Significant effect of adjuvant chemotherapy on survival in locally advanced non-small-cell lung carcinoma.
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Biomedical subjects
Publications and source records attributed to E Quoix.
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The EORTC Lung Cancer Cooperative group performed a randomised phase II study in patients with small cell lung cancer comparing the standard cyclophosphamide/doxorubicin/etoposide (CDE) regimen with two regimens containing the new and active cisplatin derivative, carboplatin, 400 mg/m2 in combination with ifosfamide, a drug without important myelotoxicity, at a dose of 5 g/m2 (IMP) or the non-myelotoxic drug vincristine twice 2 mg (VP). Of 178 evaluable patients, 63 received CDE [30 limited disease (LD), 33 extensive disease (ED)], 55 received IMP (22 LD, 33 ED) and 60 (26 LD, 34 ED) were treated with VP. The response duration was not statistically different: CDE 31 weeks, IMP 29 weeks and VP 21 weeks. The time to progression after CEE was 28 weeks, IMP 24 weeks and VP 17 weeks. This was significantly shorter after VP than after CDE (P = 0.017). The 60% response rate of the VP combination was low compared with CDE (83%) and IMP (77%). Toxicity of all three regimens was acceptable, and dose reduction for myelosuppression was necessary in only a minority of the patients. We conclude from this study that the combination of carboplatin, at the maximally tolerated dose of 400 mg/m2, in combination with ifosfamide 5 g/m2, is an active regimen with efficacy comparable with the standard CDE regimen.
Two chemotherapy regimens for patients with extensive small-cell lung cancer were prospectively compared in a randomized multicentric trial with crossover. Every four weeks, 60 consecutive previously untreated patients received either DPE (doxorubicin, cisplatin and etoposide), or CIV (carboplatin, ifosfamide and vincristine) with crossover as soon as progression or end of response were observed. Pretreatment characteristics were similar in the two groups. Fifty-seven patients were evaluated for response. The response rate was higher with the DPE regimen both in first-line (for DPE: response rate 62% (18/29), including 17% (5/29) of complete response (CR), and for CIV: response rate 29% (8/28) with no CR, p < 0.02) and in second-line after crossover (for DPE: response rate 45% (9/20) including 5% (1/20) of CR, and for CIV response rate 0%, p < 0.02). Major toxicities were equally frequent in both groups. No significant difference was found between median survival times (9.7 months for the DPE group and 10.4 months for the CIV group). We conclude that: 1) DPE is a more active regimen than CIV, both in first- and second-line; 2) no alternating scheme may be considered with these two combinations. Of particular note is the similar median survival times in the two groups, contrasting with the different activities of the two regimens.
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Vinorelbine (NVB) is a new anticancer drug belonging to the vinca alkaloid family that shows activity as a single-agent treatment in advanced non-small cell lung cancer (NSCLC). Preliminary results show a better response rate with a combination of cisplatin (CDDP) and NVB than with NVB alone. To assess whether this increased activity is secondary to a pharmacokinetic interaction, the authors compared the pharmacokinetic profiles of NVB alone and combined with CDDP in previously untreated inoperable NSCLC patients. Five patients received NVB (30 mg/m2) by short intravenous infusion, and four patients received CDDP (80 mg/m2) 1 hour after the NVB infusion (30 mg/m2). Serum NVB was assayed using a specific high-performance liquid chromatography method. The mean serum concentrations in both groups were similar. In addition, the areas under the curve calculated from 1 hour (beginning of CDDP administration) to 72 hours were 414 ng.hour/mL (standard deviation [SD]: 94) (group NVB alone) and 407.1 ng.hour/mL (SD: 32.9) (group NVB + CDDP). In conclusion, the increased activity observed with the combination NVB + CDDP is not the result of a pharmacokinetic interaction.
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The pharmacokinetics and metabolism of Navelbine (NVB) were investigated in 20 patients by a specific high performance liquid chromatographic methodology allowing the monitoring of NVB, deacetyl-NVB, and N-oxide NVB. After the i.v. (15 min) administration of 30 mg/m2 of drug, blood and urine samples were collected for, respectively, 144 and 48 h. NVB is characterized by a three compartmental kinetics, with a Cmax of 1130 +/- 139 (SEM) ng/ml. The total body clearance and apparent volume of distribution, as defined by high performance liquid chromatography, are 1.26 +/- 0.09 liter/h/kg (48.6 +/- 4.1 liters/h/m2) and 75.6 +/- 9.2 liters/kg (2918.4 +/- 307.2 liters/m2). No metabolite could be detected in serum; the urinary excretion of NVB represented 11% of the administered dose. Deacetyl-NVB could be identified as a minor urinary metabolite when no N-oxide NVB appeared in the urine samples. Two additional peaks appeared in most of urinary chromatograms as trace amounts. Thus, the major pathway of NVB, as for other Vinca alkaloids, should be hepatic clearance, as biliary elimination and/or hepatic biotransformation.
We report the results observed in a large, randomized study that compared the effects of radiotherapy alone (the standard therapy) with those of a combination of radiotherapy and chemotherapy in nonresectable squamous cell and large-cell lung carcinoma. The radiation dose was 65 Gy in each group, and chemotherapy included vindesine, cyclophosphamide, cisplatin, and lomustine. In this study, 177 patients received radiotherapy alone (group A), and 176 patients received the combined treatment (group B). The 2-year survival rate was 14% in group A and 21% in group B (P = .08). The distant metastasis rate was significantly lower in group B (P less than .001). Local control was poor in both groups (17% and 15%, respectively) and remained the major problem.
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Most patients with locally advanced non small cell lung carcinoma are treated with external thoracic radiotherapy. Because of the high incidence of distant metastasis the addition of chemotherapy has been proposed. The present randomized study was conducted from June 1983 to February 1989 and included 353 patients. The trial compared arm A, thoracic megavoltage radiotherapy alone at a total dose of 65 Gy in 26 fractions and 45 days, to arm B that comprised the same radiotherapy preceded and followed by 3 monthly cycles of VCPC (vindesine 1.5 mg/m2 d 1-2, cyclophosphamide 200 mg/m2 d 2-4, cisplatinum 100 mg/m2 d 2 and lomustine 75 mg/m2 d 3). Disease was deemed unresectable but non-metastatic after bronchoscopic, radiologic, CAT, and nuclear scans and physical examinations. Only patients in clinical, radiological, endoscopic, and histological complete remission were considered as locally controlled; these patients were monitored by fiberoptic bronchoscopy and systematic biopsies to the primary site. One hundred seventy-seven patients received thoracic radiotherapy alone and 176 received the combined modality. Twenty-seven percent of arm B patients had an objective response after 2 VCPC cycles. At the time of final assessment, performed 3 months after the end of thoracic radiotherapy in both arms, there were 20% of complete responders in arm A versus 16% in arm B. The two-year survival rate was 14% in arm A versus 21% in arm B (p = 0.08, logrank test). The distant metastasis rate was 67% in arm A versus 45% in arm B (p less than 0.001). Local control at 1 year was poor in both groups (17% and 15%, respectively). The striking effect of VCPC chemotherapy on the incidence of distant metastasis did not have a significant impact on overall survival. We conclude that thoracic tumor control remains a significant problem in unresectable non small cell lung cancer.
The benefit of chemotherapy for patients with disseminated non small cell lung cancer (NSCLC) is controversial. The introduction of cisplatinum in the combination chemotherapy for NSCLC gave rise to higher response rates. To study the question of the usefulness of cisplatinum-based chemotherapy in disseminated NSCLC we conducted a prospective randomized trial comparing best supportive care to vindesine + cisplatin. Between December 1985 and March 1988, 49 patients with stage IV NSCLC were enrolled. Of the 46 eligible patients 24 were in the chemotherapy group and 22 in the best supportive care group. The treatment groups were not significantly different in terms of age, performance status, histology. Toxicity on the chemotherapy arm grade 3 or more was observed in 17.5% for neutropenia, in 8.75% for vomiting. There was one death related to treatment. The overall response rate in the chemotherapy group was 41.7%. Patients of the chemotherapy group had a median survival time of 199 days and the patients of the best supportive care group had a median survival time of 73 days. The difference in survival is highly significant (p less than 0.001).
Small cell lung cancer (SCLC) rarely presents radiographically as a solitary pulmonary nodule (SPN). Twenty-five patients with this feature were identified among 408 individuals with SCLC at McGill University (Montreal, Quebec) from 1979 through 1984. Of these, 15 (60%) were confirmed on pathologic review as SCLC (ten intermediate cell, four oat cell, one indeterminate). Pathologic review of a control group comprising 24 other limited-disease patients who were long-term survivors (greater than 20 months) confirmed 20 (84%) as SCLC (eight intermediate cell, 12 oat cell). Ten of the 15 patients with SPN were resected whereas five had chemotherapy and/or radiotherapy as primary treatment. Postoperative chemotherapy was administered to most of the resected patients. The median survival of the 15 patients with SPN was 24 months, a significantly longer survival than the other patients with SCLC. This improved prognosis in patients with SPN may be due to smaller initial tumor burden or to a fundamental biologic difference between SPN and other forms of SCLC.
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The practice of therapeutic trials is indispensable in the management of bronchial carcinoma if one hopes to improve the results. We have questioned 134 doctors in the Alsace region who are involved in the diagnosis and treatment of bronchial cancer. We asked how they would wish to be treated if they had a small cell cancer, and if they would agree to participate in a therapeutic trial should the occasion arise. Four different clinical situations of small cell carcinoma localised to the hemithorax were presented, illustrating current controversy on the best treatment or treatments to apply. The 4 proposed protocols were refused by 50% to 84% of the doctors questioned in different cases. The greater the level of consensus on a therapeutic treatment in a given clinical situation the greater the level of refusal to participate in a randomised protocol was. The fact that at least half of the specialist doctors questioned would refuse to be included in a current therapeutic protocol which is underway for patients in Europe leads to the suggestion that before the application for new protocols experts surrogates should give their opinion in association with ethical committee.
We report a case of a 62 year old man who presented with effort dyspnoea accompanied by a cough and haemoptysis. The chest radiograph of the thorax showed atelectasis of the right upper lobe. Bronchoscopy showed evidence of a tumour like mass obstructing the right bronchus and this revealed itself to be a mass of organised fibrinous deposit in granulation tissue containing numerous colonies of Aspergillus. In fact it appeared to be an obstructive Aspergillus bronchitis, with a pseudo-tumour appearance attached to a carcinoid tumour which was obstructing the apical segment of the right upper lobe. Obstructive Aspergillus bronchitis makes up only a small percentage of overall respiratory disease caused by Aspergillus. They pose a problem of differential diagnosis with bronchopulmonary aspergillosis which is much more frequent.
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