A phase II study of cisplatin with intravenous and oral vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy with oral vinorelbine and cisplatin for locally advanced non-small cell lung cancer.

BACKGROUND: Concomitant platinum-based chemotherapy and radiotherapy (CT-RT) is the recommended treatment for unresectable locally advanced stage III non-small cell lung cancer (NSCLC). We conducted a phase II study to evaluate the efficacy and safety of fractionated oral vinorelbine with cisplatin as induction CT followed by CT-RT. METHODS: Patients with stage III NSCLC received 2 induction cycles of intravenous vinorelbine 25 mg/m2 and cisplatin 80 mg/m2 on day 1 and oral vinorelbine 60 mg/m2 on day 8. Responding patients received 2 more cycles of cisplatin 80 mg/m2 on day 1 and oral vinorelbine 20 mg on days 1, 3 and 5 concomitantly with radiotherapy 2 Gy daily, 5 days/week for a total of 66 Gy. RESULTS: Seventy patients, median age 61 years, were enrolled. Overall response rate (ORR) was 50.0%; Disease Control Rate was 81.42%. Median PFS was 14.58 months [95% CI, 10.97-18.75]. Median OS was 17.08 months [95% CI, 13.57-29.57]. One-year and 2-year survival rates were 68.6% [95% CI, 57.7-79.4] and 37%. One patient had a grade 3 pulmonary radiation injury and 26.5% had graded 1/2 esophagitis. CONCLUSION: In non-operable IIIA-IIIB NSCLC, the combination oral vinorelbine (fractionated fixed dose) plus cisplatin, during concomitant CT-RT, could offer a well-tolerated option, with comparable activity to I.V. vinorelbine-based chemoradiotherapy regimens. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01839032.

Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial.

BACKGROUND: Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC. METHODS: 148 patients with advanced (stage IIIB [wet] or IV) NSCLC expressing MUC1 by immunohistochemistry, and with performance status 0 or 1, were enrolled in parallel groups in this open-label, phase 2B study. 74 patients were allocated to the combination therapy group, and received TG4010 (10(8) plaque forming units) plus cisplatin (75 mg/m(2) on day 1) and gemcitabine (1250 mg/m(2) on days 1 and 8) repeated every 3 weeks for up to six cycles. 74 patients allocated to the control group received the same chemotherapy alone. Patients were allocated using a dynamic minimisation procedure stratified by centre, performance status, and disease stage. The primary endpoint was 6-month progression-free survival (PFS), with a target rate of 40% or higher in the experimental group. Analyses were done on an intention-to-treat basis. This study is completed and is registered with ClinicalTrials.gov, number NCT00415818. FINDINGS: 6-month PFS was 43·2% (32 of 74; 95% CI 33·4-53·5) in the TG4010 plus chemotherapy group, and 35·1% (26 of 74; 25·9-45·3) in the chemotherapy alone group. Fever, abdominal pain, and injection-site pain of any grade according to National Cancer Institute Common Toxicity Criteria were more common in the TG4010 group than in the chemotherapy alone group: 17 of 73 patients (23·3%) versus six of 72 (8·3%), 12 (16·4%) versus two (2·8%), and four (5·5%) versus zero (0%), respectively. The most common grade 3-4 adverse events were neutropenia (33 [45·2%] of patients in the TG4010 plus chemotherapy group vs 31 [43·1%] in the chemotherapy alone group) and fatigue (18 [24·7%] vs 13 [18·1%]); the only grade 3-4 events that differed significantly between groups were anorexia (three [4·1%] vs 10 [13·9%]) and pleural effusion (none vs four [5·6%]). 38 of 73 patients (52·1%) in the TG4010 plus chemotherapy group and 34 of 72 (47·2%) in the chemotherapy alone group had at least one serious adverse event. INTERPRETATION: This phase 2B study suggests that TG4010 enhances the effect of chemotherapy in advanced NSCLC. A confirmatory phase 2B-3 trial has been initiated. FUNDING: Transgene SA, Advanced Diagnostics for New Therapeutic Approaches (ADNA)/OSEO.

[Granulocyte- colony stimulating factor (G-CSF) use in clinical practice in patients receiving chemotherapy for breast cancer: The Opaline Study]. / Description des modalités pratiques de prescription d'un facteur de croissance de la lignée granulocytaire (G-CSF) chez les patientes recevant une chimiothérapie pour un cancer du sein : étude Opaline.

OBJECTIVES: To describe the French routine use of G-CSF in patients treated for breast cancer as per the EORTC recommendations. PATIENTS AND METHODS: A prospective multicenter observational study conducted between February 2008 and September 2009 in 869 breast cancer patients treated by chemotherapy (CT) and for whom G-CSF treatment will be delivered in primary (PP) or secondary prophylaxis. RESULTS: The mean age was 55 years. A total of 80.3% of CT was in neoadjuvant/adjuvant setting (NAS). PP was delivered in 78.9% of the NAS patients and 67.5% in metastatic situation. Of the 702 evaluable patients, incidences of severe (SN) and febrile neutropenias (FN) in patients who received PP were 9.3% and 4.2%, respectively. In patients who did not received G-CSF at first cycle, SN and FN were 12.4% and 7.3%, respectively. The use of PP was mainly driven by the type of CT for patients treated in the NAS and by patient or disease related risk factors in the locally advanced/metastatic setting. CONCLUSION: This study has shown that the use of G-CSF was in accordance with the 2010 updates of the EORTC recommendations. However, G-CSF appears more widely used in the routine practice.

[Standards, Options and Recommendations for the management of non-small cell lung carcinoma patients]. / Standards, Options et Recommandations 2000 pour la prise en charge des patients atteints d'un cancer bronchopulmonaire non á petites cellules (rapport abrégé).

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French cancer centers and specialists from French public university and general hospitals and private clinics. Its main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop, according to the definitions of the Standards, Options and Recommendations, clinical practice guidelines for the management of non small cell lung carcinoma patients. METHODS: Data were identified by searching Medline and the personal reference lists of members of the expert groups, then submitted for review to independent reviewers. This is a short version of the SOR guideline covering diagnosis, treatment and follow-up and includes the algorithms for the management of patients with non-small cell lung cancer.

[2000 Standards, Options and Recommendations for prognostic value of oncogenes and tumor suppressor genes in non small cell lung cancer]. / Standards, Options et Recommandations 2000 pour l'intérêt pronostique des oncogènes et gènes suppresseurs de tumeurs dans les cancers bronchopulmonaires non à petites cellules.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French cancer centers (FNCLCC), the 20 French cancer centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines for non small cell lung cancer patients according to the definitions of the Standards, Options and Recommendations project. METHODS: Data were identified by searching Medline , web sites, and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers. RESULTS: This article presents the chapter "Prognosis significance of oncogenes and tumor suppressor genes" from the full report "Standards, Options and Recommendation for non small cell lung cancer" validated in August 2000. The main recommendations are: 1) No clear clinical prognostic value of oncogenes and tumor suppressor genes (p53, bcl-2, Ki-ras, c-erbB-2, Rb, p16) in non small cell lung cancer, can be established from the available evidences (standard, level of evidence C). 2) Prospective multicenter studies should be performed to assess prognostic significance of oncogenes and tumor suppressor genes in non small cell lung cancer.

A randomised trial comparing preoperative to perioperative chemotherapy in early-stage non-small-cell lung cancer (IFCT 0002 trial).

HYPOTHESIS: There will be a detectable increase in overall survival (OS) using preoperative (PRE) as opposed to perioperative (PERI) chemotherapy in resectable StageI-II non-small-cell lung cancer (NSCLC). METHODS: This multicenter, open-label, randomised trial with a 2×2 factorial design first compared two chemotherapy strategies (PRE versus PERI), then two chemotherapy regimens (gemcitabine-cisplatin [GP] versus paclitaxel-carboplatin [TC]). The PRE group received two preoperative cycles followed by two additional preoperative cycles, while the PERI group underwent two preoperative cycles followed by two postoperative cycles, the 3rd and 4th cycles being given only to responders in both cases. RESULTS: A total of 528 patients were randomised, 267 of which were assigned to the PRE group and 261 to the PERI group. Three-year OS did not differ between the two groups (67.4% and 67.7%, respectively; hazard ratio (HR)=1.01 [0.79-1.30], p=0.92), nor did 3-year disease-free survival, response rates, toxicity, or postoperative mortality. Pathological complete response was observed in 22 (8.2%) and 16 patients (6.1%), respectively. Although quality of life did not differ significantly, chemotherapy compliance was significantly higher in the PRE group. The proportion of responders who received Cycles 3 and 4 was significantly higher in the PRE group (90.4% versus 75.2%, p=0.001). In responders, the dose intensity of Cycles 3 and 4 was higher in the PRE group than in the PERI group (mean relative dose intensity of 90.4% versus 82.6%, respectively; p=0.0007). There was no difference between GP and TC in 3-year OS (HR=0.97 [95% confidence interval (CI): 0.76-1.25], p=0.80) or response rates. However, the regimens' toxicity profiles differed. CONCLUSIONS: This study failed to demonstrate any difference in survival between patients receiving preoperative and perioperative chemotherapy in early-stage NSCLC. The increase from two to four preoperative chemotherapy cycles did not increase the pathological response rate.

Phase II study of vinflunine in malignant pleural mesothelioma.

PURPOSE: Malignant pleural mesothelioma (MPM) is a disease of increasing incidence for which treatment options are limited. This study reports the clinical efficacy data for vinflunine, a novel microtubule inhibitor, in MPM. PATIENTS AND METHODS: Patients with a histologically confirmed diagnosis of MPM were eligible for enrollment onto this multicenter phase II trial if they had not received prior chemotherapy or radiotherapy and had measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Vinflunine 320 mg/m2 by 10-minute intravenous infusion was administered on day 1 of 21-day cycles. Modifications of dose and schedule were made according to National Cancer Institute Common Toxicity Criteria version 2.0. Efficacy was assessed by an external, independent radiologist. The one-sample multiple testing procedure of Fleming was applied at the predetermined recruitment stages of 20 and 40 assessable patients. RESULTS: Sixty-seven patients were enrolled. Five patients were not assessable for tumor response. The response rate was 13.8% (95% CI, 6.5% to 24.7%). The median survival was 10.8 months (95% CI, 7.8 to 12.0 months). The most common adverse events were anemia, neutropenia, fatigue, constipation, and nausea. Of grade 3 and 4 toxicities, neutropenia and constipation were the most common (45% and 9% of patients, respectively). CONCLUSION: Vinflunine can be delivered with high-dose intensity in patients with MPM. The response rate and median survival are encouraging for a single agent. These data suggest that vinflunine should be further evaluated in the management of MPM.

Prevention of cisplatin-induced acute and delayed emesis by the selective neurokinin-1 antagonists, L-758,298 and MK-869.

BACKGROUND: Recent studies have suggested that antiemetic therapy with a triple combination of the neurokinin-1 receptor antagonist MK-869, a serotonin (5-HT(3)) antagonist, and dexamethasone provides enhanced control of cisplatin-induced emesis compared with standard therapy regimens. The authors compared the antiemetic activity of a dual combination of MK-869 and dexamethasone with that of a standard dual combination of ondansetron and dexamethasone to characterize further the efficacy and tolerability profile of MK-869. METHODS: This was a multicenter, double-blind, randomized, active agent-controlled study of 177 cisplatin-naïve patients with malignant disease. On Day 1, MK-869 was given intravenously as its water-soluble prodrug, L-758,298. Patients were randomized to one of three groups as follows. Group I received L-758,298 100 mg intravenously (i.v.), then dexamethasone 20 mg i.v., and cisplatin >or= 70 mg/m(2) on Day 1 followed by 300 mg MK-869 (tablet) orally on Days 2-5; Group II received L-758,298 100 mg i.v., then dexamethasone 20 mg i.v., and cisplatin >or= 70 mg/m(2) on Day 1 followed by placebo on Days 2-5; and Group III received ondansetron 32 mg i.v., then dexamethasone 20 mg i.v., and cisplatin >or= 70 mg/m(2) on Day 1 followed by placebo on Days 2-5. Emesis was recorded over Days 1-5 in a diary. Nausea was assessed every 24 hours by visual analog scale. Additional medication was available for emesis or nausea at any time. The primary efficacy parameters of interest were the proportion of patients without emesis and the proportion without emesis or rescue therapy on Day 1 (acute phase) and on Days 2-5 (delayed phase). RESULTS: No serious adverse events were attributed to L-758,298 or MK-869. On Day 1, the proportions of patients with no emesis and no use of rescue medication were 44% of patients in Group I, 36% of patients in Group II, 40% of patients in Groups I and II combined, and 83% of patients in Group III (P < 0.001 for Group III vs. the combined Groups I and II). The proportions of patients with no emesis and no use of rescue medication on Days 2-5 were 59% of patients in Group I, 46% of patients in Group II, and 38% of patients in Group III (P < 0.05 for Group I vs. Group III). The proportions of patients who were without emesis on Day 1 were 49% of patients in Group I, 47% of patients in Group II, and 84% of patients in Group III (P < 0.01 for Group I or II vs. Group III). On Days 2-5, however, the proportions of patients who were without emesis on Days 2-5 were 65% of patients in Group I, 61% of patients in Group II, and 41% of patients in Group III (P < 0.05 for Group I or II vs. Group III). Nausea scores in the acute phase were lower for Group III than for Group I, Group II, or Groups I and II combined (P < 0.05), although there was no significant difference among groups either for the delayed phase or overall for Days 1-5. CONCLUSIONS: Although the L-758,298 and dexamethasone combination reduced acute (Day 1) emesis compared with historic rates, dual therapy with ondansetron and dexamethasone was superior in controlling acute emesis. Continued dosing with MK-869 may enhance control of other measures of delayed emesis, such as the use of rescue medication, although confirmation is required before a definitive conclusion may be drawn. MK-869 given as dual therapy with dexamethasone was superior to ondansetron with dexamethasone for the control of delayed emesis (Days 2-5) and control of the need for rescue medication on Days 2-5.