[Randomizations!].
Explore the source record for details and available documents.
Antineoplastic Agents↗
Biomedical subjects
M Buyse
Publications and source records attributed to M Buyse.
Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group.
The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.
Antineoplastic Agents↗
Tropisetron in the prevention of acute and delayed nausea and vomiting over six courses of emetogenic chemotherapy.
Tropisetron (Navoban") suppresses nausea and vomiting induced by cancer chemotherapy by antagonizing central and peripheral 5-HT3 receptors. In this open-label study, tropisetron was evaluated in 873 patients who were either refractory to antiemetic treatment during previous chemotherapy or at high risk of emesis as a result of current chemotherapy. The most commonly used agents alone or in combination were cyclophosphamide (35%), fluorouracil (30%), carboplatin (24%) and cisplatin (21%). The primary tumors were breast cancer (27%), lung cancer (16%), gynecological cancers (12%) and lymphoma (9%). Tropisetron was administered as a 15 min infusion prior to chemotherapy and an additional oral 5 mg dose was taken by 80% of the patients on subsequent days. During course 1, complete response to tropisetron was obtained in 64% of patients on day 1, 54% on day 2, 63% on day 3, 71% on day 4 and 77% on day 5. Very similar response rates were found for the six chemotherapy courses. There were few failures after complete and partial response, at maximum 3 and 15%, respectively. Moreover, 24-38% of those with partial response and 7-29% of those with failure could achieve a complete response during the following cycle. The treatment was well tolerated, the most frequently reported adverse events being constipation (3.7%) and headache (2.6%).
Acute Disease↗
Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer.
PURPOSE: The administration of fluorouracil (5-FU) by continuous intravenous infusion (CI) is an alternative to the bolus administration of 5-FU in patients with advanced colorectal cancer. Although more than 1,200 patients have been enrolled onto randomized trials that compared these two treatment modalities, there is still no definitive evidence of an advantage of 5-FU CI, and the magnitude of this advantage, if any, is also controversial. A meta-analysis was performed to assess this benefit in terms of tumor response and survival, and to compare the toxicity profiles of these two modalities of administration of 5-FU. DESIGN: Individual data of 1,219 patients included in six randomized trials served as the basis for this meta-analysis, which was conducted by an independent secretariat in close collaboration with the investigators. RESULTS: Tumor response rate was significantly higher in patients assigned to 5-FU CI than in patients assigned to 5-FU bolus (22% v 14%; overall response odds ratio, 0.55; 95% confidence interval [95% CI], 0.41 to 0.75; P = .0002). Overall survival was also significantly higher in patients assigned to 5-FU CI (overall hazards ratio [HR], 0.88; 95% CI, 0.78 to 0.99; P = .04), although the median survival times were close. Multivariate analyses showed that randomized treatment and performance status were the only two significant predictors of tumor response, whereas the same plus primary tumor site were independent significant predictors of survival (patients with rectal cancer did somewhat better). Grade 3 or 4 hematologic toxicity was more frequent in patients assigned to 5-FU bolus (31% v 4%; P < 10(-16)), whereas hand-foot syndrome was more frequent in the 5-FU CI group (34% v 13%; P < 10(-7)). CONCLUSION: 5-FU CI is superior to 5-FU bolus in terms of tumor response and achieves a slight increase of overall survival. The hematologic toxicity is much less important in patients who receive 5-FU CI, but hand-foot syndrome is frequent in this group of patients.
Antimetabolites, Antineoplastic↗
Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors.
PURPOSE: Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS: We conducted a meta-analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome. RESULTS: Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5-FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION: Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.
Colorectal Neoplasms↗
Criteria for the validation of surrogate endpoints in randomized experiments.
The validation of surrogate endpoints has been studied by Prentice (1989, Statistics in Medicine 8, 431-440) and Freedman, Graubard, and Schatzkin (1992, Statistics in Medicine 11, 167-178). We extended their proposals in the cases where the surrogate and the final endpoints are both binary or normally distributed. Letting T and S be random variables that denote the true and surrogate endpoint, respectively, and Z be an indicator variable for treatment, Prentice's criteria are fulfilled if Z has a significant effect on T and on S, if S has a significant effect on T, and if Z has no effect on T given S. Freedman relaxed the latter criterion by estimating PE, the proportion of the effect of Z on T that is explained by S, and by requiring that the lower confidence limit of PE be larger than some proportion, say 0.5 or 0.75. This condition can only be verified if the treatment has a massively significant effect on the true endpoint, a rare situation. We argue that two other quantities must be considered in the validation of a surrogate endpoint: RE, the effect of Z on T relative to that of Z on S, and gamma Z, the association between S and T after adjustment for Z. A surrogate is said to be perfect at the individual level when there is a perfect association between the surrogate and the final endpoint after adjustment for treatment. A surrogate is said to be perfect at the population level if RE is 1. A perfect surrogate fulfills both conditions, in which case S and T are identical up to a deterministic transformation. Fieller's theorem is used for the estimation of PE, RE, and their respective confidence intervals. Logistic regression models and the global odds ratio model studied by Dale (1986, Biometrics, 42, 909-917) are used for binary endpoints. Linear models are employed for continuous endpoints. In order to be of practical value, the validation of surrogate endpoints is shown to require large numbers of observations.
Biometry↗
A biostatistical tribute to Ignaz Philip Semmelweis.
Explore the source record for details and available documents.
Austria↗
Artificial neural networks.
Explore the source record for details and available documents.
Colorectal Neoplasms↗
Economic implications of hepatic arterial infusion chemotherapy in treatment of nonresectable colorectal liver metastases. Meta-Analysis Group in Cancer.
BACKGROUND: Approximately 20% of patients with colorectal cancer die of metastases confined to the liver. A meta-analysis recently performed by our group confirmed that in these patients hepatic arterial infusion of 5-fluoro-2'-deoxyuridine, compared with intravenous chemotherapy with fluoropyrimidines or supportive care (including symptom palliation when necessary), improved tumor response. PURPOSE: Because of the high cost of hepatic arterial infusion, we undertook a cost-effectiveness analysis that related the cost of such therapy to its medical efficacy. METHODS: The patient population was drawn from the seven randomized clinical trials included in the meta-analysis and included individual data on 654 patients. Of these seven trials, five compared hepatic arterial infusion and intravenous chemotherapy and two compared hepatic arterial infusion and a control group in which some patients could be left untreated. Patients assigned to receive hepatic arterial infusion made up the hepatic arterial infusion group; the other patients constituted the control group. The measures of efficacy were survival and tumor response. Health-care costs (in 1995 U.S. dollars) were computed over the duration of patient follow-up and were derived from actual costs in two centers, one at Henri Mondor Hospital (Paris, France) and the other at Stanford University Medical Center (Palo Alto, CA). The total cost of treatment included the initial procedure, chemotherapy cycles, and main complications. RESULTS: The mean gain in life expectancy in the hepatic arterial infusion group compared with the control group was 3.2 months (standard error = 1.0 month). For patients treated by hepatic arterial infusion in Paris, the hepatic arterial infusion pump, initial hospitalization, and the entire process (including follow-up and complications) cost, on average, $8400, $15172, and $29562, respectively; in Palo Alto, these costs were $4700, $13784, and $25 208, respectively. For patients in the control groups in Paris and Palo Alto, the total treatment costs were, on average, $9926 and $5928. The additional costs of hepatic arterial infusion over control treatment were $19636 in Paris and $19280 in Palo Alto. The cost-effectiveness (i.e., the additional cost divided by the additional benefit) with respect to survival of the patients in the hepatic arterial infusion group compared with the patients in the control group was $73635 per life-year in Paris and $72300 per life-year in Palo Alto. CONCLUSIONS AND IMPLICATIONS: The cost-effectiveness of localized chemotherapy for colorectal liver metastases is within the range of accepted treatments for serious medical conditions, although it might be considered borderline by policy-makers in some countries. Prospective clinical trials should be conducted to more definitively answer this question.
Antimetabolites, Antineoplastic↗
Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases.
OBJECTIVES: The International Registry of Lung Metastases was established in 1991 to assess the long-term results of pulmonary metastasectomy. METHODS: The Registry has accrued 5206 cases of lung metastasectomy, from 18 departments of thoracic surgery in Europe (n = 13), the United States (n = 4) and Canada (n = 1). Of these patients, 4572 (88%) underwent complete surgical resection. The primary tumor was epithelial in 2260 cases, sarcoma in 2173, germ cell in 363, and melanoma in 328. The disease-free interval was 0 to 11 months in 2199 cases, 12 to 35 months in 1857, and more than 36 months in 1620. Single metastases accounted for 2383 cases and multiple lesions for 2726. Mean follow-up was 46 months. Analysis was performed by Kaplan-Meier estimates of survival, relative risks of death, and multivariate Cox model. RESULTS: The actuarial survival after complete metastasectomy was 36% at 5 years, 26% at 10 years, and 22% at 15 years (median 35 months); the corresponding values for incomplete resection were 13% at 5 years and 7% at 10 years (median 15 months). Among complete resections, the 5-year survival was 33% for patients with a disease-free interval of 0 to 11 months and 45% for those with a disease-free interval of more than 36 months; 43% for single lesions and 27% for four or more lesions. Multivariate analysis showed a better prognosis for patients with germ cell tumors, disease-free intervals of 36 months or more, and single metastases. CONCLUSIONS: These results confirm that lung metastasectomy is a safe and potentially curative procedure. Resectability, disease-free interval, and number of metastases enabled us to design a simple system of classification valid for different tumor types.
Adolescent↗
The trials of Dr. Bernard Fisher: a European perspective on an American episode.
Explore the source record for details and available documents.
Bias↗
Immunocytochemical markers in stage I lung cancer: relevance to prognosis.
PURPOSE: This study investigated the frequency of the expression and prognostic significance of a panel of immunocytochemical markers in resected non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 515 cases of pathologic stage I NSCLC were analyzed. The median follow-up time of surviving patients was 102 months. The following immunocytochemical markers were tested: blood group A and precursors of blood antigens; laminin receptor; c-erbB1/epidermal growth factor receptor (EGFR) and c-erbB2/Neu; BCl2; p53; and angiogenesis. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biologic markers using the Cox model for multivariate analysis. RESULTS: The pathologic tumor extension (pT) represented the most powerful prognostic factor for survival (P = .0008) and time to recurrence (P = .0007). None of the immunocytochemical markers emerged as an independent predictive factor for survival. Bcl2-positive tumors showed a better time to recurrence (P = .03), but the difference lost statistical significance in the multivariate analysis. Of interest, in the group of 137 patients classified as pT1N0, both EGFR expression and nonangiogenic type of vascular pattern were associated with a poorer survival (P = .02). However, data derived from subset analysis must be interpreted cautiously. CONCLUSION: Our findings do not support a relevant prognostic role of immunocytochemical markers in NSCLC. The evidence is not sufficient to alter clinical practice or even to restrict clinical trials of adjuvant treatments to predefined biologic subsets of patients.
ABO Blood-Group System↗
Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis.
Neoplastic growth is usually dependent on blood supply, and it is commonly accepted that this is provided by the formation of new vessels. However, tumors may be able to grow without neovascularization if they find a suitable vascular bed available. We have investigated the pattern of vascularization in a series of 500 primary stage I non-small-cell lung carcinomas. Immunostaining of endothelial cells has highlighted four distinct patterns of vascularization. Three patterns (which we called basal, papillary, and diffuse) have in common the destruction of normal lung and the production of newly formed vessels and stroma. The fourth pattern, which we called alveolar or putative nonangiogenic, was observed in 16% (80/500) of the cases and is characterized by lack of parenchymal destruction and absence of both tumor associated stroma and new vessels. The only vessels present were the ones in the alveolar septa, and their presence highlighted, through the whole tumor, the lung alveoli filled up by the neoplastic cells. This observation suggests that, if an appropriate vascular bed is available, a tumor can exploit it and grows without inducing neo-angiogenesis. This could have implications for strategies aimed at inhibiting tumor growth by vascular targeting or inhibition of angiogenesis.
Biomarkers, Tumor↗
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 patient's performance status into account. The issue of response as a surrogate marker for survival is taken up further in a separate paper.
Antineoplastic Combined Chemotherapy Protocols↗
Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial.
Hydroxyurea (HU) enhances the synthesis of fetal hemoglobin (HbF) and can improve the clinical course of some adult patients with sickle cell anemia (SCA). In a randomized trial, we studied the biologic effects and the clinical benefit of HU in children and young adults with severe SCA. Twenty-five patients (median age, 9 years) were randomized to receive either HU (at the initial dosage of 20 mg/kg/d) or a placebo for 6 months and were then switched to the other arm for the next 6 months. Among the 22 evaluable patients (median age, 8 years), significant increases in HbF and mean corpuscular volume occurred during the HU treatment period. The white blood cell and reticulocytes counts decreased significantly, but these changes were not clinically relevant. Sixteen of 22 patients (73%) experienced a complete disappearance of events requiring hospitalization. The number of days of hospitalization as well as the number of hospitalizations for patients on HU, as compared with those for the patients receiving placebo, were significantly reduced. We conclude that treatment with HU in children and young adults is feasible, well-tolerated, and improves the clinical course of SCA. The long-term effects of HU require further investigation.
Adolescent↗
Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer.
BACKGROUND: Metastases confined to the liver cause substantial morbidity and mortality for patients with colorectal cancer. The results of several randomized clinical trials conducted to study the effectiveness of hepatic arterial infusion (HAI) of fluoropyrimidines for the treatment of such patients have suggested that this treatment, as compared with systemic administration of fluoropyrimidines, increases the likelihood of tumor response. However, the impact of HAI on survival is unclear. PURPOSE: A meta-analysis was carried out to provide an objective and quantitative appraisal of the benefits of HAI in terms of tumor response rate and overall patient survival. METHODS: The meta-analysis was based on individual data provided by the principal investigators of six individual trials and on summary data for one trial. Of the seven trials, five compared HAI with floxuridine (5-fluoro-2'-deoxyuridine; FUDR) and intravenous chemotherapy (IVC) with FUDR (three trials) or fluorouracil (5-FU) (two-trials), and two compared HAI with FUDR and an ad libitum control group in which some patients could be left untreated. Response data were analyzed by use of a Mantel-Haenszel test on all randomized patients. Survival data were analyzed by the use of stratified logrank test. Multivariate analyses were performed with use of the logistic regression model for tumor response and the Cox regression model for survival. All P values resulted from two-sided statistical tests. The analyses were performed by an independent secretariat and were reviewed by the collaborators. RESULTS: The tumor response rate was 41% for patients allocated to HAI with FUDR or 5-FU (CR, 2%; PR, 12%). This difference was highly significant, with a response odds ratio of 0.25 (95% confidence interval = 0.16-0.40; P < 10 (-10)). Survival analyses showed a statistically significant advantage for HAI with FUDR compared with control when trials were taken into account (P = .0009) but not when the survival analysis was restricted to trials comparing HAI with FUDR and IVC with FUDR or 5-FU (P = .14). CONCLUSION: These results confirm that HAI can achieve much higher tumor response rates than systemic chemotherapy in patients with liver metastases from colorectal cancer. IMPLICATIONS: The therapeutic benefit of use of HAI with FUDR in these patients should be judged together, with an overall evaluation of this therapy in terms of convenience, toxicity, and costs. These end points should be considered in addition to tumor response and survival in further trials involving HAI.
Antimetabolites, Antineoplastic↗
Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer.
PURPOSE: To compare the efficacy and toxicity profiles of a combination of fluorouracil (5-FU) and recombinant human interferon alfa-2a ([IFN alpha 2a] Roferon-A; Hoffmann-LaRoche, Basel, Switzerland) versus 5-FU alone in the treatment of advanced colorectal cancer (ACC). PATIENTS AND METHODS: A total of 245 previously untreated ACC patients were randomized to receive either IFN alpha 2a (9 million IU) subcutaneously (SC) three times weekly with 5-FU (750 mg/m2/d) by continuous intravenous (CIV) infusion on days 1 to 5 and then, after a 1-week hiatus, as a weekly IV bolus at the same dose (IFN/ 5-FU), or 5-FU alone at the same dose schedule (5-FU). RESULTS: There were no significant differences between IFN/5-FU and 5-FU alone in the overall response rate (24% v 17%, P = .2), duration of response (median, 6.4 v 8.1 months), time to response (plateau at 3 months), time to progressive disease ([PD] median, 4.8 v 4.9 months), or survival duration (median, 13.9 v 13.2 months). Toxicity profiles were not statistically different except for constitutional symptoms, which were more frequent and more severe with IFN/5-FU. More patients interrupted treatment for adverse events (AEs) with IFN/ 5-FU (34%) than with 5-FU alone (21%) (P = .03). The number of deaths (mostly unrelated to drug treatment) during the study (8%) was similar with both regimens. CONCLUSION: The combination IFN/5-FU produced a response rate, response duration, and survival duration similar to that of 5-FU alone. The addition of IFN to 5-FU in the doses and schedules used in this study did not provide any further benefit over 5-FU alone and cannot be recommended for patients with metastatic ACC. This study confirms the value of large prospective randomized clinical trials to determine the clinical value of regimens that emerge from smaller single-center phase II studies.
Adult↗
The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer.
BACKGROUND: Although the value of primary cytoreductive surgery for epithelial ovarian cancer is beyond doubt, the value of debulking surgery after induction chemotherapy has not yet been defined. In this randomized study we investigated the effect on survival of debulking surgery. METHODS: Eligible patients had residual lesions measuring more than 1 cm in diameter after primary surgery. After three cycles of cyclophosphamide and cisplatin, these patients were randomly assigned to undergo either debulking surgery or no surgery, followed by further cycles of cyclophosphamide and cisplatin. The study end points were progression-free and overall survival. At surgery 65 percent of the patients had lesions measuring more than 1 cm. In 45 percent of this group, the lesions were reduced surgically to less than 1 cm. RESULTS: Of the 319 patients who underwent randomization, 278 could be evaluated (140 patients who underwent surgery and 138 patients who did not). Progression-free and overall survival were both significantly longer in the group that underwent surgery (P = 0.01). The difference in median survival was six months. The survival rate at two years was 56 percent for the group that underwent surgery and 46 percent for the group that did not. In the multivariate analysis, debulking surgery was an independent prognostic factor (P = 0.012). Overall, after adjustment for all other prognostic factors, surgery reduced the risk of death by 33 percent (95 percent confidence interval, 10 to 50 percent; P = 0.008). Surgery was not associated with death or severe morbidity. CONCLUSIONS: Debulking surgery significantly lengthened progression-free and overall survival. The risk of death was reduced by one third, after adjustment for a variety of prognostic factors.
Adult↗