Frank Priou

Cisplatin in Combination With Either Gemcitabine or Irinotecan in Carcinomas of Unknown Primary Site: Results of a Randomized Phase II Study—Trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01)

PURPOSE To evaluate the efficacy and toxicity of novel chemotherapy combinations including cisplatin with gemcitabine (GC) or irinotecan (IC) for patients with carcinomas of an unknown primary site. PATIENTS AND METHODS Eighty patients were randomly assigned to receive GC or IC. In the GC arm, chemotherapy consisted of cycles combining gemcitabine 1,250 mg/m2 intravenously (IV) on days 1 and 8, and cisplatin 100 mg/m2 IV on day 1 at 3-week intervals. Patients in the IC arm originally received 3-week cycles of irinotecan 200 mg/m2 IV on day 1 and cisplatin 80 mg/m2 IV on day 1. After the inclusion of 15 patients in that arm, the toxicity profile required the irinotecan doses to be reduced to 150 mg/m2 per cycle. Independent histologic and radiologic reviews were done. RESULTS A total of 78 patients were assessable for efficacy and toxicity. The median number of cycles was four in each arm. Objective responses were observed in 21 patients (55%) in the GC arm (95% CI, 34% to 66%) and in 15 patients (38%) in the IC arm (95% CI, 23% to 54%). Treatment had to be stopped because of toxicity in seven patients in the GC arm and in eight patients in the IC arm. With a median follow-up of 22 months, the median survivals were 8 and 6 months in the GC and IC arms, respectively. CONCLUSION This study demonstrates the activity of both the GC and IC regimens. There was toxicity associated with both regimens. Additional studies of combination chemotherapy regimens are required.

Multicenter Phase II Trial of Neoadjuvant Therapy With Trastuzumab, Docetaxel, and Carboplatin for Human Epidermal Growth Factor Receptor-2–Overexpressing Stage II or III Breast Cancer: Results of the GETN(A)-1 Trial

PURPOSE Trastuzumab plus chemotherapy has become the standard of care for human epidermal growth factor receptor-2 (HER-2) -positive breast cancer. Trastuzumab-based preoperative systemic therapy (PST; neoadjuvant therapy) also appears promising, warranting further investigation. PATIENTS AND METHODS Patients with HER-2-positive, stage II/III, noninflammatory, operable breast cancer requiring a mastectomy (but who wanted to conserve the breast) received trastuzumab 4 mg/kg (day 1), followed by 2 mg/kg weekly, plus docetaxel 75 mg/m2 every 3 weeks, and carboplatin (area under curve, 6) for six cycles before surgery. The primary end point was pathologic complete response (pCR) rate, determined from surgical specimens. RESULTS Seventy patients were enrolled. Most patients had clinical T2/T3 tumors (100%) or clinical N1/2 nodes (53%). Sixty-seven patients (96%) completed six cycles of therapy, one patient withdrew due to progressive disease, and two patients withdrew for toxicity. A complete or partial objective clinical response occurred in 95% of patients (85% and 10%, respectively). Surgery was breast conservative in 45 (64%) of 70 patients. In an intent-to-treat analysis, tumor and nodal pCR were seen in 27 (39%) of 70 patients. Centralized retrospective analysis of HER-2 status demonstrated a 43% pCR rate in the 24 of 56 confirmed HER-2-overexpressing (3+) and/or fluorescence in situ hybridization-positive tumors. Treatment was generally well tolerated. Grade 3/4 neutropenia and febrile neutropenia were uncommon (2%). Two patients withdrew prematurely due to a transient, asymptomatic decrease in left ventricular ejection fraction. No symptomatic cardiac dysfunction occurred. CONCLUSION PST with trastuzumab plus docetaxel and carboplatin achieved promising efficacy, with a good pCR rate and favorable tolerability in stage II or III HER-2-positive breast cancer.

Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial

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/m(2) 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.

Docetaxel reintroduction in patients with metastatic castration-resistant docetaxel-sensitive prostate cancer: a retrospective multicentre study

To investigate the potential benefit of reintroducing docetaxel chemotherapy in patients with progressive metastatic castration‐resistant prostate cancer (mCRPC) who had initially responded to first‐line docetaxel‐based regimen.

Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study

BACKGROUND Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer. METHODS Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m(2) on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites (<3 vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681. FINDINGS ORRs for the motesanib group and the placebo group did not differ significantly (49%vs 41%; absolute difference 8% [95% CI -6 to 22]; p=0.31). The ORR in the bevacizumab group (52%) was similar to that in the motesanib group. The most common grade 3 or higher adverse events included diarrhoea (18 of 92 patients in the motesanib group, none of 89 patients in the placebo group, and four of 96 patients in the bevacizumab group), fatigue (11, eight, and six), hypertension (11, one, and seven), and peripheral sensory neuropathy (ten, seven, and 19). More patients in the motesanib group had serious adverse events than did those in the placebo or bevacizumab groups (34, 26, and 21 patients, respectively); the most common of these in the motesanib group were gastrointestinal in nature. INTERPRETATION Data from this trial do not support the further investigation of motesanib at this dose and schedule in this population. FUNDING Amgen.

Phase II study of carboplatin and etoposide in patients with anaplastic progressive metastatic castration-resistant prostate cancer (mCRPC) with or without neuroendocrine differentiation: results of the French Genito-Urinary Tumor Group (GETUG) P01 trial

BACKGROUND In the evolution of metastatic castration-resistant prostate cancer (mCRPC), patients present visceral metastases with or without neuroendocrine differentiation in 20% of cases. PATIENTS AND METHODS We assessed the efficacy and toxicity of a platinum-based chemotherapy regimen in mCRPC patients with either neuroendocrine differentiation defined by high serum levels of chromogranin A (CgA) and neuron-specific enolase (NSE) or visceral metastases. Patients received the combination of carboplatin and etoposide every 3 weeks. Efficacy end points included prostate-specific antigen (PSA) and neuroendocrine marker response, objective response and toxicity. RESULTS Of the 60 patients included from April 2005 to January 2008, 78.6% had bone metastases, 46.4% had lymph node involvement and 57.1% had liver and/or lung localizations. The objective response rate was 8.9% in the 46 patients with measurable disease. A neuroendocrine response was observed in 31% of cases for NSE and 7% for CgA. The PSA response rate was 8%. The most common grade 3-4 treatment-related toxic effects were neutropenia (65.5%), thrombocytopenia (32.7%) and anemia (27.3%). There was 7.2% febrile neutropenia, with one toxicity-related death. The median follow-up was 9.3 months [95% confidence interval (CI) 0.2-27.1] and the median overall survival 9.6 months (95% CI 8.7-12.7). CONCLUSION The benefit-risk ratio of this regimen seems unfavorable due to poor response and high toxicity.

A phase III trial of docetaxel–estramustine in high-risk localised prostate cancer: A planned analysis of response, toxicity and quality of life in the GETUG 12 trial

AIM To assess docetaxel-estramustine in patients with localised high-risk prostate cancer. PATIENTS AND METHODS After staging pelvic lymph node dissection, patients with high-risk prostate cancer randomly received androgen deprivation therapy (ADT) (3 years)+DE (4 cycles of docetaxel 70 mg/m(2)/3 weeks+estramustine 10mg/kg/dd1-5) or ADT alone. Local therapy was administered at 3 months. RESULTS Four hundred and thirteen patients were accrued: T3-T4 (67%), Gleason score ~8 (42%), PSA >20 ng/mL (59%), pN+ (29%). In the chemotherapy arm, 94% of patients received the planned four cycles of docetaxel. Local treatment consisted of radiotherapy in 358 patients (87%) (median dose 74 Gy in both arms). ADT was given for 36 months in both arms. A PSA response (PSA ~0.2 ng/mL after 3 months of treatment) was obtained in 34% and 15% in the ADT+DE arm and in the ADT arm, respectively (p<0.0001). Febrile neutropenia occurred in only 2%. Moderate to severe hot flashes occurred less often in the ADT+DE arm (2% versus 22%; p<0.001). There was no toxicity-related death, no secondary leukaemia, and no excess second cancers. Chemotherapy had a negative impact on quality of life (global health status, p = 0.01; fatigue, p = 0.003; role functioning, p = 0.003; social functioning, p = 0.006) at 3 months but this effect disappeared at 1 year. CONCLUSION Docetaxel-estramustine can be combined safely with standard therapy in high-risk prostate cancer, with a promising PSA response rate and no negative impact on quality of life after 1 year. Long-term follow-up is required to assess the impact on relapse and survival.

Do Patients With Advanced Urothelial Carcinoma Benefit From Weekly Paclitaxel Chemotherapy? A GETUG Phase II Study

BACKGROUND There is no standard second-line chemotherapy for patients who relapse with advanced urothelial carcinoma. A GETUG phase II clinical trial was designed to evaluate the response rate and the palliative clinical benefit of weekly paclitaxel. PATIENTS AND METHODS Paclitaxel (80 mg/m2, 1 hour) was administered on day 1, 8, and 15 (28-day course) to 45 patients. The primary endpoint was disease control rate (objective response and stable disease). Response rate was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria; quality of life (QOL) assessment used FACT-B1 and FACT-Taxane questionnaires. RESULTS Characteristics of the patients were: M/F, 36/9; mean age, 64 years; performance status (PS) 0-1, 82%; metastatic disease, 93%; gemcitabine/platinum first-line chemotherapy, 89%; median number of cycles, 2. Grade 3/4 toxicity was uncommon. The disease control rate was 47%. One patient achieved a complete response, 3 a partial response (objective response, 9%) and 17 (38%) a stable disease. Median time to progression or death were 3 and 7 months. Among the 21 patients with controlled disease, 10% displayed QOL improvement, and 14% decreased their analgesic consumption. CONCLUSION Weekly paclitaxel is associated with limited objective response but a high rate of stabilization; QOL assessment indicates that a small group of patients might experience a clinical benefit.

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%.

Cabazitaxel dans le cancer de la prostate métastatique résistant à la castration ayant progressé pendant ou après traitement par docétaxel : l'expérience française de l'essai TROPIC

In 2010, results of the TROPIC study demonstrated that, when compared to mitxantrone, the novel taxane cabazitaxel improved median overall survival of patients with metastatic castration-resistant prostate cancer who progressed on or after docetaxel treatment. We report the data on efficacy and toxicity observed in the subgroup of patients included in the French centers. In this phase III randomized international trial, patients received prednisone and were treated with either 25 mg/m(2) cabazitaxel or 12 mg/m(2) mitoxantrone intravenously every three weeks. The primary endpoint was overall survival. The secondary endpoints included progression-free survival (PFS) and safety. Analyses were performed on the intention-to-treat population. Among the 90 patients enrolled in France, the median overall survival was 18 months for the cabazitaxel arm versus 14.3 months for the mitoxantrone arm. An improvement in PFS was also observed, with a median of 1.4 months for the mitoxatrone arm compared to a median of 2.5 months for the cabazitaxel arm. The most common grade ≥ 3 adverse events were hematologic with neutropenia, usually afebrile and digestive with 4 % of patients reporting diarrhea. These results are comparable to those reported for the overall population and the safety profile remains favorable without any toxic death related to cabazitaxel.