Summary Background Early chemotherapy might improve the overall outcomes of patients with metastatic non-castrate (ie, hormone-sensitive) prostate cancer. We investigated the effects of the addition ...of docetaxel to androgen-deprivation therapy (ADT) for patients with metastatic non-castrate prostate cancer. Methods In this randomised, open-label, phase 3 study, we enrolled patients in 29 centres in France and one in Belgium. Eligible patients were older than 18 years and had histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease; a Karnofsky score of at least 70%; a life expectancy of at least 3 months; and adequate hepatic, haematological, and renal function. They were randomly assigned to receive to ADT (orchiectomy or luteinising hormone-releasing hormone agonists, alone or combined with non-steroidal antiandrogens) alone or in combination with docetaxel (75 mg/m2 intravenously on the first day of each 21-day cycle; up to nine cycles). Patients were randomised in a 1:1 ratio, with dynamic minimisation to minimise imbalances in previous systemic treatment with ADT, chemotherapy for local disease or isolated rising concentration of serum prostate-specific antigen, and Glass risk groups. Patients, physicians, and data analysts were not masked to treatment allocation. The primary endpoint was overall survival. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00104715. Findings Between Oct 18, 2004, and Dec 31, 2008, 192 patients were randomly allocated to receive ADT plus docetaxel and 193 to receive ADT alone. Median follow-up was 50 months (IQR 39–63). Median overall survival was 58·9 months (95% CI 50·8–69·1) in the group given ADT plus docetaxel and 54·2 months (42·2–not reached) in that given ADT alone (hazard ratio 1·01, 95% CI 0·75–1·36). 72 serious adverse events were reported in the group given ADT plus docetaxel, of which the most frequent were neutropenia (40 21%), febrile neutropenia (six 3%), abnormal liver function tests (three 2%), and neutropenia with infection (two 1%). Four treatment-related deaths occurred in the ADT plus docetaxel group (two of which were neutropenia-related), after which the data monitoring committee recommended treatment with granulocyte colony-stimulating factor. After this recommendation, no further treatment-related deaths occurred. No serious adverse events were reported in the ADT alone group. Interpretation Docetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer. Funding French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, AstraZeneca, and Amgen.
Summary Background Combining targeted treatments for renal cell carcinoma has been suggested as a possible method to improve treatment efficacy. We aimed to assess the potential synergistic or ...additive effect of the combination of bevacizumab, directed against the VEGF receptor, and temsirolimus, an mTOR inhibitor, in metastatic renal cell carcinoma. Methods TORAVA was an open-label, multicentre randomised phase 2 study undertaken in 24 centres in France. Patients aged 18 years or older who had untreated metastatic renal cell carcinoma were randomly assigned (2:1:1) to receive the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly; group A), or one of the standard treatments: sunitinib (50 mg/day for 4 weeks followed by 2 weeks off; group B), or the combination of interferon alfa (9 mIU three times per week) and bevacizumab (10 mg/kg every 2 weeks; group C). Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of four and eight patients stratified by participating centre and Eastern Cooperative Oncology Group performance status. The primary endpoint was progression-free survival (PFS) at 48 weeks (four follow-up CT scans), which was expected to be above 50% in group A. Analysis was by intention to treat. The study is ongoing for long-term overall survival. This study is registered with ClinicalTrials.gov , number NCT00619268. Findings Between March 3, 2008 and May 6, 2009, 171 patients were randomly assigned: 88 to the experimental group (group A), 42 to group B, and 41 to group C. PFS at 48 weeks was 29·5% (26 of 88 patients, 95% CI 20·0–39·1) in group A, 35·7% (15 of 42, 21·2–50·2) in group B, and 61·0% (25 of 41, 46·0–75·9) in group C. Median PFS was 8·2 months (95% CI 7·0–9·6) in group A, 8·2 months (5·5–11·7) in group B, and 16·8 months (6·0–26·0) in group C. 45 (51%) of 88 patients in group A stopped treatment for reasons other than progression compared with five (12%) of 42 in group B and 15 (38%) of 40 in group C. Grade 3 or worse adverse events were reported in 68 (77%) of 88 patients in group A versus 25 (60%) of 42 in group B and 28 (70%) of 40 in group C. Serious adverse events were reported in 39 (44%) of 88, 13 (31%) of 42, and 18 (45%) of 40 patients in groups A, B, and C, respectively. Interpretation The toxicity of the temsirolimus and bevacizumab combination was much higher than anticipated and limited treatment continuation over time. Clinical activity was low compared with the benefit expected from sequential use of each targeted therapy. This combination cannot be recommended for first-line treatment in patients with metastatic renal cell carcinoma. Funding French Ministry of Health and Wyeth Pharmaceuticals.
The role of pelvic elective nodal irradiation (ENI) in the management of prostate cancer is controversial. This study analyzed the role of pelvic radiation therapy (RT) on the outcome in high-risk ...localized prostate cancer patients included in the Groupe d'Etude des Tumeurs Uro-Genitales (GETUG) 12 trial.
Patients with a nonpretreated high-risk localized prostate cancer and a staging lymphadenectomy were randomly assigned to receive either goserelin every 3 months for 3 years and 4 cycles of docetaxel plus estramustine or goserelin alone. Local therapy was administered 3 months after the start of systemic treatment. Performance of pelvic ENI was left to the treating physician. Only patients treated with primary RT were included in this analysis. The primary endpoint was biochemical progression-free survival (bPFS).
A total of 413 patients treated from 2002 to 2006 were included, of whom 358 were treated using primary RT. A total of 208 patients received pelvic RT and 150 prostate-only RT. Prostate-specific antigen (PSA) concentration, Gleason score, or T stage did not differ according to performance of pelvic RT; pN+ patients more frequently received pelvic RT than pN0 patients (P<.0001). Median follow-up was 8.8 years. In multivariate analysis, bPFS was negatively impacted by pN stage (hazard ratio HR: 2.52 95% confidence interval CI: 1.78-3.54, P<.0001), Gleason score 8 or higher (HR: 1.41 95% CI: 1.03-1.93, P=.033) and PSA higher than 20 ng/mL (HR: 1.41 95% CI: 1.02-1.96, P=.038), and positively impacted by the use of chemotherapy (HR: 0.66 95% CI: 0.48-0.9, P=.009). There was no association between bPFS and use of pelvic ENI in multivariate analysis (HR: 1.10 95% CI: 0.78-1.55, P=.60), even when analysis was restricted to pN0 patients (HR: 0.88 95% CI: 0.59-1.31, P=.53). Pelvic ENI was not associated with increased acute or late patient reported toxicity.
This unplanned analysis of a randomized trial failed to demonstrate a benefit of pelvic ENI on bPFS in high-risk localized prostate cancer patients.
Abstract Introduction The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now ...with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib. Materials and methods In a multicentric study, we retrospectively included 90 patients and studied the corresponding ccRCC at the pathological, immunohistochemical, and molecular levels. Patient and tumor characteristics were compared using univariate and multivariate analysis. All the features were then studied by Cox models for prognostic effect. Results HFI was found in 42 patients (46.7%), who had worse prognosis (Heng criteria) ( P = 0.003), liver metastases ( P = 0.036), and progressive diseases at first radiological evaluation ( P = 0.024). The corresponding ccRCC was associated with poor pathological prognostic factors that are well known in nonmetastatic ccRCC. For these patients, median progression-free survival was 4 months vs. 13 months ( P = 0.02), and median overall survival was 14 months vs. 29 months ( P = 0.006). In a multivariate Cox model integrating all the variables, only poor prognosis, according to the Heng criteria and HFI, remained independently associated with both progression-free survival and overall survival. Conclusion HFI was demonstrated for the first time to be an independent poor prognostic factor. Its potential role in predicting resistance to antiangiogenic therapy warrants further investigation.
Abstract In order to compare synchronous and metachronous metastatic clear cell renal cell carcinoma (ccRCC), we performed a pathological, immunohistochemical and molecular study on primary tumors in ...a retrospective series of 48 consecutive patients with up to ten years of follow-up. Synchronous metastatic ccRCC had a distinct phenotype that may explain their worse prognosis. Introduction Clear cell renal cell carcinomas (ccRCC) are highly metastatic tumors with metastases detected at diagnosis (synchronous) or during follow-up (metachronous). To date, there have been no reports comparing primary ccRCC of synchronous and metachronous metastatic patients, yet different in terms of prognosis. Determining whether there is a phenotypic difference between these two groups could have important clinical implications. Patients and Methods In a retrospective consecutive cohort of 98 patients with ccRCC, 48 patients had metastases including 28 synchronous and 20 metachronous presentations with a follow-up of 10 years. For each primary tumor in these metastatic patients, pathological criteria, expression of VEGF, PAR-3, CAIX and PD-L1 as detected by immunohistochemistry, and complete VHL status were analyzed. Univariate analysis was performed and survival was assessed using Kaplan-Meier curves compared by log-rank test. Results Compared to primary ccRCC in metachronous metastatic patients, primary ccRCC in synchronous metastatic patients were significantly associated with a poorer ECOG performance (p=0.045), higher pT status (p=0.038), non-inactivated VHL gene (p=0.01), sarcomatoid component (p=0.007), expression of PAR-3 (p=0.007), and overexpressions of VEGF (>50%) (p=0.017) and PD-L1 (p=0.019). Patients with synchronous metastases had a worse cancer-specific survival than patients with metachronous metastases even from metastatic diagnosis (median survival 16 months versus 46 months, respectively, p=0.01). Conclusion This long-term study is the first to support the notion that synchronous m-ccRCC has a distinct phenotype. This is probably linked to the occurrence of oncogenic events that could explain their worse prognosis. These particular metastatic patients could benefit from specific therapy.
Summary Background Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and ...estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer. Methods We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3–T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m2 and estramustine 10 mg/kg per day on days 1–5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov , number NCT00055731. Findings We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1–9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55–69) in the ADT plus docetaxel and estramustine group versus 50% (44–57) in the ADT only group (adjusted hazard ratio HR 0·71, 95% CI 0·54–0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 13% of 207 vs 22 11% of 206; p=0·57), and there were no treatment-related deaths. Interpretation Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival. Funding Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.
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