Molecular follow-up of first-line treatment by osimertinib in lung cancer: Importance of using appropriate tools for detecting EGFR resistance mutation C797S.

The C797S mutation encoded by EGFR exon 20 is classically observed as a tertiary event in EGFR-mutant non-small-cell lung carcinoma (NSCLC) primarily treated by first generation tyrosine kinase inhibitors (TKI) and secondarily treated by third-generation TKI, such as osimertinib, if the EGFR-T790M resistance mutation is detected. Recently, significant prolonged progression free survival has been observed following first-line osimertinib, in EGFR-mutant NSLC. While mechanisms of molecular resistance to first-generation TKI have been well studied, little is known about resistance induced by primary third-generation TKI treatments. We report the case of a 65 year-old female treated by first-line osimertinib for a multimetastatic exon 19-EGFR-mutant NSCLC. EGFR-C797S resistance mutation and PIK3CA mutation were detected together with the remaining EGFR-exon 19 deletion. This observation provides insights of acquired resistance to first line-osimertinib. It also highlights the importance of making molecular platforms which perform routine EGFR testing in lung cancer aware of the kind of therapeutic protocols given to the patient. Indeed, for rapid results or low-costs procedures, some targeted methods specifically targeting T790M may be used at relapse and may overlook alterations such as C797S or PIK3CA mutations. Targeted next generation sequencing is therefore a recommended option.

[An unusual development following anti-tuberculous treatment: Obstructive inflammatory granuloma]. / Une séquelle peu fréquente après traitement antituberculeux : l'obstruction granulomateuse inflammatoire.

Tuberculosis is a disease that is still a too frequent. Its treatment depends on prolonged, multi-antibiotic, chemotherapy. Progress following treatment is generally good but there is the possibility of parenchymatous or pleural sequelae such as bronchial stenosis due to post tuberculous bronchial fibrosis or bronchiolithiasis. On the other hand, bronchial obstruction after treatment by an inflammatory granuloma is rare. It causes wheezing dyspnoea. In this case, relapse of the tuberculosis was feared, possibly with the development of multi-drug resistance. Treatment with corticosteroids allowed a rapid improvement.

Pazopanib or placebo in completely resected stage I NSCLC patients: results of the phase II IFCT-0703 trial.

BACKGROUND: Adjuvant treatment in resected stage I non-small-cell lung cancer (NSCLC) is generally not recommended. Pazopanib is an oral tyrosine kinase inhibitor of VEGFR-1/2/3 and PDGFR-α/ß. We explored the feasibility and efficacy of adjuvant pazopanib in this population. PATIENTS AND METHODS: In this double-blind phase II/III trial, patients with resected stage I NSCLC were randomized to placebo or pazopanib 800 mg/day (P800) for 6 months with a two-step Fleming design. The primary endpoint was compliance (percentage of patients receiving ≥3 months pazopanib). From the interim analysis after 64 patients were included, the IDMC recommended reducing to pazopanib 400 mg/day (P400) due to insufficient compliance, with a one-step Fleming. Although unplanned, survival data were analyzed. RESULTS: A total of 71 patients were enrolled in each arm; 61% were male, 91% were smokers, median age was 60 years, 80% had pathological stage IA, and 16% had squamous cell carcinoma. Pazopanib compliance was 38% [95% confidence interval (CI) 23-55] with P800, increasing to 69% (95% CI 50-84; P = 0.027) with P400. Two patients had grade 4 toxicities with P800. The most common grade 3 toxicities were increased transaminases (16%), hypertension (13%), and diarrhea (9%) with P800, and gastrointestinal disorders (16%; 6% diarrhea) and hypertension (6%) with P400. Median follow-up was 47 months. Three-year recurrence-free survival was 76% (95% CI 65%-86%) with pazopanib and 83% (95% CI 74%-92%) with placebo [hazard ratio = 1.3 (95% CI 0.6-2.7), P = 0.53]. Five-year overall survival was 83% (95% CI 72-94) with pazopanib and 94% [95% CI 88-100] with placebo [hazard ratio = 1.8 (95% CI 0.6-5.5), P = 0.26]. CONCLUSIONS: In resected stage I NSCLC patients adjuvant 400 mg/day pazopanib but not 800 mg/day was feasible, although possibly infra-therapeutic and failed to improve relapse-free survival.

Management of malignant pleural mesothelioma: a French multicenter retrospective study (GFPC 0802 study).

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare disease with poor prognosis in spite of significant improvement in survival, due to new chemotherapy regimens. We describe here patients' profiles and management in daily practice in France. METHODS: Observational retrospective study. Data were collected from medical files. All patients with histologically proven MPM diagnosed from January 2005 to December 2008 were included in the participating sites. RESULTS: Four hundred and six patients were included in 37 sites: mean age 68.9 ± 9.8 years, male predominance (sex ratio 3.27), latency of the disease 45.7 years, epithelioïd type 83 %. Diagnosis was made using thoracoscopy in 80.8 % of patients. Radical surgery was performed in 6.2 % of cases. Chemotherapy was administered to 74.6 % of patients. First line regimens consisted mainly of platinum + pemetrexed (91 %) or pemetrexed alone (7 %). Objective response rate was 17.2 % and another 41.6 % of patients experienced disease stabilization. Half of these patients underwent second line chemotherapy (platinium + pemetrexed 31.6 %, pemetrexed alone 24.6 %), resulting in a 6 % response rate. Third-line chemotherapy (56 patients) yielded disease control in 5.4 % of cases. CONCLUSIONS: The management of MPM in France is usually in accordance with guidelines. Response rates are somewhat lower than those described in clinical trials.

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.

[Evaluation of preoperative non-invasive ventilation in thoracic surgery for lung cancer: the preOVNI study GFPC 12-01]. / Évaluation de la ventilation non invasive préopératoire avant chirurgie de résection pulmonaire. Étude préOVNI GFPC 12-01.

BACKGROUND: Surgical resection is the best treatment for stage I and II non-small cell lung cancer. Despite an improvement in the perioperative management of cancer patients and specialization of surgical teams, morbidity and mortality remains significant. Non-invasive ventilation (NIV) is an effective therapeutic option in hypercapnic respiratory failure. It also improves functional and gasometric parameters when undertaken before surgery. The objective of the preOVNI study is to demonstrate that preoperative non-invasive ventilation for 7 days, at home, reduces the postoperative respiratory and cardiovascular complications of lung resection surgery, in a high-risk population. METHODS: A prospective, randomized, controlled open-labelled multicentric French study, under the supervision of the Groupe Français de Pneumocancérologie (GFPC), comparing 7 days of preoperative non-invasive ventilation with standard treatment. Inclusion criteria are: patients suitable for lobectomy or segmentectomy for primary bronchial carcinoma and presenting with obstructive or restrictive lung disease, obesity or chronic cardiac insufficiency. The primary criterion is a composite one, including all respiratory and cardiac complications. The number of patients is 150 in each treatment arm, 300 in total. EXPECTED RESULTS: We think that preoperative NIV will be able to reduce the rate of postoperative complications. If this objective is achieved, the management of these patients could be changed.

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).

[Long-term fever after gastric banding]. / Fièvre au long cours et anneau gastrique.

We report a 65-year-old male, suffering from aspiration pneumonia after gastric banding revealed by intermittent fever inducing a delayed diagnosis. Several early and later pulmonary complications following laparoscopic gastric banding have been reported. Removal or deflation of the band should be considered in unexplained persistent fever to avoid more severe complications such as respiratory distress.

A multicenter phase II randomized trial of gemcitabine followed by erlotinib at progression, versus the reverse sequence, in vulnerable elderly patients with advanced non small-cell lung cancer selected with a comprehensive geriatric assessment (the GFPC 0505 study).

BACKGROUND: The aim of this randomized phase II trial was to evaluate the feasibility and activity of weekly gemcitabine (G) followed by erlotinib at disease progression (arm A) versus erlotinib followed by G at progression (arm B) in vulnerable elderly patients with advanced non small-cell lung cancer (NSCLC), selected on the basis of a comprehensive geriatric assessment (CGA). METHODS: Vulnerable elderly chemotherapy-naive patients with stage IIIB/IV NSCLC were selected after a CGA (socioeconomic, cognitive and emotional status, depression, nutritional status, ADL and IADL assessments). The primary endpoint was the time to second progression (TTP2). Overall survival (OS), time to first progression (TTP1) and safety were secondary endpoints. RESULTS: Between May 2006 and January 2010, 21 centers enrolled 100 patients, of whom 94 were eligible. TTP2 was 4.3 and 3.5 months in arm A and arm B, respectively; TTP1 was 2.5 and 2.2 months; and the median OS time was 4.4 and 3.9 months. The respective one-year survival rates were 27.3% and 20%. There was no major unexpected toxicity. CONCLUSION: In vulnerable elderly patients with NSCLC not selected for EGFR expression, both strategies were feasible but had modest efficacy. Further studies are needed to identify elderly patients who should receive palliative care only.

Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01).

BACKGROUND: Brain metastases (BM) occur in up to 40% of non-small-cell lung cancer (NSCLC) patients. This trial assessed the safety and efficacy of pemetrexed-cisplatin in this population. PATIENTS AND METHODS: Chemonaive NSCLC patients with BM ineligible for (radio)surgery, performance status (PS) of 0 to 2, were eligible for up to six cycles of cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) every 3 weeks. Whole -brain radiotherapy was given in case of disease progression or at chemotherapy completion. Primary end point was objective response rate (RR) on BM. Secondary end points included extracerebral and overall RR, safety profile and survival. RESULTS: Forty-three patients were enrolled. Initial characteristics were mean age 60.4 years; males 29; PS: 0 in 37.2%, 1 in 60.5% and 2 in 22.3% of patients; adenocarcinoma in 36 patients, large cell in 4 patients (nonsquamous, 93%) and squamous carcinoma in 3 patients. Functional classification of neurological status was stage I/II 86.0%, III 2.3% and IV 11.6%. Grade 3-4 hematological toxic effects were neutropenia, 11 patients (febrile neutropenia, 1 patient), and anemia, 6 patients. Non-hematological toxic effects were grade 2 urinary infection, one patient; grade 3 pneumonia, two patients; and grade 3 hypoacousia, one patient. Cerebral, extracerebral and overall RR by intent to treat analysis were 41.9%, 34.9% and 34.9%, respectively. Median survival time and time to progression were 7.4 and 4.0 months, respectively. CONCLUSION: Pemetrexed-cisplatin is an effective and well-tolerated regimen as first-line therapy for NSCLC patients with BM who always suffer a poor prognosis.

[A severe side effect of antitubercular therapy: pyrazinamide induced thrombocytopenia]. / Un effet indésirable grave du traitement antituberculeux: la thrombopénie au pyrazinamide.

The haematological side effects of antitubercular drugs are not well known. We report the observation of a patient who received Rifater for the treatment of pulmonary tuberculosis. After one month of treatment, he developed an acute pulmonary infection, with neutropenia (1218/microl) and thrombocytopenia (109,000/microl), requiring suspension of his antitubercular drugs. After the reintroduction of he again developed thrombocytopenia (6,000/microl) associated with bleeding and required treatment with intravenous immunoglobulin. The introduction of a combination of moxifloxacin, isoniazid, pyrazinamide, and ethambutol was followed by a new relapse of the thrombocytopenia. Responsibility of pyrazinamide was then suspected and later confirmed by the evolution of platelet levels after stopping and reintroducing this antibiotic. This is the third reported case of pyrazinamide induced thrombocytopenia, whose frequency is probably underestimated because of the use of compound treatment.

Phase II trial of temozolomide and cisplatin followed by whole brain radiotherapy in non-small-cell lung cancer patients with brain metastases: a GLOT-GFPC study.

BACKGROUND: Brain metastases (BM) considerably worsen the prognosis of non-small-cell lung cancer (NSCLC) patients. The usefulness and choice of chemotherapy remain uncertain in this indication since these patients are excluded from most clinical trials. We conducted a phase II study to determine the efficacy and tolerability of up-front chemotherapy with association of temozolomide and cisplatin in NSCLC patients with BM. PATIENTS AND METHODS: Fifty NSCLC patients with BM received temozolomide (200 mg/m(2)/day for 5 days every 28 days) and cisplatin (75 mg/m(2) at day 1 of each cycle), up to six cycles, followed by whole brain radiotherapy (WBRT). An evaluation was carried out every two cycles and after WBRT. WBRT was performed earlier in case of progressive disease at any time or stable disease after cycle 4. RESULTS: Eight objective responses were achieved (16%). Overall median survival was 5 months. Median time to progression was 2.3 months. Ten patients (20%) presented a grade 3/4 neutropenia and 11 patients (22%) presented a grade 3/4 thrombopenia. CONCLUSION: This study demonstrates a lack of efficacy of up-front chemotherapy with association of temozolomide and cisplatin in these patients. Nevertheless, it supports the feasibility of chemotherapy before brain radiotherapy in NSCLC patients with BM.

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.

[Immunodepression and pulmonary infections]. / Immunodépression et infections pulmonaires.

The acquired immunosuppressed states are increasingly numerous. Pneumopathies are a frequent, serious complication and etiologic diagnosis is often difficult. The nature of the micro-organism in question is a function of the immunizing type of deficiency. In neutropenias, the infections are primarily bacterial, their potential gravity being correlated with the depth of the deficiency into polynuclear, or fungic, especially in prolonged neutropenias. The aspleened states are responsible for a deficit of the macrophage system and contribute to the infections with encapsulated germs (pneumococci, klebsiellas...). The organic grafts imply an attack of cell-mediated immunity, in the particular case of the auxiliary T lymphocytes (CD4)), with a special predisposition for viral and fungic infections. During VIH infection, the immunizing deficit of CD4 lymphocytes worsens with time. At the early stage, the infections are especially bacterial. At the more advanced stages, the pulmonary pneumocystosis and tuberculosis dominate. At the late stage, finally, deep immunosuppression allows emerging of the atypical mycobacteries. In the deficiencies of humoral immunity (congenital hypogammaglobulinemias, lymphoid hemopathies B), the germs to be mentioned are the pneumococcus, Haemophilus influenzae, the salmonellas and the legionellas. Immunosuppressed pneumopathies are characterized by radio-clinical pictures of very variable gravity, ranging from focused acute pneumopathy to bilateral diffuse pneumopathy with acute respiratory distress syndrome, with phases of atypical tables with respiratory symptomatology larval or absent. The highlighting of the micro-organisms in question requires urgent complementary investigations: hemocultures, bronchiolo-alveolar washing. In certain cases, it will be possible to resort to the transtracheal puncture or transthoracic puncture guided by tomodensitometry, and if necessary to pulmonary biopsy under videothoracoscopy. Emergency of the anti-infectious treatment imposes, in general, a presumptive treatment directed according to the immunizing deficiency in question and etiologic suspicion. It will be associated, if necessary, with urgent measurements of respiratory intensive care.

[Disseminated histoplasmosis caused by Histoplasma capsulatum with cerebral involvement occurring 13 years after the primary infection]. / Histoplasmose disséminée à Histoplasma capsulatum avec atteinte cérébrale survenue 13 ans après la primo-infection.

A 49-year-old man with disseminated histoplasmosis (pulmonary and central nervous system involvement) successfully treated with ketoconazole and fluconazole combination is reported. Histoplasma capsulatum infection of the central nervous system is extremely rare in France partly because the organism is not endemic. Oral treatment with newer triazoles may be useful for central nervous system histoplasmosis, but additional information is needed to establish their effectiveness.

[Cyclophosphamide-induced interstitial pneumopathy. Course data of bronchoalveolar lavage apropos of a case and review of the literature]. / Pneumopathie interstitielle liée au cyclophosphamide. Données évolutives du lavage broncho-alvéolaire à propos d'un cas et revue de la littérature.

A patient treated with cyclophosphamide for breast cancer developed functional and clinicoradiological signs of sub-acute diffuse interstitial pneumopathy. Bronchoalveolar lavage revealed lymphocyte alveolitis. Differential diagnoses were excluded and the course was favorable after cyclophosphamide withdrawal. The bronchoalveolar lavage results obtained initially and at follow-up and two previous lavages reported in the literature demonstrate the importance of this examination in the diagnosis of drug-induced pneumopathy.