EXTRAGONADAL GERM CELL TUMOURS - Alberta Health Services

CLINICAL PRACTICE GUIDELINE GU-007
Version 1
EXTRAGONADAL GERM CELL TUMOURS
Effective Date: April 2013
The recommendations contained in this guideline are a consensus of the Alberta Provincial Genitourinary Tumour
Team synthesis of currently accepted approaches to management, derived from a review of relevant scientific
literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical
judgment in the context of individual clinical circumstances to direct care.

BACKGROUND
CLINICAL PRACTICE GUIDELINE GU-007
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Germ cell tumours (GCTs) are one of the most common cancers among young adult men. 1 An
extragonadal GCT is, by definition, a germ cell neoplasm displaying one of the histologies associated with
gonadal origin, but located outside the gonads. 2 Extragonadal GCTs are relatively uncommon, but
represent 1 to 5% of all GCTs. 3 Non-central nervous system extragonadal GCTs are found in a variety of
anatomic locations, but most commonly affect the mediastinum and retroperitoneal. 2
The mediastinum is the most common anatomic site for extragonadal germ cell tumours in adults. 3 Data
on GCT etiology suggest that mediastinal GCTs comprise approximately 54% of all extragonadal GCT
cases, while retroperitoneal GCTs comprise the remaining 45%. 4-6 The majority of these cases occur in
males aged 20 to 40 years. 7 When treated with induction chemotherapy, with or without secondary
surgery, patients with pure seminomatous extragonadal GCTs have a long term cure rate of almost 90%,
irrespective of the primary tumour site. Patients with mediastinal non-seminoma have a five-year survival
rate of 45%, whereas patients with retroperitoneal primaries have a five-year survival rte of 62%. 8
GUIDELINE QUESTION
What are the appropriate management strategies for patients with primary mediastinal or retroperitoneal
germ cell tumours?
DEVELOPMENT AND REVISION HISTORY
This guideline was reviewed and endorsed by the Alberta Provincial Genitourinary Tumour Team.
Members of the Alberta Provincial Genitourinary Tumour Team include medical oncologists, radiation
oncologists, urologists, pathologists, nurses, and pharmacists. Evidence was selected and reviewed by a
working group comprised of members from the Alberta Provincial Genitourinary Tumour Team and a
Knowledge Management Specialist from the Guideline Utilization Resource Unit. A detailed description of
the methodology followed during the guideline development process can be found in the Guideline
Utilization Resource Unit Handbook.
SEARCH STRATEGY
The Pubmed database was searched using the terms (retroperitoneal OR mediastinal) AND germ cell
AND primary, published between 1946 and 2012 April. Results were limited to clinical trials, studies in
humans, meta-analyses, and practice guidelines. The Medline database was then searched for relevant
literature using the MeSH terms “Neoplasm, germ cell and embryonal” with subheadings drug therapy,
radiotherapy, therapy, and surgery, combined with “extragonadal.” Results were limited to literature
published between 1946 and 2012 April. Studies involving fewer than ten patients with extragonadal germ
cell tumours, as well as single case studies, were excluded.
Websites of the following guideline developers were searched for relevant guidelines: National
Comprehensive Cancer Network (NCCN), British Columbia Cancer Agency (BCCA), European Society of
Medical Oncology (ESMO), National Institutes of Health and Clinical Excellence (NICE), American Society
of Clinical Oncology (ASCO), Scottish Intercollegial Guidelines Network (SIGN), Cancer Council Australia
(CCA) and Cancer Care Ontario (CCO).
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TARGET POPULATION
CLINICAL PRACTICE GUIDELINE GU-007
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These recommendations apply to postpubertal patients with primary mediastinal or retroperitoneal germ
cell tumours.
RECOMMENDATIONS
Diagnosis:
• If a patient presents with undifferentiated adenocarcinoma of unknown origin, copy number of
chromosome i12p should be performed.
• Lactate dehydrogenase (LDH), alpha fetoprotein (AFP) and gonadotropin (hCG) should be assessed.
• Patients should be classified and treated based on prognosis: 1
Table 1. Prognostic factors for germ cell tumours.
Prognosis Non-seminoma Seminoma
good Primary extragonadal retroperitoneal
Any primary localization
and low markers: AFP

CLINICAL PRACTICE GUIDELINE GU-007
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5. Patients with mediastinal GCTs who relapse have poor prognosis. Transplant should not routinely be
offered to these patients. However, depending on the results from salvage chemotherapy, patient
performance status, individual factors and patient’s desire to pursue the transplant, it may be
considered only after an honest discussion between the clinician and patient as the chance of long
term remission and cure are very low.
6. After the completion of chemotherapy, strong consideration for retroperitoneal lymph node dissection
should be given in those patients with retroperitoneal primary GCTs.
7. After the completion of chemotherapy, surgery to resect any residual masses should be strongly
considered in those patients with mediastinal primary GCTs.
Table 2. Suggested follow up schedule for germ cell tumours. 9
Group
Clinical examination and
diagnostics
Year 1
Frequency of exam (months)
Year 2 Year 3 Year 4 Year 5 Year 5-10
LDH, AFP, HCG, clinical exam
3 3 3 3 3 6
good
prognosis
X-ray of the chest or CT scan of
chest (if supradiaph. disease)
3-6* 4 6 6 6
CT scan of the abdomen/pelvis
3 4 6 6 6
LDH, AFP, HCG, clinical exam
3 3 3 3 3 6
intermediate
and poor
prognosis
X-ray of the chest or CT scan of
chest (if supradiaph. disease)
CT scan of the abdomen/pelvis
3-6*
3
3-6*
3
4-6*
4
6
6
6
6
* depending on the presence of intrathoracic disease
DISCUSSION
Diagnosis
Data from an international series of 635 patients with extragonadal GCTs (54% had mediastinal primary
GCTs and 45% had retroperitoneal primary GCTs) who were treated from 1975 to 1996 at 11 cancer
centers was analyzed. 5 The most common symptoms at initial presentation in patients with mediastinal
GCTs included dyspnea (25%), chest pain (23%) and cough (17%), fever (13%), weight loss (11%), vena
cava occlusion syndrome and fatigue or weakness (6%). For patients with retroperitoneal primary GCTs,
most common symptoms were abdominal-related (29%) and back pain (14%), followed by weight loss
(9%), fever (8%), and vena cava or other thrombosis (9%). 2,5 Around 50-75% of patients with nonseminoma
extragonadal GCTs have elevated AFP and iso-chromosome i12p. 5,6,10 Approximately 40% of
patients with mediastinal seminoma and non-seminoma and those with retroperitoneal seminoma have
elevated hCG. 5,6 A higher average percentage (about 70%) of patients with retroperitoneal non-seminoma
present with elevated hCG levels. 6 Patients should be classified and treated based on prognosis. 1
Management
Chemotherapy
All patients presenting with extragonadal germ cell tumours should be considered for enrollment in clinical
trials. Bleomycin, etoposide and cisplatin (BEP) or etoposide, ifosfamide, cisplatin (VIP) is recommended
as first-line chemotherapy, with the number of cycles given based on risk category. The recommendation
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CLINICAL PRACTICE GUIDELINE GU-007
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is in line with that of other guidelines and reviews. 2,9,11,12 VIP should be considered for those patients who
cannot tolerate bleomycin. A phase III trial by Motzer et al. (2007) randomized patients to receive either 4
cycles of BEP or 2 cycles of BEP followed by 2 cycles of cisplatin, etoposide, cyclophosphamide (CECP)
and stem cell transplant. Of the 219 patients included in this study, 11 had retroperitoneal primary GCTs
and 58 had mediastinal primary GCTs. Complete response to treatment was similar between the two
groups (55% for BEP versus 56% for CECP), as was 2-year overall survival (72% for BEP versus 71% for
CECP). However, gastrointestinal and hepatobiliary toxicity was lower in the BEP group (19% versus 42%
and 9% versus 24%, respectively). 13
Nichols et al. (1998) conducted a randomized trial of 304 patients with advanced, disseminated germ cell
tumours. Patients received either four cycles of BEP or VIP. Complete remission rate (37% VIP versus
31% BEP) and 2-year overall survival rate (74% VIP and 71% BEP) were not significantly different.
However, the use of ifosfamide instead of bleomycin led to significantly higher genitourinary and
hematologic toxicity. 14 The final analysis of Eastern Cooperative Oncology Group protocol E3887 had
similar results. After a median follow-up of 7.3 years, patients had similar progression free survival and
overall survival rates. For patients treated with BEP, overall survival was 57% and progression free
survival 49%, versus 62% and 56% in patients treated with VIP. Hematologic toxicity was greater in the
ifosfamide arm in this study as well. 15
For failure or relapse on either of these regimens and good risk disease, high dose chemotherapy (HDCT)
and peripheral blood stem cell transplantation can be given. Recommended agents for HDCT include
ifosfamide, vinblastine, carboplatin, etoposide and paclitaxel. Patients who are classified as poor risk at
relapse should be considered early for HDCT and peripheral blood stem cell transplantation, as they may
not be well enough to consider this treatment in the third line setting. Hartmann et al. (2001) conducted a
multi-centre retrospective review of 142 patients with relapsed non-seminomatous extragonadal germ cell
tumours who received platinum-based chemotherapy as first-line treatment. Patients were treated at
relapse with combinations of cisplatin, ifosfamide, vinblastine, etoposide, carboplatin and paclitaxel, and
34% of patients were treated with HDCT followed by autologous bone marrow transplantation. 16 At 45
months follow-up, 19% of patients (n=27) were alive without evidence of disease; 17 of those were treated
at relapse with conventional chemotherapy and 10 were treated with HDCT. For patients with
retroperitoneal primaries, 32% and 12% of those with mediastinal primaries treated with HDCT achieved
were alive without any evidence of disease at 45 months. Of these patients, 44% of them also received
surgery post-HDCT. 16
A randomized phase III trial of 280 patients with relapsed poor prognosis GCTs compared 4 cycles of
cisplatin, ifosfamide, and etoposide (A) with 3 cycles followed by HDCT with etoposide, carboplatin and
cyclophosphamide and haematopoietic stem cell support (B). No significant improvements in the HDCT
group were observed in regards to 3- year event free survival (35% versus 42%, p=0.16) or overall
survival (53% versus 59%). 17 Feldman et al. (2010) reported the outcomes of 107 patients with poor
prognosis GCTs (such as those with extragonadal primaries) who failed first line chemotherapy and were
subsequently treated with paclitaxel and ifosfamide, followed by high-dose carboplatin and etoposide (TI-
CE) with stem cell transplant. Five-year disease free survival was 47% for these patients, and OS was
52% (median follow-up 61 months). 18 Lorch et al. (2010) conducted a trial of HDCT in late relapse GCTs,
defined as relapse after 2 years from completion of cisplatin-based chemotherapy. Patients were treated
with HDCT followed by resection where possible. At a median follow-up of 5.6 years, 14% of patients had
no evidence of disease progression. 19
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CLINICAL PRACTICE GUIDELINE GU-007
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Patients with mediastinal GCTs who relapse have poor prognosis. Transplant should not routinely be
offered to these patients. However, depending on the results from salvage chemotherapy, patient
performance status, individual factors and patient’s desire to pursue the transplant, it may be considered
only after an honest discussion between the clinician and patient as the chance of long term remission and
cure are very low. Hidlago et al. (1997) looked specifically at patients with mediastinal non-seminoma
treated with cisplatin-based chemotherapy and considered for residual mass resection in their
retrospective review of patient records. Fifteen patients had disease confined to the mediastinum, and 12
had metastatic disease. Eleven patients (40.7%) became disease free with initial treatment; 4 of these
patients had received only platinum-based chemotherapy, 1 surgery followed by adjuvant chemotherapy,
and 6 chemotherapy followed by surgery. The remaining patients had only partial or no response to initial
treatment, and 11 received salvage treatment to which none responded. This led the authors to conclude
that in the case of mediastinal non-seminoma, the achievements of a disease-free status after initial
treatment are likely to be cured. 20
Surgery in extragonadal GCTs
In retroperitoneal germ cell tumours, strong consideration for retroperitoneal lymph node dissection should
be given after the completion of chemotherapy (recommendation #6). Consideration should also be given
to the resection of any residual masses in mediastinal primary GCTs (recommendation #7).
Gerl et al. (1996) reviewed the medical records of 51 patients with extragonadal germ cell tumours (n=35
retroperitoneal primary, n=16 mediastinal primary) treated with platinum-based chemotherapy and
surgery. Thirty five patients had seminoma, and the remaining 16 non-seminoma. Fifty percent of patients
with mediastinal primary non seminoma had no evidence of disease at a median of 96 months, whereas
65% of patients with retroperitoneal non seminoma had no evidence of disease at a median of 39 months.
Those patients with seminoma extragonadal tumours survived with no evidence of disease constituted
96% of all seminoma patients at a median of 66 months. 21 Goss et al. (1994) documented their 14 year
experience treating a total of 40 patients with extragonadal GCTs at 4 University of Toronto teaching
hospitals. After combined modality therapy, 53% of mediastinal non seminomas achieved complete
remission at a median 70 months, whereas 88% of mediastinal seminomas survived with no evidence of
disease at a median 45 months. 22
Kesler et al. (2008) reported a 25-year single institution experience of post-chemotherapy surgery for 158
patients with mediastinal primary non-seminoma GCTs. Intra-operative deaths occurred in 6% of patients,
90% of which were due to respiratory failure. Post-operative complications occurred in 18% of patients.
Interestingly, none of the patients that received a chemotherapy regimen containing bleomycin had
respiratory complications during or after surgery. 23 A retrospective study of 75 patients with primary
mediastinal non-seminomatous GCTs was conducted by Ganjoo et al. (2000). All patients received
platinum-based chemotherapy, and 62 (83%) underwent post-chemotherapy resection. Postchemotherapy
pathology was found in both a multivariate and univariate analysis to be the most important
predictor of survival (p

GLOSSARY OF ABBREVIATIONS
Acronym Description
AFP alpha fetoprotein
BEP bleomycin, etoposide, cisplatin
GCT germ cell tumour
hCG gonadotropin
HDCT high dose chemotherapy
LDH lactate dehydrogenase
TI-CE paclitaxel, ifosfamide, cisplatin, etoposide
VIP etoposide, ifosfamide, cisplatin
DISSEMINATION
CLINICAL PRACTICE GUIDELINE GU-007
Version 1
• Present the guideline at the local and provincial tumour team meetings and weekly rounds.
• Post the guideline on the Alberta Health Services website.
• Send an electronic notification of the new guideline to all members of AHS, Cancer Care.
MAINTENANCE
A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2015. If critical new
evidence is brought forward before that time, however, the guideline working group members will revise
and update the document accordingly.
CONFLICT OF INTEREST
Participation of members of the Alberta Provincial Genitourinary Tumour Team in the development of this
guideline has been voluntary and the authors have not been remunerated for their contributions. There
was no direct industry involvement in the development or dissemination of this guideline. Alberta Health
Services – Cancer Care recognizes that although industry support of research, education and other areas
is necessary in order to advance patient care, such support may lead to potential conflicts of
interest. Some members of the Alberta Provincial Genitourinary Tumour Team are involved in research
funded by industry or have other such potential conflicts of interest. However the developers of
this guideline are satisfied it was developed in an unbiased manner.
REFERENCES
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5. Bokemeyer C, Nichols CR, Droz JP, Schmoll HJ, Horwich A, Gerl A, et al. Extragonadal germ cell tumors of the
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Feb;85(2):371-378.
24. Ganjoo KN, Rieger KM, Kesler KA, Sharma M, Heilman DK, Einhorn LH. Results of modern therapy for patients
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