O Van Cutsem

Prognostic Factors for Survival in Advanced Non-small-cell Lung-cancer - Univariate and Multivariate Analyses Including Recursive Partitioning and Amalgamation Algorithms in 1,052 Patients

PURPOSE This study attempted to determine the prognostic value for survival of various pretreatment characteristics in patients with nonresectable non-small-cell lung cancer in the context of more than 10 years of experience of a European Cooperative Group. PATIENTS AND METHODS We included in the analysis all eligible patients (N = 1,052) with advanced non-small-cell lung cancer registered onto one of seven trials conducted by the European Lung Cancer Working Party (ELCWP) during one decade. The patients were treated by chemotherapy regimens based on platinum derivatives. We prospectively collected 23 variables and analyzed them by univariate and multivariate methods. RESULTS The global estimated median survival time was 29 weeks, with a 95% confidence interval of 27 to 30 weeks. After univariate analysis, we applied two multivariate statistical techniques. In a Cox regression model, the selected explanatory variables were disease extent, Karnofsky performance status, WBC and neutrophil counts, metastatic involvement of skin, serum calcium level, age, and sex. These results were confirmed by application of recursive partitioning and amalgamation algorithms (RECPAM), which led to classification of the patients into four homogeneous subgroups. CONCLUSION We confirmed by our analysis the role of well-known independent prognostic factors for survival, but also identified the effect of the neutrophil count, rarely studied, with the use of two methods: a classical Cox regression model and a RECPAM analysis. The classification of patients into the four subgroups we obtained needs to be validated in other series.

Prognostic factors for patients with small cell lung carcinoma

The purposes of this study were to identify prognostic factors for response to chemotherapy, overall survival, and long term survival of patients with small cell lung carcinoma and to construct a classification of patients on the basis of their expected overall survival.

Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: a phase III randomized study conducted by the European Lung Cancer Working Party.

PURPOSE A randomized trial was conducted in patients with small-cell lung cancer (SCLC) to determine if survival can be improved by a weekly chemotherapy regimen combining various drugs. PATIENTS AND METHODS Two hundred twenty-three patients were randomized to receive either six courses of a multiple-drug combination (MDC) regimen (Adriamycin [ADR; doxorubicin; Farmitalia Carlo Erba, Milan, Italy] 25 mg/m2 intravenously [i.v.] on day 1; etoposide [VP16] 120 mg/m2 i.v. on day 1; cyclophosphamide [CPA] 500 mg/m2 i.v. on day 1; cisplatin 60 mg/m2 i.v. on day 8; vindesine [VDS] 3 mg/m2 i.v. on day 8; vincristine [VCR] 2 mg i.v. on day 15; methotrexate [MTX] 100 mg/m2 i.v. on day 15), or a standard chemotherapy (SC) regimen (ADR 50 mg/m2 i.v. on day 1; CPA 1 g/m2 i.v. on day 1; VP16 80 mg/m2 i.v. on days 1 to 3). RESULTS In 98 MDC-treated and 101 SC-treated assessable patients, we observed 69% and 62% objective responses rates, respectively. There was no significant difference in survival, with median durations and 2-year overall survival rates of 49 and 43 weeks and 8.5% and 7.9%, respectively. There was a significant increase in response rate in favor of MDC patients with limited disease (84% v 62%). Toxicity was tolerable, although SC was more hematotoxic, with 76% (v 59%) experiencing leukopenia and 17% (v 7%) experiencing thrombocytopenia (grades III and IV). If the cumulative doses received were nearly equal to the scheduled cumulative doses in both arms, the total relative dose-intensity (RDI) was significantly higher in the SC arm. The difference was due to increased treatment delays in the MDC arm. CONCLUSION Weekly MDC failed to improve survival rates in patients with SCLC.

Response to chemotherapy has predictive value for further survival of patients with advanced non-small cell lung cancer: 10 years experience of the European Lung Cancer Working Party.

The aim of this study was the assessment of the predictive value for survival of an antitumoral response to three courses of chemotherapy in association with various pretreatment characteristics in patients with non-resectable non-small cell lung cancer treated by cisplatin- (or carboplatin)-based combination regimens. Patients considered for this study were eligible patients with advanced non-small cell lung cancer registered in one of the seven trials conducted by the European Lung Cancer Working Party from December 1980 to August 1991. All these trials tested chemotherapy regimens with platinum derivatives (cisplatin and/or carboplatin). In this population of 1052 eligible patients, 752 were assessed in this analysis. Data were prospectively collected on 23 pretherapeutic variables and objective response after three chemotherapy cycles. The predictive value of response to chemotherapy on survival (measured from the time of response assessment i.e. 12 weeks after registration in the trial) was studied by univariate analysis as well as by multivariate methods (adjustment of the impact of several covariates simultaneously on the dependent variable) with adjustment for the pretreatment prognostic variables. After three cycles of chemotherapy, the global estimated median survival time was 24 weeks with a 95% confidence interval of 22-25 weeks. By univariate analysis, we identified an objective response to chemotherapy as a highly significant discriminant marker (P < 0.0001) for further survival with estimated median survival times of 41 weeks (95% CI: 38-46) and 19 weeks (95% CI: 17-20), respectively, for the responding and non-responding patients. In a Cox regression model fitted to the data using a forward stepwise procedure, this variable was the first selected explanatory variable. Its effect was adjusted by the introduction in the model of initial disease extent, Karnofsky performance status, serum calcium level and white blood cell count. These results were consistent with those obtained by application of recursive partitioning and amalgamation algorithms (RECPAM) which led to a classification of the patients into three homogeneous subgroups. Our results, using a classical Cox regression model consistent with those highlighted by application of a RECPAM analysis, found an objective response to chemotherapy to be a predominant predictive factor for further survival, although it did not allow any conclusion about a causal relationship. The RECPAM results led to a classification of the patients into three subgroups which needs to be validated in other series.

Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party.

PURPOSE AND METHODS The European Lung Cancer Working Party (ELCWP) performed a randomized trial with the primary end point to determine if maintenance chemotherapy with 12 courses of etoposide (120 mg/m2 on days 1 and 3) and vindesine (3 mg/m2 on day 3) could improve progression-free survival in small-cell lung cancer (SCLC) patients who responded to six courses of induction chemotherapy with ifosfamide, etoposide, and an anthracycline (doxorubicin or epirubicin). RESULTS Among 235 eligible patients initially registered, 91 were randomized to receive maintenance therapy, including seven patients who were no longer responding. Among 84 randomized responders, progression-free survival was significantly improved (P = .003) by maintenance therapy, with median durations (maintenance v follow-up) of 25 versus 12 weeks after the second randomization, but survival was not significantly increased (P = .10), with median durations of 48 and 38 weeks. However, in a multi-variate analysis that took into account disease extent, maintenance therapy, Karnofsky performance status (PS), and absolute dose-intensity (ADI) of anthracycline given during induction, limited disease (LD) and maintenance were found to be independent positive predictors of survival. CONCLUSION We conclude that maintenance chemotherapy in responding patients is beneficial in SCLC.

A three-arm phase III randomised trial assessing, in patients with extensive-disease small-cell lung cancer, accelerated chemotherapy with support of haematological growth factor or oral antibiotics.

The European Lung Cancer Working Party (ELCWP) designed a 3-arm phase III randomised trial to determine the role of accelerated chemotherapy in extensive-disease (ED) small-cell lung cancer (SCLC). Eligible patients were randomised between the 3 following arms: (A) Standard chemotherapy with 6 courses of EVI (epirubicin 60 mg m–2, vindesine 3 mg m–2, ifosfamide 5 g m–2; all drugs given on day 1 repeated every three weeks. (B) Accelerated chemotherapy with EVI administered every 2 weeks and GM-CSF support. (C) Accelerated chemotherapy with EVI and oral antibiotics (cotrimoxazole). Primary endpoint was survival. 233 eligible patients were randomised. Chemotherapy could be significantly accelerated in arm B with increased absolute dose-intensity. Best response rates, in the population of evaluable patients, were, respectively for arm A, B and C, 59%, 76% and 70%. The response rate was significantly higher in arm B in comparison to arm A (P = 0.04). There was, however, no survival difference with respective median duration and 2-year rate of 286 days and 5% for arm A, 264 days and 6% for arm B and 264 days and 6% for arm C. Severe thrombopenia occurred more frequently in arm B but without an increased rate of bleeding. Non-severe infections were more frequent in arm B and severe infections were less frequent in arm C. Our trial failed to demonstrate, in ED-SCLC, a survival benefit of chemotherapy acceleration by using GM-CSF support.

A randomised phase III trial comparing consolidation treatment with further chemotherapy to chest irradiation in patients with initially unresectable locoregional non-small-cell lung cancer responding to induction chemotherapy

PURPOSE A phase III randomised trial was conducted in patients with non-metastatic unresectable non-small-cell lung cancer in order to compare, in responders to induction chemotherapy, consolidation treatment by further chemotherapy to chest irradiation. PATIENTS AND METHODS A total of 462 untreated NSCLC patients were eligible for three courses of induction chemotherapy (MIP) consisting of cisplatin (50 mg/m2), ifosfamide (3 g/m2) and mitomycin C (6 mg/m2). It was proposed that objective responders be randomised to either three further courses of MIP or to chest irradiation (60 Gy; 2 Gy per fraction given over six weeks). RESULTS An objective response rate of 35% was achieved; 115 patients (including 52% with initial stage IIIA and 44% with initial stage IIIB) were randomised to consolidation treatment, 60 of them to further chemotherapy and 55 to chest radiotherapy. There was no significant difference in survival between the two arms, with a respective median and two-year survival of 42 weeks (95% confidence intervals (95% CI: 35-51) and 18% (95% CI: 8-28) for chemotherapy and 54 weeks (95% CI: 43-73) and 22% (95% CI: 11-33) for irradiation. There was also no statistical difference for response duration between the two arms but chest irradiation was associated with a significantly greater duration of local control than chemotherapy (median duration times: 158 vs. 31 weeks, P = 0.0007). CONCLUSIONS For non-metastatic unresectable NSCLC treated by an induction chemotherapy regimen containing cisplatin and ifosfamide, if an objective response is obtained, consolidation treatments by further chemotherapy or by chest irradiation result in non-statistically different survival distributions, although a better local control duration is observed with radiotherapy.

Long-term survival after chemotherapy containing platinum derivatives in patients with advanced unresectable non-small cell lung cancer

The study set out to determine the rate of long-term survivors (LTS) in patients treated with platinum-containing chemotherapy for advanced non-small cell lung cancer (NSCLC), to identify prognostic factors predicting long-term survival (> or = 2 years) and to report the LTS natural history. Eligible patients with advanced NSCLC treated by chemotherapy in one of seven trials conducted by the European Lung Cancer Working Party from December 1980 to August 1991 were included. All patients received cisplatin and/or carboplatin. Of these, 1052 patients were eligible and 24 variables were analysed as potential prognostic factors. Actuarial 2-year and 5-year survival rates were, respectively, 7.4 and 1.8%. All patients surviving for > or = 5 years had limited disease and were treated by complementary chest irradiation and/or surgery. Univariate prognostic factor analysis for LTS identified as significant no major weight loss, limited disease, no liver metastases, normal white blood cells and neutrophils and normal lactic dehydrogenase levels. By multivariate analysis, the only significant factor was limited disease. Objective response to chemotherapy was also found to be, as disease extent, a highly significant predictor for LTS. Thus, the two best prognostic factors for LTS were non-metastatic disease and response to chemotherapy.

Prognostic factors for response to chemotherapy containing platinum derivatives in patients with unresectable non-small cell lung cancer (NSCLC)☆☆☆

PURPOSE To identify pretreatment variables predicting response to platinum derivatives containing chemotherapy in patients with unresectable non-small cell lung cancer (NSCLC). PATIENTS AND METHODS Eligible patients included in one of the 7 consecutive clinical trials conducted by the European Lung Cancer Working Party between December 1980 and August 1991. All patients received a cisplatin or carboplatin containing chemotherapy. We analyzed 22 potential prognostic factors including sex, age, histology, performance status, weight loss, type of lesions, extent of disease, main metastatic sites and several biological parameters, namely white blood cell count (WBC), neutrophil count, platelet count, hemoglobinemia, creatininemia, serum alkaline phosphatases and LDH. RESULTS On 1052 eligible patients. 107 were not assessable for response. The objective response rate was 26% (95% C.I.: 23, 29%). Univariate analysis identified as statistically significantly associated with a higher objective antitumoral response rate the following characteristics: a normal platelet count, the absence of skin metastasis, the absence of adrenal metastasis, a higher creatininemia, a normal hemoglobinemia, an older age and a normal WBC count. On a restricted set of variables including data from 777 patients, a multivariate logistic regression model disclosed age and platelet count as significantly and independently related to response rate. CONCLUSION Clinical and demographic characteristics of patients with unresectable NSCLC, as well as routine laboratory parameters, could not accurately predict response to chemotherapy in a population of patients selected for a clinical trial. Future studies on this subject should include more sophisticated variables as new biomolecular makers.

A phase II study testing paclitaxel as second-line single agent treatment for patients with advanced non-small cell lung cancer failing after a first-line chemotherapy.

The purpose of this study was to determine the activity of paclitaxel as a second-line chemotherapy for non-small cell lung cancer (NSCLC). This multicentric trial included patients who had failed to a first-line chemotherapy with platinum derivatives and/or ifosfamide. After registration, patients were treated by paclitaxel i.v. at a dose of 225 mg/m(2) given over 3 h administered every 3 weeks. Response was assessed after three courses of therapy. Sixty-seven patients were registered, one was ineligible and 64 were assessable for response. Two partial responses were observed (3% of the eligible patients; 95% confidence interval: 0-7%). No change was documented in 16 cases (24%). Tolerance was acceptable, the main toxicity being cumulative polyneuropathy. Median survival duration was 4.5 months with a 1-year rate at 19%. We concluded that paclitaxel is not active in terms of response as second-line chemotherapy for NSCLC.