Background: Radiotherapy and cisplatin-based combination chemotherapy are accepted standard-of-care treatments for metastatic seminoma with excellent survival outcomes but with established short-and long-term morbidity. Carboplatin monotherapy may be a less toxic alternative; however early historic studies at AUC7 showed inferior outcomes.Objectives: To evaluate multi-institutional data on and toxicity and longer-term survival for metastatic seminoma patients treated with the single-agent carboplatin AUC10.Methods: We undertook a multi-institutional analysis incorporating all men with the International Germ Cell Cancer Collaborative Group good-prognosis metastatic seminoma treated until 2018. Carboplatin AUC10 was given every 21 days. Toxicity, progression-free survival (PFS), disease-specific survival (DSS) and overall survival were noted. Variables predictive of progression were identified.Results and limitations: 216 patients were treated. The three-year PFS rate was 96.5%, and five-year DSS was 98.3%. There were seven relapses, of which 5 were successfully salvaged with further chemotherapy +/- surgery, and three non-seminoma-related deaths. There were no treatment-related deaths. Of 148/216 evaluable patients for toxicity, 37% and 27% suffered >/ Z grade III neutropenia and thrombocytopenia, respectively. Twelve percent of patients needed a platelet or blood transfusion (or both). The incidence of febrile neutropenia was 5%.Conclusion: For metastatic seminoma, carboplatin AUC10 harbours a similar oncological efficacy to established therapies, with a low failure risk. The major acute toxicity was myelosuppression. Our study establishes carboplatin AUC10 as another standard-of-care treatment option for good-prognosis metastatic seminoma, with a potentially lower toxicity profile than other therapies.(C) 2020 Elsevier Ltd. All rights reserved.

366 Background: Patients with stage I testicular seminoma can be managed by surveillance or treated with adjuvant radiotherapy or chemotherapy. Concerns of second malignancies induced by radiotherapy have led to a preference for adjuvant chemotherapy. The TE19 trial demonstrated the non-inferiority of a single cycle of carboplatin, given within 8 weeks of orchidectomy, to adjuvant para-aortic radiotherapy in terms of reduction in recurrence rate. This study also suggested a lower relapse rate if GFR estimation was radionuclide based. Methods: A review of case records of germ cell tumor patients within the Anglian Germ Cell Cancer Group between 10/01/2005 and 31/12/2012 was conducted to identify patients with stage I testicular seminoma who received a single cycle of adjuvant carboplatin. Tumor characteristics, clinical management, and patient outcomes were assessed. Results: A total of 336 patients with stage I seminoma who received adjuvant carboplatin were identified. The median age of diagnosis was 38 (range 21 to 78). Median tumor size was 40mm. The rete testis was involved in 131 cases (39%). A radionuclide based estimation of GFR was used in 318 patients (94.6%), the remaining patients GFR was estimated by the Cockcroft-Gault equation. The median time from orchidectomy to receiving chemotherapy was 46 days. Of the 336 patients, 22 relapsed (6.5%), with nine relapsing after 2 years (seven between 24 and 36 months, and wo after 36 months). The median time to relapse was 18 months. There was a trend towards lower progression free survival in patients whose chemotherapy was dosed based on GFR estimation by the Cockcroft-Gault equation. All relapsed patients were successfully treated with combination chemotherapy. Conclusions: These results demonstrate a higher rate of relapse for stage I seminoma patients treated with adjuvant carboplatin compared with the published data from the TE19 study. In addition they confirm that adjuvant carboplatin for treatment of stage I testicular seminoma leads to excellent outcomes in terms of long-term cure. The use of radionuclide based estimation of GFR is advised. Relapses beyond 2 years are not rare and routine cross-sectional imaging beyond this point should be considered.

Background: In a recent randomised, double-blind, phase III clinical trial among 1195 patients with metastatic castration-resistant prostate cancer (mCRPC) who had failed docetaxel chemotherapy, abiraterone acetate was shown to significantly prolong overall survival compared with prednisone alone. Here we report on the impact of abiraterone therapy on the health-related quality of life (HRQoL) observed during this trial, assessed using the validated Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire.Methods: All analyses were conducted using prespecified criteria for clinically meaningful improvement and deterioration in FACT-P total score as well as subscale scores; all respective thresholds were defined using an accepted methodology. Improvement was assessed only in patients with clinically significant functional status impairment at baseline.Results: Significant improvements in the FACT-P total score were observed in 48% of patients receiving abiraterone versus 32% of patients receiving prednisone (p < 0.0001). Also, the median time to deterioration in FACT-P total score was longer (p < 0.0001) in patients receiving abiraterone (59.9 weeks versus 36.1 weeks). Similar differences were observed in all FACT-P subscales, with the exception of the social/family well-being domain. Median time to improvement in the physical well-being domain and the trial outcome index was significantly shorter (p < 0.01) with abiraterone when compared with the prednisone arm.Conclusions: The previously demonstrated survival benefit for abiraterone is accompanied by improvements in patient-reported HRQoL and a significant delay in HRQoL deterioration when compared with prednisone. (C) 2013 Elsevier Ltd. All rights reserved.

4535 Background: Bleomycin is an integral part of combination chemotherapy in germ cell tumours. Pulmonary symptoms often dictate drug cessation and death occurs in 1-2% of patients. Circumstantial evidence suggests that continuous infusion may be less toxic. Methods: We conducted a randomized phase 3 study to see whether infusional bleomycin was associated with less pulmonary toxicity. Patients were stratified for smoking, renal dysfunction and age and were randomized to receive either conventional BEP with weekly bleomycin (3,0000 units /week iv over 30min) or the same doses but administered as a 90,000 unit infusion on day 1 over 72 hours. The primary endpoint was CT proven lung toxicity, secondary endpoints included PFS and changes in lung function testing. CT scans and lung function testing were conducted after 1 cycle, end of treatment and 1 year post treatment. Sample size of 210 was calculated to detect a difference of 16% Bleomycin damage with 80% power at the 5% level of significance using 2-sided test. Results: The median follow-up was 2.5 years. At day 21 of the treatment, 52% patients in the infusional arm had grade 1 or above toxicity compared to 55% in the conventional. At the end of treatment the results were 84% vs. 60% and at one year it was 65% vs. 59%. Repeated measures mixed effects model shows no significant difference in percentage of grade 1 and above toxicity between the two arms (Difference=1.63, P=0.09, 95% CI: -0.28, 3.54). However, there was a significantly higher level of grade 2 and above toxicity in patients in the infusion arm (difference=0.8; 95% CI 0.11 to 1.49). Toxicity level was the highest at the end of treatment and in older patients (Age>30). Lung function testing between the two arms failed to show any differences. Two-years PFS rate was 93% in both arms (hazard ratio infusion vs conventional was 0.91; 95% CI 0.33 to 2.52). There was an association between toxicity after 1 cycle and subsequent toxicity at end of treatment and at 1 year (p=0.003). Conclusions: Infusional bleomycin has no advantage over standard administration of bleomycin. Clinical trial information: 08648791.

Objective. Metastatic seminoma is a highly curable disease. Standard treatment comprises of combination chemotherapy. The short-and long-term toxicities of this treatment are increasingly recognised and the possibility of over treatment in such a curable disease should be considered. We have therefore assessed the use of single agent carboplatin at a dose of AUC 10 in patients with good prognosis metastatic seminoma. Materials and methods. Patients with good prognosis metastatic seminoma treated with carboplatin (AUC 10) were identified at our institution and affiliated institutions. Treatment was three weekly for a total of three or four cycles. Outcome and toxicities were analysed. Results. With a median follow-up of 36 months, 61 patients in total were treated with carboplatin AUC 10, all good prognosis by the IGCCCG criteria. Forty-eight percent had stage IIA/IIB disease and 52% had greater than stage IIB disease. Thirty-one patients (51%) had a complete response following treatment. Three-year survival was 96.3% with a three-year progression free survival of 93.2%. The main treatment toxicity was haematological with 46% having grade 3, 24% having grade 4 neutropenia and 54% experiencing grade 3/4 thrombocytopenia. There were no treatment related deaths. Conclusion. Single agent carboplatin at a dose of AUC 10 is an effective treatment for good prognosis metastatic seminoma. The outcome compares favourably to previously published outcomes of combination chemotherapy. Although haematological toxicity is a concern, single agent carboplatin treatment for good prognosis metastatic seminoma could be considered a treatment option and is associated with less toxicity than combination regimens currently used.

Background Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events).Methods Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2: 1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00091442.Findings Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20.2 months (IQR 18.4-22.1), median overall survival for the abiraterone group was longer than in the placebo group (15.8 months [95% CI 14.8-17.0] vs 11.2 months [10.4-13.1]; hazard ratio [HR] 0.74, 95% CI 0.64-0.86; p<0.0001). Median time to PSA progression (8.5 months, 95% CI 8.3-11.1, in the abiraterone group vs 6.6 months, 5.6-8.3, in the placebo group; HR 0.63, 0.52-0.78; p<0.0001), median radiologic progression-free survival (5.6 months, 5.6-6.5, vs 3.6 months, 2.9-5.5; HR 0.66, 0.58-0.76; p<0.0001), and proportion of patients who had a PSA response (235 [29.5%] of 797 patients vs 22 [5.5%] of 398; p<0.0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]).Interpretation This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up.

4529 Background: Cisplatin-based chemotherapy with or without high dose chemotherapy remains the standard approach in managing relapsed germ cell tumors (GCT). The feasibility of IPO was first described in 2006.Non cisplatin-based therapies offer the advantage of differing side effect profiles which may be useful to certain patients.Here we describe the outcome of an expanded cohort of these patients. Methods: The results of 72 consecutive patients were reviewed (18% had metastatic mediastinal GCTs). IPO was used either as 2nd line treatment (n=29) of which 20 had HDCT or 3rd line (n=43) of which 32 had HDCT. IPO consisted of oxaliplatin 100mg/m2, irinotecan 200mg/m2 and weekly pac litaxel 80mg/m2 ( IPO) every 3 weeks for 3-4 cycles with the intention of high dose carboplatin , thiotepa and topotecan as consolidation (HDCT). Results: The 2 year PFS and 3 year OS for the whole cohort was 28.4% (95%CI 17.3-40.5%) and 31.6% (95%CI: 20.1-43.8 %) respectively. The overall response was as follows; CR – 3%, m-ve PR 41%, m+ve PR 18%, SD 17%, PD 20%. In the second line setting, the 2 year PFS was 41.8% (95%CI: 21.7-60.8%) and 3y OS 45.8% (95%CI: 24.2-65.1%). The 2 year PFS according to the IGCCCG2 prognostic score was Intermediate = 34%, High risk =50% and very high risk = 30%. In the 3rd line setting the 2 year PFS was 20.9% (95%CI 9.5-35.4%) and 3 year OS was 23.8% (95%CI 11.7-38.2). For HDCT the 2 y PFS was good risk= 52%, Intermediate =29% and poor risk= 0%. There were 2 treatment related deaths from IPO, and 4 from HDCT. Grade 3 or 4 toxicities were as follows (>5%): neutropenia 35%, thrombocytopenia 18%, infection 15%, diarrhea 11%, lethargy 8%. Conclusions: IPO is a safe, non-nephrotoxic day care regimen which produces encouraging responses particularly in high risk cases. Where cisplatin is contra-indicated this is may be a useful alternative.

BACKGROUND:Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.METHODS:We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.RESULTS:After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group.CONCLUSIONS:The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.).

Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trialBCG-induced inflammation might increase the permeability of the bladder mucosa such that mitomycin can reach the target tissue more easily and exert its anticancer effect. Full-Text PDF ErrataHarland SJ. Electromotive drug delivery and bladder cancer. Lancet Oncol 2006; 7: 6–7—Reference 3 should read: Di Stasi SM, Giannantoni A, Giurioli A, et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol 2006; 7: 43–51. Full-Text PDF

This article reviews the structure-activity characteristics, mode of action, pharmacokinetics and clinical utility of a group of chemically dissimilar antitumour agents which have as a common structural feature the N-methyl moiety. The importance of this feature is shown by the fact that molecules without a substituent on the nitrogen or compounds with N-alkyl groups other than methyl are usually inactive in experimental systems. This observation is supported by structure-activity studies with N-alkyl derivatives of s-triazines, triazenes, formamides, hydrazines and nitrosoureas. Representatives of these structural types which have found clinical application are, respectively, hexamethylmelamine, dacarbazine, N-methylformamide, procarbazine and streptozotocin. Mode of action studies have shown that dacarbazine, procarbazine and streptozotocin can give rise to species capable of methylating nucleic acid. This may be the lesion which produces antitumour activity. The mechanism of action of N-methylmelamines and N-methylformamide remains unclear. There is good evidence that, with the exception of N-methylnitrosoureas, host metabolism is prerequisite for activity with these agents.

ThioTEPA is given intravesically in a variety of schedules to treat superficial bladder cancer. In this study, the influence of the dose of ThioTEPA and the volume of instillate on the dose rate to the tumour and the systemic uptake of ThioTEPA was investigated in eight patients with pTa or pTl disease. Each patient received four courses of ThioTEPA consisting of 30 mg of drug/30 ml of distilled water, 30 mg/60 ml, 60 mg/30 ml and 60 mg/60 ml. Blood and urine samples were obtained for 8 h following instillation, and ThioTEPA and TEPA levels were measured. The AUC∞ values (areas under the concentration-time curve, extrapolated to infinity) in plasma were approximately 2 factors higher at the two 60-mg doses. However, the AUC value in the bladder was nearly 70% higher when 60 mg of drug was instilled in 30 ml of distilled water as compared with 60 mg in 60 ml. Thus, by decreasing the volume of instillate it is possible to increase the dose rate to the tumour without increasing the systemic toxicity.

Summary. This article reviews the structure-activity characteristics, mode of action, pharmacokinetics and clinical utility of a group of chemically dissimilar antitumour agents which have as a common structural feature the Nmethyl moiety. The importance of this feature is shown by the fact that molecules without a substituent on the nitrogen or compounds with N-alkyl groups other than methyl are usually inactive in experimental systems. This observation is supported by structure-activity studies with N-alkyl derivatives of s-triazines, triazenes, formamides, hydrazines and nitrosoureas. Representatives of these structural types which have found clinical application are, respectively, hexamethylmelamine, dacarbazine, N-methylformamide, procarbazine and streptozotocin. Mode of action studies have shown that dacarbazine, procarbazine and streptozotocin can give rise to species capable of methylating nucleic acid. This may be the lesion which produces antitumour activity. The mechanism of action of N-methylmelamines and N-methylformamide remains unclear. There is good evidence that, with the exception of N-methylnitrosoureas, host metabolism is prerequisite for activity with these agents. Although not pronounced, the clinical activity of Nmethyl antitumour agents is useful, particularly as activity is not associated with severe haematological toxicity. Furthermore, responses may be observed in patients resistant to bifunctional alkylating agents. It is concluded that the drugs reviewed herein show a degree of coincidence in terms of their biological properties which may warrant a common classification. The term N-methyl antitumour agent is proposed.