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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.
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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 1. Sonne SB, Kristensen DM, Novotny GW et al. Testicular dysgenesis syndrome suggested during the meeting closely resembled most recently and the origin of carcinoma in situ testis. Int J Androl 2008; 31: 275–287.
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