Annals of Oncology Advance Access published September 30, 2014

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1 Annals of Oncology Advance Access published September 30, 2014 Annals of Oncology 00: 1 6, 2014 doi: /annonc/mdu375 One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group T. Tandstad 1 *, O. Ståhl 2, U. Håkansson 3, O. Dahl 4,5, H. S. Haugnes 6,7, O. H. Klepp 8, C. W. Langberg 9, A. Laurell 10, J. Oldenburg 9, A. Solberg 1, K. Söderström 11, E. Cavallin-Ståhl 2, U. Stierner 12, R. Wahlquist 13, N. Wall 14 & G. Cohn-Cedermark 15,16 on behalf of SWENOTECA 1 The Cancer Clinic, St Olavs University Hospital, Trondheim, Norway; 2 Department of Oncology, Skane University Hospital, Lund; 3 Department of Urology, Skåne University Hospital, Malmö, Sweden; 4 Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen; 5 Haukeland University Hospital, Bergen; 6 Institute of Clinical Medicine, University of Tromsø, Tromsø; 7 University Hospital of North Norway, Tromsø; 8 Department of Oncology, Ålesund Hospital, Ålesund; 9 Department of Oncology, Oslo University Hospital, Oslo, Norway; 10 Department of Oncology, Uppsala University Hospital, Uppsala; 11 The Cancer Clinic, Norrland University Hospital, Umeå; 12 Department of Oncology, Sahlgrenska University Hospital, Göteborg, Sweden; 13 Department of Urology, Oslo University Hospital, Oslo, Norway; 14 Institute of Clinical and Experimental Medicine, University of Linköping, Linköping; 15 Department of Oncology-Pathology, Karolinska Institute, Stockholm; 16 Department of Oncology, Karolinska University Hospital, Stockholm, Sweden Received 1 June 2014; revised 4 July 2014; accepted 30 July 2014 Background: SWENOTECA has since 1998 offered patients with clinical stage I (CS I) nonseminoma, adjuvant chemotherapy with one course of bleomycin, etoposide and cisplatin (BEP). The aim has been to reduce the risk of relapse, sparing patients the need of toxic salvage treatment. Initial results on 312 patients treated with one course of adjuvant BEP, with a median follow-up of 4.5 years, have been previously published. We now report mature and expanded results. Patients and methods: In a prospective, binational, population-based risk-adapted treatment protocol, 517 Norwegian and Swedish patients with CS I nonseminoma received one course of adjuvant BEP. Patients with lymphovascular invasion (LVI) in the primary testicular tumor were recommended one course of adjuvant BEP. Patients without LVI could choose between surveillance and one course of adjuvant BEP. Data for patients receiving one course of BEP are presented in this study. Results: At a median follow-up of 7.9 years, 12 relapses have occurred, all with IGCCC good prognosis. The latest relapse occurred 3.3 years after adjuvant treatment. The relapse rate at 5 years was 3.2% for patients with LVI and 1.6% for patients without LVI. Five-year cause-specific survival was 100%. Conclusions: The updated and expanded results confirm a low relapse rate following one course of adjuvant BEP in CS I nonseminoma. One course of adjuvant BEP should be considered a standard treatment in CS I nonseminoma with LVI. For patients with CS I nonseminoma without LVI, one course of adjuvant BEP is also a treatment option. Key words: testicular cancer, adjuvant chemotherapy, nonseminoma introduction The Swedish and Norwegian Testicular Cancer Group (SWENOTECA) has developed management protocols and initiated studies for patients with testicular cancer since All hospitals treating testicular cancer in Norway and Sweden participate, accruing 600 patients annually. Currently, 42% of patients with testicular cancer are diagnosed with nonseminoma and 60% of these present in clinical stage I (CS I) [1]. The treatment of CS I nonseminoma has long been controversial. Since *Correspondence to: Dr Torgrim Tandstad, The Cancer Clinic, St Olavs University Hospital, Postbox 3250 Sluppen, 7006 Trondheim, Norway. Tel: ; Fax: ; torgrim.tandstad@stolav.no the introduction of cisplatin-based chemotherapy retroperitoneal lymph node dissection (RPLND), adjuvant chemotherapy (ACT) and active surveillance have been acceptable treatment options with excellent cause-specific survival rates. However, acute and potential morbidity and toxicities differ [2], and different follow-up schedules are required. The most robust prognostic factor for occult metastatic disease in CS I nonseminoma is the presence of lymphovascular invasion (LVI) in the primary tumor. From recent large and unselected patient series, we know that the risk of relapse following surveillance without ACT in patients with and without LVI is 50% and 15%, respectively [3 5]. Two courses of ACT with bleomycin, etoposide and cisplatin (BEP) effectively prevent risk of relapse [6 9], and is an established treatment option in The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oup.com.

2 patients with LVI. On the other hand, RPLND is decreasingly used in CS I nonseminoma and has been omitted as a standard treatment option in most guidelines [10 14]. However, the difference in treatment burden between two courses of BEP as ACT and the three courses of BEP, which are sufficient in the majority of patients who relapse while on surveillance, is by many considered to be too small to justify unnecessary ACT in 50% of CS I patients. SWENOTECA initiated a prospective study in 1995 in which CS I nonseminoma patients without LVI were treated with one course of adjuvant cisplatin, vinblastine and bleomycin (CVB) and patients with LVI were treated with two courses of CVB. The results were disappointing, with an unexpected high level of toxicity and low efficacy [15], and as a consequence SWENOTECA changed the adjuvant treatment to one course of BEP in Preliminary results were published in 2009 [7]. With a median follow-up of 4.5 years promising low relapse rates irrespective of LVI status were found. Since then, the study population has been expanded, and we now present long-term results of this prospective population-based study of ACT with one course of BEP in patients with CS I nonseminoma. patients and methods Between 31 May 1998 and 2 December 2010, a total of 517 Swedish and Norwegian men with CSI nonseminoma were treated with one course of adjuvant BEP. All were included in a prospective, community-based, multicenter SWENOTECA management program. CSI was confirmed by a second staging 6 8 weeks following orchiectomy. The clinical staging procedure consisted of clinical examination, CT of chest, abdomen and pelvis. The serum tumor markers β-human chorionic gonadotropin, α-fetoprotein and lactate dehydrogenase were assessed before, directly after orchiectomy and thence weekly until normal values were reached. The Swedish and Norwegian medical ethical committees approved the management program. adjuvant treatment Administered chemotherapy was the BEP regimen consisting of cisplatin 20 mg/m 2 daily day 1 5, etoposide 100 mg/m 2 daily day 1 5, and bleomycin 30 mg daily days 1, 5 and 15. Prophylactic granulocyte colony-stimulating factor or antibiotics were not used. Therapy was given 6 10 weeks following orchiectomy. Patients with LVI were recommended one course of adjuvant BEP whereas patients without LVI could choose between surveillance and one course of adjuvant BEP. All patients were informed, both in writing and orally, about possible pros and cons of the different treatment options. treatment of relapse In case of relapse, treatment with chemotherapy and/or surgery was given according to a current SWENOTECA protocol for metastatic disease [16]. In isolated tumor marker-negative relapses in the retroperitoneal lymph nodes, primary RPLND was recommended. Residual disease after chemotherapy was surgically removed. In patients with retroperitoneal relapse exceeding 2 cm (largest transversal diameter) before chemotherapy, postchemotherapy RPLND was recommended to all patients irrespective of size of residual tumor. Currently, postchemotherapy RPLND is only recommended in patients not in complete remission (CR), i.e. with residual disease exceeding 1 cm in largest transversal diameter. follow-up All patients were observed according to a standardized follow-up protocol. The protocol has, however, changed during the time-frame of the study, resulting in less frequent abdominal imaging during later years. Most patients have been followed according to the follow-up schedule earlier reported [7]. Due to the experimental nature of one course of adjuvant BEP, the earlier follow-up schedule recommended a minimum of 10 years follow-up. During the 10 years of follow-up, abdominal imaging was frequently carried out, between 12 and 14 times. Currently, the recommended SWENOTECA follow-up schedule for patients treated with one course of adjuvant BEP comprises 5 years of followup. Follow-up includes clinical examination with measurement of tumor markers every 6 months the first 3 years, then yearly until end of follow-up. Abdominal imaging and chest X-ray are scheduled once a year the first 3 years and at the 5-year checkup. Magnetic resonance imaging is now the recommended modality for abdominal imaging. Additionally, tumor markers are evaluated on an outpatient basis with 2-month interval the first year, and 3-month intervals the second year. statistical analysis Annals of Oncology Relapse rates were defined with date of orchiectomy as reference time. Patients without relapse were censored at last documented follow-up or Table 1. Deceased patients Age at death Time from orchiectomy to death, years Relapse Cause of death, details No relapse Suicide No relapse Suicide No relapse Acute myocardial infarction. Smoker. Autopsy carried out with finding of extensive atherosclerotic disease No relapse Traffic death No relapse Acute myeloid leukemia (M7, i12p). Diagnosed 2.5 months after adjuvant BEP was given. Autopsy carried out Yes, multiple Testicular cancer No relapse Heart failure No relapse Multiple myeloma No relapse Rectal cancer No relapse Alcohol related cardiac disease. Autopsy carried out. 2 Tandstad et al.

3 Annals of Oncology Table 2. Duration of follow-up, relapse rates, time to relapse, and survival Risk group No. of patients Median age (range), years Median follow-up (years) Relapses Time to relapse (years) No. K-M RR (%) Median Range 5-year OS, 10-year OS (%) 5-year CSS, 10-year CSS (%) All (15 71) , , 99.6 With LVI , , 99.3 Without LVI , , 100 LVI uncertain , , 100 K-M RR, relapse rate, estimated using Kaplan Meier survival curves; OS, overall survival estimated using Kaplan Meier survival curves; CSS, causespecific survival estimated using Kaplan Meier survival curves; LVI, lymphovascular invasion. death from other causes. Overall survival was defined from the date of orchiectomy until death from any cause; cancer-specific survival was defined from the date of orchiectomy until death from germ-cell tumor or treatment. Patients without events were censored at the date survival was confirmed by the national population registries. Relapse rates and survival were estimated by Kaplan Meier survival curves. Follow-up time extended from date of orchiectomy until date of last documented follow-up or death. Median follow-up times are reported as a descriptive measure for patients within the groups specified. Based on the results from risk-adapted treatment in the SWENOTECA program and results from large unselected patient series, we have estimated the burden of treatment using different treatment scenarios in patients with CSI nonseminoma. The approaches were either surveillance for all, one course of adjuvant BEP for all, or a risk-adapted strategy with BEP 1 for patients with LVI and surveillance for patients without LVI. results A total of 517 patients with CS I nonseminoma were given ACT with one BEP. The median age of patients was 29.5 years (range years). The median follow-up was 7.9 years (range years). Overall 76% of the patients have follow-up exceeding 5 years, and 30% with follow-up exceeding 10 years. Very few patients were lost to follow-up, and only 2.7% of patients have follow-up <2 years. Ten patients have died, one from progressive testicular cancer (Table 1). This patient suffered multiple relapses and died at the age of 59, 7.8 years after orchiectomy. The 5-year overall- and cause-specific survival was 99.0% and 100%, respectively. The 10-year overall- and causespecific survival was 96.9% and 99.6%, respectively. Details regarding deceased patients are presented in Table 1. Of the 517 patients, 258 (50%) were diagnosed with LVI. In the remaining 259 patients, 255 (49%) were diagnosed without LVI and, in 4 patients, the pathologist concluded with uncertainty in regard to LVI status. patients with LVI In 258 patients with LVI, eight relapses occurred, resulting in a relapse rate of 3.2%; 95% confidence interval (CI) Median time to relapse was 1.1 years (range years) after orchiectomy (Table 2, Figure 1). All relapsing patients had retroperitoneal lymph node metastasis, with two patients also presenting with synchronous lymph nodes metastasis above the diaphragm. All relapses were good prognosis according to the IGCCC classification [17]. Seven relapsing patients received initial salvage chemotherapy with postchemotherapy RPLND. Relapse-free rate Time (years) Figure 1. Kaplan Meier curves for relapse-free rates by risk group; (A) patients without lymphovascular invasion; (B) patients with lymphovascular invasion. One marker-negative patient was cured with primary RPLND alone. Another patient was cured for a second relapse occurring 1 year after completion of the first relapse treatment and had no evidence of disease 7 years after additional follow-up. One patient experienced several relapses and eventually died from metastatic testicular cancer (Table 3). patients without LVI Of 255 patients without LVI, 4 were diagnosed with relapse, resulting in a relapse rate of 1.6%, 95% CI (Table 2, Figure 1). Median time to relapse was 1.2 years (range years) after orchiectomy. All relapses occurred in the retroperitoneum only, with IGCCC good prognosis. Two patients were treated with primary RPLND only, whereas the remaining two patients were treated initially with salvage chemotherapy followed by postchemotherapy RPLND. No patient without LVI died from testicular cancer (Table 2). diagnosis of relapse Nine of 12 relapsing patients had negative markers at relapse, and all nine marker-negative relapses were detected by abdominal imaging. Three patients had elevated tumor markers at relapse, one in combination with finding on abdominal 9 10 A B doi: /annonc/mdu375 3

4 4 Tandstad et al. Table 3. Patients with relapses, details Age at diagnosis LVI status Time to relapse, years TM at relapse Site of relapse Modality of detection Clinical stage a, IGCCC group at relapse Treatment of relapse Chemotherapy, if any Histology, surgery Comments 27 Without LVI 0.9 Mk Retroperitoneum CT abdomen CS2, Good risk CHT, RPLND BEP 2 (SD) Teratoma NED 26 Without LVI 0.9 Mk Retroperitoneum MRI abdomen CS2, Good risk RPLND Teratoma NED 38 Without LVI 1.2 Mk Retroperitoneum CT abdomen CS2, Good risk Biopsy, CHT, BEP 3, PEI 1 Nonseminoma, NED RPLND necrosis 33 Without LVI 1.8 Mk Retroperitoneum CT abdomen CS2, Good risk RPLND Sarcoma NED 40 With LVI 0.3 Mk Retroperitoneum CT abdomen CS2, Good risk CHT, RPLND BEP 1, PEI 2 (SD) Teratoma NED 36 With LVI 0.9 Mk Retroperitoneum MRI abdomen CS2, Good risk RPLND Teratoma NED 51 With LVI 0.9 Mk Retroperitoneum, Neck CT abdomen CS3, Good risk RPLND, CHT, surgery PEI 4 Nonseminoma, necrosis Multiple relapses, deceased of testicular cancer 23 With LVI 1.1 Mk+ Retroperitoneum TM, symptoms CS2, Good risk CHT, RPLND BEP 2, PEI 2 Necrosis 2. relapse treated with PEI, RPLND and RT. NED. 27 With LVI 1.2 Mk+ Retroperitoneum CT abdomen, TM CS2, Good risk CHT, RPLND BEP 2, PEI 2 Necrosis NED 34 With LVI 2.6 Mk Retroperitoneum CT abdomen CS2, Good risk CHT, RPLND BEP 4 Necrosis NED 27 With LVI 3.3 Mk+ Retroperitoneum TM CS2, Good risk CHT, RPLND BEP 2, PEI 2 Necrosis NED 26 With LVI 3.6 Mk Retroperitoneum, mediastinum CT abdomen CS3, Good risk Surgery, CHT EP 4 Seminoma NED a Clinical stage according to Royal Marsden classification. LVI, lymphovascular invasion; TM, tumor markers; IGCCC, international germ-cell consensus classification; Mk, tumor marker negative; Mk+, tumor marker positive; CT, computed tomography; RPLND, retroperitoneal lymph node dissection; CHT, chemotherapy; NED, no evidence of disease; BEP, bleomycin, etoposide, cisplatin; PEI, cisplatin, etoposide, ifosfamide; EP, etoposide, cisplatin; SD, stable disease; RT, radiotherapy; MRI, magnetic resonance imaging. Annals of Oncology

5 Annals of Oncology imaging, one with elevated tumor markers as the only sign of relapse and the last patient experienced abdominal pain in addition to having elevated tumor markers. All relapsing patients are in CR, except one who died of testicular cancer (Table 3). The median follow-up since relapse in living patients is 8.7 years (range years). discussion To our knowledge, this is the largest study on adjuvant treatment in CS I nonseminoma and provide mature long-term data on the use of one course of adjuvant BEP. The results confirm our previous findings of a low relapse rate and excellent survival. In accordance with previous studies on one course of adjuvant BEP, the long-term results of the present study do not indicate that relapse occurring after ACT tend to be refractory to salvage chemotherapy. Neither does ACT with one BEP seem to merely postpone relapse, and thus result in a late wave of metastasis [18, 19]. A limitation of this study is the lack of randomization, however the population-based, prospective design of this study, should ensure a high external validity. One planned randomized study failed to accrue patients, and there are no planned randomized studies in this patient population. A prospective UK study in high-risk patients, NCT (111-Trial), have soon finished accrual and will give additional confirmation ofthe results ofbep 1. The rationale of ACT in CS I disease is to minimize the risk of late effects inflicted by the more extensive salvage treatment necessary to cure a relapse. Secondary cancers and cardiovascular disease constitute the most serious late effects, while other late and long-term effects include pulmonary toxicity, nephrotoxicity, neurotoxicity, ototoxicity, infertility, hypogonadism as well as several psychosocial sequelae [20]. So far, short ACT such as one adjuvant BEP does not seem to compromise long-term hypogonadism, neurotoxicity, fertility, paternity or cognition [18, 21 23] although data regarding secondary cancers and cardiovascular disease are still lacking. However, mounting evidence indicates the risk of late toxicity to increase with the burden of treatment [21, 24 26]. One course of adjuvant BEP reduced the risk of relapse by 90% 95%, both in patients with and without LVI. In this study, patients with LVI constitute 50% of the treated patients, due to the fact that patients without LVI had a choice between surveillance or one course of adjuvant BEP. We know that patients with LVI represents about 33% of the total CS I nonseminoma population [7]. Only 9 of 517 (1.7%) patients were treated with salvage chemotherapy. Although a RPLND was recommended treatment in marker-negative relapse in retroperitoneal lymph nodes, 2 such patients were given initially salvage chemotherapy. Both were found to have teratoma at postchemotherapy RPLND, and may not have needed chemotherapy. Accordingly, it is possible that only 7 of 517 (1.4%) patients actually required salvage chemotherapy. In a corresponding unselected population of CS I nonseminoma managed by surveillance, the expected number of patients requiring salvage therapy would have been 129 (25%). Today, some groups recommend surveillance for all patients with CS I nonseminoma irrespective of risk factors such as LVI [27]. Undoubtedly, surveillance remains an acceptable option for patients without LVI, of which 85% are cured by orchiectomy alone. Overtreatment of patients with LVI is the obvious disadvantage of surveillance in patients with LVI as 50% will later require salvage chemotherapy compared with 2.3% following one course of adjuvant BEP. The treatment burden in these patients will comprise three to four courses of salvage chemotherapy, possibly followed by a postchemotherapy RPLND as well as other residual tumor resections. Additionally, the psychological distress from having a recurrence after primary surveillance is poorly studied. Table 4 presents a calculated overview of the expected burden of treatment following ACT with one BEP or surveillance in CS I nonseminoma. The calculation visualizes the massive reduction in patients exposed to salvage chemotherapy, particular in the group of patients with LVI. Although the gain is less in patients without LVI, one course of adjuvant BEP close to eliminates the risk of patients later being exposed to salvage chemotherapy. In patients without LVI, this must be balanced against the fact that 85% of patients will be cured by surveillance alone. As one course of adjuvant BEP was experimental treatment, our patients were followed a minimum of 10 years. Although late relapses still may be possible, they are expected to be rare, and not more common than in patients on surveillance. No relapse later than 5 years were detected in this patient series with 75% of patients followed more than 5 years. Five years follow-up in CS I nonseminoma patients treated with one adjuvant BEP course seems to be sufficient. Table 4. Assumed burden of chemotherapy, different treatment strategies Treatment All a LVI+ LVI Surveillance b BEP 1 c Surveillance b BEP 1 c Surveillance b BEP 1 c Number of patients Relapses Total number of chemotherapy courses given Patients exposed to salvage therapy i.e. 3 courses of chemotherapy 245 (24.5%) 10 (1%) 490 (49%) 23 (2.3%) 147 (14.7%) 4 (0.4%) a Assuming: one-third of patients with lymphovascular invasion (LVI) and two-third of patients without LVI. b Based on a risk of relapse of 50% in patients with LVI, 15% in patients without LVI and 25% in an unselected population. c Based on treatment results from this study, where only 25% of relapsing patients without LVI and 75% of patients with LVI required salvage chemotherapy. doi: /annonc/mdu375 5

6 One course of adjuvant BEP should, together with surveillance, be considered a standard option in patients with CSI nonseminoma. One course of adjuvant BEP is recommended by SWENOTECA to patients with LVI. The evidence on safety and efficacy of one course of BEP now exceeds that of two courses of BEP and, in our opinion, two courses of adjuvant BEP represent overtreatment in this patient population. Patients with CS I nonseminoma should be informed about the possibility of adjuvant treatment, and the possible extent of treatment following relapse after surveillance. As an option to active surveillance, SWENOTECA also offer patients without LVI one course of adjuvant BEP. A well-informed patient is mandatory, and patient autonomy must be pursued. acknowledgements We thank all patients involved in the study. Investigators at the following hospitals participated in the study: Haukeland University Hospital, Bergen; Borås Hospital, Borås; Mälarsjukhuset Hospital, Eskilstuna; Gävle Hospital, Gävle; Sahlgrenska University Hospital, Göteborg; County Hospital Ryhov, Jönköping; Central Hospital, Karlstad; Linköping University Hospital, Linköping; Skåne University Hospital, Lund; Skåne University Hospital, Malmö; Oslo University Hospital, Oslo; Stavanger University Hospital, Stavanger; Danderyd Hospital, Stockholm; Karolinska University Hospital Solna, Stockholm; Karolinska University Hospital Södersjukhuset, Stockholm; Sundsvall Hospital, Sundsvall; University Hospital of North Norway, Tromsø; St Olavs University Hospital, Trondheim; Umeå University Hospital, Umeå; Uppsala University Hospital, Uppsala; Västerås Hospital, Västerås; Växjö Central Hospital, Växjö; Ålesund Hospital, Ålesund; Örebro University Hospital, Örebro. We also thank all other hospitals participating in the SWENOTECA network. funding The work of SWENOTECA have been partially funded by The National Cancer Fund of Sweden. disclosure The authors have declared no conflict of interest. references 1. Nationell rapport för Testikkelcancerregistret. Seminom och Non-seminom 2012: Regionalt cancercentrum Stockholm/Gotland og Syd de Wit R, Fizazi K. Controversies in the management of clinical stage I testis cancer. J Clin Oncol 2006; 24: Daugaard G, Petersen PM, Rorth M. Surveillance in stage I testicular cancer. APMIS 2003; 111: 76 83; discussion Kollmannsberger C, Moore C, Chi KN et al. Non-risk-adapted surveillance for patients with stage I nonseminomatous testicular germ-cell tumors: diminishing treatment-related morbidity while maintaining efficacy. Ann Oncol 2010; 21: Sturgeon JF, Moore MJ, Kakiashvili DM et al. Non-risk-adapted surveillance in clinical stage I nonseminomatous germ cell tumors: the Princess Margaret Hospital s Experience. 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