinic
clinic
visit*
visit*
visit*
visit*
CT of chest, abdomen after adjuvant treatment and if CT appears normal, no
further routine CT scans.
* each clinic visit involves an assessment of symptoms, clinical examination, chest x-ray and
tumour markers (AFP and HCG); LDH has not been shown to be helpful in the follow up in
patients with germ cell tumours (see section 4.2)/
§ May include CT of pelvis as well (if prior inguinoscrotal surgery)
For high risk stage I NSGCT surveillance, it is suggested that CT scans of thorax and abdomen
should be done at 3, 6, 9, 12, and 24 months.
13.3FOLLOW-UP strategy FOR METASTATIC SEMINOMA
Table 9: Suggested follow-up protocol for metastatic seminoma (postradiotherapy for stage
IIA/B, postchemotherapy for stages II-IV)
STRATEGY
Year 1
Year 2
Year 3
Year 4
Year 5
Years 6-10
After radical
radiotherapy
or
chemotherapy
3-monthly
clinic
visit*
3-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
annual
clinic
visit*
If post-treatment CT abdomen and pelvis scan is normal, no further routine
CT scans. If post-treatment CT scan is abnormal, repeat the CT scan
every six months for 18 months but stop as soon as CT scan is normal or
appearance is stable.
* each clinic visit involves an assessment of symptoms, clinical examination, chest X-ray and
tumour markers (AFP and HCG): LDH has not been shown to be helpful in the follow up in
patients with germ cell tumours (see section 4.2);
37
Management of Adult Testicular Germ Cell Tumours
13.4FOLLOW-UP STRATEGY FOR METASTATIC NSGCT
Table 10: Suggested follow-up protocol for metastatic NSGCT
STRATEGY
Year 1
Year 2
Year 3
Year 4
Year 5
Years 6-10
After
chemotherapy
(+/- resection
of residual
masses)
monthly
clinic
visit* for
6 months,
then
2-monthly
for 6
months
3-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
6-monthly
clinic
visit*
annual
clinic
visit*
CT of chest, abdomen after treatment and if CT appears normal, no further
routine CT scans. If post-treatment CT is abnormal, then ongoing imaging
of the area of abnormality is required.
* each clinic visit involves an assessment of symptoms, clinical examination, chest X-ray and
tumour markers (AFP and HCG): LDH has not been shown to be helpful in the follow up in
patients with germ cell tumours (see section 4.2);
38
14 PROVISION OF INFORMATION
14 Provision of information
This section reflects the issues likely to be of most concern to patients and their carers. These
points are provided for use by health professionals when discussing testicular germ cell tumours
with patients and carers and in guiding the production of locally produced information materials.
14.1INFORMATION AND COMMUNICATION
One of the major concerns to this group of patients and their carers is their fear of the
unpredictable nature of the disease. Initial explanation by the doctor is not always understood
or retained. Nurses can play a key role in ensuring that the necessary information is repeated
tactfully, with sensitivity and in terms which patients and carers can understand.
;;
he provision of appropriate information should be made available to patients and their
T
carers to promote maximum understanding and to assist coping mechanisms. Access
to written materials, computerised information and a named nurse should be readily
available at all stages of disease management.
;;
It is imperative that the patient’s general practitioner and other community services are
well informed and involved in treatment and follow up.
14.2CHECKLIST FOR PROVISION OF INFORMATION
This section gives examples of the information patients/carers may find helpful at the key stages
of the patient journey. The checklist was designed by members of the guideline development
group based on their experience and their understanding of the evidence base. The checklist
is neither exhaustive nor exclusive.
Testicular cancer can be very traumatic for patients and their families, both in terms of the
acute illness and the potential for long term complications. There are many issues with which
families may have to cope and they need support and reassurance from healthcare professionals
throughout the patient journey.
PATIENT AWARENESS
As early presentation is crucial, health awareness is to be supported and encouraged.
Education, particularly through schools and youth groups, should be planned to encompass
signs and symptoms of testicular cancer and to encourage young men to be aware of the shape,
size and feel of their scrotum so that changes or abnormalities may be noted and reported.
Awareness should be raised of predisposing factors (uncorrected testicular maldescence, or
surgical correction carried out after the age of 10 years) and that having a first-degree relative
with a history of testicular cancer may increase their risk up to tenfold although it remains
low in absolute terms.145
INITIAL PRESENTATION AND REFERRAL FROM GP TO UROLOGIST
ƒƒ E nsure patients presenting with a suspected testicular malignancy have an understanding
of the necessity of referral to a specialist, usually an urgent referral within two weeks.
ƒƒ Explain to patients that testicular cancer is usually diagnosed by scrotal ultrasound, then
surgery.
ƒƒ Explain the aetiology of testicular cancer and inform them of the excellent prognosis.
ƒƒ Offer specialist nurse support from the Cancer Centre as early as possible.
39
Management of Adult Testicular Germ Cell Tumours
DIAGNOSIS: UROLOGY
ƒƒ Explain the cause of testicular cancer to patients.
ƒƒ Reassure patients by offering advice on curability and prognosis.
ƒƒ Advise patients of the need for blood tests (for tumour markers)and staging CT scan, usually
three weeks postsurgery.
ƒƒ Offer patients verbal and written information outlining a clear pathway of how they will
be treated and cared for.
ƒƒ Allow sufficient time to discuss the following issues and ensure patients are involved in
discussions:
-- sexual function/relationships
-- introduce discussion of fertility and sperm storage
-- body image/insertion of prosthesis at time of orchidectomy
-- depression and anxiety.
ƒƒ Discuss the immediate effects of the orchidectomy and advise on the following:
-- recovery period, eg how long to stay off work and when to resume physical activity
-- managing the prosthesis
-- pain relief.
ƒƒ Ensure patients are aware of where they can go for further information and support (see
section 14.4).
TREATMENT: ONCOLOGY
ƒƒ I nform patients of treatment plans/options and advise them on the timeframe for treatment.
ƒƒ Offer support and written information to help patients make an informed choice. The
following should be discussed:
-- advantages and disadvantages of treatment
-- stage of cancer and how this effects treatment choice and prognosis
-- side effects from treatment (including cardiovascular and secondary cancer risks)
and how they can be managed
-- confirm decisions on fertility and sperm storage
-- participation in clinical trials, if appropriate.
ƒƒ Ensure patients are given information on how to access a named nurse who can offer
support and advice at all stages of treatment.
ƒƒ Discuss the importance of lifestyle changes including:
-- diet
-- exercise
-- smoking/alcohol/drugs.
ƒƒ Advise patients of where they can receive information on financial issues (see section 14.4).
ƒƒ Discuss the possibility of hormone deficiency and advise patients when hormone
replacement therapy is likely to be offered.
ƒƒ Ensure patients understand the importance of attending follow-up appointments (usually
for at least 5 years) and inform them of how they are likely to be followed up, ie by whom,
where and when.
40
14 PROVISION OF INFORMATION
POST-TREATMENT: ONCOLOGY/GP
ƒƒ Discuss the fear of recurrence and offer reassurance on curability and prognosis.
ƒƒ Advise patients on the importance of checking the remaining testicle.
ƒƒ Inform patients of the need to carry out further tests, eg blood tests, chest X-rays and CT
scans at regular intervals.
ƒƒ The following issues should be discussed with patients:
-- returning to work and insurance issues. Insurance companies should note the
excellent prognosis for most men with testicular tumours
-- depression, anxiety and psychosexual issues and the availability of specialist
services
-- infertility and information about fertility clinics
-- stored sperm
-- symptoms for monitoring late effects.
ƒƒ The following issues should be discussed with patients who have had a relapse:
-- treatment choices
-- physical effects of treatment
-- treatment outcomes
-- referral to other specialists as required to manage toxicities of treatment.
14.3
PSYCHOSEXUAL ISSUES
Despite good treatment outcomes and excellent prognosis, there remains a significant risk
of psychological morbidity associated with the complex physical and emotional affects of
the disease and treatments. Psychosexual research studies provide limited evidence as they
address variable questions from patients, usually in small numbers, who have had different
levels of treatment. They serve to highlight, however, areas of concern, ie body image, sexual
function, relationship issues, fertility, gender disruption, stress and depression. Therefore, health
professionals are advised to be alert to these issues, assess their patients and make referrals to
specialists when appropriate.
41
Management of Adult Testicular Germ Cell Tumours
14.4SOURCES OF FURTHER INFORMATION
14.4.1national organisations
Macmillan Cancer Support (Scotland)
Osborne House, 1-5 Osborne Terrace
Edinburgh EH12 5HG
Tel: 0131 346 5346 • Fax: 0131 346 5347
www.macmillan.org.uk
Email: [email protected]
The Scottish office of the UK charity, which supports people with cancer (and their families)
with specialist information, treatment and care.
Maggie’s Centres Scotland
www.maggiescentres.org
Email: [email protected]
Maggie’s provides practical, emotional and social support to people with cancer, their family
and friends. Built alongside NHS cancer hospitals and staffed with professional experts,
Maggie’s Centres are warm and welcoming, full of light and open space, with a big kitchen
table at their heart.
Maggie’s Dundee
Tom McDonald Avenue, Ninewells Hospital
Dundee DD2 1NH
Tel: 01382 632999 • Fax: 01382 632998
Email: [email protected]
Maggie’s Edinburgh
The Stables, Western General Hospital
Crewe Road South
Edinburgh EH4 2XU
Tel: 0131 537 3131 • Fax: 0131 537 3130
Email: [email protected]
Maggie’s Fife
Victoria Hospital, Hayfield Road
Kirkcaldy KY2 5AH
Tel: 01592 647997 • Fax: 01592 649646
Email: [email protected]
Maggie’s Glasgow
The Gatehouse, Western Infirmary
10 Dumbarton Road
Glasgow G11 6PA
Tel: 0141 330 3311 • Fax: 0141 330 3363
Email: [email protected]
Maggie’s Highlands
Raigmore Hospital, Old Perth Road
Inverness IV2 3UJ
Tel: 01463 706306 • Fax: 01463 706305
Email: [email protected]
Maggie’s Lanarkshire
Flat 78, Residential accommodation
Wishaw General Hospital
50 Netherton Road
Wishaw ML2 ODP
Tel: 01698 358392 • Fax: 01698 366943
Email: [email protected]
42
14 PROVISION OF INFORMATION
Marie Curie Cancer Care (Scotland)
29 Albany Street
Edinburgh EH1 3QN
Tel: 0131 456 3710 • Fax: 0131 456 3711
www.mariecurie.org.uk
Marie Curie Cancer Care, a care charity, provides practical nursing care at home and
specialist care across its ten Marie Curie centres.
Tak Tent Support (Scotland)
Flat 5, 30 Shelley Court
Gartnavel Complex
Glasgow G12 0YN
Tel: 0141 211 0122
Email: [email protected]
www.taktent.org
Tak Tent offers information, support, education and care for people with cancer, their
families and friends and professionals. They have support groups throughout Scotland.
Teenage Cancer Trust
www.teenagecancertrust.org
Teenage Cancer Trust funds specialist cancer units in NHS hospitals that are designed
specifically for young people. It also funds clinical and research staff, an education
programme for schools, family support networks and an annual conference for young cancer
patients.
Orchid
St Bartholomew’s Hospital, Dominion House
London EC1A 7BE
Tel: 020 7601 7167 • Fax: 020 7600 1155
www.orchid-cancer.org.uk
Orchid aims to raise awareness of prevention, diagnosis and treatment of testicular cancer. It
provides a range of awareness and information leaflets.
Urological Cancer Charity (UCAN)
Polwarth Building, Foresterhill
Aberdeen, AB25 2ZD
www.ucanhelp.org.uk
UCAN is a charity dedicated to raising awareness of urological cancers, and improving
support and quality of life for people and families who are affected.
14.4.2
Other organisations
Cancer Research UK/CancerHelp UK
Tel: 0800 800 4040
www.cancerhelp.org.uk
CancerHelp UK is a free information service about cancer and cancer care for people
with cancer and their families. It is provided by Cancer Research UK. The site includes a
comprehensive range of information including cancer prevention, diagnosis, treatment and
follow up.
Testicular Cancer Awareness Scotland (TCAS)
Tel: 01875 341158
Email: [email protected]
www.freewebs.com/tcas/index.htm
Human Fertilisation and Embryology Authority
www.hfea.gov.uk
For advice about sperm storage and fertility clinics.
43
Management of Adult Testicular Germ Cell Tumours
14.4.3
USEFUL PUBLICATIONS FOR PATIENTS AND CARERS
Testicular cancer. Cancerbackup
Available from Cancerbackup/Macmillan Cancer Support, Osborne House, 1-5 Osborne
Terrace, Edinburgh, EH12 5HG, Tel: 0131 346 5346, Fax: 0131 346 5347,
www.macmillan.org.uk
NHS Health Scotland
Woodburn House
Canaan Lane
Edinburgh EH10 4SG
Leaflets on testicular self examination, healthy living, diet, exercise
44
15 IMPLEMENTING THE GUIDELINE
15Implementing the guideline
This section provides advice on the resource implications associated with implementing the
key clinical recommendations, and advice on audit as a tool to aid implementation.
Implementation of national clinical guidelines is the responsibility of each NHS Board and is an
essential part of clinical governance. Mechanisms should be in place to review care provided
against the guideline recommendations. The reasons for any differences should be assessed
and addressed where appropriate. Local arrangements should then be made to implement the
national guideline in individual hospitals, units and practices.
15.1Auditing current practice
A first step in implementing a clinical practice guideline is to gain an understanding of current
clinical practice. Audit tools designed around guideline recommendations can assist in this
process. Audit tools should be comprehensive but not time consuming to use. Successful
implementation and audit of guideline recommendations requires good communication between
staff and multidisciplinary team working.
The guideline development group has identified the following as key points to audit to assist
with the implementation of this guideline:
ƒƒ S cotland-wide audit of survivors of testicular cancer linked to hospital admissions and death
registry for ICD-10 coded cardiovascular disease for patients diagnosed 1980-1990, 19902000 and 2000-2010.
ƒƒ Survey of survivors of testicular cancer and their GPs regarding information needs for long
term follow up.
ƒƒ Audit of long term side effects of treatment for germ cell tumours.
ƒƒ Audits of compliance with local imaging and staging protocols.
Core data for subsequent audit should include an assessment of:
ƒƒ
ƒƒ
ƒƒ
ƒƒ
ƒƒ
ƒƒ
ƒƒ
ƒƒ
ƒƒ
ƒƒ
ƒƒ
ƒƒ
ƒƒ
ƒƒ
15.2
any delay in patients presenting to a doctor
timing from presentation to referral and further investigation
preoperative investigations
number of patients offered and receiving a testicular prosthesis
number of patients offered and having sperm stored
time from surgery to seeing oncologist
number of patients having biopsy of contralateral testis
adequacy of and time for completion of staging
details of radiotherapeutic management
details of chemotherapeutic management
details of further surgical management
details of timing of clinic follow up and subsequent investigations
details of toxicity of treatment
survival and relapse details.
resource implications of key recommendations
No resource implications for key recommendations were identified.
45
Management of Adult Testicular Germ Cell Tumours
16The evidence base
16.1
systematic literature review
The evidence base for this guideline was synthesised in accordance with SIGN methodology.
A systematic review of the literature was carried out using an explicit search strategy devised
by a SIGN Information Officer. Databases searched include Medline, Embase, CINAHL and
the Cochrane Library. The year range covered was 1998-2010. The main searches were
supplemented by material identified by individual members of the development group. Each
of the selected papers was evaluated by two members of the group using standard SIGN
methodological checklists before conclusions were considered as evidence.
16.1.1
literature search for patient issues
At the start of the guideline development process, a SIGN Information Officer conducted a
literature search for qualitative and quantitative studies that addressed patient issues of relevance
to management of testicular germ cell tumours. Databases searched include Medline, Embase,
CINAHL and PsycINFO, and the results were summarised and presented to the guideline
development group. A copy of the Medline version of the patient search strategy is available
on the SIGN website.
16.2
recommendations for research
The guideline development group was not able to identify sufficient evidence to answer all of
the key questions asked in this guideline. The following areas for further research have been
identified:
ƒƒ C
linical studies to investigate the exact prevalence of late effects, mechanisms and potential
intervention studies
ƒƒ The optimum management of poor prognosis germ cell tumours
ƒƒ The optimum management of relapsed germ cell tumours
ƒƒ The optimum management of seminoma IIA/B
ƒƒ The role of PET/CT in prediction of response to chemotherapy
ƒƒ The role of PET/CT in the management of late relapses
ƒƒ The diagnostic accuracy of PET/CT for residual tumours
ƒƒ Identification of the benefits and optimum structure of rehabilitation programmes
ƒƒ Investigation into psychosexual and gonadal function in men following treatment for germ
cell tumours.
16.3
review and updating
This guideline was published in 2011 and will be considered for review in three years. Any
updates to the guideline in the interim period will be noted on the SIGN website: www.sign.ac.uk
46
17 DEVELOPMENT OF THE GUIDELINE
17Development of the guideline
17.1introduction
SIGN is a collaborative network of clinicians, other healthcare professionals and patient
organisations and is part of NHS Quality Improvement Scotland. SIGN guidelines are developed
by multidisciplinary groups of practising clinicians using a standard methodology based on a
systematic review of the evidence. Further details about SIGN and the guideline development
methodology are contained in “SIGN 50: A Guideline Developer’s Handbook”, available at
www.sign.ac.uk
17.2
the guideline development group
Dr Grahame Howard
(Chair)
Mr Sudhir Borgaonkar
Dr Margaret Brooks
Dr John Brush
Mrs Juliet Brown
Dr David Dodds
Dr Helen Gregory
Dr Ken Grigor
Mr David Hendry
Dr Farida Hamza-Mohamed
Ms Sheila Liggatt
Dr Graham Macdonald
Mr Param Mariappan
Mr Brian McGlynn
Dr Moray Nairn
Mr Kenneth Pallister
Dr Morag Seywright
Dr Joan Vlayen
Dr Ashita Waterston
Dr Jeff White
Mr Phil Wilson Consultant Clinical Oncologist, Western General Hospital, Edinburgh
Consultant Urologist, Raigmore Hospital, Inverness
Consultant Radiologist, Lorn and Islands Hospital, Oban
Consultant Radiologist, Western General Hospital, Edinburgh
SIGN Information Officer
Consultant Clinical Oncologist, Beatson West of Scotland Cancer Centre, Glasgow
General Practitioner and Associate Specialist in Medical Genetics Cancer, Aberdeen
Consultant Pathologist, Western General Hospital, Edinburgh
Consultant Urologist, Gartnavel Hospital and Beatson West of Scotland Cancer Centre, Glasgow
SIGN Programme Manager
Clinical Nurse Specialist, Western General Hospital, Edinburgh
Consultant Clinical Oncologist, Aberdeen Royal Infirmary
Consultant Urologist, Western General Hospital, Edinburgh
Urology Cancer Specialist Nurse, Ayr Hospital
SIGN Programme Manager
Patient Representative, Glasgow
Consultant Pathologist, Western Infirmary, Glasgow
Endocrinologist and Cancer Guideline Specialist, Kenniscentrum - Centre d’Expertise, Belgium
Consultant Medical Oncologist, Beatson West of Scotland Cancer Centre, Glasgow
Consultant Medical Oncologist, Beatson West of Scotland Cancer Centre, Glasgow
Patient Representative, Glasgow
47
Management of Adult Testicular Germ Cell Tumours
The membership of the guideline development group was confirmed following consultation
with the member organisations of SIGN. All members of the guideline development group
made declarations of interest and further details of these are available on request from the
SIGN Executive.
Guideline development and literature review expertise, support and facilitation were provided
by the SIGN Executive. All members of the SIGN Executive make yearly declarations of interest
and further details of these are available on request. In particular, the following staff are thanked
for their involvement.
Ms Mary Deas
Distribution and Office Coordinator
Mrs Lesley Forsyth
Events Coordinator and Executive Secretary to SIGN Council
Mrs Karen Graham
Patient Involvement Officer
Miss Katie Kerr
Administrative Assistant
Mr Stuart Neville
Publications Designer
Miss Gaynor Rattray
Guideline Coordinator
17.2.1acknowledgements
SIGN would like to acknowledge the guideline development group responsible for the
development of SIGN 28 Management of Adult Testicular Germ Cell Tumours, on which this
guideline is based and Dr Alan James, Consultant Clinical Oncologist and Dr Peter Correra
Specialist Registrar in Clinical Oncology, Beatson West of Scotland Cancer Centre, Glasgow,
for their contribution to Annex 2 of this guideline.
17.3
consultation and peer review
17.3.1public consultation
The draft guideline was available on the SIGN website for a month to allow all interested
parties to comment. All contributors made declarations of interest and further details of these
are available on request from the SIGN Executive.
17.3.2specialist review
This guideline was also reviewed in draft form by the following independent expert referees,
who were asked to comment primarily on the comprehensiveness and accuracy of interpretation
of the evidence base supporting the recommendations in the guideline. The guideline group
addresses every comment made by an external reviewer, and must justify any disagreement
with the reviewers’ comments. All expert referees made declarations of interest and further
details of these are available on request from the SIGN Executive.
SIGN is very grateful to all of these experts for their contribution to the guideline.
Dr Grant Baxter Consultant Radiologist, Western Infirmary, Glasgow
Dr Sara Davies
Public Health Consultant, Scottish Government, Edinburgh
Ms Kathryn Elwis
MacMillan Clinical Nurse Specialist – Testicular Cancer, University College London Hospitals NHS Foundation Trust, London
Mr Chris Goodman
Consultant Urological Surgeon, King’s Cross Hospital, Dundee
Dr Stephen Harland
Consultant Medical Oncologist, University College Hospital, London
Mr Graham Hollins
48
Consultant Urologist, Ayr Hospital
17 DEVELOPMENT OF THE GUIDELINE
Dr Alan Horwich
Consultant Clinical Oncologist, Royal Cancer Hospital, London
Dr Robert Huddart
Reader in Urological Oncology, The Institute of Cancer Research, Surrey
Dr Derek King
Consultant Paediatric Haematologist, Royal Aberdeen Children’s Hospital
Mr Alan McNeill
Consultant Urological Surgeon and Clinical Lead, Western General Hospital, Edinburgh
Mr David Paul
Lay Representative, Glasgow
Mr Khaver Qureshi
Consultant Urological Surgeon, Gartnavel General Hospital, Glasgow
Dr Martin Russell
Consultant Clinical Oncologist, Beatson West of Scotland Cancer Centre, Glasgow
Professor Bertrand Tombal
Head of Urology Service, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Dr Michael Williams
Consultant Clinical Oncologist, Addenbrookes Hospital, Cambridge
17.3.3sign editorial group
As a final quality control check, the guideline is reviewed by an editorial group comprising
the relevant specialty representatives on SIGN Council to ensure that the specialist reviewers’
comments have been addressed adequately and that any risk of bias in the guideline development
process as a whole has been minimised. The editorial group for this guideline was as follows:
Dr Keith Brown
Chair of SIGN; Co-Editor
Ms Beatrice Cant
SIGN Programme Manager
Dr Roberta James
Acting Programme Director of SIGN
Dr Elizabeth Junor
Royal College of Radiologists
Dr Sara Twaddle
Director of SIGN; Co-Editor
49
Management of Adult Testicular Germ Cell Tumours
Abbreviations
50
AFP
alpha-fetoprotein
AUC7
area under the curve rate of 7 mg/ml per minute
BEP
bleomycin, etoposide, cisplatin
BNF
British National Formulary
BOP/VIP
bleomycin, vincristine, cisplatin/etoposide, ifosphamide, cisplatin
BTTP&R
British Testicular Tumour Panel and Registry
CECT
contrast-enhanced computed tomography
CI
confidence interval
CIS
carcinoma in situ
CNS
central nervous system
CT
computed tomography
CV
cardiovascular
CVD
cardiovascular disease
DBP
diastolic blood pressure
EDTA
ethylene diamine tetra-acetic acid
EORTC
European Organisation for Research and Treatment of Cancer
EP
etoposide and cisplatin
FDG
fluorodeoxyglucose
GP
general practitioner
Gy
gray
HCG
human chorionic gonadotrophin
HDCT
high-dose chemotherapy
HFEA
Human Fertilisation and Embryology Authority
ICD-10
International Classification of Diseases, 10th revision
ICRU
International Commission on Radiation Units
IGCCC
International Germ Cell Consensus Classification
IU
international unit
LATENT
Late Adverse Treatment Effects in Netherlands Testis Cancer patients
LDH
lactate dehydrogenase
LDL
low density lipoprotein
MI
myocardial infarction
MRC
Medical Research Council
MRI
magnetic resonance imaging
MTA
multiple technology appraisal
MTI malignant teratoma intermediate
MTU malignant teratoma undifferentiated
NHS QIS
NHS Quality Improvement Scotland
ABBREVIATIONS
NICE
National Institute for Health and Clinical Excellence
NSGCT
non-seminomatous germ cell tumour
OCT4
octamer-binding transcription factor 4
PET
positron emission tomography
PET/CT
positron emission tomography/computed tomography
PLAP
placental alkaline phosphatase
POMB/ACE
cisplatin, vincristine, methotrexate, bleomycin/actinomycin D, cyclophosphamide,
etoposide
PVB
cisplatin, vinblastine, bleomycin
RCT
randomised controlled trial
RMH
Royal Marsden Hospital
RPLND
retroperitoneal lymph node dissection
RT
radiotherapy
SCORE
Systematic Coronary Risk Evaluation
SBP
systolic blood pressure
SIGN
Scottish Intercollegiate Guidelines Network
SIR
standardised incidence ratio
SMC
Scottish Medicines Consortium
SMN
second malignant neoplasm
SMR
standardised mortality ratio
TD
teratoma differentiated
TIP
paclitaxel, ifosphamide and cisplatin
TRISST
Trial of imaging and schedule in seminoma testis
UICC Union for International Cancer Control
VIP
etoposide, ifosphamide, cisplatin
WHO
World Health Organisation
51
Management of Adult Testicular Germ Cell Tumours
Annex 1
Key questions addressed in this update
The update of this guideline is based on a series of structured key questions that define the target
population, the intervention, diagnostic test, or exposure under investigation, the comparison(s)
used and the outcomes used to measure efficacy, effectiveness, or risk. These questions form
the basis of the systematic literature search.
THE KEY QUESTIONS USED TO DEVELOP THE GUIDELINE
TREATMENT
Key question
See section
1. In patients with a diagnosed testicular germ cell tumour, when is biopsy
of the contralateral testis indicated? Consider pick up rate of intratubular
germ cell neoplasia and toxicity
6.1
2. In adult males with stage I testicular seminoma, which of the following
interventions:
ƒƒ surveillance,
ƒƒ chemotherapy (adjuvant),
ƒƒ radiotherapy (adjuvant)
8.1
has the best outcome on survival, long term toxicity and quality of life
(including comments on pathological risk factors)?
52
3. In adult males with stage I testicular NSGCT what is the optimal
surveillance ie has the best outcome on picking up relapse at an early
stage?
ƒƒ schedules (CT v MRI and what is scanned)
ƒƒ tumour markers
8.2
4. In adult males with stage IIA and IIB seminoma, which of the following
interventions have the best outcome on survival, long term toxicity and
quality of life?
ƒƒ radiotherapy and chemotherapy
ƒƒ radiotherapy alone
9.1.2
5. In adult males with good prognosis metastatic NSGCT which
chemotherapy regimen has the best outcome in terms of response and
toxicity?
9.2.1
6. In adult males with residual mass post chemotherapy which is the best
cross-sectional imaging to predict residual active disease?
ƒƒ CT scanning,
ƒƒ MRI
ƒƒ PET
10.1
7. In post chemotherapy patients (both seminomas and non-seminomas)
which patients should have residual masses resected and which has the
best outcome on survival (compared with surveillance)? Consider all sites,
relevance and types of pathologies, surgical toxicity
10.2
ANNEXES
8. In adult males with relapsed testicular germ cell tumours (seminoma and
non-seminoma), is there evidence of any chemotherapy schedule (eg VIP,
TIP, BEP POMB-ACE , high dose) having better outcomes on survival,
response rate, toxicity?
11
9. In view of the potential late physical effects emerging due to the standard
treatments for testicular germ cell cancer, what information should be
given to patients and their GPs regarding?
ƒƒ cardiovascular toxicity
ƒƒ second cancers (exclude new germ cell primary tumours)
12
10. What new evidence is there for good practice in preparation of testicular
germ cell tumour histopathology?
Annex 2
14.2
53
Management of Adult Testicular Germ Cell Tumours
Annex 2
Pathology of testicular germ cell tumours
CLASSIFICATION
The main classifications in common use are those of the British Testicular Tumour Panel and
Registry (BTTP&R)146 and the World Health Organization (WHO).147 Pathology reports should
include both the BTTP&R and the WHO classifications (see Table 11).
Table 11: Comparison of British (BTTP&R) and WHO classifications
British
WHO
Seminoma
Seminoma
Spermatocytic seminoma
Spermatocytic seminoma
Teratoma
Non-seminomatous germ cell tumour
-- teratoma differentiated (TD)
-- teratoma
-- malignant teratoma intermediate
(MTI)
-- embryonal carcinoma/yolk sac tumour with
teratoma
-- malignant teratoma
undifferentiated (MTU)
-- embryonal carcinoma
-- yolk sac tumour
-- yolk sac tumour
-- malignant teratoma trophoblastic
-- choriocarcinoma
PATHOLOGICAL EXAMINATION AND SAMPLING OF ORCHIDECTOMY SPECIMENS
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 of the cut surface, the extent of replacement of the testis, and macroscopic evidence
of extension into rete testis, epididymis, tunica vaginalis or spermatic cord. The number and
site of blocks taken for histology should be stated.
Blocks should be taken from the resection margin of cord, middle cord, lower cord and from
the interface between testis and rete testis. These blocks should be taken before cutting into the
tumour in order to reduce the chance of tumour cells being deposited at these sites. Seminoma
macroscopically is usually pale, uniform, solid and well demarcated, although large areas of
yellow necrosis may be present. NSGCT 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 including samples of the main tumour and any
satellite lesions. Haemorrhagic foci are sampled because such areas may 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).
54
;;
he orchidectomy specimen should be placed in an adequate volume (at least 5:1) of
T
formalin fixative.
;;
fter taking blocks from the cord the specimen should be bivalved through the rete
A
testis and epididymis as soon as it arrives in the pathology department in order to allow
proper fixation. It should not normally be bivalved by the surgeon in theatre unless there
is going to be undue delay in the specimen being transported to pathology.
;;
t least one block of tumour should be taken for each centimetre of maximum tumour
A
dimension and blocks should be taken from the surrounding testis, the rete testis and
adjacent epididymis, the lower and mid portions of cord and the resection margin of cord.
ANNEXES
HISTOLOGICAL EXAMINATION OF TESTICULAR TUMOURS
The histology report should describe all the different tumour elements present, and should
indicate if there is extension through the tunica albuginea to involve tunica vaginalis and
involvement of rete testis, epididymis, or spermatic cord. The report should give both the
BTTP&R and WHO classifications (see Table 11).
The condition of the residual testicular tissue should be described paying particular attention
to tubular atrophy and the presence or absence of carcinoma in situ.
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 2002
UICC tumour, node, metastasis classification 6th edition (see Table 12).148
Table 12: Pathological tumour staging
pT0 no evidence of primary tumour (eg histological scar tissue in testis)
pTis intratubular germ cell neoplasia (carcinoma in situ)
pT1 tumour limited to testis and epididymis without blood or lymphatic vascular invasion.
Tumour may invade tunica albuginea but not tunica vaginalis
pT2 tumour limited to testis and epididymis with blood or lymphatic vascular invasion or
tumour extending through tunica albuginea to involve tunica vaginalis
pT3 tumour invasion of spermatic cord with or without lymphatic/vascular invasion
pT4 tumour invasion of scrotum with or without lymphatic/vascular invasion
The incidence of relapse of clinical stage I NSGCTs after orchidectomy is related to the presence
of blood or lymphatic vascular invasion, and a detailed examination should be made to detect
this.62 Vascular invasion implies invasion of blood vessels or lymphatic vessels.
2+
CThe presence or absence of blood or lymphatic vascular invasion should be specified.
SEMINOMA
Classical seminomas contain large polygonal cells with clear cytoplasm and distinct cell
boundaries. There is little cellular pleomorphism. There is usually a prominent lymphocytic
infiltrate in the stroma and aggregates of epithelioid histiocytes forming non-caseating granulomas
are also common in association with the tumour. Areas of necrosis, which can be extensive,
may occur. The tumour is usually well demarcated from the surrounding testis.
Some seminomas show greater cellular pleomorphism and more mitotic figures. The lymphocytic
and histiocytic infiltrate is less prominent and there is often a more infiltrative border. These
have been termed ‘anaplastic’ seminomas. Seminomas with these features can histologically
mimic embryonal carcinoma but show immunocytochemical features of classical seminoma
and appear to respond as well as classical seminomas to therapy. The stage of pure seminoma
is more important than its histological appearance.
Seminomas may contain syncytiotrophoblastic giant cells which secrete HCG, but seminoma
cells do not produce AFP. Seminomas usually stain for placental alkaline phosphatase (PLAP),
CD117 and octamer-binding transcription factor 4 (OCT4) but not for AFP or for cytokeratin.
Spermatocytic seminoma is a separate entity from classical seminoma and occurs in older men.149
This tumour consists of solid sheets of cells resembling spermatocytes and shows prominent
cellular pleomorphism and mitotic activity. It does not have a lymphocytic or histiocytic infiltrate
in the stroma and is not associated with CIS. It does not stain for OCT4, PLAP, HCG, AFP,
cytokeratin or lymphocyte markers. Pure spermatocytic seminoma does not metastasise, and no
further therapy is indicated after orchidectomy. Rare cases of spindle cell sarcoma development
have been described in spermatocytic seminoma.
Where the initial pathology sections show pure seminoma but the patient has an elevated
serum AFP the entire tumour should be processed for histology to investigate for small foci of
NSGCT within the tumour.
55
Management of Adult Testicular Germ Cell Tumours
NON-SEMINOMATOUS GERM CELL TUMOUR
Tumours consisting of well differentiated tissues only are classed as teratoma by WHO
and teratoma differentiated (TD) by BTTP&R. Although these tumours do not contain any
histologically malignant elements they must not be considered benign neoplasms when they
arise in the post-pubertal testis.
Tumours consisting only of undifferentiated malignant tumour are classed as embryonal
carcinoma (WHO) or malignant teratoma undifferentiated (MTU) by BTTP&R.
NSGCTs may also contain extra embryonic structures such as yolk sac elements (yolk sac
tumour) and trophoblastic elements (malignant teratoma trophoblastic or choriocarcinoma).
In the WHO classification NSGCTs containing a mixture of different germ cell tumour types
are classed as mixed germ cell tumours and all the tumour elements present are listed in the
pathology report. Tumours containing a mixture of embryonal carcinoma or yolk sac tumour
and teratoma (TD) are classified as malignant teratoma intermediate (MTI) in the BTTP&R
classification.
Combined tumours containing both seminoma and NSGCT also occur.
All the components which are recognised within an NSGCT should be mentioned in the
pathology report.
Embryonal carcinoma usually stains positively for cytokeratin, CD30 and OCT4. There may
also be some positivity for PLAP although this is usually weaker and more patchy than PLAP
positivity in seminoma. Yolk sac tumour elements are positive for cytokeratin and focally for AFP.
Epidermoid cyst of the testis, consisting only of a squamous epithelial lined cyst with no skin
appendages or any other tissue elements, has sometimes been considered to be a monodermal
NSGCT,150 but there is no associated CIS and the lesion should be treated as a benign condition
not requiring further therapy.
REVIEW PATHOLOGY
Germ cell tumours of the testis are not common, and many pathologists do not see a sufficient
number of cases to be fully experienced in giving a comprehensive report, which is essential
for further clinical management. 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. The case should be discussed at a specialist
multidisciplinary team meeting which should include the specialist pathologist before a decision
is taken on definitive treatment.
56
;;
he pathology should be reviewed by specialist pathologists at the referral treatment
T
centres.
;;
ll types of tumour component identified should be recorded in the pathology report
A
using both the WHO and BTTP&R classifications.
;;
he extent of tumour invasion should be specified with particular reference to involvement
T
of rete testis, tunica vaginalis, epididymis, cord and resection margins and noting the
presence or absence of vascular invasion.
;;
The 2002 UICC 6th edition pathological stage (pT category) should be given.
ANNEXES
PATHOLOGY OF RESIDUAL TUMOUR MASSES
In the UK, primary retroperitoneal lymph node dissection (RPLND) is not performed routinely
in patients with a testicular germ cell tumour, however, residual masses after chemotherapy for
NSGCT should be surgically excised and examined pathologically. The specimen should be
measured and the resection margins inked. It should be extensively sampled so that all residual
viable tumour elements can be identified and adequacy of excision assessed. Untreated germ
cell tumour metastases to lymph nodes or extranodal sites are usually similar in appearance to
the primary tumour in the testis, but after successful treatment, metastatic deposits are replaced
by necrotic tissue or fibrosis with no evidence of residual malignancy. Differentiated teratoma
elements are more resistant to therapy than embryonal carcinoma, therefore residual masses
following treatment for metastatic malignant teratoma intermediate (mixed embryonal carcinoma
and teratoma) often show areas of fibrosis and necrosis, and also foci of differentiated teratoma
without evidence of residual embryonal carcinoma.
The pathology report should indicate whether the resection specimen consists only of fibrosis and
necrosis. If viable tumour is present the report should state whether it consists of differentiated
teratoma only or whether there is viable histologically malignant germ cell tumour present eg
embryonal carcinoma or yolk sac tumour. Transformation to non-germ cell malignancy may
also occur. The resection margins should be examined carefully and their status recorded in
the pathology report.
;;
esected residual masses should be extensively sampled in order to look for residual
R
viable tumour.
;;
articular mention should be made of the presence or absence of viable differentiated
P
teratoma, histologically malignant germ cell tumour, or transformation to non-germ cell
malignancy.
;;
The adequacy of excision of viable tumour elements should be stated.
PATHOLOGICAL EXAMINATION OF BIOPSIES FROM THE CONTRALATERAL TESTIS
SUGGESTED PROCEDURE: A contralateral biopsy should be 0.3-1.0 cm in maximum dimension
and should be removed atraumatically without squeezing the tissue or handling it with forceps.
Open biopsy is considered the normal procedure but needle biopsy may be adequate.26
There are differing practices concerning the fixation of contralateral testicular biopsies. The
morphological detail is better with Bouin’s fixative than with formalin and cytological artefacts
mimicking CIS can be produced by formalin fixation. Immunocytochemical demonstration of
PLAP and OCT4 (present in CIS cells) is, however, more reliable on formalin rather than Bouin’s
fixed tissue. Ideally, if both fixatives are available, two biopsies should be taken for fixation in
Bouin’s and formalin respectively and any immunocytochemistry should be performed on the
formalin fixed biopsy. Bouin’s fixation should be for a minimum of two hours and a maximum
of 24 hours. Further fixation in Bouin’s fluid results in poor histological sections.
;;
Paraffin sections should be stained routinely with haematoxylin and eosin.
;;
omment should be made on the presence or absence of CIS, the degree of
C
spermatogenesis, and evidence of atrophy of seminiferous tubules.
;;
Immunocytochemical assessment for PLAP and OCT4 is helpful in the diagnosis of CIS.
57
Management of Adult Testicular Germ Cell Tumours
Annex 3
CNS metastases in germ cell tumours - sample management
protocol
Central nervous system (CNS) metastases are rare in germ cell tumours, tending to occur in
poor-risk patients. About one per cent of patients in the report of the International Germ Cell
Cancer Collaborative Group35 had brain metastases at initial diagnosis. Evidence is sparse and
retrospective, and treatment should be individualised. It is clear however that neurosurgery,
chemotherapy and radiotherapy all play a potential role in each patient.
CATEGORISATION OF CNS INVOLVEMENT WITH CNS DISEASE
Patients with CNS spread can be readily subdivided into three distinct categories:
Group 1 - CNS disease at presentation (including within weeks of starting definitive
chemotherapy). All IGCCC poor-risk patients (mediastinal primary, MTT histology
(choriocarcinoma element), HCG at presentation >10,000 IU/L) are at risk; many patients are
asymptomatic. All poor risk or symptomatic patients should have CNS staging (MRI scanning)
as standard. Radical treatment is feasible and cure can be achieved.
Group 2 - Isolated CNS relapse. Chemotherapy-resistant clones, or sanctuary site growth are
theorised as causes of this rare phenomenon. CNS symptoms or asymptomatic rising markers
in face of responding/no systemic disease should raise suspicion and prompt investigation.
Radical treatment is feasible and cure can be achieved.
Group 3 - Multi-site relapsed metastatic disease including CNS disease. This situation requires
palliation and cure is highly unlikely.
THERAPEUTIC OPTIONS
Group 1 - Early neurosurgical resection should be considered due to the risk of haemorrhage
and is appropriate for large deposits causing significant pressure symptoms. The mainstay of
management is systemic chemotherapy. Radiotherapy carries a high risk of significant sequelae,
including neurocognitive decline. If complete radiological response is achieved, withhold
adjuvant radiotherapy. If residual disease is present on postchemotherapy imaging, neurosurgical
resection is advised; if unresectable, stereotactic radiosurgery is an option. Only in the event of
a viable resected tumour, or unresectable disease, wide-field radiotherapy (whole brain, 40-45
Gy) as adjuvant is recommended, depending on performance status.
Group 2 - Local therapy is recommended. There is no clearly defined role for second line
chemotherapy. Neurosurgical resection should be attempted; if unresectable, stereotactic
radiosurgery is unproven but an option. Focal therapy should be followed by adjuvant whole
brain radiotherapy.
Group 3 - Management depends on individual cases. Symptomatic sites should be appropriately
targeted, with chemotherapy/radiotherapy. If CNS disease is the priority, palliative neurosurgical
resection or palliative radiotherapy may be justified. Long term survival is unusual, and
performance status must be considered.
Adapted from the Beatson West of Scotland Cancer Centre151,152
58
REFERENCES
References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. Information and Statistics Division Scotland. Male Genital Organ
Cancers. [cited 09 November 2010]. Available from url: http://
www.isdscotland.org/isd/1488.html#Summary statistics for male
genital organ cancers
Thomas R, Dearnaley D, Nicholls J, Sampson S, Horwich A. An
analysis of surveillance for stage I combined teratoma/seminoma
of the testis Br J Cancer 1996;74(1):59-62.
Grigor KM. A new classification of germ cell tumours of the testis.
Eur Urol 1993;23(1):93-100.
Guidance on prescribing. In: The British National Formulary No.
60. London: British Medical Association and Royal Pharmaceutical
Society of Great Britain; 2010.
Thornhill JA, Conroy RM, Kelly DG, Walsh A, Fennelly JJ,
Fitzpatrick JM. Public awareness of testicular cancer and the value
of self examination. Br Med J 1986;293(6545):480-1.
Thornhill JA, Fennelly JJ, Kelly DG, Walsh A, Fitzpatrick JM.
Patients’ delay in the presentation of testis cancer in Ireland. Br J
Urol 1987;59(5):447-51.
Howard GCW, Conkey DS, Peoples S, McLean DB, Hargreave
TB, Tulloch DN, et al. The management and outcome of patients
with germ-cell tumours treated in the Edinburgh Cancer Centre
between 1988 and 2002. Clinical Oncology 2005;17(6):435-40.
Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark
G, Fizazi K, et al. Guidelines on testicular cancer. [cited 09 Dec
2010]. Available from url: http://www.uroweb.org/fileadmin/
tx_eauguidelines/2009/Full/Testis_Cancer.pdf
Hewitt G, Logan CJ, Curry RC. Does vasectomy cause testicular
cancer? Br J Urol 1993;71(5):607-8.
Mead GM. Testis. In: Price P, Sikora K, editors. treatment of cancer.
3rd ed. London: Chapman & Hall; 1995. p.627-46.
Rustin GJ, Vogelzang NJ, Sleijfer DT, Nisselbaum JN. Consensus
statement on circulating tumour markers and staging patients with
germ cell tumours. Prog Clin Bio Res 1990;357:277-84.
Andipa E, Liberopoulos K, Asvestis C. Magnetic resonance imaging
and ultrasound evaluation of penile and testicular masses. World
J Urol 2004;22(5):382-91. Epub 2004 Aug 6.
See WA, Hoxie L. Chest staging in testis cancer patients: imaging
modality selection based upon risk assessment as determined
by abdominal computerized tomography scan results. J Urol
1993;150(3):874-8.
Pizzocaro G, Zanoni F, Salvioni R, Milani A, Piva L, Pilotti
S. Difficulties of a surveillance study omitting retroperitoneal
lymphadenectomy in clinical stage I nonseminomatous germ cell
tumors of the testis. J Urol 1987;138(6):1393-6.
Tinkler SD, Howard GC, Kerr GR. Sexual morbidity following
radiotherapy for germ cell tumours of the testis. Radioth Oncol
1992;25(3):207-12.
Adshead J, Khoubehi B, Wood J, Rustin G. Testicular implants
and patient satisfaction: a questionnaire-based study of men after
orchidectomy for testicular cancer. BJU Int 2001;88(6):559-62.
Bodiwala D, Summerton DJ, Terry TR. Testicular prostheses:
Development and modern usage. Ann R Coll Surg Engl
2007;89(4):349-53.
Chapple A, McPherson A. The decision to have a prosthesis: A
qualitative study of men with testicular cancer. Psychooncology
2004;13(9):654-64.
Howard GC, Hargreave T. Normal and abnormal testicular
development and descent (testicular maldescent, malignancy,
cancer therapy and fertility). In: Hargreave TB, editor. Male
Infertility. 2nd ed. London: Springer-Verlag; 1994. p.217-34.
Howard GC, Clarke K, Elia MH, Hutcheon AW, Kaye SB, Windsor
PM, et al. A Scottish national mortality study assessing cause of
death, quality of and variation in management of patients with
testicular non-seminomatous germ-cell tumours. The Scottish
Radiological Society and the Scottish Standing Committee of the
Royal College of Radiologists. Br J Cancer 1995;72(5):1307-11.
Moynihan C. Testicular cancer: the psychosocial problems of
patients and their relatives. Cancer Surv 1987;6(3):477-510.
McBride S. Attendance of cancer follow-up clinical: does it increase
anxiety or provide reassurance for men successfully treated for
testicular cancer. Unpublished Masters Degree 1997;
Moynihan C, Bliss JM, Davidson J, Burchell L, Horwich A.
Evaluation of adjuvant psychological therapy in patients
with testicular cancer: randomised controlled trial. BMJ
1998;316(7129):429-35.
24. Manivel JC, Reinberg Y, Niehans GA, Fraley EE. Intratubular
germ cell neoplasia in testicular teratomas and epidermoid cysts.
Correlation with prognosis and possible biologic significance.
Cancer 1989;64(3):715-20.
25. Read G, Stenning SP, Cullen MH, Parkinson MC, Horwich A,
Kaye SB, et al. Medical Research Council prospective study of
surveillance for stage I testicular teratoma. Medical Research
Council Testicular Tumors Working Party. J Clin Oncol
1992;10(11):1762-8.
26. Giwercman A, von der Maase H, Skakkebaek NE. Epidemiological
and clinical aspects of carcinoma in situ of the testis. Eur Urol
1993;23(1):104-10.
27. Skakkebaek NE, Berthelsen JG, Visfeldt J. Clinical aspects of
testicular carcinoma-in-situ. Int J Androl 1981;4(Suppl. 4):153-62.
28. Harland SJ, Cook PA, Fossa SD, Horwich A, Mead GM, Parkinson
MC, et al. Intratubular germ cell neoplasia of the contralateral
testis in testicular cancer: defining a high risk group. J Urol
1998;160(4):1353-7.
29. Grigor KM, Rorth M. Should the contralateral testis be biopsied?
Round table discussion. Eur Urol 1993;23(1):129-35.
30. von der Maase H, Rorth M, Walbom-Jorgensen S, Sorensen BL,
Christophersen IS, Hald T, et al. Carcinoma in situ of contralateral
testis in patients with testicular germ cell cancer: study of 27 cases
in 500 patients. Br Med J 1986;293(6559):1398-401.
31. Bang AK, Petersen JH, Petersen PM, Andersson AM, Daugaard G,
Jorgensen N. Testosterone Production is Better Preserved After 16
than 20 Gray Irradiation Treatment Against Testicular Carcinoma
In Situ Cells. Int J Radiat Oncol Biol Phys 2009;75(3):672-6.
32. Petersen PM, Giwercman A, Daugaard G, Rorth M, Petersen
JH, Skakkebaek NE, et al. Effect of graded testicular doses of
radiotherapy in patients treated for carcinoma-in-situ in the testis.
J Clin Oncol 2002;20(6):1537-43.
33. Bottomley D, Fisher C, Hendry WF, Horwich A. Persistent
carcinoma in situ of the testis after chemotherapy for advanced
testicular germ cell tumours. Br J Urol 1990;66(4):420-4.
34. von der Maase H, Meinecke B, Skakkebaek NE. Residual
carcinoma-in-situ of contralateral testis after chemotherapy. Lancet
1988;1(8583):477-8.
35. International Germ Cell Consensus Classification: a prognostic
factor-based staging system for metastatic germ cell cancers.
International Germ Cell Cancer Collaborative Group. J Clin Oncol
1997;15(2):594-603.
36. Thomas G, Jones W, VanOosterom A, Kawai T. Consensus
statement on the investigation and management of testicular
seminoma 1989. Prog Clin Biol Res 1990;357:285-94.
37. American College of Radiology. ACR Appropriateness Criteria®:
Staging of testicular malignancy.; 2009. Available from
url: http://www.acr.org/SecondaryMainMenuCategories/
quality_safety/app_criteria/pdf/ExpertPanelonUrologicImaging/
StagingofTesticularMalignancyDoc18.aspx
38. White PM, Howard GC, Best JJ, Wright AR. The role of computed
tomographic examination of the pelvis in the management of
testicular germ cell tumours. Clin Radiol 1997;52(2):124-9.
39. The Royal College of Radiologists. Recommendations for Cross
Sectional Imaging in Cancer Management: Computed Tomography
- CT, magentic Resonance Imaging - MRI, Positron Emission
Tomography - PET-CT. Issue 2. London: The Royal College of
Radiologists; 2006. Available from url: http://www.rcr.ac.uk/
publications.aspx?PageID=149&PublicationID=227
40. Martin JM, Panzarella T, Zwahlen DB, Chung P, Warde P.
Evidence-based guidelines for following stage 1 seminoma. Cancer
2007;109(11):2248-56.
41. Groll RJ, Warde P, Jewett MA. A comprehensive systematic review
of testicular germ cell tumor surveillance. Crit Rev Oncol Hematol
2007;64(3):182-97.
42. Warde P, Specht L, Horwich A, Oliver T, Panzarella T,
Gospodarowicz M, et al. Prognostic factors for relapse in stage
I seminoma managed by surveillance: a pooled analysis. J Clin
Oncol 2002;20(22):4448-52.
43. van den Belt-Dusebout AW, de Wit R, Gietema JA, Horenblas S,
Louwman MW, Ribot JG, et al. Treatment-specific risks of second
malignancies and cardiovascular disease in 5-year survivors of
testicular cancer. J Clin Oncol 2007;25(28):4370-8.
44. van den Belt-Dusebout AW, Nuver J, de Wit R, Gietema JA,
ten Bokkel Huinink WW, Rodrigus PT, et al. Long-term risk of
cardiovascular disease in 5-year survivors of testicular cancer. J
Clin Oncol 2006;24(3):467-75.
45. Fossa SD, Horwich A, Russell JM, Roberts JT, Cullen MH, Hodson
NJ, et al. Optimal planning target volume for stage I testicular
seminoma: A medical research council randomized trial. J Clin
Oncol 1999;17(4):1146-54.
59
Management of Adult Testicular Germ Cell Tumours
46. Jones WG, Fossa SD, Mead GM, Roberts JT, Sokal M, Horwich A,
et al. Randomized trial of 30 versus 20 Gy in the adjuvant treatment
of stage I Testicular Seminoma: a report on Medical Research
Council Trial TE18, European Organisation for the Research and
Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol
2005;23(6):1200-8.
47. Bokemeyer C, Schmoll HJ. Treatment of testicular cancer and
the development of secondary malignancies. J Clin Oncol
1995;13(1):283-92.
48. Travis LB, Fossa SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm
H, et al. Second cancers among 40,576 testicular cancer patients:
focus on long-term survivors. J Natl Cancer Inst 2006;97(18):135465.
49. Bauman GS, Venkatesan VM, Ago CT, Radwan JS, Dar AR, Winquist
EW. Postoperative radiotherapy for Stage I/II seminoma: results for
212 patients. Int J Radiat Oncol Biol Phys 1998;42(2):313-7.
50. Bachaud JM, Berthier F, Soulie M, Malavaud B, Plante P, Rischmann
P, et al. Second non-germ cell malignancies in patients treated for
stage I-II testicular seminoma. Radiother Oncol 1999;50(2):191-7.
51. Zagars GK, Ballo MT, Lee AK, Strom SS. Mortality after cure of
testicular seminoma. J Clin Oncol 2004;22(4):640-7.
52. Huddart RA, Norman A, Shahidi M, Horwich A, Coward D,
Nicholls J, et al. Cardiovascular disease as a long-term complication
of treatment for testicular cancer. J Clin Oncol 2003;21(8):1513-23.
53. Oliver RT, Mason MD, Mead GM, von der Maase H, Rustin GJ,
Joffe JK, et al. Radiotherapy versus single-dose carboplatin in
adjuvant treatment of stage I seminoma: a randomised trial. Lancet
2005;366(9482):293-300.
54. Dieckmann KP, Bruggeboes B, Pichlmeier U, Kuster J, Mullerleile
U, Bartels H. Adjuvant treatment of clinical stage I seminoma: is a
single course of carboplatin sufficient? Urology 2000;55(1):102-6.
55. Aparicio J, Germa JR, Garcia del Muro X, Maroto P, Arranz
JA, Saenz A, et al. Risk-adapted management for patients with
clinical stage I seminoma: the Second Spanish Germ Cell Cancer
Cooperative Group study. J Clin Oncol 2005;23(34):8717-23.
56. Powles T, Robinson D, Shamash J, Moller H, Tranter N, Oliver T.
The long-term risks of adjuvant carboplatin treatment for stage I
seminoma of the testis. Ann Oncol 2008;19(3):443-7.
57. Cullen MH. Management of stage I non-seminoma: surveillance
and chemotherapy. In: Horwich A, editor. Testicular cancer
investigation and management. London: Chapman & Hall; 1991.
p.46-166.
58. Freedman LS, Jones WG, Peckham MJ. Histopathology in the
prediction of relapse of patients with stage I testicular teratoma
treated by orchidectomy alone. Lancet 1987;2(8554):294-7.
59. Van Ossterom AJ. Surveillance of stage I non seminomatous
testicular cancer - preliminary report of EORTC Co-operative Group
Surveillance Study. Adv Biosci 1994;91:195-9.
60. Horwich A. Questions in the management of seminoma. Clin
Oncol 1990;2(5):249-53.
61. Rustin GJ, Mead GM, Stenning SP, Vasey PA, Aass N, Huddart
RA, et al. Randomized trial of two or five computed tomography
scans in the surveillance of patients with stage I nonseminomatous
germ cell tumors of the testis: Medical Research Council Trial TE08,
ISRCTN56475197--the National Cancer Research Institute Testis
Cancer Clinical Studies Group. J Clin Oncol 2007;25(11):1310-5.
62. Cullen MH, Stenning SP, Parkinson MC, Fossa SD, Kaye SB,
Horwich AH, et al. Short-course adjuvant chemotherapy in highrisk stage I nonseminomatous germ cell tumors of the testis: A
Medical Research Council report. J Clin Oncol 1996;14(4):110613.
63. Patterson H, Norman AR, Mitra SS, Nicholls J, Fisher C, Dearnaley
DP, et al. Combination carboplatin and radiotherapy in the
management of stage II testicular seminoma: Comparison with
radiotherapy treatment alone. Radiother Oncol 2001;59(1):5-11.
64. Krege S, Beyer J, Souchon R, Albers P, Albrecht W, Algaba F, et
al. European consensus conference on diagnosis and treatment of
germ cell cancer: a report of the second meeting of the European
Germ Cell Cancer Consensus group (EGCCCG): part I. Eur Urol
2008;53(3):478-96.
65. Classen J, Souchon R, Hehr T, Bamberg M. Treatment of early stage
testicular seminoma. J Cancer Res Clin Oncol 2001;127(8):475-81.
66. Classen J, Schmidberger H, Meisner C, Souchon R, Sautter-Bihl ML,
Sauer R, et al. Radiotherapy for stages IIA/B testicular seminoma:
final report of a prospective multicenter clinical trial. J Clin Oncol
2003;21(6):1101-6.
67. Evensen JF, Fossa SD, Kjellevold K, Lien HH. Testicular seminoma:
Analysis of treatment and failure for stage II disease. Radiother
Oncol 1985;4(1):55-61.
68. Mason BR, Kearsley JH. Radiotherapy for stage 2 testicular
seminoma: The prognostic influence of tumor bulk. J Clin Oncol
1856;6(12):1856-62.
60
69. Zagars GK. The role of radiotherapy in advanced abdominal
metastases from testicular seminoma. Syst Ther G U Cancers
1989;38:292-7.
70. Doornbos JF, Hussey DH, Johnson DE. Radiotherapy for pure
seminoma of the testis. Radiology 1975;116:401-4.
71. Duchesne GM, Horwich A, Dearnaley DP, Nicholls J, Jay G,
Peckham MJ, et al. Orchidectomy alone for stage I seminoma of
the testis. Cancer 1990;65(5):1115-8.
72. Einhorn LH, Williams SD. Chemotherapy of disseminated
seminoma. Cancer Clin Trials 1980;3(4):307-13.
73. Loehrer Sr PJ, Birch R, Williams SD, Greco FA, Einhorn LH.
Chemotherapy of metastatic seminoma: The Southeastern Cancer
Study Group experience. J Clin Oncol 1987;5(8):1212-20.
74. Horwich A, Oliver RT, Fossa SD, Wilkinsons P, Mead GM, Stenning
S. A randomised MRC trial comparing single agent carboplatin
with the combination of etoposide and cisplatin in aptients with
an advanced metastatic seminoma. Proc Ann Meet Am Soc Clin
Oncol 1996;15:A668.
75. Feldman DR, Bosl GJ, Sheinfeld J, Motzer RJ. Medical treatment
of advanced testicular cancer. JAMA 2008;299(6):672-84.
76. Shelley MD, Burgon K, Mason MD. Treatment of testicular germcell cancer: a Cochrane evidence-based systematic review. Cancer
Treat Rev 2002;28(5):237-53.
77. Hansen SW, Groth S, Daugaard G, Rossing N, Rorth M. Long-term
effects on renal function and blood pressure of treatment with
cisplatin, vinblastine, and bleomycin in patients with germ cell
cancer. J Clin Oncol 1988;6(11):1728-31.
78. Platinum compounds. In: The British National Formulary No. 60.
London: British Medical Association and Royal Pharmaceutical
Society of Great Britain; 2010.
79. O’Sullivan JM, Huddart RA, Norman AR, Nicholls J, Dearnaley DP,
Horwich A. Predicting the risk of bleomycin lung toxicity in patients
with germ-cell tumours. Annals of Oncology 2003;14(1):91-6.
80. Culine S, Kerbrat P, Kramar A, Theodore C, Chevreau C, Geoffrois
L, et al. Refining the optimal chemotherapy regimen for good-risk
metastatic nonseminomatous germ-cell tumors: a randomized trial
of the Genito-Urinary Group of the French Federation of Cancer
Centers (GETUG T93BP). Ann Oncol 2007;18(5):917-24.
81. Lewis CR, Fossa SD, Mead G, Ten Bokkel Huinink W, Harding MJ,
Mill L, et al. BOP/VIP - A new platinum-intensive chemotherapy
regimen for poor prognosis germ cell tumours. Ann Oncol
1991;2(3):203-11.
82. Durand RE, Goldie JH. Interaction of etoposide and cisplatin in air
in an in vitro tumour model. Cancer Treat Rep 1987;71:673-9.
83. Samson MK, Rivkin SE, Jones SE. Dose-response and dose-survival
advantage for high versus low-dose cisplatin combined with
vinblastine and bleomycin in disseminated testicular cancer. A
Southwest Oncology Group study. Cancer 1984;53(5):1029-35.
84. Nicholls CR, Williams SD, P.J. L, Greco FA, Crawford ED,
Weetlaufer J, et al. Randomised study of cisplatin dose intensity
in poor-risk germ cell tumours: a Southeastern Cancer Study
Group and Southwest Oncology Group protocol. J Clin Oncol
1991;9:1161-72.
85. Kaye SB, Mead GM, Fossa S, Cullen M, DeWit R, Bodrogi I,
et al. Intensive induction-sequential chemotherapy with BOP/
VIP-B compared with treatment with BEP/EP for poor-prognosis
metastatic nonseminomatous germ cell tumor: A randomized
Medical Research Council/European Organization for Research
and Treatment of Cancer study. J Clin Oncol 1998;16(2):692-701.
86. Hitchins RN, Newlands ES, Smith DB, Begent RHJ, Rustin GJS,
Bagshawe KD. Long-term outcome in patients with germ cell
tumours treated with POMB/ACE chemotherapy: Comparison of
commonly used classification systems of good and poor prognosis.
Br J Cancer 1989;59(2):236-42.
87. Bokemeyer C, Harstrick A, Metzer B. Sequential high dose VIPchemotherapy plus PBSC support for advanced germ cell cancer.
Ann Oncol 1996;7(Suppl 5):55.
88. Sirohi B, Huddart R. The management of poor-prognosis,
non-seminomatous germ-cell tumours. Clinical Oncology
2005;17(7):543-52.
89. Kollmannsberger C, Oechsle K, Dohmen BM, Pfannenberg
A, Bares R, Claussen CD, et al. Prospective comparison of
[18F]fluorodeoxyglucose positron emission tomography with
conventional assessment by computed tomography scans and
serum tumor markers for the evaluation of residual masses in
patients with nonseminomatous germ cell carcinoma. Cancer
2002;94(9):2353-62.
90. Hinz S, Schrader M, Kempkensteffen C, Bares R, Brenner W,
Krege S, et al. The role of positron emission tomography in the
evaluation of residual masses after chemotherapy for advanced
stage seminoma. J Urol 2008;179(3):936-40.
REFERENCES
91. Cremerius U, Effert PJ, Adam G, Sabri O, Zimny M, Wagenknecht
G, et al. FDG PET for detection and therapy control of metastatic
germ cell tumor. J Nucl Med 1998;39(5):815-22.
92. Einhorn LH, Williams SD, Mandelbaum I, Donohue JP.
Surgical resection in disseminated testicular cancer following
chemotherapeutic cytoreduction. Cancer 1981;48(4):904-8.
93. Napier MP, Naraghi A, Christmas TJ, Rustin GJS. Long-term followup of residual masses after chemotherapy in patients with nonseminomatous germ cell tumours. Br J Cancer 2000;83(10):127480.
94. Freiha FS, Shortliffe LD, Rouse RV. The extent of surgery
after chemotherapy for advanced germ cell tumors. J Urol
1984;132(5):915-7.
95. Hendry WF, A’Hern RP, Hetherington JW, Peckham MJ, Dearnaley
DP, Horwich A. Para-aortic lymphadenectomy after chemotherapy
for metastatic non-seminomatous germ cell tumours: Prognostic
value and therapeutic benefit. Br J Urol 1993;71(2):208-13.
96. Whillis D, Coleman RE, Lessells AM, Hargreave TB, Cornbleet MA,
Howard GCW. Surgery following chemotherapy for metastatic
testicular teratoma. Br J Urol 1991;68(3):292-5.
97. Berney DM, Shamash J, Hendry WF, Arora A, Jordan S, Oliver
RT. Prediction of relapse after lymph node dissection for germ
cell tumours: Can salvage chemotherapy be avoided? Br J Cancer
2001;84(3):340-3.
98. Fizazi K, Oldenburg J, Dunant A, Chen I, Salvioni R, Hartmann
JT, et al. Assessing prognosis and optimizing treatment in patients
with postchemotherapy viable nonseminomatous germ-cell tumors
(NSGCT): Results of the sCR2 international study. Ann Oncol
2008;19(2):259-64.
99. Eastham JA, Wilson TG, Russell C, Ahlering TE, Skinner DG,
Donohue JP. Surgical resection in patients with nonseminomatous
germ cell tumor who fail to normalize serum tumor markers after
chemotherapy. Urology 1994;43(1):74-80.
100. Ong TA, Winkler MH, Savage PM, Seckl MJ, Christmas TJ.
Retroperitoneal lymph node dissection after chemotherapy in
patients with elevated tumour markers: indications, histopathology
and outcome. BJU Int 2008;102(2):198-202.
101. Janetschek G, Hobisch A, Hittmair A, Holtl L, Peschel R,
Bartsch G. Laparoscopic retroperitoneal lymphadenectomy after
chemotherapy for stage IIB nonseminomatous testicular carcinoma.
J Urol 1999;161(2):477-81.
102. Duchesne GM, Stenning SP, Aass N, Mead GM, Fossa SD, Oliver
RTD, et al. Radiotherapy after chemotherapy for metastatic
seminoma - A diminishing role. European Journal of Cancer Part
A 1997;33(6):829-35.
103. Kirk D, Kaye SB. Retroperitoneal Surgery: management strategies
in malignant teratoma. Adv Biosci 1994;91:333.
104. Fossa SD, Stenning SP, Gerl A, Horwich A, Clark PI, Wilkinson
PM, et al. Prognostic factors in patients progressing after cisplatinbased chemotherapy for malignant non-seminomatous germ cell
tumours. Br J Cancer 1999;80(9):1392-9.
105. Collette L, Sylvester RJ, Stenning SP, Fossa SD, Mead GM, de Wit
R, et al. Impact of the treating institution on survival of patients with
“poor-prognosis” metastatic nonseminoma. European Organization
for Research and Treatment of Cancer Genito-Urinary Tract Cancer
Collaborative Group and the Medical Research Council Testicular
Cancer Working Party. Journal of the National Cancer Institute
1999;91(10):839-46.
106. The International Prognostic Factors Study Group. Prognostic
Factors in Patients With Metastatic Germ Cell Tumors Who
Experienced Treatment Failure With Cisplatin-Based First-Line
Chemotherapy. J Clin Oncol 2010;28(33):4906-11.
107. Beyer J, Kramar A, Mandanas R, Linkesch W, Greinix A, Droz JP,
et al. High-dose chemotherapy as salvage treatment in germ cell
tumors: a multivariate analysis of prognostic variables. J Clin Oncol
1996;14(10):2638-45.
108. Pico JL, Rosti G, Kramar A, Wandt H, Koza V, Salvioni R, et al.
A randomised trial of high-dose chemotherapy in the salvage
treatment of patients failing first-line platinum chemotherapy for
advanced germ cell tumours. Ann Oncol 2005;16(7):1152-9.
109. Bhatia S, Abonour R, Porcu P, Seshadri R, Nichols CR, Cornetta
K, et al. High-dose chemotherapy as initial salvage chemotherapy
in patients with relapsed testicular cancer. J Clin Oncol
2000;18(19):3346-51.
110. Einhorn LH, Williams SD, Chamness A, Brames MJ, Perkins SM,
Abonour R. High-dose chemotherapy and stem-cell rescue for
metastatic germ-cell tumors. NEJM 2007;357(4):340-8.
111. Rick O, Beyer J, Kingreen D, Schwella N, Krusch A, Schleicher J,
et al. High-dose chemotherapy in germ cell tumours: a large single
centre experience. European Journal of Cancer 1998;34(12):18838.
112. Beyer J, Stenning S, Gerl A, Fossa S, Siegert W. High-dose versus
conventional-dose chemotherapy as first-salvage treatment in
patients with non-seminomatous germ-cell tumors: a matched-pair
analysis. Ann Oncol 2002;13(4):599-605.
113. Lorch A, Kollmannsberger C, Hartmann JT, Metzner B, SchmidtWolf IG, Berdel WE, et al. Single versus sequential high-dose
chemotherapy in patients with relapsed or refractory germ cell
tumors: a prospective randomized multicenter trial of the German
Testicular Cancer Study Group. J Clin Oncol 2007;25(19):2778-84.
114. Motzer RJ, Sheinfeld J, Mazumdar M, Bains M, Mariani T, Bacik
J, et al. Paclitaxel, ifosfamide, and cisplatin second-line therapy
for patients with relapsed testicular germ cell cancer. J Clin Oncol
2000;18(12):2413-8.
115. Loehrer PJ, Sr., Gonin R, Nichols CR, Weathers T, Einhorn
LH. Vinblastine plus ifosfamide plus cisplatin as initial salvage
therapy in recurrent germ cell tumor. Journal of Clinical Oncology
1998;16(7):2500-4.
116. Mead GM, Cullen MH, Huddart R, Harper P, Rustin GJ, Cook PA,
et al. A phase II trial of TIP (paclitaxel, ifosfamide and cisplatin)
given as second-line (post-BEP) salvage chemotherapy for patients
with metastatic germ cell cancer: a medical research council trial.
Br J Cancer 2005;93(2):178-84.
117. Kollmannsberger C, Rick O, Derigs HG, Schleucher N, Schöffski
P, Beyer J, et al. Activity of oxaliplatin in patients with relapsed
or cisplatin-refractory germ cell cancer: a study of the German
Testicular Cancer Study Group. J Clin Oncol 2002;20(8):2031-7.
118. Motzer RJ, Bajorin DF, Schwartz LH, Hutter HS, Bosl GJ, Scher
HI, et al. Phase II trial of paclitaxel shows antitumour activity in
patients with previous treated germ cell tumours. J Clin Oncol
1994;12:2277-83.
119. Bedano PM, Brames MJ, Williams SD, Juliar BE, Einhorn LH.
Phase II study of cisplatin plus epirubicin salvage chemotherapy
in refractory germ cell tumors. Journal of Clinical Oncology
2006;24(34):5403-7.
120. Kollmannsberger C, Beyer J, Liersch R, Schoeffski P, Metzner B,
Hartmann JT, et al. Combination chemotherapy with gemcitabine
plus oxaliplatin in patients with intensively pretreated or refractory
germ cell cancer: a study of the German Testicular Cancer Study
Group. Journal of Clinical Oncology 2004;22(1):108-14.
121. Porcu P, Bhatia S, Sharma M, Einhorn LH. Results of treatment
after relapse from high-dose chemotherapy in germ cell tumors. J
Clin Oncol 2000;18(6):1181-6.
122. Information and Statistics Division Scotland. Childhood, adolescent
and young adult cancer. [cited 15 December 2010]. Available from
url: http://www.isdscotland.org/isd/1631.html
123. Information and Statistics Division Scotland. Childhood, adolescent
and young adult cancer. [cited 21 December 2010]. Available from
url: http://www.isdscotland.org/isd/1631.html
124. Sweeney C. History of testicular cancer chemotherapy: maximizing
efficacy, minimizing toxicity. Sem Urol Oncol 2001;19(3):170-9.
125. de Wit R, Roberts JT, Wilkinson PM, de Mulder PH, Mead GM,
Fossa SD, et al. Equivalence of three or four cycles of bleomycin,
etoposide, and cisplatin chemotherapy and of a 3- or 5-day
schedule in good-prognosis germ cell cancer: a randomized study
of the European Organization for Research and Treatment of Cancer
Genitourinary Tract Cancer Cooperative Group and the Medical
Research Council. Journal of Clinical Oncology 2001;19(6):162940.
126. Fossa SD, Gilbert E, Dores GM, Chen J, McGlynn KA, Schonfeld S,
et al. Noncancer causes of death in survivors of testicular cancer.
J Natl Cancer Inst 2007;99(7):533-44.
127. Fossa SD, Aass N, Harvei S, Tretli S. Increased mortality rates in
young and middle-aged patients with malignant germ cell tumours.
Br J Cancer 2004;90(3):607-12.
128. Meinardi MT, Gietema JA, van der Graaf WT, van Veldhuisen
DJ, Runne MA, Sluiter WJ, et al. Cardiovascular morbidity in
long-term survivors of metastatic testicular cancer. J Clin Oncol
2000;18(8):1725-32.
129. Fenton DW, Verma S, Venner P, Sawhney R, Mackey JR. The lack
of long-term effect of Cisplatin based combination chemotherapy
on serum cholesterol for treatment of testicular cancer. J Urol
2002;168(5):1971-4.
130. Oh JH, Baum DD, Pham S, Cox M, Nguyen ST, Ensor J, et al. Longterm complications of platinum-based chemotherapy in testicular
cancer survivors. Med Oncol 2007;24(2):175-81.
131. Nuver J, Smit AJ, Sleijfer DT, van Gessel AI, van Roon AM, van
der Meer J, et al. Microalbuminuria, decreased fibrinolysis, and
inflammation as early signs of atherosclerosis in long-term survivors
of disseminated testicular cancer. Eur J Cancer 2004;40(5):701-6.
132. Sagstuen H, Aass N, Fossa SD, Dahl O, Klepp O, Wist EA, et al.
Blood pressure and body mass index in long-term survivors of
testicular cancer. J Clin Oncol 2005;23(22):4980-90.
61
Management of Adult Testicular Germ Cell Tumours
133. Haugnes HS, Aass N, Fossa SD, Dahl O, Klepp O, Wist EA,
et al. Components of the metabolic syndrome in long-term
survivors of testicular cancer. Ann Oncol 2007;18(2):241-8.
134. Garcia-Serra AM, Zlotecki RA, Morris CG, Amdur RJ.
Long-term results of radiotherapy for early-stage testicular
seminoma. Am J Clin Oncol 2005;28(2):119-24.
135. Majewski W, Majewski S, Maciejewski A, Kolosza Z,
Tarnawski R. Adverse effects after radiotherapy for early
stage (I,IIa,IIb) seminoma. Radiother Oncol 2005;76(3):25763.
136. Chevreau C, Mazerolles C, Soulie M, Gaspard MH, Mourey
L, Bujan L, et al. Long-term efficacy of two cycles of BEP
regimen in high-risk stage I nonseminomatous testicular
germ cell tumors with embryonal carcinoma and/or vascular
invasion. Eur Urol 2004;46(2):209-14.
137. Haugnes HS, Aass N, Fossa SD, Dahl O, Klepp O, Wist
EA, et al. Predicted cardiovascular mortality and reported
cardiovascular morbidity in testicular cancer survivors. J
Cancer Surviv 2008;2(3):128-37.
138. Schairer C, Hisada M, Chen BE, Brown LM, Howard R,
Fossa SD, et al. Comparative mortality for 621 second
cancers in 29356 testicular cancer survivors and 12420
matched first cancers. J Natl Cancer Inst 2007;99(16):124856. Epub 2007 Aug 8.
139. Richiardi L, Scelo G, Boffetta P, Hemminki K, Pukkala E,
Olsen JH, et al. Second malignancies among survivors of
germ-cell testicular cancer: a pooled analysis between 13
cancer registries. Int J Cancer 2007;120(3):623-31.
140. Robinson D, Moller H, Horwich A. Mortality and incidence
of second cancers following treatment for testicular cancer.
Br J Cancer 2007;96(3):529-33.
141. Howard R, Gilbert E, Lynch CF, Hall P, Storm H, Holowaty
E, et al. Risk of leukemia among survivors of testicular
cancer: a population-based study of 42,722 patients. Ann
Epidemiol 2008;18(5):416-21.
142. Travis LB, Andersson M, Gospodarowicz M, van Leeuwen
FE, Bergfeldt K, Lynch CF, et al. Treatment-associated
leukemia following testicular cancer. J Natl Cancer Inst
2000;92(14):1165-71.
143. Fatigante L, Ducci F, Campoccia S, Nocita AM, Paci E,
Crocetti E, et al. Long-term results in patients affected
by testicular seminoma treated with radiotherapy: risk of
second malignancies. Tumori 2005;91(2):144-50.
144. Scottish Intercollegiate Guidelines Network. Management
of Colorectal Cancer (SIGN publication 67). Edinburgh:
SIGN; 2003. Available from url: http://www.sign.ac.uk/
guidelines/fulltext/67/index.html
145. Forman D, Oliver RT, Brett AR, Marsh SG, Moses JH,
Bodmer JG, et al. Familial testicular cancer: a report of the
UK family register, estimation of risk and an HLA class 1
sib-pair analysis. Br J Cancer 1992;65(2):255-62.
146. Pugh RC, editor. Pathology of the testis. Oxford: Blackwell
Scientific; 1976.
147. Mostofi FK, Sesterhenn I, Sobin LH, editors. Histological
typing of testis tumours. 2nd ed. Berlin: Springer; 1998.
148. Sobin LH, Wittekind CH, editors. UICC: TNM classification
of malignant tumours. 5th ed. New York: John Wiley; 1997.
149. Skakkebaek NE, Berthelsen JG, Giwercman A, Muller
J. Carcinoma-in-situ of the testis: possible origin from
gonocytes and precursor of all types of germ cell tumours
except spermatocytoma. Int J Androl 1987;10(1):19-28.
150. Reinberg Y, Manivel JC, Llerena J, Niehans G, Fraley EE.
Epidermoid cyst (monodermal teratoma) of the testis. Br J
Urol 1990;66(6):648-51.
151. Forquer JA, Harkenrider M, Fakiris AJ, Timmerman RD,
Cavaliere R, Henderson MA, et al. Brain metastasis from
non-seminomatous germ cell tumor of the testis. Expert Rev
Anticancer Ther 2007;7(11):1567-80.
152. Fossa SD, Bokemeyer C, Gerl A, Culine S, Jones WG,
Mead GM, et al. Treatment outcome of patients with
brain metastases from malignant germ cell tumors. Cancer
1999;85(4):988-97.
62
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