IFCT-1502 CLINIVO: real-world evidence of long-term survival with nivolumab in a nationwide cohort of patients with advanced non-small-cell lung cancer.

BACKGROUND: Immunotherapy using inhibitors targeting immune checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) is currently the standard of care in patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We carried out a nationwide cohort retrospective study of consecutive patients with advanced, refractory NSCLC who received nivolumab as second to later lines of treatment as part of the expanded access program. Key objectives were to assess the efficacy and safety of nivolumab and the efficacy of first post-nivolumab treatment. RESULTS: Nine hundred and two patients were enrolled: 317 (35%) with squamous cell carcinoma and 585 (65%) with non-squamous cell carcinoma. Median age was 64 years; there were 630 (70%) men, 795 (88%) smokers, 723 (81%) patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0/1, 197 (22%) patients with brain metastases, and 212 (27%) with liver metastases. Best response was partial response for 16.2% and stable disease (SD) for 30.5%. Progression-free survival and overall survival (OS) rates at 2, 3, and 5 years were 8% and 25%, 6% and 16%, and 4% and 10%, respectively. At multivariate analysis, ECOG PS ≥2 [hazard ratio (HR) = 2.13, 95% confidence interval (95% CI) 1.78-2.55, P < 0.001], squamous histology (HR = 1.17, 95% CI 1.01-1.36, P = 0.04), and presence of central nervous system metastases (HR = 1.29, 95% CI 1.08-1.54, P = 0.005) were significantly associated with lower OS. Four hundred and ninety-two patients received at least one treatment after discontinuation of nivolumab, consisting of systemic therapies in 450 (91%). Radiation therapy was delivered to 118 (24%) patients. CONCLUSION: The CLINIVO cohort represents the largest real-world evidence cohort with the use of immune checkpoint inhibitor in advanced, metastatic NSCLC after failure of first-line chemotherapy, with long-term follow-up and analysis of subsequent therapies. Our data confirm the efficacy of nivolumab in a cohort larger than that reported in landmark clinical trials and identify prognostic factors, which reinforces the need for accurate selection of patients for treatment with immune checkpoint inhibitors. Our data indicate that oligoprogression is frequent after nivolumab exposure and provide a unique insight into the long-term survival.

Radiation-induced lung toxicity predictors: Retrospective analysis of 90 patients treated with stereotactic body radiation therapy for stage I non-small-cell lung carcinoma.

BACKGROUND: The main complication after hypofractionated radiotherapy for lung carcinoma is radiation-induced lung toxicity, which can be divided into radiation pneumonitis (acute toxicity, occurring within 6 months) and lung fibrosis (late toxicity, occurring after 6 months). The literature describes several predictive factors related to the patient, to the tumor (volume, central location), to the dosimetry and to biological factors. MATERIALS AND METHODS: This study is a retrospective analysis of 90 patients treated with stereotactic body irradiation for stage I non-small-cell lung carcinoma between December 2010 and May 2015. RESULTS: Radiation pneumonitis was observed in 61.5% of the patients who were mainly asymptomatic (34%). Chronic obstructive pulmonary disease was not predictive of radiation pneumonitis, whereas active smoking was protective. Centrally located tumors were not more likely to result in this complication if the radiation schedule utilized adapted fractionation. In our study, no predictive factor was identified. Whereas the mean lung dose was a predictive factor in 3D radiotherapy, the lung volume irradiated at high doses seemed to be involved in the pathogenesis after hypofractionated radiotherapy. CONCLUSION: The discovery of predictive factors for radiation pneumonitis is difficult due to the rarity of this complication, especially with an 8×7.5Gy schedule. Radiation pneumonitis seems to be correlated with the volume irradiated at high doses, which is in contrast to the known knowledge about the organs in parallel. This finding leads us to raise the hypothesis that vessel damage, organs in series, occurring during hypofractionated radiotherapy could be responsible for this toxicity.

[Vaccines for the treatment of non-small cell lung cancer]. / Les thérapies vaccinales dans le cancer bronchique.

Antigen-specific immunotherapy also known as cancer vaccination offers a novel approach for the treatment of non-small cell lung cancer patients. It relies on specific priming of the immune system in order to provoke or increase adaptive antitumor immune response against the vaccine component. Several molecules have been developed in lung cancer, based on whole-tumor cells, dendritic cells, peptides, recombinant proteins, or viral vectors. The aim of this review is to describe the mechanism of action of these vaccines and the results of the main clinical studies.

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. / Réponse prolongée sous paclitaxel après immunothérapie par pembrolizumab dans le cancer bronchique.

INTRODUCTION: Pembrolizumab, a humanized monoclonal antibody IgG4 anti-PD-1, having offered promising results in patients suffering from non-small cell lung cancer metastatic and heavily pretreated. OBSERVATION: We report here the case of an unexpected good response after pembrolizumab failure obtained with paclitaxel in a 68-year-old patient with stage IV lung adenocarcinoma. Moreover, the response duration with paclitaxel was more than fourteen months. CONCLUSION: Our case suggests a mutual potentiation of chemotherapy and immunotherapy, and raises the issue of the treatment sequence to favor.

Oral single-agent chemotherapy in older patients with solid tumours: A position paper from the International Society of Geriatric Oncology (SIOG).

Compared with intravenous (i.v.) chemotherapy, oral administration is convenient, requires fewer healthcare resources, is generally preferred by patients, and may be appropriate in older people with breast, colorectal and lung cancers. The effects of organ dysfunction on drug metabolism and drug interactions in patients with multiple comorbidities must be considered but are not specific to oral chemotherapy. Single-agent oral chemotherapy with capecitabine or vinorelbine is active in older patients with advanced or metastatic breast cancer. Choice of treatment is based mainly on different safety profiles. In the adjuvant treatment of colorectal cancer (CRC), single-agent oral capecitabine is an effective alternative to i.v. fluorouracil (5-FU) regimens. In metastatic CRC, oral, single-agent capecitabine has recently shown encouraging median overall survival in combination with bevacizumab. In non-small cell lung cancer, fit older patients, like their younger counterparts, benefit from platinum-based doublets, with carboplatin preferred to cisplatin. Single agent vinorelbine is an option for those less suited to combination chemotherapy, and oral may be an alternative to i.v. administration. For elderly cancer patients in general, metronomic chemotherapy combines good tolerability with acceptable activity.

[Safety culture assessment in a university pulmonary medicine department]. / Mesure de la culture de sécurité des soins dans un service universitaire de pneumologie.

INTRODUCTION: Improvement in treatment safety is a major issue in Western healthcare systems, with the aim of reducing the number of treatment associated undesirable events. The safety culture, defined as an integrated and coherent collection of individual and organizational behavior that seeks continuously to reduce harm to patients, possibly related to treatment, could fulfill this aim. METHODS: We have used an adaption of the American "Hospital Survey on Patient Safety" questionnaire (HSOPSC), which examines professionals' perception of treatment safety, to assess the safety culture in our respiratory medicine service in the Strasbourg University Hospital. RESULTS: Of the 110 questionnaires distributed to the service personnel, 93 were returned (85 %). The level of treatment safety was judged "acceptable" for 56 % of the personnel, "very good" for 32 %, against "weak" or "failing" for 10 %. Of the 10 dimensions explored, 8 were considered to need improvement and 2 had a level of positive responses greater than 50 %. CONCLUSIONS: Treatment safety culture seems to be an area to develop in our service. A strong safety culture should allow health care professionals to adhere better to treatment safety mechanisms.

[Stereotactic body radiation radiotherapy for oligometastatic non-small cell lung cancer (NSCLC): A case report]. / Radiothérapie exclusive curative chez un patient atteint d'un carcinome bronchique non à petites cellules de stade IV oligométastatique : cas clinique et revue de la littérature.

Metastatic non-small cell lung cancer is associated with a poor prognosis, and palliative chemotherapy is the mainstay of treatment. However, long-time survival has been observed in oligometastatic patients treated with locally ablative therapies to all sites of metastatic disease. An 80-year-old man was diagnosed with an adenocarcinoma of the lung. The right upper lobe lesion was classified cT2aN0M0 and was treated with stereotactic body radiation therapy at the dose of 60Gy in eight fractions. A few months after, he successively presented with two brain metastases and one left adrenal metastasis, with a complete response on the primary tumor. The three secondary lesions were treated with stereotactic body radiation therapy alone. Thirty months after the diagnosis and 12months after metastases' apparition, primary and brain lesion kept controlled (complete response). Oligometastatic non-small cell lung cancer management is not clear. Locally ablative therapies such as stereotactic body radiation therapy, surgery and radiofrequency are efficient and should be considered. A phase III study should evaluate radical treatment strategies in such patients.

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.

Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network.

BACKGROUND: There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations. PATIENTS AND METHODS: EGFR exon 18 and/or exon 20 mutations were collected from 10 117 non-small-cell lung cancer (NSCLC) samples analysed at 15 French National Cancer Institute (INCa)-platforms of the ERMETIC-IFCT network. RESULTS: Between 2008 and 2011, 1047 (10%) samples were EGFR-mutated, 102 (10%) with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (P < 0.001). Median overall survival (OS) of metastatic disease was 21 months [95% confidence interval (CI) 12-24], worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; hazard ratio [HR] for death 0.27, 95% CI 0.08-0.87, P = 0.03). Under EGFR-tyrosine kinase inhibitors (TKIs), median OS was 14 months (95% CI 6-21); disease control rate was better for complex mutations (6 of 7, 86%) than for single mutations (16 of 40, 40%) (P = 0.03). CONCLUSIONS: Rare EGFR-mutated NSCLCs are heterogeneous, with resistance of distal exon 20 insertions and better sensitivity of exon 18 or complex mutations to EGFR-TKIs, probably requiring individual assessment.

[An analysis of 20 consecutive patients treated with stereotactic body radiotherapy on Novalis Tx(®) for stage I non-small-cell lung cancer]. / Analyse des résultats d'une série de 20 patients traités par irradiation hypofractionnée en conditions stéréotaxiques par Novalis Tx(®) pour un cancer bronchopulmonaire non à petites cellules de stade I.

PURPOSE: Recent clinical results of dose escalation with stereotactic body radiation therapy to increase local tumour control for patients with stage I non-small-cell lung cancer who either refuse surgery or are medically inoperable resulted in making it a standard treatment in this setting. This treatment technique was implemented at the Paul-Strauss Centre, Strasbourg, in 2010. The objective of this study is to describe and analyze the data of the first 20 treated patients. PATIENTS AND METHODS: From October 2010 to May 2012, 20 patients were treated with this technique for T1N0M0 or T2N0M0 lung tumour. The indication was proposed by the multidisciplinary thoracic oncology team meeting, and approved by the technical committee of the Department of Radiotherapy. After the realization of a dosimetric CT Scan (4DCT or three phases-free breathing and deep breath-hold inspiration and expiration) and after performing a ((18)F)-FDG PET scan in the treatment position, all patients were treated on Novalis Tx(®) linear accelerator, with arctherapy or modulated intensity radiotherapy (IMRT). A protocol has been defined for the prescribed dose, depending on the size and location of the tumor, central or peripheral. The patients underwent follow-up during treatment and at 1 month, 3-4 months, 6 and 9 months to assess outcomes and toxicities. RESULTS: The mean age was 72.6 years (52-89). Seventeen patients had one or more pulmonary comorbidities. The mean delivered dose was 59.9 Gy (40-70) in 4 Gy to 17.5 Gy fractions. The mean gross tumour volume was 14.9 mL (median 7.2, 0.9 to 73.5) and the mean planning target volume was 77.8 mL (median 49.5; 17-300). The mean initial SUV max was 7.7 (1.8 to 16.7). Dose constraints and planning target volume coverage recommended by the protocol were achieved in the majority of cases. The mean lung V20 was 7.63% (1.2 to 17.7) and the mean dose delivered to the planning target volume was 94.6% (88-99). The duration of treatment was 21 days (median: 23; 8-27), and no change or interruption of prescribed treatment has occurred. Median follow-up was 6.6 months, and crude rates of objective response for patients evaluated were 85% (11/13 patients) at 3 months and 100% at 6 and 9 months. The complete response rate at 3 and 6 months were 0 (0/13 patients) and 50% (5/10 patients). Two patients had metastatic disease in the 6 months following treatment. Concerning pulmonary toxicity at 3 months, 6 patients developed G2 radiation pneumonitis and three patients G3, with positive evolution. CONCLUSION: The analysis of the results of this series, comparable with those described in literature, shows that lung stereotactic radiotherapy is an effective and well-tolerated treatment for inoperable patients. The extension of the indications could be envisaged based on the results of ongoing trials.

From randomized trials to the clinic: is it time to implement individual lung-cancer screening in clinical practice? A multidisciplinary statement from French experts on behalf of the French intergroup (IFCT) and the groupe d'Oncologie de langue francaise (GOLF).

BACKGROUND: Despite advances in cancer therapy, mortality is still high except in early-stage tumors, and screening remains a challenge. The randomized National Lung Screening Trial (NLST), comparing annual low-dose computed tomography (LDCT) and chest X-rays, revealed a 20% decrease in lung-cancer-specific mortality. These results raised numerous questions. The French intergroup for thoracic oncology and the French-speaking oncology group convened an expert group to provide a coherent outlook on screening modalities in France. METHODS: A literature review was carried out and transmitted to the expert group, which was divided into three workshops to tackle specific questions, with responses presented in a plenary session. A writing committee drafted this article. RESULTS: The multidisciplinary group favored individual screening in France, when carried out as outlined in this article and after informing subjects of the benefits and risks. The target population involves subjects aged 55-74 years, who are smokers or have a 30 pack-year smoking history. Subjects should be informed about the benefits of quitting. Screening should involve LDCT scanning with specific modalities. Criteria for CT positivity and management algorithms for positive examinations are given. CONCLUSIONS: Individual screening requires rigorous assessment and precise research in order to potentially develop a lung-cancer screening policy.

Cost-effectiveness of three strategies for second-line erlotinib initiation in nonsmall-cell lung cancer: the ERMETIC study part 3.

Several clinical and biological parameters are known to influence the efficacy of second-line erlotinib therapy for nonsmall cell lung cancer (NSCLC), but their medico-economic impact has not been evaluated. The objective of this study was to compare the incremental cost-effectiveness ratios of strategies for second-line erlotinib initiation in NSCLC: clinically guided initiation (nonsmoking females with adenocarcinoma received erlotinib; all other patients received docetaxel) and biologically guided selection (patients with epidermal growth factor receptor (EGFR) mutation received erlotinib; patients with wild-type EGFR or unknown status received docetaxel), compared with initiation with no patient selection (strategy reference). A Markov model was constructed. Outcomes (overall and progression-free survival), transition probabilities and direct medical costs (from the French third-party payer's perspective) were prospectively collected for individual patients treated with either erlotinib or docetaxel, from treatment initiation to disease progression. Published data were used to estimate utilities and post-progression costs. Sensitivity analyses were performed. The biologically and clinically guided strategies were both more efficient (incremental quality-adjusted life-yrs equal to 0.080 and 0.081, respectively) and less expensive (cost decrease equal to €5,020 and €5,815, respectively) than the no-selection strategy, and the biologically guided strategy was slightly less expensive than the clinically guided strategy. Sensitivity analyses confirmed the robustness of the results. The cost-effectiveness of second-line NSCLC treatment is improved when patients are selected on either clinical or biological grounds.

[Atypical metastatic site of lung adenocarcinoma]. / Site métastatique atypique d'un adénocarcinome bronchique.

The case concerns a 40 years old smoker male, treated for an adenocarcinoma of the left upper lobe, metastatic in muscle extended to the right femur cortex. The patient had first a surgical excision of the mass of the thigh, an intramedullary femoral nailing, and six courses of chemotherapy (cisplatin-vinorelbine) with concurrent thoracic radiotherapy. This treatment led to disease stability. One year later, hematuria revealed a bladder tumor. Cystoscopy with biopsy concluded to an adenocarcinoma pulmonary origin. The PET-scanner showed an uptake of the bladder mass, a hypermetabolic right adrenal gland and subcutaneous left shoulder nodule. The patient had a partial cystectomy associated with enterocystoplasty and left ureteral reimplantation, plus excision of the subcutaneous nodule located in the left shoulder and a right adrenalectomy during the same time. All of the sites were metastasis from adenocarcinoma of pulmonary origin. A salvage chemotherapy was initiated. In the vast majority of cases, bladder metastasis as primary bladder tumours is revealed by hematuria, cystitis or sometimes vague pelvic pain. Our case is a very unusual bladder metastatic site from lung cancer. We will discuss the different procedures and the therapeutic strategies on the basis of the published data.

[Epidemiological novelties in lung cancer]. / Épidémiologie du cancer bronchique primitif : aspects classiques et nouveautés.

Lung cancer is the most common cause of cancer-related mortality throughout the world representing around 18% of the total. There is still a male predominance but this is becoming less pronounced and in the US, lung cancer is now the most common cause of cancer-related mortality in women. In France, it had risen to second place in women in 2005 after having been in 6th place in 1975. Median age at diagnosis differs according to countries and health system and is around 70 years in the US and around 65 years in France. The distribution of histological subtypes has changed considerably during recent decades with an increasing frequency of adenocarcinoma at the expense of squamous cell carcinoma. The main risk factor for lung cancer remains active tobacco smoking but the attributable risk of smoking varies from one country to another and according to gender. In Japan, the great majority of lung cancer in women is not attributable to active tobacco smoking. Environmental tobacco smoke exposure has a less important role than active tobacco smoking although it is not negligible. The specific impact of smoking cannabis is difficult to assess precisely as, in most cases, it is mixed with tobacco. However, despite important differences with tobacco smoke, cannabis exposure doubles the risk of developing lung cancer. Occupational risk factors have for a long time been neglected and thus occupational lung cancers have been under-reported. Finally, lung cancer in never-smokers is driving considerable interest as it represents by itself the 7th largest cause of mortality due to cancer. Risk factors involved might be air pollution (indoors and outdoors) but also hormone replacement therapy in women.

[Muscular metastasis from primary lung cancer: about seven cases]. / Métastases musculaires de cancers bronchiques: à propos de sept cas.

Muscular metastasis from primary bronchial carcinoma are rare. We report seven cases with different clinical features. In most cases, these metastasis first manifested as a painful mass and revealed the cancer. Localisation of muscular metastasis was assessed by various imaging techniques (RMI, CT scan and ultrasonography). All cases were assessed by biopsy and were associated with primary adenocarcinoma or undifferentiated large cell carcinoma of the lung. Three patients underwent wide excision, leading to an improvement of general condition. All patients were treated with platinum-based chemotherapy. With reference to our cases, imaging of the metastases will be illustrated and clinical and therapeutic features will be discussed.

Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01).

BACKGROUND: We recently published the results of the PCI99 randomised trial comparing the effect of a prophylactic cranial irradiation (PCI) at 25 or 36 Gy on the incidence of brain metastases (BM) in 720 patients with limited small-cell lung cancer (SCLC). As concerns about neurotoxicity were a major issue surrounding PCI, we report here midterm and long-term repeated evaluation of neurocognitive functions and quality of life (QoL). PATIENTS AND METHODS: At predetermined intervals, the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and brain module were used for self-reported patient data, whereas the EORTC-Radiation Therapy Oncology Group Late Effects Normal Tissue-Subjective, Objective, Management, Analytic scale was used for clinicians' assessment. For each scale, the unfavourable status was analysed with a logistic model including age, grade at baseline, time and PCI dose. RESULTS: Over the 3 years studied, there was no significant difference between the two groups in any of the 17 selected items assessing QoL and neurological and cognitive functions. We observed in both groups a mild deterioration across time of communication deficit, weakness of legs, intellectual deficit and memory (all P < 0.005). CONCLUSION: Patients should be informed of these potential adverse effects, as well as the benefit of PCI on survival and BM. PCI with a total dose of 25 Gy remains the standard of care in limited-stage SCLC.

[Management and outcome of French elderly patients with lung cancer: an IFCT survey]. / IFCT 02-02 : la prise en charge du cancer bronchique chez les patients âgés de 70 ans et plus en France.

BACKGROUND: Lung cancer in the elderly is considerably increasing in frequency, representing a public health issue. Those patients are underrepresented in clinical trials and probably not optimally treated. METHODS: We performed a survey of the management and the outcome of lung cancer patients aged 70 and more in France between August 2002 and September 2003 according to age categories (70-74, 75-79 and > or =80 years). One thousand six hundred and twenty-seven patients were analysed for descriptive data and 1595 for survival. RESULTS: Median age was 75 (70-96) and male:female ratio was 4.26 with a decrease across the age categories from 5.1 to 3.0. Tobacco-linked comorbidities were frequent. The median value of Charlson's index was 2. About 58% had a performance status (PS) 0 or 1, 30% a PS 2 and 12% a PS>2. The proportion of never-smokers (11.6%) increased significantly with age categories. Regarding imaging procedures, as much as 83.3% of the patients had at least a chest CT-scan and a brain CT-scan (or MRI) and an abdominal ultrasound or CT-scan. Best Supportive Care (BSC) as only treatment was administered to 16.1% of the patients. Among patients specifically treated, 22.9% were operated, 21.8% received mediastinal irradiation and 71.5% chemotherapy. Overall, median survival time was 9.14 months with 23.5% deaths occurring before 3 months. Low category of age, good PS, non-smoking and high body mass index (BMI) were favorable independent prognostic factors of survival. Age, PS and tobacco smoking were prognostic of early death. CONCLUSIONS: A large majority of elderly lung cancer patients in France are managed like younger counterparts regarding diagnostic procedures and treatment. Age remains an independent prognostic factor as well for overall survival as for early death.