Efflux pump ABCB1 single nucleotide polymorphisms and dose reductions in patients with metastatic renal cell carcinoma treated with sunitinib.

UNLABELLED: There is growing evidence that sunitinib plasma levels have an impact on treatment outcome in patients with metastatic renal cell carcinoma (mRCC). We studied the impact of single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics, and additionally, sunitinib pharmacodynamics on dose reductions of the tyrosine kinase inhibitor. METHODS: We retrospectively analyzed germ-line DNA retrieved from mRCC patients receiving sunitinib as first-line therapy. We genotyped 11 key SNPs, respectively, in ABCB1, NR1/2, NR1/3 and CYP3A5, involved in sunitinib pharmacokinetics as well as VEGFR1 and VEGFR3, which have been suggested as regulators of sunitinib pharmacodynamics. Association between these SNPs and time-to-dose-reduction (TTDR) was studied by Cox regression. RESULTS: We identified 96 patients who were treated with sunitinib and from whom germ-line DNA and data on dose reductions were available. We observed an increased TTDR in patients carrying the TT-genotype in ABCB1 rs1125803 compared to patients with CC- or CT-genotypes (19 vs. 7 cycles; p = 0.031 on univariate analysis and p = 0.012 on multivariate analysis) and an increased TTDR in patients carrying the TT/TA-variant in ABCB1 rs2032582 compared to patients with the GG- or GT/GA-variant (19 vs. 7 cycles; p = 0.046 on univariate analysis and p = 0.024 on multivariate analysis). CONCLUSION: mRCC patients carrying the rs1128503 TT-variant or the TT/TA-variant in rs2032582 in ABCB1, which encodes for an efflux pump, do require less dose reductions due to adverse events compared to patients with the wild type or heterozygote variants in these genes.

Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized Phase II trial.

OBJECTIVES: To report the final analysis of a Phase II trial, which investigated the safety and efficacy of the specific endothelin A receptor antagonist zibotentan (AstraZeneca, Macclesfield, UK) in patients with metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Patients with CRPC and bone metastases who were pain free or mildly symptomatic for pain were randomized to receive once-daily oral tablets of zibotentan 10 mg, 15 mg or placebo. The primary endpoint was the time to progression and secondary endpoints included overall survival, change in the number of bone metastases, and safety. RESULTS: In total, 312 patients were randomized (placebo, n= 107; zibotentan 10 mg, n= 107; zibotentan 15 mg, n= 98). The median duration of study treatment and median follow-up time were 4 and 22 months, respectively. At the final analysis, there were no statistical differences of the primary outcome of time to progression between treatment groups, although an improvement in overall survival was observed in the zibotentan groups compared to placebo. Consistent with the previous analyses for overall survival, hazard ratios (HRs) of less than one were sustained for both zibotentan 15 mg (HR, 0.76; 80% CI, 0.61-0.94; P= 0.103) and 10 mg (HR, 0.83; 80% CI, 0.67-1.02; P= 0.254). The most commonly reported adverse events considered to be related to zibotentan treatment were peripheral oedema, headache and nasal congestion. CONCLUSIONS: The results obtained in the present study support endothelin A receptor antagonism as an approach for treating patients with CRPC. To confirm the survival signal observed in the present study, zibotentan is being investigated further in the ENdoTHelin A USE (ENTHUSE) Phase III clinical trial programme.

Effect of Adding Docetaxel to Androgen-Deprivation Therapy in Patients With High-Risk Prostate Cancer With Rising Prostate-Specific Antigen Levels After Primary Local Therapy: A Randomized Clinical Trial.

IMPORTANCE: Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer setting. OBJECTIVE: To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease. DESIGN, SETTING, AND PARTICIPANTS: This open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (≤6 vs >6 months), and intention-to-treat analysis was used. INTERVENTIONS: Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2 (every 3 weeks [6 cycles]), or ADT alone (1 year). MAIN OUTCOMES AND MEASURES: The primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life. RESULTS: Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio [HR], 0.85; 95% CI, 0.62-1.16; P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43; P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients [48.0%]), febrile neutropenia (10 [8.0%]), and thrombocytopenia (4 [3.0%]). There was no significant between-arm difference in overall quality of life. CONCLUSIONS AND RELEVANCE: Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease. TRIAL REGISTRATION: French Health Products Safety Agency identifier: 030591; ClinicalTrials.gov identifier: NCT00764166.

Sunitinib Prior to Planned Nephrectomy in Metastatic Renal Cell Carcinoma: Angiogenesis Biomarkers Predict Clinical Outcome in the Prospective Phase II PREINSUT Trial.

Purpose: The PREINSUT study characterized factors predictive of response to sunitinib given before planned nephrectomy in patients with metastatic renal cell carcinoma (mRCC).Patients and Methods: This French multicenter, prospective, open-label, phase II trial (NCT00930345) included treatment-naïve patients with clear-cell mRCC. Patients received two cycles of sunitinib before nephrectomy. The primary objective was to evaluate the potential of circulating angiogenesis-related biomarkers measured before and on treatment for identifying responders based on primary renal tumor (PRT) size change. Secondary objectives were to evaluate the ability of biomarkers to predict progression-free survival (PFS) and overall survival (OS).Results: Thirty-two patients were enrolled. The median PFS was 4.5 months, and the median OS was 12.4 months. OS was significantly longer in responding patients (28.8 vs. 11.1 months; P = 0.03). Of 27 patients evaluable for PRT response, nine (33.3%) had a ≥10% decrease in PRT size. Baseline biomarkers significantly associated with outcome were endothelial progenitor cells (PRT response); vascular endothelial growth factor (VEGF)-A, stromal cell-derived factor-1 (SDF-1), soluble VEGF receptors (sVEGFR)1 and 2 (PFS); and SDF-1 and sVEGFR1 (OS). During treatment, changes in biomarkers associated with outcome were SDF-1 and platelet-derived growth factor (PDGF)-BB (PRT response), sVEGFR2 (PFS), and SDF-1 and sVEGFR1 (OS). There was no correlation between plasma sunitinib or its active metabolite steady-state trough concentrations and clinical outcome.Conclusions: Angiogenesis-related parameters that could reflect hypoxia seem to be associated with worse outcome in mRCC. As blood biomarkers are not subjected to tumor heterogeneity and allow longitudinal follow-up, circulating angiogenesis profile has a promising place in antiangiogenic therapy guidance. Clin Cancer Res; 24(22); 5534-42. ©2018 AACR.

[Gastric or duodenal metastases from clear cell renal cell carcinoma. Report of two cases and review of the literature]. / Métastases gastriques et duodénales de cancer du rein à cellules conventionnelles.

INTRODUCTION: Gastric or duodenal metastases from clear cell renal cell carcinoma are exceptional. According to autopsy series, the incidence of gastrointestinal metastases is 0.06 to 4% for all cancers and 0.2 and 0.7% for renal cancers. OBJECTIVE: To define the diagnostic and therapeutic management of these rare sites in the light of 2 cases of gastric metastases from renal cancer seen in our institution and a review of the literature. RESULTS: These two patients with gastric or duodenal metastases from renal cancer can be added to the 15 cases found in the literature. These 17 cases consisted of 5 cases of duodenal metastases and 12 cases of gastric metastases and were described in 14 articles (2 articles comprised 2 and 3 cases, respectively). Metastases were the presenting sign of the cancer in 3 cases or occurred during follow-up after nephrectomy in 14 cases after a mean of 6.6 years (range: 2 years-14 years). The mean number of metastatic sites was 2.5 (range: 1-5). Presenting symptoms were mainly upper or lower gastrointestinal bleeding (14 out of 17 cases) or anaemia (2 cases). Gastroscopy established the diagnosis and allowed biopsies and control of acute bleeding. For patients with a solitary metastasis and in good general condition, gastrectomy was performed as complementary treatment. For patients with multiple or inoperable metastases, treatment consisted of either endoscopic resection, embolization of the metastasis, or immunotherapy. The benefit of surgery in terms of survival could not be demonstrated due to the short follow-up (mean: 8.6 months; range: 1 to 36 months). The median overall survival of this group has not been reached, but is greater than 6 months. CONCLUSION: Surgical resection of the metastasis is the preferred treatment in the case of a solitary metastasis and absence of contraindication related to the general state. In the other cases, endoscopic resection or embolization of the metastasis can be proposed, with or without systemic immunotherapy. None of these treatments has been shown to be superior in terms of survival in this indication. The place of targeted anti-tumour treatments such as anti-angiogenic drugs has not been evaluated

Prognostic Value of Baseline Neutrophil-to-Lymphocyte Ratio in Metastatic Urothelial Carcinoma Patients Treated With First-line Chemotherapy: A Large Multicenter Study.

BACKGROUND: A high neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation and is associated with poor survival in localized or metastatic cancer. This study assessed the prognostic value of NLR after first-line chemotherapy (CT) in patients with metastatic urothelial carcinoma (mUC). PATIENTS AND METHODS: Two hundred eighty consecutive patients treated with first-line platinum-based CT at 4 centers in France and Turkey between 2002 and 2014 were included. The association of NLR and Memorial Sloan Kettering Cancer Center (MSKCC) scores with overall survival (OS) and progression-free survival (PFS) was determined by univariate Cox models. RESULTS: Median OS was 10.6 months (follow-up, 42.8 months). In univariate analysis, high NLR was associated with worse OS (hazard ratio [HR] for death = 1.36; 95% confidence interval [CI], 1.23-1.51; P < .0001); the result was similar after adjustment for MSKCC prognostic group (HR = 1.28; 95% CI, 1.14-1.43; P < .0001). Low NLR was associated with longer PFS (HR = 1.18; 95% CI, 1.05-1.33; P < .005). When NLR was divided in terciles, OS in the lowest tercile (NLR 0.6-2.78) was 12.4 to 16.6 (median, 13.4) months versus 5.3 to 9.9 (median, 7.3) months in the highest tercile (NLR 4.70-48.9) (P = .001). Similar trends were observed for PFS (5.6-8.9 [median, 7.6] months vs. 3.1-5.7 [median, 4.8] months) in patients with NLR values in the lowest versus highest tercile, respectively (P = .021). CONCLUSION: High pre-CT NLR was an independent prognostic factor for poor OS and PFS in mUC patients. The prognostic value of NLR, as either a continuous or categorical variable, compared favorably with MSKCC score but was easier to assess and monitor.

Metastatic chromophobe renal cell carcinoma treated with targeted therapies: A Renal Cross Channel Group study.

BACKGROUND: Treatment of non-clear cell renal cell carcinoma (RCC) remains controversial despite several recent prospective studies of targeted therapies (TT). Often Vascular Endothelial growth Factor (VEGF) and Mammalian Target of Rapamycin (mTOR) inhibitors are used, extrapolating the data from use of these agents in clear cell RCC. METHODS: We performed a retrospective data analysis within the Renal Cross Channel Group to determine metastatic chromophobe RCC (mChRCC) outcomes in the TT era. The end-points were overall response, overall survival (OS) and time to treatment failure (TTF). The two latter were estimated using the Kaplan-Meier method. RESULTS: 91 mChRCC patients from 26 centres were included. Median follow-up from the date of first metastasis was 6.1 years (range: 0-13.9). Median OS was 37.9 months (95% confidence interval [CI]: 21.4-46.8) from the diagnosis of metastatic disease. Among the 61 patients who received TT, 50 (82%) were treated with anti-angiogenic (AA) and 11 with mTOR inhibitors. Median TTF and OS in patients receiving a first line of AA was 8.7 months (95% CI: 5.2-10.9) and 22.9 months (95% CI: 17.8-49.2) versus 1.9 months (95% CI: 1.0-6.0) and 3.2 months (95% CI: 2.3-not evaluable) with mTOR inhibitors, respectively. A stratified log-rank test was used to compare AA and mTOR inhibitors TT, while controlling the effect of the International Metastatic RCC Database Consortium risk group and no significant difference between AA and mTOR inhibitors was observed for TTF (p = 0.26) or for OS (p = 0.55). CONCLUSION: We report the largest retrospective cohort of patients with mChRCC treated with TT and no significant difference between AA and mTOR inhibitors was observed for TTF and OS.

[Alternative prescription schedules of sunitinib in metastatic kidney cancer: from the underground to the light?]. / Schémas de prescription alternatif du sunitinib dans le cancer du rein métastatique : de l'underground au grand public ?

Sunitinib was the first targeted therapy improving progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) in the first line of treatment. Classically, sunitinib is administered at a dose of 50 mg/day during four weeks followed by two weeks off (schedule 4/6). This schedule has two pitfalls: intermittent exposure with two weeks "off" and the increase in toxicity during the fourth week. Several alternative prescription schedules were studied with the aim of limiting the intensity of toxicity while maintaining efficacy. This review summarizes the published data on alternative schedules of sunitinib in terms of safety and efficacy. All articles and abstracts on alternative schedule of sunitinib in the mRCC were reviewed. Clinical trials were also searched. Studies evaluating the continuous schedule have not provided evidence of its superiority compared to the 4/6 schedules in terms of activity, tolerance or dose-intensity. Retrospective data of patients treated in a schedule two weeks of treatment "on" one week "off" (schedule 2/3) with sunitinib 50 mg/day show PFS that seem superior to those obtained with a schedule 4/ 6, while having a better safety profile. The alternating schedule of sunitinib 2/3 (50 mg/day) may be a better alternative to schedule 4/6 in terms of tolerance. If toxicity occurs with 50 mg/day on a schedule 4/6, it would probably offer a better alternative in terms of efficiency than dose reduction. The results of ongoing and future studies are expected to prospectively validate the concept.

A risk-adapted study of cisplatin and etoposide, with or without ifosfamide, in patients with metastatic seminoma: results of the GETUG S99 multicenter prospective study.

BACKGROUND: Whether patients with good prognosis and intermediate/poor prognosis advanced seminoma should be treated differently has not been defined. OBJECTIVE: To assess a risk-adapted chemotherapy regimen in patients with advanced seminoma. DESIGN, SETTING, AND PARTICIPANTS: A total of 132 patients were included in this prospective study. Patients with a good prognosis according to the International Germ Cell Cancer Collaboration Group (IGGCCG) were treated with four cycles of cisplatin-etoposide (EP). Patients with an intermediate prognosis according to the IGCCCG (or a poor prognosis according to the Medical Research Council classification) were treated with four cycles of VIP (EP and ifosfamide) and granulocyte colony-stimulating factor (G-CSF). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Survival curves were estimated using the Kaplan-Meier method. RESULTS AND LIMITATIONS: The median follow-up was 4.5 yr (range: 0.4-11.6 yr). Among 108 patients (82%) with a good prognosis who received EP, grade 3-4 toxicity included neutropenia (47%) and neutropenic fever (12%). Among the 24 patients (18%) with an intermediate/poor prognosis who received VIP plus G-CSF, toxicity included grade 3-4 neutropenia (36%), neutropenic fever (23%), thrombocytopenia (23%), anemia (23%), and a toxicity-related death (n=1; 4%). The 3-yr progression-free survival (PFS) rate was 93% (range: 85-97%) in the good prognosis group and 83% (range: 63-93%) in the intermediate/poor prognosis group (p=0.03 for PFS). The 3-yr overall survival (OS) rate was 99% (range: 92-100%) and 87% (range: 67-95%), respectively (p<0.005 for OS). Only four patients died of seminoma or its treatment. CONCLUSIONS: A risk-adapted chemotherapy policy for advanced seminoma yielded an excellent outcome with a 3-yr OS rate of 96%.

Do anti-angiogenic therapies prevent brain metastases in advanced renal cell carcinoma?

BACKGROUND: We analyzed renal cell carcinoma (RCC) brain metastasis (BM) risk factors and compared BM occurrence in metastatic RCC (mRCC) treated with or without anti-angiogenic agents (AA). METHODS: Data from all consecutive metastatic RCC patients (patients) treated in a french cancer center between 1995 and 2008 were reviewed. Patients had histologically confirmed advanced RCC without synchronous BM at the time of metastasis diagnosis. AA were sorafenib, sunitinib and bevacizumab. We also included patients treated with mTor inhibitors, temsirolimus and everolimus, as they also demonstrated anti-angiogenic activities. Characteristics of the two groups treated with or without AA were compared with a Fisher exact test. Impact of AA on overall survival (OS) and cumulative rate of brain metastasis (CRBM) was explored by Kaplan-Meier method. RESULTS: One hundred and ninety-nine patients with advanced RCC were identified, 51 treated with AA and 148 without AA. The median follow-up duration was 40 months. BM occurred in 35 patients. Characteristics between AA treated and non-AA treated groups were unbalanced and favoring better prognostic factors in AA treated group. Median OS was 24 months. AA treatment was not associated with a lower CRBM (HR = 0.58 [0.26-1.30], P = 0.187). Median survival free of BM was 11.8 months, CI95% (4.95-18.65) in the group without AA treatment and 28.9 months in the AA group, CI95% (18.64-39.16). Alkaline phosphatase (AP) was an independent prognostic factor for BM (P = 0.05). In multivariate Cox model, after adjustment to AP, AA did not improve the CRBM (aHR = 0.53 [0.22-1.32]). CONCLUSION: In this retrospective study, AA did not decrease significantly the CRBM. Elevated AP was a predictive factor for BM in mRCC.

Complete remission with tyrosine kinase inhibitors in renal cell carcinoma.

PURPOSE: Complete remission (CR) is uncommon during treatment for metastatic renal cell carcinoma (mRCC) with tyrosine kinase inhibitors (TKIs), but it may occur in some patients. It remains a matter of debate whether therapy should be continued after CR. METHODS: A multicenter, retrospective analysis of a series of patients with mRCC who obtained CR during treatment with TKIs (sunitinib or sorafenib), either alone or with local treatment (surgery, radiotherapy, or radiofrequency ablation), was performed. RESULTS: CR was identified in 64 patients; 36 patients had received TKI treatment alone and 28 had also received local treatment. Most patients had clear cell histology (60 of 64 patients), and all had undergone previous nephrectomy. The majority of patients were favorable or intermediate risk; however, three patients were poor risk. Most patients developed CR during sunitinib treatment (59 of 64 patients). Among the 36 patients who achieved CR with TKI alone, eight continued TKI treatment after CR, whereas 28 stopped treatment. Seventeen patients who stopped treatment (61%) are still in CR, with a median follow-up of 255 days. Among the 28 patients in CR after TKI plus local treatment, 25 patients stopped treatment, and 12 of these patients (48%) are still in CR, with a median follow-up of 322 days. CONCLUSION: CR can occur after TKI treatment alone or when combined with local treatment. CR was observed at every metastatic site and in every prognostic group.

Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial.

BACKGROUND: The endothelin-A receptor (ETAR) has been implicated in the progression of prostate cancer. OBJECTIVES: To investigate the safety and efficacy of the specific ETAR antagonist ZD4054 in patients with metastatic hormone-resistant prostate cancer (HRPC). DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, randomised, parallel-group, multicentre, phase 2 trial in patients attending cancer centres with HRPC and bone metastases who were pain free or mildly symptomatic for pain. INTERVENTION: Patients were randomised to receive once-daily oral tablets of ZD4054 10 mg, or ZD4054 15 mg, or placebo. MEASUREMENTS: The primary end point was time to progression, defined as clinical progression, requirement for opiate analgesia, objective progression of soft-tissue metastases, or death in the absence of progression. Secondary end points included overall survival, time to prostate-specific antigen (PSA) progression, and safety. Statistical significance was preset at 20%. RESULTS AND LIMITATIONS: A total of 312 patients were randomised (ZD4054 10 mg, n=107; ZD4054 15 mg, n=98; placebo, n=107). At the primary analysis, median time to progression was 3.6 mo, 4.0 mo, and 3.8 mo in the placebo, ZD4054 10 mg, and ZD4054 15 mg groups, respectively, with no statistically significant difference between ZD4054 groups and placebo (hazard ratio [HR] vs placebo for the ZD4054 10mg group: 0.88 [80% CI: 0.71-1.09]; HR vs placebo for the ZD4054 15 mg group: 0.83 [80% CI: 0.66-1.03]). However, a signal for prolonged overall survival was observed in the ZD4054 treatment groups versus placebo, based on 40 deaths. At a subsequent analysis after 118 deaths, this survival benefit was confirmed (HR vs placebo for the ZD4054 10 mg group, 0.55 [80% CI: 0.41-0.73], p=0.008; HR vs placebo for the ZD4054 15 mg group, 0.65 [80% CI: 0.49-0.86], p=0.052) but the differences in time to progression remained nonsignificant. Median overall survival was 17.3 mo, 24.5 mo, and 23.5 mo in the placebo group, the ZD4054 10 mg group, and the ZD4054 15 mg group, respectively. Discordance between results for time to progression and overall survival may be due to the sensitivity of the definition of progression. Adverse events were in line with the expected pharmacologic effects of an ETAR antagonist. CONCLUSIONS: The primary end point of time to progression was not achieved in this study, but an improvement was seen in overall survival in both active treatment arms. ZD4054 was well tolerated. TRIAL REGISTRATION: Clinicaltrials.gov NCT00090363.

Nonseminomatous germ cell tumors: assessing the need for postchemotherapy contralateral pulmonary resection in patients with ipsilateral complete necrosis.

OBJECTIVES: Our objective was to explore the pathologic components of residual masses after primary chemotherapy in patients with metastatic nonseminomatous germ cell tumors. METHODS: A multicenter retrospective study was conducted of 71 patients with thoracic residual masses (39 patients had bilateral lung metastasis) after first-line cisplatin-based chemotherapy for disseminated nonseminomatous germ cell tumors. Among the 71 patients, 52 also had a retroperitoneal lymph node dissection. RESULTS: Pathologic findings in postchemotherapy residual masses included complete necrosis, teratoma, and viable cancer in 31%, 55%, and 14% of patients, respectively. Discordant pathologic findings were evidenced between retroperitoneal lymph node and thoracic (lung or mediastinal lymph nodes) residual masses in 27% of patients. When a bilateral pulmonary resection was performed, only 2 (5%) of 39 patients had discordant histologic findings between the two lungs. Among patients who had necrosis only in residual masses from their first lung (n = 20), 19 (95%) also had necrosis only in contralateral lesions. A single patient had necrosis only in the first lung and some teratoma in the contralateral lung. CONCLUSIONS: This report shows a high rate (95%) of pathologic concordance between the two lungs. Avoiding contralateral lung surgery could therefore be considered when complete necrosis is found in the first lung after induction chemotherapy for nonseminomatous germ cell tumor.

Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract.

PURPOSE: Vinflunine (VFL) is a new microtubule inhibitor that has activity against transitional cell carcinoma of urothelial tract (TCCU). We conducted a randomized phase III study of VFL and best supportive care (BSC) versus BSC alone in the treatment of patients with advanced TCCU who had experienced progression after a first-line platinum-containing regimen. PATIENTS AND METHODS: The study was designed to compare overall survival (OS) between patients receiving VFL + BSC (performance status [PS] = 0: 320 mg/m(2), every 3 weeks; PS = 0 with previous pelvic radiation and PS = 1: 280 mg/m(2) subsequently escalated to 320 mg/m(2)) or BSC. RESULTS: Three hundred seventy patients were randomly assigned (VFL + BSC, n =253; BSC, n = 117). Both arms were well balanced except there were more patients with PS more than 1 (10% difference) in the BSC arm. Main grade 3 or 4 toxicities for VFL + BSC were neutropenia (50%), febrile neutropenia (6%), anemia (19%), fatigue (19%), and constipation (16%). In the intent-to-treat population, the objective of a median 2-month survival advantage (6.9 months for VFL + BSC v 4.6 months for BSC) was achieved (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12) but was not statistically significant (P = .287). Multivariate Cox analysis adjusting for prognostic factors showed statistically significant effect of VFL on OS (P = .036), reducing the death risk by 23% (HR = 0.77; 95% CI, 0.61 to 0.98). In the eligible population (n = 357), the median OS was significantly longer for VFL + BSC than BSC (6.9 v 4.3 months, respectively), with the difference being statistically significant (P = .040). Overall response rate, disease control, and progression-free survival were all statistically significant favoring VFL + BSC (P = .006, P = .002, and P = .001, respectively). CONCLUSION: VFL demonstrates a survival advantage in second-line treatment for advanced TCCU. Consistency of results exists with significant and meaningful benefit over all efficacy parameters. Safety profile is acceptable, and therefore, VFL seems to be a reasonable option for TCCU progressing after first-line platinum-based therapy.

Randomized trial comparing bleomycin/etoposide/cisplatin with alternating cisplatin/cyclophosphamide/doxorubicin and vinblastine/bleomycin regimens of chemotherapy for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors: Genito-Urinary Group of the French Federation of Cancer Centers Trial T93MP.

PURPOSE: Two chemotherapy regimens for intermediate- and poor-risk metastatic nonseminomatous germ cell tumors were compared for efficacy and toxicity. PATIENTS AND METHODS: From February 1994 to February 2000, 190 patients were randomly assigned between either four cycles of BEP (bleomycin 30 mg d1, d8, d15; etoposide 100 mg/m(2) d1-5; cisplatin 20 mg/m(2) d1-5) or four to six alternating cycles of CISCA/VB (cyclophosphamide 400 mg/m(2) d1-2, doxorubicin 35 mg/m(2) d1-2, cisplatin 100 mg/m(2) d3/vinblastine 2.5 mg/m(2) d1-5, bleomycin 25 mg/m(2) d1-5). Risk was initially defined according to the Institut Gustave Roussy (Villejuif, France) prognostic model based on serum alpha-fetoprotein and human chorionic gonadotropin levels only. Patients were retrospectively assigned into the International Germ Cell Consensus Classification. RESULTS: Among 185 assessable patients, favorable responses did not differ statistically between the two arms: 49 in the CISCA/VB arm (56%; 95% CI, 45% to 66%), 57 in the BEP arm (65%; 95% CI, 55% to 75%). The CISCA/VB regimen induced more significant hematologic and mucous toxicities compared with the BEP arm. The 5-year event-free survival rates were 37% (95% CI, 27% to 47%) and 47% (95% CI, 37% to 57%) in CISCA/VB and BEP arms, respectively (hazard ratio [HR] = 0.76; 95% CI, 0.52 to 1.11; P = .15). With a median follow-up of 7.8 years, the 5-year overall survival rates were 59% (95% CI, 47% to 67%) and 69% (95% CI, 58% to 77%) in CISCA/VB and BEP arms, respectively (HR = 0.73; 95% CI, 0.46 to 1.18; P = .24). CONCLUSION: Because of equivalent efficacy and lesser toxicity, the standard treatment for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors remains four cycles of BEP.

Medroxyprogesterone, interferon alfa-2a, interleukin 2, or combination of both cytokines in patients with metastatic renal carcinoma of intermediate prognosis: results of a randomized controlled trial.

BACKGROUND: Few randomized trials have compared the survival benefit of interferon-alfa over controls in metastatic renal cell carcinoma, and none has been performed using interleukin-2. The Programme Etude Rein Cytokines (PERCY) Quattro trial was designed to evaluate both cytokines for their survival benefit to intermediate prognosis patients, who represent the majority of candidates for these treatments. METHODS: Patients were randomized in a 2-by-2 factorial design to medroxyprogesterone acetate 200 mg daily, interferon-alfa 9 million IU 3 times a week, subcutaneous interleukin-2 9 million IU daily, or a combination of both cytokines. Tumor response was evaluated at Week 12 and Month 6; progression-free patients received further identical treatment for a maximum of 3 additional months. Primary endpoint was overall survival; secondary endpoints were disease-free survival, response rate, toxicity, and quality of life. Survival was analyzed on an intent-to-treat basis. RESULTS: From January 2000 to July 2004, 492 patients were enrolled. Analysis was performed after a 29.2-month median follow-up (range, 0 months to 54.6 months). There were no significant survival differences between the 244 interferon-alfa-treated patients and 248 noninterferon-alfa patients (hazard ratio, 1.00; 95% CI, 0.81-1.24) or between the 247 interleukin-2 and 245 noninterleukin-2-treated patients (hazard ratio, 1.07; 95% CI, 0.87-1.33; log rank, 0.99 and 0.52, respectively). Grade 3-4 toxicities were significantly more frequent in cytokine-treated patients than in medroxyprogesterone-treated patients. CONCLUSIONS: Subcutaneous interleukin-2 and/or interferon-alfa provide no survival benefit in metastatic renal cancers of intermediate prognosis, and they induce a significant risk of toxicity. Newly available angiogenesis inhibitors should be preferred for these patients.