Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non-Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy.

PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life.PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m2 (49 patients) or 75 mg/m2 (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks. RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7.1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P < .001), as was median survival (7.0 v 4.6 months; log-rank test, P = .047). The difference was more significant for docetaxel 75 mg/m2 patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P = .010; 1-year survival, 37% v 11%; χ2 test, P = .003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m2, three of whom died, and in one patient treated with docetaxel 75 mg/m2. Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups. CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m2, the benefits of docetaxel therapy outweigh the risks.

Predictive factors of positive circumferential resection margin after radiochemotherapy for rectal cancer: the French randomised trial ACCORD12/0405 PRODIGE 2.

Circumferential resection margin (CRM) appears as a new powerful prognostic factor of survival after surgery for rectal cancer. We aimed to evaluate predictive factors of positive CRM following preoperative radiochemotherapy in a French trial. Patients with rectal cancer were randomised in long course preoperative radiotherapy 45 Gy plus capecitabine versus 50 Gy plus capecitabine and oxaliplatin. Mesorectal excision was performed 6 weeks after treatment. Impact of clinical, pathological and surgical variables on positive CRM (≤1 mm) were analysed by multivariate analysis. Of 565 randomised patients, CRM was recorded in 390 cases and was positive in 8% (30/390). Patients with 50 Gy plus capecitabine and oxaliplatin had a 6% rate of positive CRM while those treated by 45 Gy plus capecitabine had a 10% rate (p=0.128). Three independent predictive factors of positive CRM were identified: abdominoperineal resection (APR) (odds ratio OR=3.24; p=0.004), vascular tumour invasion (OR=2.78; p=0.026) and poor histological response (modified Dworak 0-2) (OR=9.01; p=0.003). Significant predictive factors of positive CRM are related to type of surgery, especially APR, and poor histological prognostic factors. Intensification of neoadjuvant radiochemotherapy does not seem to have a major role in this study.

Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial.

PURPOSE: To compare the quality of life (QoL) of patients receiving oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) or gemcitabine as first-line chemotherapy and to assess whether pretreatment QoL predicts survival in patients with metastatic pancreatic cancer. PATIENTS AND METHODS: Three hundred forty-two patients with performance status 0 or 1 were randomly assigned to receive FOLFIRINOX (oxaliplatin, 85 mg/m(2); irinotecan, 180 mg/m(2); leucovorin, 400 mg/m(2); and fluorouracil, 400 mg/m(2) bolus followed by 2,400 mg/m(2) 46-hour continuous infusion, once every 2 weeks) or gemcitabine 1,000 mg/m(2) weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. QoL was assessed using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30 every 2 weeks. RESULTS: Improvement in global health status (GHS; P < .001) was observed in the FOLFIRINOX arm and improvement in emotional functioning (P < .001) was observed in both arms, along with a decrease in pain, insomnia, anorexia, and constipation in both arms. A significant increase in diarrhea was observed in the FOLFIRINOX arm during the first 2 months of chemotherapy. Time until definitive deterioration ≥ 20 points was significantly longer for FOLFIRINOX compared with gemcitabine for GHS, physical, role, cognitive, and social functioning, and six symptom domains (fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation). Physical functioning, constipation, and dyspnea were independent significant prognostic factors for survival with treatment arm, age older than 65 years, and low serum albumin. CONCLUSION: FOLFIRINOX significantly reduces QoL impairment compared with gemcitabine in patients with metastatic pancreatic cancer. Furthermore, baseline QoL scores improved estimation of survival probability when added to baseline clinical and demographic variables.

Results of the GYNECO 02 study, an FNCLCC phase III trial comparing hysterectomy with no hysterectomy in patients with a (clinical and radiological) complete response after chemoradiation therapy for stage IB2 or II cervical cancer.

BACKGROUND: Concomitant chemoradiation (CRT) (including brachytherapy) is considered the standard management for stage IB2 or II cervical cancer in many countries. Nevertheless, some of them discuss completion surgery (hysterectomy [HT]) after CRT. The aim of this study was to investigate the therapeutic impact of such surgery. METHODS: A randomized trial was opened in France in 2003 to evaluate the interest in HT after CRT. Inclusion criteria were: (a) stage IB2 or II cervical cancer without extrapelvic disease on conventional imaging; (b) pelvic external radiation therapy (45 Gy with or without parametrial or nodal boost) with concomitant cisplatin chemotherapy (40 mg/m2 per week) followed by uterovaginal brachytherapy (15 Gy to the intermediate risk clinical target volume); and (c) complete clinical and radiological response 6-8 weeks after brachytherapy. Patients were randomized between HT (arm A) and no HT (arm B). Unfortunately this trial was closed because of poor accrual: 61 patients were enrolled (in 2003-2006) and are reported on here. RESULTS: Thirty one and 30 patients were enrolled, respectively, in arm A and arm B. Twelve patients recurred (five of them died): respectively, eight and four in arm A and arm B. The 3-year event-free survival rates were 72% (standard error [SE], 9%) and 89% (SE, 6%) (not significant [NS]) in arm A and arm B, respectively. The 3-year overall survival rates were 86% (SE, 6%) and 97% (SE, 3%) (NS) in arm A and arm B, respectively. CONCLUSIONS: Results of the current trial seem to suggest that completion HT had no therapeutic impact in patients with clinical and radiological complete response after CRT (but this conclusion is limited by the lack of power).

Docetaxel- and 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced pancreatic cancer: a FNCLCC-ACCORD/0201 randomized phase II trial's pre-planned analysis and case report of a 5.5-year disease-free survival.

BACKGROUND: To explore possible improvement in the treatment of locally advanced pancreatic carcinoma (LAPC) we performed a randomized, non-comparative phase II study evaluating docetaxel - plus either daily continuous 5 FU or weekly cisplatin concurrent to radiotherapy. We report here the results of the docetaxel plus 5 FU regimen stopped according to the interim analysis. The docetaxel plus cisplatin arm was continued. METHODS: Forty (40) chemotherapy-naive patients with unresectable LAPC were randomly assigned (1:1) to either continuous fluorouracil (5-FU) 200 mg/m(2)/day (protracted IV) and docetaxel (DCT) 20 mg/m(2)/week or DCT 20 mg/m2 and cisplatin (CDDP) 20 mg/m(2), plus concurrent radiotherapy for a period of 6 weeks. The radiation dose to the primary tumor was 54 Gy in 30 fractions. The trial's primary endpoint was the 6-month crude non-progression rate (NPR). Secondary endpoints were tolerance, objective response rate, and overall survival. Accrual was to be stopped if at 6 months more than 13 disease progressions were observed in 20 patients. RESULTS: Eighteen (18) progressions occurred at 6 months in the 5-FU-DCT arm. Six-month NPR was 10% (95%CI: 0-23). Six and 12-month survivals were 85% (95%CI: 64-95) and 40% (95%CI: 22-61); median overall survival was 10.1 months. Median progression-free survival was 4.3 months. We report the case of one patient who was amenable to surgery and has been in complete response (CR) for 5.5 years. Toxicities grade ≥ 3 were reported in 75% of patients; no treatment-related death occurred. Severe toxicities were mainly vomiting (35%), abdominal pain (10%) and fatigue (10%). CONCLUSIONS: Combination of 5-FU, docetaxel and radiotherapy has inadequate efficacy in the treatment of LAPC despite good tolerance for the 5-FU-DCT regimen. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00112697.

Proposal for size justification of expanded cohort at phase-2-recommended dose.

PURPOSE: Most current dose-seeking phase 1 trials include an expanded cohort at phase-2-recommended dose (P2RD) to better characterize the drug safety or to obtain a better estimate of secondary endpoints. Nevertheless, the sample size of this expanded cohort has generally not been justified. MATERIALS AND METHODS: We reviewed 330 phase 1 trials (1998-2008). We estimated the rate of patients experiencing dose-limiting toxicity (DLT) at P2RD. Next, we estimated the probability of observing 1, 2 or 3 DLT in different fictive cohorts (from 8 to 22 patients). RESULTS: In the literature, the rate of patients experiencing DLT at P2RD was 367/2433, or 15.0%. We drew a table estimating the probability of observing 1, 2 or 3 DLTs in the different fictive cohorts. For example, in a cohort of 16 patients, the probabilities of observing 1, 2 or 3 DLTs are about 92.6%, 91.3 and 91.1% respectively. CONCLUSION: This simple tool could provide a justification for the sample size of an expanded cohort when DLT remains the metric for dose-seeking.

Sequential administration of docetaxel followed by cisplatin-vindesine: a pilot study in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).

In this phase II study, the feasibility and efficacy of sequential chemotherapy were tested with agents shown to be active as monotherapy. Patients with chemotherapy-naive, locally advanced or metastatic non-small cell lung cancer were selected for the study. Treatment involved four cycles of docetaxel (100 mg/m(2) on day 1, every 3 weeks) (sequence A), followed by four cycles of cisplatin-vindesine (cisplatin 120 mg/m(2) on day 1 and vindesine 3 mg/m(2) on days 1, 8, 15, and 22, every 4 weeks) (sequence B). Responding patients received 3 cycles of docetaxel 100 mg/m(2) (day 1, every 3 weeks) as consolidation (sequence C). Thirty-two patients entered the study with thirty being evaluable for efficacy. Four patients showed a partial response and one patient a complete response, resulting in an objective response rate of 16.7 %. The median survival time (intent-to-treat) was 11 months (95 %CI = 8.0-15.4 months) with an estimated 1-year survival rate of 47%. The median time to progression was 17.6 weeks in the evaluable population. Main grade 4 toxicity was neutropenia (21.8 % and 68.2 % of patients in sequence A and B, respectively) while grade 3 peripheral neuropathy was documented in five patients during sequence B. There were no treatment-related deaths. Sequential chemotherapy may show promise for the treatment of advanced non-small cell lung cancer. Given the feasibility of this pilot study, sequential chemotherapy concept should be investigated with newer cisplatin-based regimens using this approach in larger prospective studies.

Alpha-1-acid glycoprotein as an independent predictor for treatment effects and a prognostic factor of survival in patients with non-small cell lung cancer treated with docetaxel.

PURPOSE: To identify predictors of treatment outcome and survival in patients with non-small cell lung cancer (NSCLC) treated with docetaxel. EXPERIMENTAL DESIGN: The data were collected from 180 NSCLC patients enrolled in six docetaxel Phase II studies at a dose of 100 mg/m(2). Clinical end points for this study were safety reported as the first course adverse events requiring dose reduction, and efficacy was measured by response rate and survival. The independent variables included docetaxel dose, individual estimates of clearance, area under the plasma concentration time curve, extent of previous treatment, and covariables related to the patient's demographics, extent of disease, and performance status. The data were analyzed using a logistic regression model for response and severe adverse events and a Cox multivariate regression model for survival. RESULTS: Docetaxel exposure as measured by the area under the plasma concentration time curve was the only significant predictor (P < 0.0001) of severe toxicity during the first course of therapy. Baseline alpha1-acid glycoprotein (AAG) was the only significant predictor of response with an odds ratio of 0.44 for changes in AAG from 1.11 to 1.85 grams/liter (P = 0.0039). Cumulative dose, AAG, and extent of disease were independent predictors of survival (P < 0.005). The median survival varied from 15.6 months for patients with a low AAG (AAG < or = 1.11 grams/liter) to 5.5 months for patients with a high AAG (AAG >/= 1.85 grams/liter). CONCLUSION: AAG appears to be an independent predictor of response and a major objective prognostic factor of survival in patients with NSCLC treated with docetaxel chemotherapy.