Pascal Piedbois

Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group.

PURPOSE To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer. PATIENTS AND METHODS A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points. RESULTS The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX). CONCLUSION All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.

Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After Resection of Colorectal Liver Metastases: FFCD ACHBTH AURC 9002 Trial

PURPOSE Complete resection of liver metastases of colorectal origin is the only potentially curative treatment. In order to decrease recurrences, the use of adjuvant systemic chemotherapy after liver resection is controversial because no randomized study demonstrated its benefit. PATIENTS AND METHODS In a multicenter trial, we randomly assigned 173 patients with completely resected (R0) hepatic metastases from colorectal cancer to surgery alone and observation (87 patients) or to surgery followed by 6 months of systemic adjuvant chemotherapy with a fluorouracil and folinic acid monthly regimen (86 patients). The main outcome criterion was disease-free survival. Secondary outcome measures were overall survival and treatment-related toxicity. RESULTS The intention-to-treat analysis was based on 171 patients, after a median follow-up of 87 months (SE = 5.8). The 5-year disease-free survival rate, after adjustment for major prognostic factors, was 33.5% for patients in the chemotherapy group and 26.7% for patients in the control group (Cox multivariate analysis: odds ratio for recurrence or death = 0.66; 95% CI, 0.46 to 0.96; P = .028). With regard to secondary outcome measures, a trend towards increased overall survival was observed but did not reach statistical significance (5-year overall survival: chemotherapy group, 51.1% v control group, 41.1%; odds ratio for death, 0.73; 95% CI, 0.48 to 1.10; P = .13). CONCLUSION Despite a suboptimal regimen, which was the standard at the beginning of the study, adjuvant intravenous systemic chemotherapy provided a significant disease-free survival benefit for patients with resected liver metastases from colorectal cancer.

Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis

BACKGROUND Treatment of advanced colorectal cancer has progressed substantially. However, improvements in response rates have not always translated into significant survival benefits. Doubts have therefore been raised about the usefulness of tumour response as a clinical endpoint. METHODS This meta-analysis was done on individual data from 3791 patients enrolled in 25 randomised trials of first-line treatment with standard bolus intravenous fluoropyrimidines versus experimental treatments (fluorouracil plus leucovorin, fluorouracil plus methotrexate, fluorouracil continuous infusion, or hepatic-arterial infusion of floxuridine). Analyses were by intention to treat. FINDINGS Compared with bolus fluoropyrimidines, experimental fluoropyrimidines led to significantly higher tumour response rates (454 responses among 2031 patients vs 209 among 1760; odds ratio 0.48 [95% CI 0.40-0.57], p<0.0001) and better survival (1808 deaths among 2031 vs 1580 among 1760; hazard ratio 0.90 [0.84-0.97], p=0.003). The survival benefits could be explained by the higher tumour response rates. However, a treatment that lowered the odds of failure to respond by 50% would be expected to decrease the odds of death by only 6%. In addition, less than half of the variability of the survival benefits in the 25 trials could be explained by the variability of the response benefits in these trials. INTERPRETATION These analyses confirm that an increase in tumour response rate translates into an increase in overall survival for patients with advanced colorectal cancer. However, in the context of individual trials, knowledge that a treatment has benefits on tumour response does not allow accurate prediction of the ultimate benefit on survival.

Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis.

PURPOSE The modulation of fluorouracil (FU) by folinic acid (leucovorin [LV]) has been shown to be effective in terms of tumor response rate in patients with advanced colorectal cancer, but a meta-analysis of nine trials previously published by our group failed to demonstrate a statistically significant survival difference between FU and FU-LV. We present an update of the meta-analysis, with a longer follow-up and the inclusion of 10 newer trials. PATIENTS AND METHODS Analyses are based on individual data from 3,300 patients randomized in 19 trials on an intent-to-treat basis. Two trials had multiple comparisons, leading to a total of 21 pair-wise comparisons. FU doses were similar in both arms in 10 pair-wise comparisons, 15% to 33% higher in the FU-alone arm in six comparisons, and more than 66% higher in five comparisons. RESULTS Overall analysis showed a two-fold increase in tumor response rates (11% for FU-LV v 21% for FU-LV v 11% for FU [corrected] alone; odds ratio, 0.53; 95% CI, 0.44 to 0.63; P <.0001) and a small but statistically significant overall survival benefit for FU-LV over FU alone (median survival, 11.7 v 10.5 months, respectively; hazards ratio, 0.90; 95% CI, 0.87 to 0.94; P =.004), which were primarily seen in the first year. We observed a significant interaction between treatment benefit and dose of FU, with tumor response and overall survival advantages of FU-LV over FU-alone being restricted to trials in which a similar dose of FU was prescribed in both arms. CONCLUSION This updated analysis demonstrates, on a large data set, that FU-LV improves both response rate and overall survival compared with FU alone and that this benefit is consistent across various prognostic factors.

Progression-Free Survival Is a Surrogate for Survival in Advanced Colorectal Cancer

PURPOSE The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer. PATIENTS AND METHODS Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects. RESULTS In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS. CONCLUSION PFS is an acceptable surrogate for OS in advanced colorectal cancer.

Effect of dose rate on local control and complications in definitive irradiation of T1-2 squamous cell carcinomas of mobile tongue and floor of mouth with interstitial iridium-192.

From 1971 to 1988, 134 T1 and 145 T2 biopsy-proven squamous cell carcinomas of mobile tongue and floor of mouth were definitively managed by iridium-192. Implantations were performed using either guide gutters or afterloading plastic catheters. The prescribed dose at the reference isodose (85% of the basal dose rate, Paris system) was 60-70 Gy. Total dose was not adjusted to dose rate or tumor volume. Results of the 279 implants have been analysed to look for a possible influence of dose rate on local control and necrosis. Follow-up patients free of local recurrence is 1-180 months with average of 51 months. The 279 tumors were divided in four groups according to dose and dose rate: greater than or equal to 62.5 Gy and greater than or equal to 0.5 Gy/h (n = 130), greater than or equal to 62.5 Gy and less than 0.5 Gy/h (n = 36), less than 62.5 Gy and greater than or equal to 0.5 Gy/h (n = 81), less than 62.5 Gy and less than 0.5 Gy/h (n = 32). The four groups were comparable according to age, sex, tumor diameter and macroscopic aspect. At 5 years, the estimated local control (Kaplan Meier) was 93, 87, 79 and 52%, respectively (dose adjusted to dose rate: p less than 0.001, dose rate adjusted to dose: p less than 0.01, Log-rank); the necrosis rate was 44, 24, 37 and 5%, respectively (dose adjusted to dose rate: p = 0.08, dose rate adjusted to dose: p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Phase III Study Comparing a Semimonthly With a Monthly Regimen of Fluorouracil and Leucovorin As Adjuvant Treatment for Stage II and III Colon Cancer Patients: Final Results of GERCOR C96.1

PURPOSE This randomized, 2 x 2 factorial study compared a semimonthly regimen (fluorouracil [FU] and leucovorin [LV] semi-monthly is LV5FU2) with a monthly regimen of FU and LV (mFU/LV) as well as 24 weeks versus 36 weeks of each regimen as adjuvant treatment of stage II and III colon cancer. PATIENTS AND METHODS LV5FU2 was administered semimonthly for 2 days as racemate (dl) or levogyre (l-; 200 or 100 mg/m(2)) as a 2-hour infusion, followed by 400 mg/m(2) FU bolus and a 600-mg/m(2) FU 22-hour continuous infusion. FU and LV were administered monthly (mFU/LV) for 5 days as dl- or l-LV 15-minute infusion, followed by a 400 mg/m(2) FU 15-minute infusion. The primary end point was disease-free survival (DFS). RESULTS Between September 1996 and November 1999, 905 patients with stage II (43%) and III (57%) colon cancer were enrolled. The median follow-up was 6 years. There was no statistically significant difference between mFU/LV and LV5FU2 in terms of DFS (150 v 148 events; hazard ratio [HR],1.01; 95% CI, 0.806 to 1.269; P = .94) and overall survival (OS; 104 v 103 events; HR,1.02; 95% CI, 0.77 to 1.34; P = .91). No statistical difference was observed between 24 or 36 weeks of chemotherapy. Median survival from metastatic relapse was 24 months. The survival of patients with metastatic relapse (n = 243) was significantly longer for patients with a longer time from random assignment to relapse (< 1, 1 to 2, >or= 2 years; log-rank test for trend P, .0497). CONCLUSION DFS and OS were not statistically different between treatment groups and treatment durations. These data confirm the value of LV5FU2 as control arm in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer and Pan-European Trials in Adjuvant Colon Cancer studies.

Meta-analysis when only the median survival times are known: A comparison with individual patient data results

BACKGROUND The hazard ratio (HR) is the most appropriate measure for time to event outcomes such as survival. In systematic reviews, HRs can be calculated either from the raw trial data obtained as part of an individual patient data (IPD) meta-analysis or from the appropriate trial-level summary statistics. However, the information required for the latter are seldom reported in sufficient detail to allow reviewers to calculate HRs. In contrast, the median survival and survival rates at specific time points are frequently presented. We aimed to evaluate retrospectively the performance of meta-analyses using median survival times and survival rates by comparing them with meta-analyses using IPD to calculate HRs. METHODS IPD from thirteen published meta-analyses (MAs) in cancers with high mortality rates were used. Median survival and survival rates were calculated from the IPD rather than taken from publications so that the same trials, patients, and extended follow-up are used in each analysis. RESULTS AND CONCLUSIONS We show that using median survival times or survival rates at a particular point in time are not reasonable surrogate measures for meta-analyses of survival outcomes and that, wherever possible, HRs should be calculated. Individual trial publications reporting on time to event outcomes, therefore, should provide more detailed statistical information, preferably logHRs and their variances, or their estimators.

On the relationship between response to treatment and survival time

In this paper we review several approaches which have been used to investigate the relationship between survival time and response to treatment. We show that the approaches based on summary data are subjected to various types of biases (publication bias, confounding by prognostic features, ecologic bias) and are therefore of doubtful value. We also discuss several approaches based on individual patient data. Comparisons of survival by response are generally subject to length-biased sampling, and are therefore inadequate. The landmark method is adequate when responses occur soon after starting treatment, but not when responses may appear later in the course of the disease. For responses which can occur over extended periods of time, response must be considered as a time-dependent covariate. Using data from randomized trials in advanced colorectal cancer, we show that response is a potent and independent prognostic factor for survival in this disease. Analyses using the landmark method yield results essentially equivalent to those in which response is considered as a time-dependent covariate. The hazard rate of responders is about half that of non-responders, after taking the patients performance status into account. The issue of response as a surrogate marker for survival is taken up further in a separate paper.

Radiotherapy in the management of epidemic Kaposi's sarcoma: a retrospective study of 643 cases.

PURPOSE To report to the literature the largest published series of epidemic Kaposis sarcoma (EKS), treated with radiation therapy, to summarize and discuss our 10 years experience in the treatment of this malignancy. METHODS AND MATERIALS From June 1986 to December 1996, 643 patients with acquired immunodeficiency syndrome (AIDS)-related epidemic Kaposis sarcoma were treated with radiation therapy (RT) at the Cancerology Department of Henri Mondor University Hospital. The patients, 640 men and 3 women had an average age of 38.5 years (range 20-68 years). Three hundred eighty-seven patients (60.1 %) had received previous treatment for their Kaposis sarcoma (KS). In total, 6777 fields were irradiated, as follows: face 1342 (19.8%), eyelid and conjunctiva 362 (5.3%), trunk 1903 (28.1%), upper and lower limbs 2866 (42.3%), genitals 189 (2.8%). and oral cavity 115 fields (1.7%). Radiation therapy consisted of 4 MV or 45-70 kV X-rays, depending on tumor size and location. Doses ranged from 10 to 30 Gy, according to tumor response and toxicity. RESULTS Objective response (CR and PR) was observed in 92% (5947/6464) of all cases, treated for cutaneous form of EKS. All patients with irradiated oral lesions had an objective response. The overall tolerance was acceptable for the cutaneous lesions. By contrast, in oral lesions, mucosal reactions were often observed after relatively low doses of radiotherapy. CONCLUSIONS Doses of 15 Gy for oral lesions, 20 Gy for lesions involving eyelids, conjunctiva, and genitals, have been shown to be sufficient to produce shrinkage of the tumor and good palliation of the symptoms. For the cutaneous EKS, we propose 30 Gy given in a local field, using a fractionated scheme with small size applicators. Radiotherapy has its own place in the management of EKS, as an efficient treatment.