Biomedical subjects
Publications and source records attributed to J P Pignon.
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The prognostic weight of histological and biological factors was compared with that of known clinical prognostic factors in a population of 108 consecutive previously untreated patients with head and neck squamous cell carcinoma. Parameters studied were: tumour vascularisation, mitotic index, histological differentiation, nuclear grade, keratinisation, desmoplasia, growth pattern, inflammation, tumour emboli in peripheral vessels, keratins 6, 13, 19 immunohistochemical expression, cytofluorometric ploidy and S-phase. In multivariate analysis (Cox), only age and nodal status had a significant impact on the overall survival, whereas T stage was the only significant factor associated with locoregional failure. The cumulative incidence of metastases was correlated not only with age, T and N stage, but also with histological differentiation. All the other histological and biological factors studied failed to provide further prognostic information. These findings may help to select patients with high metastatic risk.
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To determine whether neural invasion or other clinico-pathological factors are prognostic, we performed a retrospective study on 339 rectal carcinomas. The overall 5-year survival was 62%. In the multivariate analysis, age over 60 years, a distance from the anal verge of less than 6 cm, the number of positive lymph nodes, neural invasion and tumour penetration were found to be prognostic. A scoring system identified five prognostic groups of patients. Neural invasion is an independent prognostic factor in our scoring system and it is suggested that this parameter should be taken into consideration for postsurgical treatment.
Currently, North American intergroup trials are conducted according to the Intergroup Guidelines, which require that a lead group take responsibility for data management. Intergroup studies conducted in this manner have been very successful in rapidly accruing large numbers of patients to trials addressing significant questions, but it has been difficult for group statistical centres to cope with the resultant peaks in data flow. Our groups recently succeeded in combining the data from three independently designed and conducted trials to carry out a planned pooled analysis. This experience has led us to employ the same approach to data management in designing a forthcoming intergroup trial. We will use a common protocol and capture the same data elements on our forms, but each group will be responsible for the collection and quality control of its own data. A common data set will be created and updated periodically during the study, and will be used for the final analysis. We suggest that this model has advantages over the current approach to data management on intergroup trials, but still retains the features which distinguish an intergroup study from meta-analysis.
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Numerous reviews of adenocarcinoma arising in Barrett's esophagus have been reported, but detailed pathologic findings or survival analysis have rarely been provided. This retrospective study analyzed 67 patients (mean age, 64 years; male-to-female ratio, 10:1) with an adenocarcinoma arising in Barrett's esophagus treated by surgical resection. Prevalence of smokers was 63%, alcohol users, 45%, and patients with hiatal hernia, 73%. Five patients had another synchronous cancer, and seven patients, previous esophageal surgery. Forty percent of the tumors were well differentiated, 31% moderately differentiated, 15% poorly differentiated, 7% mucinous, and 6% composed of signet-ring cells. Depth of invasion in the esophageal wall was limited to mucosa in 13% of cases and submucosa in 18%. Invasive adenocarcinomas extended to the muscular layer in 12% of cases, to adventitia in 33%, and to periesophageal tissue in 24%. Vascular and perineural neoplastic invasion was present in 67 and 38% of cases. Regional lymph node involvement and distant metastases were found in 51 and 9% of cases. Overall, 1-, 2-, and 5-year survival rates were 63, 41, and 32%, respectively. Five-year survival rate was significantly better for patients with superficial cancer limited to mucosa or submucosa (82 vs. 12%) or without regional lymph node involvement (59 vs. 10%). Tumor differentiation, vascular and perineural invasion, extranodal spread, distant metastases, and resection margins status also had a significant prognostic value on univariate analysis. In a multivariate Cox regression analysis for overall survival, depth of invasion in the esophageal wall and regional lymph node involvement were independent prognostic factors. Careful pathologic staging is of value in determining the prognosis of patients with adenocarcinoma arising in Barrett's esophagus.
BACKGROUND: This study, which investigates prehepatectomy immunostimulation with recombinant interleukin-2 (rIL-2), had two goals: to evaluate the tolerance of rIL-2 in association with major hepatectomy, and to verify whether preoperative immunostimulation is effective (neoadjuvant immunotherapy). In animal experiments, the conjunction of shed tumor cells into the circulation during surgery and severe surgery-induced immunodepression can promote the dissemination of the disease. Perioperative immunostimulation by rIL-2 reduces the incidence of metastases in animals. STUDY DESIGN: This prospective phase I-II randomized study included 19 patients with potentially resectable hepatic metastases from adenocarcinomas of the colon and rectum. Two-thirds were randomized to the rIL-2-treated group and one-third to the control group. Preoperative rIL-2 was administered by continuous intravenous infusion over five days and stopped two days before major hepatectomy. The dose of rIL-2 was gradually increased, from 3 x 10(6) IU/m2/day to 12 x 10(6) IU/m2/day. At least three patients were studied at each dose level before increasing the rIL-2 dose. Nineteen patients were eligible for the study (12 in the rIL-2 group and seven in the control group). Toxicity during infusion and intraoperative and postoperative complications were evaluated. Immunological monitoring consisted of repeated determination of lymphocyte counts and phenotypic analysis of lymphocyte subpopulations. Non-major histocompatibility complex-restricted cytotoxicity was assayed against K562 and DAUDI tumor cell lines. RESULTS: Toxicity during rIL-2 infusion was acceptable, similar to that of other phase I studies, and surgery was never delayed. Morbidity and mortality rates after major hepatectomy were not different between the two groups and it appeared that prehepatectomy rIL-2 at a dose of 12 x 10(6) IU/m2/day was well tolerated. During the postoperative course, the mean lymphocyte count was higher in the rIL-2 group (p < 0.05), without qualitative modification of the lymphocyte subsets. Immunological modifications were dose related. High cytotoxicity against K562 and DAUDI cells was constant at the 12 x 10(6) dose level. CONCLUSIONS: Preoperative five-day infusion of rIL-2 before major hepatectomy for colorectal metastases is well tolerated and reverses postoperative immunodepression.
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If meta-analyses of randomized trials were better in quality and were correctly interpreted, then there would be far less reasons for criticisms. The large number of meta-analyses to date are ample evidence of the usefulness of this technique in giving a synoptic appraisal of apparently discordant trials, but their shortcomings should be known. The first step needed to optimize the quality of meta-analyses is to improve the quality of randomized clinical trials. A registry of randomized trials is the best way to decrease publication bias. Meta-analyses based on individual data provided by each trialist allow a better appreciation of the quality of a trial, an increase of the statistical power, and for some covariates to be taken into account; such is not generally the case for those based on published data. Trialists should collect and conserve relevant data on ongoing trials and ensure that these trials are registered. These data would serve for the conduct of future unbiased meta-analyses, the duration of which would be reduced considerably, and unnecessary trials would be avoided.
The main advantage of interim analyses is that a randomized trial can be concluded in advance. As a consequence, the cost is reduced and the protection of the individual is increased from an ethical point of view. Formal statistical methods are, however, necessary to control the overall significance level and the power of the trial. Group sequential analysis and triangular test properties are compared in the setting of randomized trials with a long-term follow-up. Potential biases secondary to the conduct of the first analyses on a small number of events are discussed. Conservative methods which employ stringent criteria for the first analyses should be used to avoid loss of power in subsequent comparisons of long-term survival when early stopping occurs. Early stopping leads to less precision in the estimation of the treatment effect as the size of the sample is reduced. Furthermore, the observed effect could be biased upwards when trials are stopped early because the effect is larger than expected and biased downwards because the effect is lower than expected. Finally, as the ultimate goal of a trial is to alter therapeutic strategies, data should always be consistent so that the medical community can be convinced that treatment management should be modified.
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Combined chemotherapy has demonstrated a degree of efficacy in gastric carcinoma. As 5-fluorouracil (5FU) and cisplatinum are two of the most active drugs, we have tested the efficacy of combined 5FU and cisplatinum in a prospective phase II trial. Cycles were administered every 4 weeks and consisted of 5FU 1000 mg/m2/day 5 days continuous intravenous (i.v.) infusion and cisplatinum 100 mg/m2 on day 2. Cycles were repeated according to tolerance and efficacy. 87 patients entered the study, 57 with metastatic or recurrent tumour (M) and 30 with locally advanced gastric cancer (LAGC). The response rate for the 83 evaluable patients was 43% [95% confidence interval (CI) 30-56%]. There were four complete responses (5%), 32 partial responses (39%), 34 cases of stable disease and 13 cases of progressive disease. Responses were more frequent in patients with a good performance status (P = 0.02), with their primary located in the cardia (P = 0.003), with a non-linitis plastica tumour form (P = 0.003) or a tumour containing less than 50% of independent cells (P = 0.016). Median survival was 9 months for the total population. It was better in patients with a good performance status (P = 0.01), and those who did not have linitis plastica (P = 0.005). Toxicity was acceptable, although grade 3-4 neutropenia was reported in 22% of the cycles, mucositis in 14% and 3 patients died of septic complications. The combination of 5FU and cisplatinum is effective in terms of tumour response in advanced gastric cancer and warrants testing with the other active regimens.
Locally advanced gastric adenocarcinomas (LAGC) have a poor prognosis, particularly when tumours are bulky, located in the cardia or in the event of locoregional lymph node involvement. Patients bearing these tumours were entered in a phase II trial of neoadjuvant chemotherapy, combining continuous intravenous 5-fluorouracil (5FU) (1000 mg/m2 for 5 days) and cisplatinum (CDDP) (100 mg/m2 on day 2) repeated every 4 weeks, for one to six cycles according to response and tolerance. 30 patients have been entered, 26 after clinical evaluation (CAT scan and upper gastrointestinal endoscopy) and 4 with unresectable tumours at prior laparotomy. Median age was 60 years, 15/30 patients had a tumour of the cardia, 15/30 had enlarged lymph nodes and 7/30 had linitis plastica (diffuse type). A mean number of three cycles was administered (range 1-6). 27 of the 30 patients were evaluable for response. One patient achieved a complete response (CR) and 14 a partial response (56%; 95% confidence interval 38-74%). No patient had tumour progression, and only 1/6 with linitis plastica responded. 28 patients underwent surgery, and 23 had a macroscopically complete resection (77% of the 30 entered patients); RO resections were performed in 60% of the cases, mainly after an objective response (13/15 versus 4/12 in nonresponders). No pathological CR were seen. Grade 4 neutropenia was observed in eight cycles (5 patients), with five septic complications and one death due to toxicity. Four postoperative complications were observed: 2 cases of severe pneumonia and 2 subphrenic abscesses. One postoperative death, due to intravascular disseminated coagulation, was observed at day 30. Median survival was 16 months and the 1-, 2- and 3-year survival was 67, 42 and 38%, respectively. Patients with linitis plastica had a significantly shorter survival (P < 0.002). We conclude that neodjuvant chemotherapy is feasible in LAGC, although randomised trials are warranted to demonstrate its efficacy on survival and resection rates.
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BACKGROUND: Moderate increases in the initial doses of certain chemotherapeutic drugs, such as cisplatin and cyclophosphamide, may prolong overall survival in patients with limited small-cell lung cancer. METHODS: We conducted a prospective study of 105 patients with limited small-cell lung cancer. The patients were randomly assigned to receive higher or lower initial doses of cisplatin (100 or 80 mg per square meter of body-surface area) and cyclophosphamide (300 or 225 mg per square meter daily for four days); all patients received the same doses of doxorubicin and etoposide. The first course of chemotherapy was followed by five additional courses and by three courses of radiotherapy. All patients received the lower doses of cisplatin and cyclophosphamide and the same doses of doxorubicin and etoposide from the second through the sixth cycle of chemotherapy. RESULTS: The median follow-up was 33 months. The two-year survival rate for the 55 patients who received the higher doses of chemotherapy was 43 percent, as compared with 26 percent for the 50 patients who received the lower doses (P = 0.02). The rates of complete response at six months were 67 percent in the higher-dose group and 54 percent in the lower-dose group (P = 0.16). Disease-free survival at two years was 28 percent in the higher-dose group, as compared with 8 percent in the lower-dose group (P = 0.02). Side effects from treatment were not increased in the higher-dose group. CONCLUSIONS: Higher initial doses of cyclophosphamide and cisplatin improve disease-free and overall survival in patients with limited small-cell lung cancer.
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