Bernard Lebeau

A meta-analysis of thoracic radiotherapy for small-cell lung cancer.

BACKGROUND In spite of 16 randomized trials conducted during the past 15 years, the effect of thoracic radiotherapy on the survival of patients with limited small-cell lung cancer remains controversial. The majority of these trials did not have enough statistical power to detect a difference in survival of 5 to 10 percent at five years. This meta-analysis was designed to evaluate the hypothesis that thoracic radiotherapy contributes to a moderate increase in overall survival in limited small-cell lung cancer. METHODS We collected individual data on all patients enrolled before December 1988 in randomized trials comparing chemotherapy alone with chemotherapy combined with thoracic radiotherapy. Trials that included only patients with extensive disease were excluded. RESULTS The meta-analysis included 13 trials and 2140 patients with limited disease. A total of 433 patients with extensive disease were excluded. Overall, 1862 of 2103 patients who could be evaluated died; the median follow-up period for the surviving patients was 43 months. The relative risk of death in the combined-therapy group as compared with the chemotherapy group was 0.86 (95 percent confidence interval, 0.78 to 0.94; P = 0.001), corresponding to a 14 percent reduction in the mortality rate. The benefit in terms of overall survival at three years (+/- SD) was 5.4 +/- 1.4 percent. Indirect comparison of early with late radiotherapy and of sequential with non-sequential radiotherapy did not reveal any optimal time for treatment. There was a trend toward a larger reduction in mortality among younger patients: the relative risk of death in the combined-therapy as compared with the chemotherapy group ranged from 0.72 for patients less than 55 years old (95 percent confidence interval, 0.56 to 0.93) to 1.07 (0.70 to 1.64) for patients over 70. CONCLUSIONS Thoracic radiotherapy moderately improves survival in patients with limited small-cell lung cancer who are treated with combination chemotherapy. Identification of the optimal combination of chemotherapy and radiotherapy will require further trials.

Preoperative Chemotherapy Followed by Surgery Compared With Primary Surgery in Resectable Stage I (Except T1N0), II, and IIIa Non–Small-Cell Lung Cancer

PURPOSE To evaluate whether preoperative chemotherapy (PCT) could improve survival in resectable stage I (except T1N0), II, and IIIA non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS A randomized trial compared PCT to primary surgery (PRS). PCT consisted of two cycles of mitomycin (6 mg/m(2), day 1), ifosfamide (1.5 g/m(2), days 1 to 3) and cisplatin (30 mg/m(2), days 1 to 3), and two additional postoperative cycles for responding patients. In both arms, patients with pT3 or pN2 disease received thoracic radiotherapy. RESULTS Three hundred fifty-five eligible patients were randomized. Overall response to PCT was 64%. There were two preoperative toxic deaths. Postoperative mortality was 6.7% in the PCT arm and 4.5% in the PRS arm (P =.38). Median survival was 37 months (95% confidence interval [CI], 26.7 to 48.3) for PCT and 26.0 months (95% CI, 19.8 to 33.6) for PRS (P =.15). Survival differences between both arms increased from 3.8% (95% CI, 1.3% to 25.1%) at 1 year to 8.6% (95% CI, 2.64% to 24.4%) at 4 years. A quantitative interaction between N status and treatment was observed, with benefit confined to N0 to N1 disease (relative risk [RR], 0.68; 95% CI, 0.49 to 0.96; P =.027). After a nonsignificant excess of deaths during treatment, the effect of PCT was significantly favorable on survival (RR, 0.74; 95% CI, 0.56 to 0.99; P =.044). Disease-free survival time was significantly longer in the PCT arm (P =.033). CONCLUSION Although impressive differences in median, 3-year, and 4-year survival were observed, they were not statistically significant, except for stage I and II disease.

A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma

Postoperative radiotherapy is commonly used to treat patients with completely resected nonsmall cell lung carcinoma, but its effect on overall survival has not been established.

Chronic liver injury during obstructive sleep apnea

Patients with obstructive sleep apnea (OSA) are at risk for the development of fatty liver as a result of being overweight. Several data suggest that OSA per se could be a risk factor of liver injury; ischemic hepatitis during OSA has been reported, and OSA is an independent risk factor for insulin resistance. Therefore, we investigated liver damage and potential mechanisms in 163 consecutive nondrinking patients with nocturnal polysomnographic recording for clinical suspicion of OSA. Serum levels of liver enzymes were measured in all patients. Liver biopsy was offered to patients with elevated liver enzymes. Intrahepatic hypoxia was assessed by the expression of vascular endothelial growth factor (VEGF) on liver biopsy specimens. Severe OSA (apnea‐hypopnea index [AHI] > 50/hr) was seen in 27% of patients; 52% had moderate OSA (AHI 10‐50/hr), and 21% had no OSA. Overall, 20% had elevated liver enzymes. Independent parameters associated with elevated liver enzymes were body mass index (BMI) (OR: 1.13; CI: 1.03‐1.2) and severe OSA (OR: 5.9; CI: 1.2‐29). Liver biopsy was performed in 18 of 32 patients with elevated liver enzymes and showed steatohepatitis in 12 cases, associated with fibrosis in 7 cases. Patients with severe OSA were more insulin‐resistant according to homeostasis model assessment, had higher percentage of steatosis as well as scores of necrosis and fibrosis, despite similar BMI. Hepatic immunostaining used as an indirect marker of hypoxia was not different between patients with or without severe OSA. In conclusion, severe OSA is a risk factor for elevated liver enzymes and steatohepatitis independent of body weight. Promotion of insulin resistance is probably involved. Further studies are needed to determine whether hypoxia contributes directly to liver injury. (HEPATOLOGY 2005;41:1290–1296.)

Fiberoptic bronchoscopy for the early diagnosis of subglottal inhalation injury : comparative value in the assessment of prognosis

The aim of this study was to determine the value of bronchoscopy in the early diagnosis of inhalation injury. A total of 130 burn patients underwent bronchoscopy on admission to a specialized center. In order to validate the method and the bronchoscopists conclusions, they underwent staged bronchial biopsies. Using the histologic findings as the «gold standard,» bronchoscopy proved to be sensitive (sensitivity, 0.79) and highly specific (specificity, 0.94) for the diagnosis of inhalation injury. In addition, it was more reliable than the circumstances of the injury, the clinical findings, and complementary tests. In a one-dimensional analysis, bronchoscopy-proven inhalation injury was one of the most strongly predictive variables for the onset of ARDS and death

Failure of the perioperative PCV neoadjuvant polychemotherapy in resectable bronchogenic non-small cell carcinoma results from a randomized phase II trial

In 1985, the authors began a phase II study to assess the PCV perioperative polychemotherapy (cisplatin 100 mg/m2, cyclophosphamide 600 mg/m2, vindesine 3 mg/m2) in patients with resectable bronchogenic non‐small cell carcinoma. Patients were randomized to receive either two preoperative courses of PCV chemotherapy, surgery, and two postoperative courses of PCV chemotherapy (PCV group) or immediate surgery (surgery group). A staging procedure using the CT scan was performed before randomization and, additionally, before surgery in the PCV group. There were 26 randomized patients, 13 in each group. In the PCV group, 11 patients agreed to receive the two preoperative courses of chemotherapy. A response was observed in five patients (45%), and a progression was observed in four patients (36%) leading to a cancellation of surgery in two of them. Postoperative care was the same for each group. Although no death could be related to chemotherapy, it was decided to stop entering new patients into this trial because of the rate of preoperative progression in the PCV group.

Pulmonary veno-occlusive disease after neoadjuvant mitomycin chemotherapy and surgery for lung carcinoma

Pulmonary veno-occlusive disease (PVOD), an uncommon cause of pulmonary hypertension (PH) has been reported following treatment of a variety of different malignancies with various chemotherapy. We report here the cases of two patients with non-small cell lung cancer (NSCLC) who developed fatal PH after combined treatment with surgery and a mitomycin containing perioperative chemotherapy (PCT). PVOD was documented at autopsy in one patient and was strongly suspected in the other patient who had an identical clinical presentation and in whom the work-up looking for another cause of PH was negative. Mitomycin was incriminated in both cases. Without questioning the potential interest of perioperative chemotherapy in resectable NSCLC, these observations illustrate the risks related to the combination of pneumotoxic chemotherapy and thoracic surgery.

Randomized phase II trial of gefitinib or gemcitabine or docetaxel chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2 or 3 (IFCT-0301 study)

BACKGROUND To compare 3 treatment strategies in chemotherapy naive patients with advanced NSCLC and a PS 2-3. PATIENTS AND METHODS Patients were assigned to gefitinib 250mg daily (n=43) or to gemcitabine (1250mg/m(2) d 1, 8 q 21d) (n=42) or docetaxel (75mg/m(2) d 1 q 21d) (n=42). Treatments were taken until progression or toxicity. The primary endpoint was progression-free survival. Secondary end points were response and overall survival. RESULTS Disease control rates were 20.9%, 33.4% and 38.1%, respectively. Median PFS was 1.9 months in the gefitinib arm, 2.0 months in the gemcitabine arm and 2.0 months in the docetaxel arm (HR gemcitabine versus gefitinib: 0.74, 95%CI: [0.48; 1.16], HR docetaxel versus gefitinib: 0.67, 95%CI: [0.43; 1.05]). Median survival times were 2.2, 2.4 and 3.5 months, respectively (HR gemcitabine versus gefitinib: 0.76, 95%CI: [0.48; 1.20], HR docetaxel versus gefitinib: 0.69, 95%CI: [0.44; 1.09]). There were more grade 3-4 adverse events in the docetaxel arm when compared with either the gefitinib arm or the gemcitabine arm. CONCLUSION In unselected NSCLC patients with PS 2-3, gefitinib, gemcitabine and docetaxel achieved similar results. Docetaxel was associated with higher rates of adverse events.

Standard combination versus alternating chemotherapy in small cell lung cancer A randomised clinical trial including 394 patients

PURPOSE to compare standard and alternating administration of chemotherapy combinations in small cell lung cancer (SCLC) patients. MATERIAL AND METHODS in a multicenter clinical trial, 394 previously untreated SCLC patients were randomised to receive, every 4 weeks, eight courses of either a standard regimen with CCNU, cyclophosphamide, adriamycin (CCA) and VP16 or an alternating regimen (CCA regimen alternating with cisplatin-vindesine-VP16). RESULTS overall response rate was higher in the standard group (78%) than in the alternating group (64%) (P = 0.0001). Complete response rate was also higher in the standard group (32%) than in the alternating group (18%) (P = 0.004). The median survival in the overall SCLC population was 306 days in the standard group and 272 days in the alternating group (P = 0.08). In limited SCLC patients, median survival was higher in the standard group (421 days) than in the alternating group (328 days) (P = 0.01). Grade III/IV haematological toxicity was lower in patients in the alternating group (25 versus 47%) (P < 0.001). CONCLUSION the standard regimen was better than the alternating regimen for patients with limited forms of SCLC. The alternating regimen, associated with better haematological safety and ensuring a fairly similar survival, may be considered in patients with extensive SCLC. Pleiomorphic resistance mechanisms to chemotherapy make it difficult to define a non-cross-resistant chemotherapy regimen.

Oral second- and third-line lomustine-etoposide-cyclophosphamide chemotherapy for small cell lung cancer.

PURPOSE There is no standard therapy for progressive or recurrent small cell lung cancer (SCLC). Lomustine, etoposide and cyclophosphamide oral chemotherapy were evaluated in a feasibility study of efficacy survival and toxicity. PATIENTS AND METHODS 71 patients were included in this study, 36 in second-line and 35 in third-line chemotherapy. They received lomustine (CCNU) 80 or 120mg on D1 only, etoposide 100mg from D1 until D6 up to D14 and cyclophosphamide 100mg from D1 until D6 up to D14 every 4 weeks. The dosages of CCNU and duration of administration of the other two drugs were adapted to an original therapeutic risk level table on D1 and throughout treatment. Evaluation based on clinical status, response and weekly blood counts was performed before each cycle until progression. RESULTS 70 patients were evaluable. They received between 1 and 20 cycles of treatment (mean=3.7 for second-line and 3.0 for third-line treatment). Complete responses were observed for 3 patients in each line, and partial responses were noted in 13 patients in second-line and 8 patients in third-line, resulting in a total response rate of 27/70=38%. Median-survival time estimated from the start of second- or third-line treatment was the same in the two subgroups: 4.4 months, but the patients in two subgroups presented different clinical characteristics. Haematological toxicity was severe with three toxic deaths as frequently observed in this setting, but hospitalisations were uncommon during this fully oral treatment that provided a very good quality of life for these out-patients. Consumption of health care resources for this low-cost and ambulatory treatment was limited. CONCLUSION The similar efficacy with acceptable safety, the ease of administration in out-patients and the economical advantages justify comparison of this oral chemotherapy with conventional intravenous chemotherapy. A randomised phase II trial is on-going in France for second-line SCLC patients on this theme.