PURPOSE: The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990.MATERIALS AND METHODS: Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,542 patients with complete information on potentially relevant variables. The results were validated in an independent data set.RESULTS: Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided ( https://www.eortc.org/IGCCCG-Update ).CONCLUSION: The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.

Modern treatments cure most testicular cancer patients, so an important goal is to minimise toxicity. Fertility and sexual functioning are key issues for patients. We have evaluated these outcomes in a cross-sectional study of long-term survivors of testicular cancer. In total, 680 patients treated between 1982 and 1992 completed the EORTC Qly-C-30(qc30) questionnaire, the associated testicular cancer specific module and a general health and fertility questionnaire. Patients have been subdivided according to treatment received: orchidectomy either alone (surveillance, S n=169), with chemotherapy (C, n=272), radiotherapy (R, n=158), or both chemotherapy and radiotherapy (C/RT n=81). In the surveillance group, 6% of patients had an elevated LH, 41% an elevated FSH and 11% a low (<10 nmol l⁻¹) testosterone. Hormonal function deteriorated with additional treatment, but the effect in general was small. Low testosterone was more common in the C/RT group (37% P=0.006), FSH abnormalities were more common after chemotherapy (C 49%, C/RT 71% both P<0.005) and LH abnormalities after radiotherapy (11% P<0.01) and chemotherapy (10%, P<0.001). Baseline hormone data were available for 367 patients. After treatment, compared to baseline, patients receiving chemotherapy had significantly greater elevations of FSH (median rise of 6 (IQR 3–9.25) iu l⁻¹ compared to 3 (IQR 1–5) iu l⁻¹ for S; P<0.001) and a fall (compared to a rise in the surveillance group) in median testosterone levels (−2 (IQR −8.0 to −1.5) vs 1.0. (IQR −4.0–4.0) P<0.001). Patients with low testosterone (but not elevated FSH) had lower quality of life scores related to sexual functioning on the testicular cancer specific module and lower physical, social and role functioning on the EORTC Qly C-30. Patients with a low testosterone also had higher body mass index and blood pressure. Treatment was associated with reduction in sexual activity and patients receiving chemotherapy had more concerns about fathering children. In total, 207 (30%) patients reported attempting conception of whom 159 (77%) were successful and a further 10 patients were successful after infertility treatment with an overall success rate of 82%. There was a lower overall success rate after chemotherapy (C 71%; CRT 67% compared to S 85% (P=0.028)). Elevated FSH levels were associated with reduced fertility (normal FSH 91% vs elevated 68% P<0.001). In summary, gonadal dysfunction is common in patients with a history of testicular cancer even when managed by orchidectomy alone. Treatment with chemotherapy in particular can result in additional impairment. Gonadal dysfunction reduces quality of life and has an adverse effect on patient health. Most patients retain their fertility, but the risk of infertility is likely to be increased by chemotherapy. Screening for gonadal dysfunction should be considered in the follow-up of testicular cancer survivors.

PURPOSE: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium. MATERIALS AND METHODS: Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients. RESULTS: Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH. CONCLUSION: PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.

Objectives: To test the feasibility of a randomised trial in muscle‐invasive bladder cancer ( MIBC ) and compare outcomes in patients who receive neoadjuvant chemotherapy followed by radical cystectomy ( RC ) or selective bladder preservation ( SBP ), where definitive treatment [ RC or radiotherapy ( RT )] is determined by response to chemotherapy. Patients and Methods: SPARE is a multicentre randomised controlled trial comparing RC and SBP in patients with MIBC staged T2–3 N0 M0, fit for both treatment strategies and receiving three cycles of neoadjuvant chemotherapy. Patients were randomised between RC and SBP before a cystoscopy after cycle three of neoadjuvant chemotherapy. Patients with ≤T1 residual tumour received a fourth cycle of neoadjuvant chemotherapy in both groups, followed by radical RT in the SBP group and RC in in the RC group; non‐responders in both groups proceeded immediately to RC following cycle three. Feasibility study primary endpoints were accrual rate and compliance with assigned treatment strategy. The phase III trial was designed to demonstrate non‐inferiority of SBP in terms of overall survival ( OS ) in patients whose tumours responded to neoadjuvant chemotherapy. Secondary endpoints included patient‐reported quality of life, clinician assessed toxicity, loco‐regional recurrence‐free survival, and rate of salvage RC after SBP . Results: Trial recruitment was challenging and below the predefined target with 45 patients recruited in 30 months (25 RC ; 20 SBP ). Non‐compliance with assigned treatment strategy was frequent, six of the 25 patients (24%) randomised to RC received RT . Long‐term bladder preservation rate was 11/15 (73%) in those who received RT per protocol. OS survival was not significantly different between groups. Conclusions: Randomising patients with MIBC between RC and SBP based on response to neoadjuvant chemotherapy was not feasible in the UK health system. Strong clinician and patient preferences for treatments impacted willingness to undergo randomisation and acceptance of treatment allocation. Due to the few participants, firm conclusions about disease and toxicity outcomes cannot be drawn.

BACKGROUND: Testicular cancer is curable in the majority of men, and persisting treatment toxicity is a concern. The authors report a cross‐sectional study of the long‐term effects of chemotherapy (C) on neurologic function and development of Raynaud phenomenon.METHODS: Seven hundred thirty‐nine patients who were treated between 1982 and 1992 gave consent to enter the study. Patients were classified according to the receipt of C (n = 384) or no C (n = 355). Patients completed a general health questionnaire and a quality‐of‐life form (the European Organization for Research and Treatment of Cancer Quality‐of‐Life C30 questionnaire with testicular module). Symptom scores of 3 or 4 were considered clinically significant. Patients were assessed in the clinic, and clinical history was used to diagnose Raynaud phenomenon (RP) and tinnitus. Examinations included peripheral nerve function testing for light touch and vibration sense. Five hundred seventy‐seven patients underwent audiometry.RESULTS: On physician assessment, peripheral neuropathy and RP were more common after C (21.7% vs 9.1% [P<.001] and 20.3% vs 1.7% [P<.001], respectively). Similar results were obtained for symptom scores (12.5% vs 5.5% [P = .002] and 9.7% vs 3.7% [P<.001], respectively). On multivariate analysis, for peripheral neuropathy, the significant predictors were cisplatin dose, carboplatin dose, and age. For RP, the significant predictor was bleomycin. Significant differences in hearing thresholds were noted at 8000 hertz only and, on multivariate analysis, were related to age, cisplatin dose, and vincristine dose. Auditory symptom scores did not differ between groups.CONCLUSIONS: With long‐term follow‐up, peripheral neuropathy and RP remained detectable in approximately 20% of patients and caused significant symptoms in 10% of patients. Detectable effects on high frequency remained but caused little symptomatic problem. These effects persisted and were related to the cumulative chemotherapy dose. Cancer 2010. © 2010 American Cancer Society.

To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer. In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 × 2 factorial design. The primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years). Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT - sRT) was 6.4% (95% confidence interval -7.3%, 16.8%) under an intention to treat analysis and 2.6% (-12.8%, 14.6%) in the "per-protocol" population. In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.