Pascale Jacoulet

Third-Line Chemotherapy in Advanced Non-small Cell Lung Cancer: Identifying the Candidates for Routine Practice

Background: The interest of first- and second-line treatments in non-small cell lung cancer (NSCLC) has been demonstrated by successive randomized trials. Improvements in lung cancer care have routinely allowed a significant proportion of patients to be considered for third-line treatment. Methods: A retrospective analysis was performed, including all consecutive patients with advanced NSCLC, who received at least three lines of systemic antineoplastic treatment at our institution. Results: From a population of 613 patients treated with first-line treatment, a total of 173 patients received third-line treatment (cytotoxic chemotherapy in 131 patients; epidermal growth factor (EGFR) tyrosine kinase inhibitors in 42 patients). Only 13 patients (8%) received less than 75% of the theoretical dose intensity; 22 patients (13%) presented with severe toxicities. Symptom relief and performance status (PS) improvement were observed in 121 (92% of the 131 patients with symptoms) and 90 patients (52%), respectively. Using multivariate analysis, survival after third-line treatment was significantly increased in patients younger than 70 years-old (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.53–0.99, p = 0.047), who smoked less than 10 pack-years (HR = 0.82, 95% CI: 0.57–0.93, p = 0.036), with no cancer-related symptoms (HR = 0.75, 95% CI: 0.61–0.92, p = 0.007), a weight loss inferior to 5 kg since the beginning of second-line (HR = 0.63, 95% CI: 0.52–0.75, p = 0.013), a PS 0 to 1 (HR = 0.81, 95% CI: 0.76–0.86, p = 0.008), and no extrathoracic tumor spread at initiation of third-line treatment (HR = 0.67, 95% CI: 0.47–0.94, p = 0.042). Disease control after both first- and second-line treatments was the strongest predictor of prolonged survival after third-line treatment (HR = 0.47, 95% CI: 0.33–0.67, p = 0.001). Conclusions: Patients with advanced NSCLC may benefit from third-line treatment. The best candidates can be identified using standard prognostic factors, such as PS, and disease control after first- and second-line treatments.

Summary report of the Standards, Options and Recommendations for the management of patients with non-small-cell lung carcinoma (2000)

In France, primary lung cancer (all types combined) is the leading cause of cancer mortality in men, and the third in women, after breast and colorectal cancer. In 1995, lung cancer was responsible for 23.5% of cancer deaths in men and 6.4% in women. The incidence of lung cancer is higher in men than in women, and the mortality rate is nine times higher in men than in women. The lung cancer mortality rate is constantly increasing in France, particularly in the north of the country. The increase in incidence between 1975 and 1995 was more marked in women. In France, the 5-year survival rates (11.5% for men and 16% for women) are among the highest in Europe.

Phase I study of vinorelbine and carboplatin in advanced non-small cell lung cancer

Thirty-one patients with previously untreated advanced non-small cell lung cancer were included in a Phase I study to determine the optimal dose of Carboplatin (CBDCA) which preserves the best Navelbine (NVB) dose-intensity. NVB was administered at a 30-mg/m2 fixed-dose on days 1-8/q 3 weeks, whereas CBDCA doses were planned to be escalated from 275 to 400 mg/m2 on day 1/q 3 weeks for six successive groups of patients. The toxicity limiting dose of CBDCA in the combination was 350 mg/m2 on day 1/q 3 weeks because of repetitive Grade IV neutropenia, and the optimal dose of CBDCA was 325 mg/m2 on day 1/q3 weeks, offering a 86.4% NVB and a 92.6% CBDCA relative dose-intensity for the first 9 weeks. Responses were observed at each step. This study demonstrates the feasibility and the efficacy of the NVB-CBDCA combination. It suggests that dose-intensity calculation can be helpful to determine the recommended dose for Phase II studies of new drug combinations.

Concurrent cisplatin/etoposide chemotherapy plus twice daily thoracic radiotherapy in limited stage small cell lung cancer: a phase II study

Thirty-one previously untreated patients with limited stage small-cell lung cancer (LSCLC) were included in a prospective study, to investigate the feasability and the efficacy of a combined modality treatment using concurrent hyperfractionated chest irradiation and cisplatin (P) plus etoposide (E) chemotherapy. All patients received intravenously P=75 mg/m(2) at day 1, plus E=120 mg/m(2) days 1-3, at 3-week intervals for six cycles. Irradiated patients received 45 Gy in two daily fractions, 5 days a week, from week 4 to week 6. During week 5, prophylactic cranial irradiation was initiated, in one daily fraction of 2.5 Gy for a total dose of 25 Gy. Twenty-nine patients were evaluable for response. Twenty-two (76%) achieved a complete response, five (17%) had a partial response. Five patients are currently alive. The overall response rate was 93% (CI 95% (83.7-100)). The median survival time was 14 months and the 2-year survival rate was 25%. Main toxicities were grade 3-4 esophagitis in half of the patients and myelosuppression. The results are not as optimistic as other studies using a similar regimen.

Phase I study of paclitaxel (Taxol) plus vinorelbine (Navelbine) in patients with untreated stage IIIb and IV non-small cell lung cancer.

A dose escalation study of paclitaxel in combination with vinorelbine was conducted in 21 patients with previously untreated stage IIIb or IV non-small cell lung cancer (NSCLC). All three patients treated with the initial dose of paclitaxel 135 mg/m(2) administered as a 1-h intravenous infusion and vinorelbine 25 mg/m(2) experienced dose-limiting toxicity (febrile neutropenia). After modification of the dosing schedule, the MTD of paclitaxel was found to be 115 mg/m(2) when combined with vinorelbine 20 mg/m(2) on day 1, followed by vinorelbine 20 mg/m(2) on day 5. Partial responses were achieved in 24% of patients, with a median duration of response of 126 days (range from 84 to 484 days) and a 1-year survival rate of 42%. In conclusion, haematologic toxicity (febrile neutropenia/neutropenia) severely restricts the dosing schedule of combined paclitaxel and vinorelbine, and possibly limits anti-tumour efficacy.

Phase II study of alternating doses of vinorelbine in combination with cisplatin for non-small cell lung cancer (NSCLC): a disappointing experience

UNLABELLED In both Phase III trials of vinorelbine-cisplatin (VP) versus single-agent vinorelbine, the received vinorelbine dose intensities were 18.8 and 21.1 mg/m2 per week in the VP arms. Vinorelbine was administered at the weekly dose of 30 mg/m2. A new structure of the vinorelbine-cisplatin regimen delivering alternating doses of vinorelbine (35 mg/m2 on weeks 1, 3, 5 and 17.5 mg/m2 on weeks 2 and 4) was reported to increase the vinorelbine dose intensity in patients with non-small cell lung cancer (NSCLC). To further analyze the ability of such an alternating vinorelbine schedule to enhance vinorelbine delivery, a Phase II study of VP was conducted in NSCLC patients using the previously published alternating doses of vinorelbine for 6 cycles. Cisplatin was administered on weeks 1, 5 and every 6 weeks thereafter, at a dose of 75 mg/m2 in the first 14 patients and at a dose of 100 mg/m2 in the 18 remaining patients. The intended vinorelbine dose intensity was 26.25 mg/m2 per week. The median delivered dose intensities of vinorelbine calculated during the first 8-week period were: all patients, 17.9 mg/m2 per week; patients treated with cisplatin 75 mg/m2, 18.1 mg/m2 per week; patients receiving cisplatin 100 mg/m2, 17.9 mg/m2 per week; naive patients 18.2 mg/m2 per week and previously treated patients. 13.2 mg/m2 per week. Reductions and delays in the vinorelbine treatment mostly occurred on weeks 3 and 7, which are times of high-dose treatments (35 mg/m2) according to the protocol. The partial response rate was 34% (95% C.I. = 26-42%). Median survival was 21 weeks. The main toxicities were febrile neutropenia (nine patients, including two septic deaths) and constipation Grades 3 and 4 (five patients). CONCLUSION The use of alternating doses of vinorelbine within the VP regimen did not lead to higher vinorelbine delivered dose intensities than those reported with a standard weekly 30 mg/m2 administration.

Infection pulmonaire à Mycobacterium malmoense compliquée d'un aspergillome

Summary A 49 year old man was medically treated, first in 1986 and then in 1988, for atypical primary pulmonary infection caused by Mycobacterium malmoense. Since no clinical or bacteriological improvement of both smear and culture was observed, upper right bilobectomy was performed in december 1988. Oral treatment with rifabutin, clofazimine, ethambutol and isoniazid was clinically and bacteriologically successful in May 1989. In 1990, Aspergillus flavus infection developed in a sequeleae cavity located in the posterior segment of the upper left lobe. To our knowledge the Mycobacterium malmoense-Aspergillus flavus association has not yet been described.

Immunoprevalence and magnitude of HLA-DP4 versus HLA-DR-restricted spontaneous CD4+ Th1 responses against telomerase in cancer patients

ABSTRACT Cumulative evidence supports that CD4+ Th1 cells play a key role in antitumor immunity. We previously reported the presence of spontaneous HLA-DR-restricted CD4+ Th1 responses against telomerase reverse transcriptase (TERT) in various cancers by using promiscuous HLA-DR epitopes. Here, we described novel highly immunogenic HLA-DP4-binding epitopes from TERT named TERT541–555, TERT573–587, TERT613–627 and TERT911–925 and addressed the question about the immunoprevalence and magnitude of the naturally occurring antitumor CD4+ T cell responses restricted by HLA-DP4 or HLA-DR, the two most common HLA class II. Direct comparative study of spontaneous anti-TERT CD4+ T cell responses in a cohort of 87 lung cancer patients showed that HLA-DP4 and HLA-DR sustained specific Th1 responses in 10.1% and 25.2% of cancer patients respectively (p = 0.01). The magnitude of the HLA-DR-restricted responses was two to three times significantly higher than HLA-DP one (p = 0.005). Similar results were found in other cancers such as melanoma, breast cancer, renal cell carcinoma and colon cancer. Thus, our results describe for the first time in a large cohort of cancer patients a high immunoprevalence of HLA-DR-restricted spontaneous anti-TERT Th1 immunity compared to HLA-DP restriction. These results provide a new tool for comprehensive monitoring of antitumor CD4+ Th1 response in various cancers.