Patients with non-small-cell lung cancer harbouring a BRAF mutation: a multicentre study exploring clinical characteristics, management, and outcomes in a real-life setting: EXPLORE GFPC 02-14.

Background: Mutations in BRAF are rare oncogene mutations, found in 2% of non-small-cell lung cancers (nsclcs). Little information is available about the management of patients with BRAF-mutated nsclc, except for those included in clinical trials. We undertook the present study to assess the clinical characteristics, management, and outcomes of those patients in a real-life setting. Methods: This retrospective multicentre observational study included all patients with BRAF-mutated nsclc diagnosed between January 2012 and December 2014. Results: Patients (n = 59) from 24 centres were included: 57.6% men; mean age: 64.5 ± 14.5 years; 82% with a performance status of 0-1 at diagnosis; smoking status: 40.3% current, 32.6% former; 93% with adenocarcinoma histology; 75% stage iv; 78% with V600E mutations; 2 with EGFR and 2 with ALK co-mutations. Of the stage iv patients, 79% received first-line therapy (14.2% anti-BRAF), and 48% received second-line treatment (23.8% anti-BRAF). Response rate and progression-free survival were, respectively, 51.7% and 8.7 months [95% confidence interval (ci): 6.4 months to 15.2 months] for first-line therapy and 35.3% and 4.1 months (95% ci: 2 months to 10.9 months) for second-line treatments. The 2-year overall survival was 58.5% (95% ci: 45.8% to 74.8%). Outcomes in patients with stage iv nsclc harbouring BRAF V600E mutations (n = 32) did not differ significantly from those of patients with other BRAF mutations. Conclusions: In this real-world analysis, most nsclc patients with a BRAF mutation were men and current or former smokers. Survival appears to be better in these BRAF-mutated patients than in nsclc patients without an oncogenic driver.

[Hypofractionad radiotherapy for elderly with head and neck cancer]. / Radiothérapie hypofractionnée des cancers ORL chez le sujet âgé.

Thirty percent of patients with head and neck cancer are over 70 years. Radiotherapy approach in elderly is a challenge. On one hand, radiotherapy side effects, as well as the number of sessions required, could be a burden. On the other hand, omission of local treatment is not an option due to the symptoms of the tumor. Patients in good general condition may receive standard fractionnated radiotherapy. For frail patients unsuitable for standard fractionated radiotherapy, more convenient shorter course of radiotherapy are commonly used. Physicians have to choose the best radiotherapy schedule according to the objective of the treatment. In case of palliative intend: hypofractionated radiotherapy delivered with a single short course could be recommanded. This course could be followed by other subsequent courses if the patient's condition improves during the treatment. For patients treated in curative intend, the choice of hypofractionation schedule depends on the general condition: split course hypofractionated radiotherapy for unfit patients, or accelerated radiotherapy with concomitant boost for fit patients. In all cases, a high-quality radiotherapy technique and appropriate supportive care are mandatory to minimize the side effects. The ELAN RT trial, soon to be completed, will rule on the non-inferiority of hypofractionated radiotherapy compared to standard radiotherapy for unfit patients.

Classic biphasic pulmonary blastoma: A case report and review of the literature.

Pulmonary blastomas represent about 0.5% of primary pulmonary malignancies. The prognosis is poor. Standard treatment consists of surgical excision. There are no published series on which to judge the efficacy of chemotherapy or radiation therapy. We describe an unusual case of classic biphasic pulmonary blastoma (CBPC), with long-term survival despite numerous and varied cancer-related events and review the literature. Our 71-year-old Caucasian woman presented with history of blood in sputum in 2009. Right lower lobectomy yielded a diagnosis of sarcomatoid carcinoma (pneumoblastoma). Unusually, our patient is still alive 7 years after initial surgery, despite metastatic first relapse after 2 years. Metastatic progression was confirmed histologically on three separate occasions during the disease course. The patient received a combination of cisplatin (or carboplatin) and etoposide on three separate occasions. Molecular biology studies of CBPC are needed to identify effective treatments, and a patient registry should be created.

Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: results from the IFCT-0802 trial†.

BACKGROUND: This randomized phase II-III trial sought to evaluate the efficacy and safety of adding bevacizumab (Bev) following induction chemotherapy (CT) in extensive small-cell lung cancer (SCLC). PATIENTS AND METHODS: Enrolled SCLC patients received two induction cycles of CT. Responders were randomly assigned 1:1 to receive four additional cycles of CT alone or CT plus Bev (7.5 mg/kg), followed by single-agent Bev until progression or unacceptable toxicity. The primary end point was the percentage of patients for whom disease remained controlled (still in response) at the fourth cycle. RESULTS: In total, 147 patients were enrolled. Partial response was observed in 103 patients, 74 of whom were eligible for Bev and randomly assigned to the CT alone group (n = 37) or the CT plus Bev group (n = 37). Response assessment at the end of the fourth cycle showed that disease control did not differ between the two groups (89.2% versus 91.9% of patients remaining responders in CT alone versus CT plus Bev, respectively; Fisher's exact test: P = 1.00). Progression-free survival (PFS) since randomization did not significantly differ, with a median PFS of 5.5 months [95% confidence interval (CI) 4.9% to 6.0%] versus 5.3 months (95% CI 4.8% to 5.8%) in the CT alone and CT plus Bev groups, respectively [hazard ratio (HR) for CT alone: 1.1; 95% CI 0.7% to 1.7%; unadjusted P = 0.82]. Grade ≥2 hypertension and grade ≥3 thrombotic events were observed in 40% and 11% of patients, respectively, in the CT plus Bev group. Serum vascular endothelial growth factor (VEGF) and soluble VEGF receptor titrations failed to identify predictive biomarkers. CONCLUSION: Administering 7.5 mg/kg Bev after induction did not improve outcome in extensive SCLC patients.

Randomized open-label non-comparative multicenter phase II trial of sequential erlotinib and docetaxel versus docetaxel alone in patients with non-small-cell lung cancer after failure of first-line chemotherapy: GFPC 10.02 study.

BACKGROUND: Concomitant administration of erlotinib with standard chemotherapy does not appear to improve survival among patients with non-small-cell lung cancer (NSCLC), but preliminary studies suggest that sequential administration might be effective. OBJECTIVE: To assess the efficacy and tolerability of second-line sequential administration of erlotinib and docetaxel in advanced NSCLC. METHODS: In an open-label phase II trial, patients with advanced NSCLC, EGFR wild-type or unknown, PS 0-2, in whom initial cisplatin-based chemotherapy had failed were randomized to sequential erlotinib 150 mg/d (day 2-16)+docetaxel (75 mg/m(2) d1) (arm ED) or docetaxel (75 mg/m(2) d1) alone (arm D) (21-day cycle). The primary endpoint was the progression-free survival rate at 15 weeks (PFS 15). Secondary endpoints included PFS, overall survival (OS), the overall response rate (ORR) and tolerability. Based on a Simon optimal two-stage design, the ED strategy was rejected if the primary endpoint was below 33/66 patients at the end of the two Simon stages. RESULTS: 147 patients were randomized (median age: 60±8 years, PS 0/1/2: 44/83/20 patients; males: 78%). The ED strategy was rejected, with only 18 of 73 patients achieving PFS15 in arm ED at the end of stage 2 and 17 of 74 patients in arm D. In arms ED and D, respectively, median PFS was 2.2 and 2.5 months and median OS was 6.5 and 8.3 months. CONCLUSION: Sequential erlotinib and docetaxel was not more effective than docetaxel alone as second-line treatment for advanced NSCLC with wild-type or unknown EGFR status.

Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study.

BACKGROUND: The optimal treatment of large-cell neuroendocrine carcinoma (LCNEC) of the lung remains unclear. Here, our primary objective was to assess the efficacy of cisplatin-etoposide doublet chemotherapy in advanced LCNEC. Accuracy of the pathological diagnosis and treatment toxicity were assessed as secondary objectives. PATIENTS AND METHODS: Prospective, multicentre, single-arm, phase II study with a centralised review of treatment-response and pathological data. Patients had untreated performance status (PS) 0/1 stage IV/IIIB LCNEC and received cisplatin (80 mg/m22 d1) and etoposide (100 mg/m22 d1-3) every 21 days. RESULTS: Eighteen centres included 42 patients (mean age, 59 ± 9 years; 69% men; median of four cycles/patient). At least one grade-3/4 toxicity occurred in 59% of patients (neutropaenia, thrombocytopaenia, and anaemia in 32%, 17%, and 12%, respectively). The median progression-free survival (PFS) and overall survival (OS) were 5.2 months (95% confidence interval, CI, 3.1-6.6) and 7.7 months (95% CI, 6.0-9.6), respectively. The centralised pathologist review reclassified 11 of 40 (27.5%) patients: 9 as small-cell lung cancer, 1 as undifferentiated non-small-cell lung cancer, and 1 as atypical carcinoid. Survival data were not significantly changed by excluding the reclassified patients. CONCLUSIONS: The pathological diagnosis of LCNEC is difficult. The outcomes of advanced LCNEC treated with cisplatin-etoposide doublets are poor, similar to those of patients with advanced small-cell lung carcinoma (SCLC).

Experience of multidisciplinary assessment of elderly patients with cancer in a French general hospital during 1 year: a new model care study.

OBJECTIVES: Our main aim was to describe and explore a multidisciplinary approach to the management of elderly patients with cancer, who constitute a heterogeneous population. MATERIALS AND METHODS: This descriptive study was performed between October 2009 and September 2010. Patients with cancer ≥ 70 years of age were included. Some underwent a simplified multidimensional geriatric assessment with a Charlson score administered by an oncologist, and the evaluation was submitted to a geriatrician who decided whether or not a complete a comprehensive geriatric assessment (CGA) (n=54) should be done. Another group of patients directly underwent a CGA (n=49), and a few patients included in a specific trial underwent a geriatric assessment (n=8). Each patient was classified as fit, vulnerable, or frail by a multidisciplinary team. RESULTS: 111 patients were included (median age: 81 years [range: 65-96]; 60 males). The most frequent types of cancer were lung (n=29), gastrointestinal (n=20) and head and neck (n=14). Median Charlson score was 2.1 [range: 0-9]. Standard therapy was given to 37/41 (90%) fit, 19/41 (42%) vulnerable, and 6/29 (21%) frail patients. Thirteen frail patients received best supportive care. A social worker was mobilized for 2/41 (5%) fit, 14/41 (34%) vulnerable, and 11/29 (38%) frail patients. CONCLUSIONS: Our study outlines the possibilities of cooperation between geriatricians and oncologists in a general hospital. This collaboration could modify therapeutic schedules especially in frail and vulnerable patients.

[Comprehensive geriatric assessment and complications after resection for lung cancer]. / Evaluation gériatrique et morbidité après exérèse pulmonaire pour cancer bronchique.

BACKGROUND: With the expanding elderly population comes an increasing prevalence of lung cancer. Surgery remains the mainstay of treatment for early-stage non-small cell lung cancer. Standard treatment strategies have mostly been validated in young adults. Curative resection is feasible in older patients but careful preoperative evaluation is needed, taking into account the physiologic changes that occur with ageing. A tool used by geriatricians, a comprehensive geriatric assessment, can contribute to our understanding of physiologic age through an evaluation of prognostic factors that are independent predictors of morbidity. PATIENTS: Study 08-05 of the French Lung Oncology Group is a prospective, national, multicentre study. All patients aged over 70 years with a suspicion of lung cancer, receiving curative lung resection, will be included. After inclusion, a comprehensive geriatric assessment (evaluating such diverse areas as functional status, nutritional status, cognition, psychological functioning, and social support) will be performed. The primary outcome is the value of the comprehensive geriatric assessment in predicting the risk of post-operative complications after lung resection for cancer. Post-operative morbidity at 30-days after pulmonary resection will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. The follow-up period is one year. EXPECTED RESULTS: This global assessment may help to initiate specific care plans for the management of lung cancer in the elderly.

[Pregnancy and lung cancer: a case report and review of the literature]. / Grossesse et cancer du poumon: à propos d'un cas et revue de la littérature.

Lung cancer is a frequent pathology among women, as a result of tobacco increase. Lung cancer among pregnant women is especially rare when revealed by Pancoast-Tobias syndrome. Foetal injury is possible. The approach is multidisciplinary. Prognosis is bad.

[Randomised phase II study evaluating oral combination chemotherapy (CCNU, cyclophosphamide, etoposide) and intravenous chemotherapy as second-line treatment for relapsed small cell bronchial carcinoma (Trial GFPC0501)]. / Etude de phase 2, randomisée, évaluant une polychimiothérapie orale (CCNU, Cyclophosphamide, étoposide) et une polychimiothérapie intraveineuse dans les cancers bronchiques à petites cellules en seconde ligne en rechute (essai GFPC0501).

BACKGROUND: There is no standard second-line treatment for small cell lung cancer (SCLC). The prognosis of these patients is poor and special attention should be paid to both quality of life and economic factors. METHODS: The aim of this phase II randomised trial (GFPC0501) is to compare, in patients with progressive SCLC after first-line platinum based chemotherapy, oral multi drug chemotherapy (CCNU, cyclophosphamide, etoposide) and classical intravenous chemotherapy with cyclophosphamide, doxorubicin and vincristine (CAV) in terms of tolerability, efficacy (response rate, median one year survival and overall survival), quality of life and consumption of health care resources. Based on a two-stage Bryant and Day approach, this study will require a total of 138 patients with an interim analysis of the first 38. EXPECTED RESULTS: This trial will provide information on several aspects of second-line chemotherapy for patients with SCLC. Thirty six patients have been enrolled in 16 centres by December 2006 and the results of the interim analysis will be available in June 2007.

Randomized multicentric phase II study of carboplatin/gemcitabine and cisplatin/vinorelbine in advanced non-small cell lung cancer GFPC 99-01 study (Groupe français de pneumo-cancérologie).

PURPOSE: To evaluate the efficacy and safety of gemcitabine and carboplatin in the treatment of previously untreated patients with advanced non-small cell lung cancer (NSCLC). METHODS: A randomized phase II study was conducted by the Groupe Français de Pneumo-Cancérologie (GFPC) in 15 centers. The patients were randomized in either arm A (GC): gemcitabine 1250 mg/m2 on days 1 and 8+carboplatin AUC 6 mg/(mLmin) on day 1; or in arm B (VP): vinorelbine 30 mg/m2 weekly+cisplatin 80 mg/m2 on day 1. Treatment cycles were repeated every 3 weeks. RESULTS: A total of 100 patients were randomized with stage IV or stage III NSCLC with malignant pleural effusion: 51 patients in arm A and 49 patients in arm B. A total of 190 cycles were administered in the GC arm and 172 cycles in the VP arm, with a median of four cycles per patient in each arm. The dose intensity was 84.9% for gemcitabine, 99.8% for carboplatin, 97.7% for cisplatin and 67.7% for vinorelbine. The objective response rates were 19.6% (95% CI, 9.8-33.1) for GC and 29.2% (95% CI, 17.0-44.1) for VP in an ITT analysis. The response duration was 169 days in arm A and 226 days in arm B. The TTP was similar with 140 days (GC) and 148 days (VP), respectively. Overall survival rates were 334 days in the GC combination and 304 days in the VP combination. Overall, the treatment was safe and toxicities observed were different in each arm: neutropenia was the most common toxicity in the VP treatment, whereas thrombocytopenia was more frequent in the GC combination. Anemia was similar in both arms. Non-haematologic toxicity was mild. One toxic death in arm A and three toxic deaths in arm B were observed. CONCLUSION: In terms of response rate, the gemcitabine-carboplatin combination was not efficient enough to allow further phase III study. Survival data are in the same range as the standard arm. This chemotherapy is feasible and may represent an alternative to a standard cisplatin-based regimen, allowing treatment in an outpatient setting.

[Non small-cell lung cancer in elderly. Which management?]. / CBNPC et personnes âgées. Quels critères de sélection?

Geriatric oncology has become recognised as a discrete speciality. Although there is a strong evidence base for using chemotherapy in patients with advanced non-small cell lung cancer, cisplatin administration is associated with significant toxicity and the evaluation of the risk benefit ratio should be particularly rigorous in elderly patients. With aging, hepatic metabolism, renal excretion, volume of distribution and albumin concentration decrease and drug concentration increases. To plan treatment for elderly patients, a multidimensional geriatric evaluation including not only performance status and the identification of comorbidities, but also an assessment of creatinine clearance, functional (activities of daily living), mental (mini-mental state evaluation and geriatric depression index) and nutritional status should be undertaken. On the basis of this comprehensive geriatric assessment it should be possible to identify three groups of older cancer patients; fit, vulnerable and frail and thus to propose appropriate treatment. Accepting that the ideal form of geriatric assessment remains to be defined, a comprehensive assessment to allow individualised treatment in elderly patients is mandatory.

Docetaxel and concurrent radiotherapy after two cycles of induction chemotherapy with cisplatin and vinorelbine in patients with locally advanced non-small-cell lung cancer. A phase II trial conducted by the Groupe Francais de Pneumo-Cancerologie (GFPC).

CONTEXT: The most satisfactory treatment for patients with locally advanced non-small-cell lung cancer (NSCLC) is combination chemotherapy-radiotherapy (CT-RT). The optimal treatment modalities remain to be determined. OBJECTIVE: We conducted a multicenter phase II trial of the docetaxel-radiotherapy combination after induction chemotherapy with cisplatin-vinorelbine. The main endpoint was the objective response rate. PATIENTS AND METHODS: Patient with inoperable stage locally advanced NSCLC received induction chemotherapy consisting of two cycles of cisplatin 100 mg/m2 on D1 and vinorelbine 25 mg/m2 on D1, D8, D15 and D22. Patients with responses or stable disease then received concurrent RT-CT consisting of 25 mg/m2/week docetaxel and single-fraction radiotherapy (66 grays (Gy) in 33 fractions) over 6.5 weeks. RESULTS: Fifty-six patients were enrolled from 1 July 2000 to 31 December 2001. Sixteen patients left the trial after induction chemotherapy, eight for progression, five for toxicity, and two for intercurrent events. One patient underwent surgery after induction chemotherapy. In total, 40 of the 56 patients received RT-CT. Twelve (30%) of these 40 patients experienced grade III or IV pulmonary or esophageal toxicity. In the intention-to-treat analysis, the objective response rate was 46.4% (95% CI 33.0-60.2). The median time to progression was 6.2 months [1.1-26.0]. The median survival time was 13 months [0.3-44.9 months]. Nine patients progressed during RT-CT, six with brain metastases. CONCLUSION: Weekly docetaxel with concurrent radiotherapy, following chemotherapy is acceptable. The tumor response rate is moderate. Further trials are required to determine the risk-benefit relationship of this treatment schedule, and the possible benefit of adding other cytotoxic drugs.

Phase II randomized multicenter study evaluating a treatment regimen alternating docetaxel and cisplatin-vinorelbine with a cisplatin-vinorelbine control group in patients with stage IV non-small-cell lung cancer: GFPC 97.01 study.

BACKGROUND: The potential absence of cross-resistance between cisplatin and docetaxel in non-small-cell lung cancer (NSCLC) suggests that alternating regimens of cisplatin-based chemotherapy and docetaxel might increase the activity of chemotherapy in stage IV NSCLC. PATIENTS AND METHODS: Randomized, multicenter, non-comparative phase II study in patients with stage IV NSCLC (Eastern Cooperative Oncology Group performance status of 0-2). Patients randomized to alternating treatment group (A) received docetaxel 100 mg/m2 on days (D) 1 and 43 alternating with cisplatin 100 mg/m2 on D22 and vinorelbine 30 mg/m2 on D22, D29 and D36. Those randomized to the control group (B) received cisplatin 80 mg/m2 on D1, D22 and D43 and vinorelbine 30 mg/m2 once a week from D1 to D57. Treatment was continued for a further 6 weeks in the event of objective response or stabilization. RESULTS: Seventy patients were enrolled (group A: 38, group B: 32). More premature treatment discontinuations due to toxicity were observed in group A (median number of cycles: 3) than in group B (median number of cycles: 5). The intention-to-treat objective response rate was 10.8% [95% confidence interval (CI) 0.8% to 20.8%] in group A compared with 25% (95% CI 10% to 40%) in group B, the median time to treatment failure being 10.2 weeks and 17.3 weeks, respectively. The median survival and 1-year survival were 29.1 weeks and 39% in group A compared with 41.6 weeks and 42% in group B. Febrile neutropenia occurred in 5.9 and 4.9% of the cycles in group A and group B, respectively. Non-hematological toxicity was moderate in the two groups. CONCLUSIONS: The addition of docetaxel alternating with cisplatin-vinorelbine did not enhance the activity of this combination. The development of sequential regimens might be a more promising way of exploiting the absence of cross-resistance between these two drugs.

[Acute bronchospasm due to periwinkle alkaloid and mitomycin association]. / Bronchospasme aigu d à l'association alcaloïde de la pervenche-mitomycine.

We report six cases in which patients presented with acute dyspnoea following injections of either vindesine or vinorelbin. These patients were receiving chemotherapy in association with cisplatin, mitomycin, and vindesine or vinorelbin, for inoperable bronchial cancer. Three of the patients had evidence of airflow obstruction before these incidents. The clinical picture suggested bronchospasm and appeared in the two hours following an injection of the vinca alkaloid and a significant time away from the administration of the mitomycin. Additional respiratory support was necessary in one patient, the bronchial spasm stopped spontaneously in three cases, and following bronchodilator in two. The respiratory toxicity of vinca alkaloids (vindesine, vinblastin) was observed in 4% of the cases, uniquely when they were associated with mitomycin. Vinorelbin seems to possess the same respiratory toxicity. The bronchospasm, sometimes very severe, seems to occur in the two hours following the injection in the case of the cytotoxics and some time after the administration of mitomycin. The recurrence of the bronchospasm is a constant feature when the vinca alkaloid is readministered. This side effect is different to the pulmonary fibrosis due to mitomycin. Clinical follow up and spirometry is thus necessary in those patients receiving chemotherapy in which vinca alkaloids and mitomycin are associated and the regime should be followed after each administration of a vinca derivative. After the first episode of dyspnoea, it is probably wise to stop the administration of these anti-mitotics to prevent any further respiratory side-effects which could be more severe.

[Contribution of pulmonary gallium scintigraphy to the diagnosis of pulmonary tuberculosis]. / Contribution de la scintigraphie pulmonaire au gallium dans le diagnostic de la tuberculose pulmonaire.

Radioisotope scanning of the lungs with gallium 67 was performed in 13 patients whose radiological images were suggestive of pulmonary tuberculosis. The purpose of the study was to assess the value of that method as a complement to bacteriology in active pulmonary tuberculosis. Provided the lung tissue is not totally destroyed, gallium 67 is strongly taken up by the tuberculous lesions. However, scanning cannot be regarded as a routine examination, as it is costly and delivers a non-negligible dose of radiations. All it can do is to serve as a guide for more invasive investigations.