Annals of Oncology Advance Access published November 14, 2012
Maintaining success, reducing treatment burden,focusing on survivorship: highlights from the thirdEuropean consensus conference on diagnosis andtreatment of germ-cell cancer
J. Beyer1, P. Albers2, R. Altena3, J. Aparicio4, C. Bokemeyer5, J. Busch6, R. Cathomas7,E. Cavallin-Stahl8, N. W. Clarke9, J. Claßen10, G. Cohn-Cedermark11, A. A. Dahl12, G. Daugaard13,U. De Giorgi14, M. De Santis15, M. De Wit16, R. De Wit17, K. P. Dieckmann18, M. Fenner19,K. Fizazi20, A. Flechon21, S. D. Fossa12, J. R. Germá Lluch22, J. A. Gietema3, S. Gillessen23,A. Giwercman24, J. T. Hartmann25, A. Heidenreich26,†, M. Hentrich27, F. Honecker5, A. Horwich28,
R. A. Huddart29, S. Kliesch30, C. Kollmannsberger31, S. Krege32, M. P. Laguna33,L. H. J. Looijenga34, A. Lorch2, J. P. Lotz35, F. Mayer36, A. Necchi37, N. Nicolai38, J. Nuver3,K. Oechsle5, J. Oldenburg39, J. W. Oosterhuis34,†, T. Powles40, E. Rajpert-De Meyts41, O. Rick42,G. Rosti43,†, R. Salvioni38, M. Schrader44, S. Schweyer45, F. Sedlmayer46, A. Sohaib47,
R. Souchon48, T. Tandstad49, C. Winter2 & C. Wittekind501Department of Hematology and Oncology, Vivantes Klinikum Am Urban, Berlin; 2Department of Urology, University Hospital, Düsseldorf, Germany; 3Department ofMedical Oncology, University Medical Center, Groningen, The Netherlands; 4Department of Medical Oncology, University Hospital La Fe, Valencia, Spain; 5Department of
Medical Oncology, BMT and Pulmonology University Hospital, Hamburg; 6Department of Urology, Charite University Hospital, Berlin, Germany; 7Department of Internal
Medicine, Kantonsspital Graubünden, Switzerland; 8Department of Oncology, University Hospital, Lund, Sweden; 9Department of Urology, The Christie Hospital,
Manchester, UK; 10Department of Radiation Oncology, St. Vincentius Hospital, Karlsruhe, Germany; 11Department of Oncology, Karolinska Institute and University
Hospital, Stockholm, Sweden; 12National Resource Center for Late Effects, Department of Onocology, The Norwegian Radium Hospital and University of Oslo, Oslo,
Norway; 13Department of Oncology, Rigshospitalet, Copenhagen, Denmark; 14Department of Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura deiTumori (I.R.S.T.), Meldola, Italy; 153rd Medical Department, Kaiser-Franz-Josef-Spital, ACR-ITR VIEnna, LBI-ACR VIEnna, Vienna, Austria; 16Department of Hematology
and Oncology, Vivantes Klinikum Neukölln, Berlin, Germany; 17Department of Medical Oncology, Erasmus University, Rotterdam, The Netherlands; 18Department of
Urology, Albertinen Hospital, Hamburg; 19Department of Hematology and Oncology, Medizinische Hochschule, Hannover, Germany; 20Department of Medicine, Institute
Gustave Roussy, Villejuif; 21Department of Medical Oncology, Centre Léon Bérard, Lyon, France; 22Department of Medical Oncology, IDIBELL, Institut Català
d’Oncologia, Barcelona, Spain; 23Department of Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland; 24Reproductive Medicine Center, Skane University Hospital,Malmö, Sweden; 25Department of Medical Oncology, University Hospital Schleswig-Holstein, Kiel; 26Department of Urology, University Hospital, Aachen, Germany;27Department of Hematology and Oncology, Harlaching Hospital, Munich, Germany; 28Department of Radiotherapy, The Royal Marsden Hospital, London; 29Departmentof Radiotherapy, Institute of Cancer Research, The Royal Marsden Hospital, London, UK; 30Center for Reproductive Medicine and Andrology, University Hospital,
Münster, Germany; 31Division of Medical Oncology, University of British Columbia, Vancouver, Canada; 32Department of Urology, Hospital Maria Hilf, Krefeld, Germany;33Department of Urology, Academic Medical Center, University of Amsterdam, Amsterdam; 34Department of Pathology, Erasmus Medical Center, Rotterdam, TheNetherlands; 35Department of Clinical Oncology, Hopital Tenon, Paris, France; 36Department of Hematology and Oncology, University Hospital, Tübingen, Germany;
Departments of 37Medical Oncology, Medical Oncology Unit 2; 38Surgery, Urology Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; 39Clinical Cancer
Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; 40Department of Medical Oncology, St. Bartholomews Hospital, London, UK;41Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark; 42Department of Medicine, Hospital Reinhardshöhe, Bad Wildungen, Germany;43Department of Medical Oncology, Ospedale Civile Ca’ Foncello, Treviso, Italy; 44Department of Urology, University Hospital, Ulm; 45Gemeinschaftspraxis Pathologie,Starnberg, Germany; 46Department of Radiotherapy and Radiation Oncology, Paracelsus Medical University Hospital, Salzburg, Austria; 47Department of Diagnostic
Radiology, The Royal Marsden Hospital, London, UK; 48Department of Radiation Oncology, University Hospital, Tübingen, Germany; 49Department of Oncology,
St Olavs Hospital, Trondheim, Norway; 50Institute of Pathology, University Hospital, Leipzig, Germany
Received 22 May 2012; revised 17 September 2012; accepted 1 October 2012
*Correspondence to: Prof Dr J. Beyer, Department of Hematology and Oncology,
Vivantes Klinikum Am Urban, Dieffenbachstrasse 1, Berlin D-10967, Germany.
Tel: +49-30-130-222 100; Fax: +49-30-130-222-105; E-mail: joerg.beyer@vivantes.de
†Invited and involved in the preparation of the conference, but unable to attend.
The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permitsnon-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals. permissions@oup.com.
In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer
(GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and
2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and
treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol
2004; 15: 1377–1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis andtreatment 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: 478–496; Krege S, Beyer J, Souchon R et al. European consensus conferenceon diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer
Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497–513]. A panel of 56 of 60 invited GCC experts from allacross Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late
toxic effects as well as on survivorship issues.
The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all
actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years.
Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all
aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous
recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented atthe conference to address the most controversial areas for a poll of expert opinions. Here, we present the main
recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.
Key words: consensus conference, diagnosis, germ-cell cancer, late toxic effects, long-term follow-up, treatment
Immunohistochemistry must include detection of alpha-
fetoprotein (AFP) and human chorionic gonadotropin (HCG)for identification of yolk sac tumor and choriocarcinoma,
Germ-cell cancer (GCC), cytogenetically characterized by
respectively []. Vascular invasion can be detected
abnormalities of 12p, is the most frequent malignancy in male
morphologically, supported by immunohistochemical detection
Caucasians aged 15–40 years. The majority of patients present
of CD31/FVIII. Recent studies demonstrate that applications of
with a primary tumor in the testis. However, as GCC may also
pluripotency-related markers (OCT4, NANOG, AP-2γ or
occur in midline structures of the body, an extragonadal germ-
LIN28) are highly informative for the detection of CIS/TIN,
cell cancer (EGCC) should always be considered in young men
seminoma and EC, to be combined with different fixation
with a retroperitoneal, supraclavicular or mediastinal mass.
protocols []. Because of the clinical importance, it is highly
Important insights have recently been obtained regarding
recommended that all histological specimens be assessed by a
the etiology of GCC. These relate to the recognition of
pathologist experienced in GCC pathology , ].
established risk factors, supposed to be interlinked to each
The issue of a contralateral biopsy in patients with a
other according to the so-called testicular dysgenesis syndrome
unilateral gonadal GCC divided opinions [While the need
and disorders of sex development []. In addition, high-risk
for informing all patients about the pros and cons of a
alleles have been identified The most significant
contralateral biopsy remained undisputed, only about a third of
conclusion is that all these parameters are in accordance with
panelists recommended a contralateral biopsy at least to high-
an embryonic initiation of the pathogenesis of GCC, i.e. related
to the initial formation and secondary development of the
followed by radiotherapy with 16–20 Gy to
A histopathological examination of the orchiectomy
specimen will establish the diagnosis in patients with gonadal
detection and the possibility of assessing spermatogenesis,
GCC. The histopathological report must address the following
fertility is counterbalanced by infertility in 100% and in
issues: localization and size of the tumor, multiplicity, tumor
hypogonadism in ∼30% of patients after radiotherapy with the
extension (rete testis, tunica albuginea, tunica vaginalis,
subsequent need for testosterone supplementation, the
spermatic cord, scrotum), pT category according to the most
majority of panelists opted against routine biopsies to detect
recent International Union Against Cancer (UICC)
CIS/TIN. Yet, as the majority of patients with untreated CIS/
classification, histological type (WHO-ICD-O-M), the presence
TIN in the contralateral testis will eventually develop overt
or absence of carcinoma-in situ/testicular intraepithelial
GCC within the next 10 years, surveillance programs, e.g. by
neoplasia (CIS/TIN) (synonymous: intratubular germ-cell
regular clinical examination and testicular ultrasound, are
neoplasia) and the presence or absence of vascular invasion of
mandatory and the patients need to be informed that a
blood or lymphatic vessels. In tumors with mixed structures,
contralateral GCC might develop with subsequent
each individual component and its estimated relative
hypogonadism and need for testosterone replacement after
proportion must be documented. Similarly, evidence of
syncytiotrophoblasts should be indicated in seminoma as well
In EGCC, the necessity of testicular biopsies in patients with
as any sarcomatous elements in spermatocytic seminoma as
proven EGCC was likewise questioned. The majority of
recommended by the World Health Organization [
panelists voted against performing biopsies in EGCC patients
when both of the testes were normal upon clinical examination
lymph-node dissection (RPLND) or before a definitive
Spiral computerized tomography (CT)scans of the thorax, abdomen and pelvis remain the staginginvestigation of choice (Table ) [Diagnostic imaging of
the brain is recommended in patients with visceral metastases
and mandatory in the presence neurological symptoms
Clinical stage I in seminoma and non-seminoma is defined as
Magnetic resonance tomography imaging (MRI) as an
disease limited to the testes with no radiological evidence of
alternative staging procedure to CT scanning should be
metastatic disease and normal serum tumor markers after
reserved to selected patient populations (e.g. intolerance to
intravenous contrast agents) and to institutions with special
In respect to the optimal management of seminoma stage I,
the discussion revealed a spectrum of opinions among
panelists (Table The first discussion circled around the issue
computerized tomography scanning (PET–CT) has no role as
of prognostic factors. In contrast to the initial analyses from
a staging procedure due to its low additional diagnostic yield
the Canadian group, rete testis infiltration and tumor size >4
over CT or MRI scans and its additional radiation exposure
cm could not be validated in two prospective series for the
identification of seminoma patients with a high risk of occult
Serum tumor markers AFP, HCG and lactate dehydrogenase
metastases However, contrary to these most recent
(LDH) should be determined in all patients before and after
publications, about one half of the panelists still believed that
orchiectomy and in patients with metastatic disease also
these factors are useful in decision making in seminoma stage I
immediately before chemotherapy. In metastatic patients, these
pre-chemotherapy markers—and not the pre-orchiectomy
since at least the negative predictive value of these
markers—should be used for the correct allocation to the
factors has been prospectively shown in the most recent
Spanish trial The second discussion focused on the
optimal management strategy. Here, no consensus could be
attention should be paid to patients with radiological stage I
achieved. Whereas one-third of panelists considered
disease and elevated tumor markers: patients should be
surveillance the preferred treatment strategy in all stage I
monitored with frequent post-orchiectomy serum marker
seminoma regardless of the risk factors for relapse, others
determinations until complete marker normalization before
opted for surveillance in ‘low-risk’ patients with a relapse rate
these patients are classified as having true stage I disease. All
of 5%–12%, and adjuvant treatment in ‘high-risk’ patients as
other patients with an increase of serum tumor markers after
had been pursued in the Spanish cooperative trial The
orchiectomy must be considered as having metastatic disease.
Patients with normal serum tumor markers and equivocalretroperitoneal metastases in CT or MRI scans should be
Table 2. Strategies in clinical stage I seminoma and non-seminoma
followed closely by repeat scanning or in case of a non-seminoma may receive upfront staging retroperitoneal
Table 1. Initial management of patients with suspected GCC
Orchiectomy in patients with gonadal diseasec
Option of semen cryopreservation in patients scheduled for chemotherapy
aAlso after orchiectomy in all patients with elevated markers as well as
immediately before chemotherapy in patients with metastatic disease.
bCT or MRI scan also of the brain in patients with visceral metastasesand/or neurological symptoms or signs.
aValidity of risk factors have been challenged in recent analyses.
cOrchiectomy should be delayed until completion of chemotherapy in
bRadiotherapy was a less favored adjuvant treatment option due to the
patients with advanced disease at initial presentation and/or imminent
long-term risk of induction of secondary malignancies.
organ failure. Patients with normal testes and suspected extragonadal
cIndicated, e.g. in stage I patients with retroperitoneal lymph-nodes of
germ-cell cancer (EGCC) may or may not have a testicular biopsy.
equivocal size who are unwilling to accept surveillance (see the text for
GCC, germ-cell cancer; AFP, alpha-fetoprotein; HCG, human chorionic
AUC, area under the curve; Gy, Gray; BEP, bleomycin, etoposide, cisplatin;
tomography; MRI, magnetic resonance imaging.
RPLND, retroperitoneal lymph-node dissection.
use of radiotherapy as adjuvant treatment was less favored
Table 3. First-line chemotherapy regimens in metastatic seminoma and
among panelists compared with single-agent carboplatin,
because of concerns about the induction of secondary tumorseven by reduced radiation doses and fields. On the other hand,
a minority of panelists still considered surveillance, adjuvant
carboplatin and adjuvant radiation as equal options
In non-seminoma, vascular invasion remains the most
important prospectively validated and most widely accepted
risk factor that can be used for treatment stratification [
Patients without vascular invasion have a low risk of occult
metastatic disease/relapse of around 14%. In contrast, the
patients with vascular invasion in the primary tumor have a
high risk of occult metastatic disease and relapse of ∼50%. Yet,
aThree cycles BEP in IGCCCG ‘good prognosis’ patients; four cycles BEP
the clinical decisions based upon these data remained
in IGCCCG ‘intermediate prognosis’ and ‘poor prognosis’ patients.
controversial (Table ). About one-third of panelists each
bFour cycles EP only in IGCCCG ‘good prognosis’ patients with
favored surveillance in all non-seminoma stage I irrespective of
the risk factors, surveillance in low risk and one or two
cFour cycles VIP only in IGCCCG ‘intermediate risk‘ and ‘poor risk’
adjuvant cycles of cisplatin, etoposide, bleomycin (BEP) in
patients with contraindications to bleomycin.
high-risk patients, respectively. Therefore, adjuvant
VIP, cisplatin, etoposide and ifosfamide.
chemotherapy remained the favored strategy in high-riskclinical stage I non-seminoma. Upfront staging RPLND in all
treatment, who have a higher risk of febrile neutropenia.
patients was favored only by a small minority of panelists
Growth factor support, empiric antibiotic treatment and
antiemetic prophylaxis should be given according to the
published guidelines. In ‘good prognosis’ patients according
Thus, the optimal management of clinical stage I seminoma
to IGCCCG (Table ), three cycles of BEP were preferred to
and non-seminoma remains an area of debate. The risks and
four cycles of EP The latter were recommended to
benefits of each strategy must be discussed with patients in
be used in ‘good prognosis’ patients with contraindications
respect to its immediate and long-term impact, and the patient
to bleomycin. Despite the recent European intergroup trial
actively involved in the final decision. Non-compliance with
that prospectively compared four cycles of BEP with or
surveillance strategies remained some areas of concern, which
without additional paclitaxel four cycles of BEP remain the
standard treatment in patients with ‘intermediate prognosis’
]. Four cycles of BEP also remain the standard
treatment in patients with ‘poor prognosis’
In intermediate and poor prognosis patients with
In early-stage IIA seminoma with small retroperitoneal lymph-
contraindications to bleomycin, the equally effective
node metastases <2 cm, radiotherapy was still considered as an
combination of cisplatin, etoposide and ifosfamide (VIP)
adequate treatment option, but chemotherapy was seen as an
should be used instead of BEP (Table ). Until the
alternative or even preferred option among panelists avoiding
publication of an ongoing French prospective, randomized
trial, the majority of panelists did not recommend
intensification of first-line treatment by high-dose
seminoma, the majority of panelists favored chemotherapy
chemotherapy (HDCT) or recommended to limit the use of
with three cycles of BEP or four cycles of cisplatin and
HDCT to patients with the highest risk of treatment failure
(e.g. extensive liver, bone or brain metastases)
Patients with an inadequate tumor marker decline
Patients with metastatic seminoma and non-seminoma
should continue to complete first-line treatment
should be classified according to the IGCCCG prognostic
classification [According to the panelists, classic
‘Indiana BEP’ remains the standard of care in metastatic
switching to intensifying chemotherapy in patients with an
seminoma and non-seminoma [, ]. Pre- and post-
inadequate marker decline [, To avoid overtreatment,
hydration helps us to prevent renal toxicity. Routine
caution should be exercised in initiating chemotherapy in
furosemide or mannitol is not required. Neutropenic fever
stage IIA non-seminoma with normal markers and equivocal
after BEP is infrequent and growth factor support is rarely
or minimally enlarged retroperitoneal nodes. As some of
needed except in individual patients with very advanced
these patients may indeed have pathological stage I disease,
metastatic disease and in patients undergoing salvage
close surveillance or staging RPLND is recommended.
Table 4. Prognostic classification of metastatic seminoma and non-seminoma according to IGCCCG []
(seminoma: 90% patients, 86% survival; non-seminoma: 56% patients; 92% survival)
and no extrapulmonary visceral metastases
gonadal or retroperitoneal primary tumor location
and no extrapulmonary visceral metastases
(seminoma: 10% patients, 72% survival; non-seminoma: 28% patients; 80% survival)
gonadal or retroperitoneal primary tumor location
and no extrapulmonary visceral metastases
AFP, alpha-fetoprotein; HCG, human chorionic gonadotropin; LDH, lactate dehydrogenase; ULN, upper limit of normal.
Patients with IGCCCG intermediate or poor
prognosis, those with >10% viable tumor residuals as well as
Seminoma with residual tumors after chemotherapy should not
those with positive surgical margins have a better progression-
be scheduled for post-chemotherapy residual tumor resections
free, but not overall survival with adjuvant chemotherapy.
(PC-RTR) due to the high morbidity and small therapeutic gain
Adjuvant chemotherapy should, therefore, be discussed with
of the procedure in this group of patients. Seminoma with lesions
these patients, but a surveillance strategy is also justified
≥3 cm can be evaluated by PET–CT not earlier than 8 weeks
As the success of PC-RTR highly depends on the experience
after completion of chemotherapy—the only subgroup of GCC
and skill of the urologic surgeon, the panelists attempted a
patients in whom PET–CT is recommended
definition of an expert center for residual tumor surgery: 20
interventions per surgeon per year as well as immediate and
negative predictive value of PET–CT scans is high, and seminoma
ad hoc access to an interdisciplinary team of vascular surgeons,
with negative PET–CT scans should be followed irrespective of
liver surgeons and, possibly, also orthopedic surgeons as well as
the size of the residual lesion. The positive predictive value of a
availability of high-level postoperative support
PET–CT scan is less reliable. In PET–CT positive patients after
chemotherapy either biopsy, close observation with serial CTscans or, possibly, repeat PET–CT scans were recommended bythe majority of panelists
According to the panelists, PC-RTR is recommended in all
non-seminoma patients with residual tumors ≥ 1 cm within
Patients with seminoma or non-seminoma who relapse after
surveillance should be treated as patients with de novo
metastatic disease with three to four cycles of BEP depending
right template plus all areas of initial tumor sites. Only a
on their IGCCCG score This extends to the patients who
minority of panelists opted for a full bilateral resection in all
relapse after adjuvant carboplatin or adjuvant radiotherapy,
although the optimal management and outcome in stage I
seminoma who relapse after adjuvant treatment are currently
well as pulmonary residual lesions, no consensus as to the
unknown. Also unknown is the optimal management and
optimal management could be achieved although a great
outcome in stage I non-seminoma who relapse after one or
majority of panelists felt that some form of pulmonary
two cycles of adjuvant BEP, who should be considered for four
resections was required even in patients with necrosis in the
cycles of conventional-dose salvage chemotherapy (Table
Seminoma and non-seminoma patients who relapse after full
cisplatin-based first-line chemotherapy can be treated using
panelist would not consider PC-RTR even in non-seminoma, if
either conventional-dose chemotherapy (CDCT) or HDCT
the residual tumor is <1 cm in diameter
]. Their prognosis should be assessed using the most
recent international prognostic score No consensus could
Patients with vital cancer at the time of PC-RTR may or may
be reached in respect to their optimal first-salvage management
not be scheduled for two cycles of adjuvant chemotherapy
The opinions were divided among panelists and
discussion, a minority argued against using any HDCT in GCC
ranged from using HDCT in all relapsed patients irrespective
despite retrospective data in favor of HDCT in the first-salvage
of prognostic factors, to a risk-adapted approach using CDCT
setting and the fact that no conventional-dose regimen has
in low-risk and HDCT in patients with a high risk of failure, as
proven to induce long-term remissions in a relevant number of
well as to not using HDCT at all outside clinical trials, neither
patients when given as second or subsequent salvage treatment
in first nor in subsequent salvage treatments (Table ). In the
[]. HDCT should be delivered as two or three sequentialcycles using high-dose carboplatin and etoposide withoutadditional agents such as ifosfamide, cyclophosphamide or
Table 5. Salvage chemotherapy in relapsed seminoma and non-seminoma
Oxaliplatin, gemcitabine and paclitaxel or combinations
thereof have shown activity in the second or third-salvage
setting and may be applied as single agents or combinations, if
these drugs had not been used previously Transient
responses can also be achieved using oral etoposide.
Patients with complete remissions should be followed,
patients with residual masses after salvage chemotherapy
should be scheduled for PC-RTR within 4–6 weeks after the
normalization of tumor markers or when a low-level marker
plateau has been reached. Extensive surgery of all residual
lesions after completion of chemotherapy is an essential part of
High-dose regimens [, ] (require stem cell support)
Desperation surgery refers to the situation of a high-level
marker plateau or overtly rising markers after administration of
salvage chemotherapy in patients with potentially resectable
disease. With this approach, long-term survival may be
Paclitaxel given as a 24 h continuous intravenous infusion.
achieved in some patients. No conclusive data allow a definitive
Carboplatin may be dosed to an area under the curve (AUC) of eight
prognostic assessment. HCG elevation and high AFP levels
before surgery, residual retroperitoneal disease >5 cm and aprevious RPLND have been reported to portend a poor
Table 6. Risk factors in seminoma and non-seminoma after failure of
prognosis [However, according to the panelists,
desperation surgery should be attempted in all patients inwhom no reasonable chemotherapeutic options are available,
and who have cancer that can potentially be completely
Some discussions circled around the optimal definition of late
relapse. There was a clear vote that the term late relapse should
be limited to relapses occurring 2 years or later after full
cisplatin-based chemotherapy. This definition excludes patients
who relapse after adjuvant treatment or during surveillance
who are usually cured by chemotherapy alone. Patients with
late relapse represent a rare subgroup with an adverse
prognosis as well as a high frequency of teratoma and/or
non-GCC elements, who will have to be managed differently
Patients with late relapse relapses >2 years have an inferior prognosis.
resectable late relapse should undergo immediate surgical
CR, complete remission; NED, no evidence of disease after surgery;
removal of all tumor manifestations at an experienced
PRm−, partial remission and negative tumor markers; PRm+, partial
reference center irrespective of serum tumor marker levels
remission and positive tumor markers; SD, stable disease; PD, progressive
[, ]. No consensus could be achieved, however, on the
disease; AFP, alpha-fetoprotein; HCG, human chorionic gonadotropin.
management of unresectable late relapse, although the majority
Testicular cancer patients are at risk to experience fertility
distress and difficulty in fathering children. Fertility problemsoften precede GCC diagnosis and infertility is an accepted risk
factor for GCC development ]. The fatherhood rate among
Human immunodeficiency virus (HIV)-positive GCC patients
testicular cancer survivors wishing to father a child is ∼70%
should be managed in an identical fashion to patients without
within 15 years having a strong correlation with treatment
an HIV infection. However, highly active antiretroviral therapy
intensity. Compared with the general population, the 10-year
should be given concurrently during chemotherapy and
post-treatment paternity rate remains significantly reduced
antimicrobial prophylaxis instituted, if CD4 counts fall below
]. No increased risk of malformations is found in
children of GCC survivors Patients should be counseled
about these figures and pre-chemotherapy semen
In patients with advanced metastatic GCC and/or those with
impeding organ failure orchiectomy should be postponed until
Male hypogonadism after treatment as defined by total
testosterone serum levels <8 nmol/l is frequent and varies
between 11% and 35% among GCC survivors [
threatening treatment-related complications or even death in
Therefore, the determination of testosterone is
these patients can be reduced by avoiding full-dose
recommended during follow-up and replacement offered to
chemotherapy as initial treatment ]. However, data on how
all patients with low testosterone levels and/or symptoms
to optimally administer such a pre-phase induction
chemotherapy are scarce. The majority of panelists considered
2 days of cisplatin plus etoposide an acceptable way to start
There is about a two- to threefold increased risk of late
chemotherapy in patients with a very high-tumor burden and
cardiovascular toxicity (coronary heart disease, myocardial
normal renal function and continue with four cycles of full-
infarction, congestive heart failure and stroke) among GCC
dose BEP or VIP from day 11 onwards, when the patients have
survivors treated with chemotherapy or radiotherapy compared
with the general population, which is more prominent in GCC
In patients presenting with additional acute
patients treated at a younger age or treated with a combination
renal failure, bleomycin should not be used. The majority of
of chemotherapy and radiation Overall, the
panelists opted to start pre-phase induction chemotherapy
cumulative risk of such events over 20 years may be as high as
either with carboplatin alone or with the combination of
18%. Death mainly from coronary heart disease accounts for a
carboplatin and etoposide and continue with four cycles of
higher overall non-cancer mortality among long-term GCC
full-dose BEP or VIP from on day 11 onwards when the
survivors. The exact reasons for late cardiovascular toxicity are
patients have stabilized and recovered with their renal function
unknown, but may be related to a direct endovascular damage
and accelerated atherosclerosis or vascular ageing induced by
In patients with chronically impaired renal function,
cisplatin. The onset of a Raynaud phenomenon might possibly
there was no consensus on the issue of replacing cisplatin by
represent a clinical biomarker to identify survivors with
augmented atherosclerosis, who could benefit from
Patients with brain metastases present a particular challenge.
The frequency of metabolic syndrome is also increased and
There was consensus that these patients have an inferior
occurs in ∼20%–30% of long-term GCC survivors ].
prognosis compared with other GCC patients. At initial
Particularly relevant is the fact that the onset of metabolic
diagnosis, panelists recommended immediate upfront
syndrome is much earlier than expected from the general
chemotherapy. Opinions were divided, however, in respect to
population starting ∼3–5 years after GCC treatment [].
Other clinical or subclinical organ toxicities such as
pulmonary toxicity, renal toxicity, ototoxicity and neurological
unfavorable patients relapsing with brain metastases, the
sequelae are frequent and dose-related [].
majority of panelists voted for full salvage chemotherapy, but
According to the available data, the relative risk of a second
again no consensus could be achieved in respect to additional
solid non-germ-cell tumor is approximately doubled after
radiotherapy or chemotherapy. The combination of both
treatment modalities is associated with a threefold increased
There was a strong and unequivocal vote to immediately
risk. The figures are particularly high for malignancies in the
transfer patients with advanced disease and particularly those
gastrointestinal and urinary tract. Solid second tumors usually
with imminent organ failure to units experienced in treating
occur ≥10 years after treatment as opposed to chemotherapy-
these high-risk patients: with an agreement of about two-thirds
induced leukemias which commonly emerge within one decade
of the panelists these were defined as centers treating >10
after treatment. The estimated cumulative risk of leukemia is
patients for metastatic GCC per year including 5 for salvage or
0.5% and 2%, after cumulative etoposide doses of <2 g/m2 and
Health-related quality of life (HRQoL) in long-term GCC
[–]. Several aspects should be considered in designing
survivors seems to be similar to the normal male population,
follow-up schedules: the schedules should be straightforward
but persisting long-term treatment-related side-effects show a
and easy to follow, the risk of recurrence has to be taken into
strong association with both impaired physical and mental
account (e.g. high versus low risk), the localization of relapse
HRQoL [, ]. The level of anxiety is higher in GCC
should be considered (e.g. retroperitoneal versus pulmonary
survivors than in the general male population, possibly
relapses) and the time to relapse should be incorporated into
‘triggered’ by the fear of recurrence. Anxiety and fear of
follow-up plans (e.g. early versus late relapses). Except in rare
recurrence might be higher in single or unemployed men and
clinical circumstances or suspected late relapse, it was
those with a lower education. GCC survivors with a more
recommended that no routine CT scans be carried out beyond
‘neurotic personality’ (e.g. higher level of nervousness and
vulnerability to stress) also seemed to have a higher level ofanxiety and fear of recurrence and to report more side-effects
The prevalence of self-reported chronic fatigue and cognitive
Whereas many of the discussions during the Third European
complaints are common among patients with GCC, but not
Consensus Conference on Diagnosis and Treatment of GCC
significantly related to cognitive test performance. No studies
represented optimizing and fine tuning of the treatment
have so far demonstrated an elevated rate of objectively
particularly of GCC patients with rare presentations and those,
assessed cognitive difficulties in long-term GCC survivors
who are ‘difficult-to-treat’, the goals for the majority of GCC
patients are straightforward: (i) close multidisciplinary
As there will be an increasing number of GCC survivors in
collaboration in diagnosis and management; (ii) active
all European countries, the aspects of late toxic effects and
involvement of patients in management decisions;
HRQoL should be addressed in the management of all GCC
(iii) reducing treatment burden by offering surveillance
survivors []. GCC survivors need counseling on a healthy
strategies to clinical stage I patients whenever possible;
lifestyle in order to minimize the risk factors such as smoking
(iv) maintaining cure and optimizing treatment as well as
and physical inactivity. Patients should be screened and treated
supportive care for patients with metastatic disease;
for known risk factors such as high blood pressure,
(v) optimizing the care for GCC survivors by addressing
hyperlipidemia and testosterone deficiency. And, perhaps most
issues such as fertility, late toxic effects and HRQoL through
importantly, GCC patients should be provided with a written
development of straightforward and rational follow-up and
cancer survivorship plan at the end of their treatment that
addresses late toxic effects and HRQoL in addition to the risks
There was a strong and uniform consensus that these goals
of recurrence and cancer-specific follow-up.
can best be achieved by centralization of care at experiencedcenters particularly for patients with intermediate and poorprognosis at initial presentation as well as for all relapsed GCC
patients. Too many patients with GCC still suffer from
The dramatic increase in the exposure to medical radiation
unnecessary toxic effects or even die without ever having had
since the 1980s from 0.5 mSv to ∼3.0 mSv is threatening for
the chance of optimal expert treatment.
young GCC patients because of the related risk of radiation-induced secondary tumors [–]. Many follow-up
recommendations that have been published most likely exposeGCC survivors to unnecessary radiation. Statistically, in long-
The authors are most grateful to Lawrence Einhorn and Sophie
term GCC survivors, the risks from radiation exposure might
Fossa for giving the introductory overviews as well as to all
even be higher than the risk, e.g. from a late relapse GCC [].
attendees of the meeting, particularly Larry Einhorn, Craig
The issue of replacing CT by MRI scan was one area of
Nichols and Doug Banks, for the vivid discussions. We also
controversy, but considered as not feasible in the majority of
like to thank Mr. Bernhard Hoelzl for nonprofit fundraising
European countries by the majority of panelists. Rather every
effort should be made to reduce the frequency of CT scans andlimit their total number. Similarly, it was stressed that PET–CT
scanning has no role in the follow-up of GCC patients.
There were controversial discussions and several E-votes on
The authors have declared no conflicts of interest.
the issues of follow-up No consensus as to an
authoritative follow-up schedule or recommendation for anoptimal follow-up duration could be reached. However, those
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DEBORAH G. ANDERS, DDS, PA 3094 US 70 HWY GENERAL DENTISTRY BLACK MOUNTAIN, NC 28711 PATIENT REGISTRATION AND HEALTH HISTORY REVIEW SELF: Date_______________________ Patient’s Full Name_____________________________ How do you prefer to be addressed? ______________ Address________________________________________________ Home Phone # ______________________ City_______________________