Final results of the IFCT-0803 study, a phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non-squamous, non-small-cell lung cancer.

PURPOSE: Roughly 20% of patients with non-small-cell lung cancer exhibit locally advanced, unresectable, stage III disease. Concurrent platinum-based chemoradiotherapy is the backbone treatment, which is followed by maintenance immunotherapy, yet with poor long-term prognosis. This phase II trial (IFCT-0803) sought to evaluate whether adding cetuximab to cisplatin and pemetrexed chemoradiotherapy would improve its efficacy in these patients. MATERIALS AND METHODS: Eligible patients received weekly cetuximab (loading dose 400mg/m2 day 1; subsequent weekly 250mg/m2 doses until two weeks postradiotherapy). Chemotherapy comprised cisplatin (75mg/m2) and pemetrexed (500mg/m2), both delivered on day 1 of a 21-day cycle of maximally four. Irradiation with maximally 66Gy started on day 22. Disease control rate at week 16 was the primary endpoint. RESULTS: One hundred and six patients were included (99 eligible patients). Compliance exceeded 95% for day 1 of chemotherapy cycles 1 to 4, with 76% patients receiving the 12 planned cetuximab doses. Maximal grade 3 toxicity occurred in 63% patients, and maximal grade 4 in 9.6%. The primary endpoint involving the first 95 eligible patients comprised two (2.1%) complete responses, 57 (60.0%) partial responses, and 27 (28.4%) stable diseases. This 90.5% disease control rate (95% confidence interval [95% CI]: 84.6%-96.4%) was achieved at week 16. After median 63.0-month follow-up, one-year and two-year survival rates were 75.8% and 59.5%. Median overall survival was 35.8months (95% CI: 23.5-NR), and median progression-free survival 14.4months (95% CI: 11.2-18.8), with one-year and two-year progression-free survival rates of 57.6% and 34.3%. CONCLUSION: These survival rates compare favourably with published data, thus justifying further development of cetuximab-based induction chemoradiotherapy.

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.

Nivolumab-refractory patients with advanced non-small-cell lung cancer.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionised cancer care especially in lung cancer. New response patterns have been described under ICIs such as pseudo-progression or hyper-progressive disease (HPD). The definition of HPD is yet to be consensual. The aim of this study was to suggest a clinical definition of nivolumab-refractory patients and find factors associated with this entity. METHODS: We performed a multi centric retrospective study including all patients who received nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC) during the French authorisation for temporary use in 2015. RESULTS: 303 patients were included in the cohort and 292 had details on the number of nivolumab injections received. 57 patients (20%) were nivolumab-refractory. These patients had worse PS at nivolumab initiation (p < 0.0001), shorter duration of treatment before nivolumab (p = 0.028) and had dramatically shorter nivolumab overall survival (p < 0.0001) than patients who did not present with refractory disease. CONCLUSION: Nivolumab-refractory disease can affect up to 20% of patients treated with nivolumab for advanced NSCLC with dramatically shortened survival rates. Further studies are needed to understand the precise mechanisms leading to refractory disease as well as its management.

Efficacy and safety of gefitinib during pregnancy: case report and literature review.

The incidence of lung cancer is rising in pregnancy, which is diagnosed on stage III-IV in 98%. Almost half of these patients are non-smokers, who are associated with more epidermal growth factor receptor (EGFR)-mutated lung cancer. As cytotoxic chemotherapy is associated with poor outcome for mothers and prematurity for children this will probably lead to repeatedly question the use of EGFR-Tyrosine kinase inhibitors (TKI) (i.e. gefitinib and erlotinib) during pregnancy for EGFR-mutated lung cancer. EGFR-TKIs are recommended as the first line targeted therapy in case of advanced non small cell lung carcinoma (NSCLC) with an activating EGFR mutation but not recommended during pregnancy due to lack of data. We report clinical and pharmacological data for gefitinib during pregnancy in both the mother and fetus and resume the literature on the subject. A 33-year-old pregnant mother exhibited a disseminated EGFR-mutated lung carcinoma with respiratory distress at 26 weeks of pregnancy. Gefitinib administration was associated with rapid maternal respiratory improvement allowing a planned cesarian section on week 35, giving birth to a healthy baby (2575g) with regular development at 24 months of follow-up. The mother exhibited a progression-free survival of 42 weeks with an overall survival of 22 months. Gefitinib residual concentration was found in cord blood at 25.7ng/mL, confirming a transplacental transfer, but at only 20% of the maternal concentration measured at the same time (i.e. 127.1ng/mL). Gefitinib concentration in amniotic fluid, which represents chronic fetal exposure to the drug, was also 20% of the maternal residual concentration (16.9ng/mL) and reflected no fetal accumulation of the drug, despite both long half time elimination of gefitinib (i.e. 48h) and long time exposure (i.e. 55 days). This low transplacental transfer is an important report, as potential side effect toxicity on the fetus is likely correlated to gefitinib blood concentration.

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.

[Radiofrequency treatment of lung tumours]. / Le traitement par radiofréquence des tumeurs pulmonaires.

Formal surgical resection is the standard treatment for patients with an operable non-small cell lung tumour and for selected patients with limited lung metastases, even if only a small number of patients are suitable for formal surgical resection due to comorbidities. CT-guided radiofrequency treatment is a minimally invasive therapeutic option that has been successfully applied to different organs, and for the lung is considered to be an alternative to surgery for patients who are not candidates for surgery. The procedure is well-tolerated and the complication rate is acceptable.

[Effect of tinzaparin on survival in non-small-cell lung cancer after surgery. TILT: tinzaparin in lung tumours]. / Effet de la tinzaparine sur la mortalité du cancer bronchique non à petites cellules opéré.

BACKGROUND: Experimental and clinical findings suggest that low molecular-weight heparins may improve overall survival in patients with cancer. The evidence is still limited and additional studies are needed to confirm these preliminary findings. METHODS: Patients with completely resected stage I, II or IIIA (T3N1) histologically confirmed non-small-cell lung cancer will be included in a prospective, controlled, randomized, multicenter open trial. Patients in the control group will receive usual postoperative care including chemotherapy when indicated. Patients in the experimental group will receive tinzaparin given subcutaneously as a daily 100 IU/kg dose for 90 days along with usual postoperative care. Patients will be followed-up for three to eight years. Main end-point is the overall survival. Five hundred and fifty patients are needed to demonstrate a 10% absolute increase in survival in the experimental group. EXPECTED RESULTS: A 10% absolute increase in the survival rate is expected in the patients receiving tinzaparin.

[IFCT-0302 trial: randomised study comparing two follow-up schedules in completely resected non-small cell lung cancer]. / Protocole IFCT-0302: essai randomisé de deux schémas de surveillance dans les cancers bronchiques non à petites cellules complètement réséqués.

BACKGROUND: The authorities advocate a minimalist attitude towards the follow-up of resected bronchial carcinoma (clinical examination and chest x-ray). A survey showed that 70% of French respiratory physicians have chosen to use the CT scanner and often endoscopy. The published data are equivocal and are often based on retrospective studies. Lung cancer is a good model for a study of post-operative surveillance. Recurrences often occur in easily observed areas, they may be detected while still asymptomatic and are sometimes potentially curable. Second primary tumours may develop at the same site. METHODS: The Intergroupe Francophone de Cancerologie Thoracique (IFCT) has initiated a trial comparing simple follow-up (clinical examination, chest x-ray) with a more intensive follow-up (CT scan, fibreoptic bronchoscopy). The surveillance will take place every 6 months for 2 years and then annually until 5 years. EXPECTED RESULTS: The main aim is to determine whether intensive follow-up improves patient survival. The opposite question is equally important. If an expensive and demanding follow-up does not affect the chances of cure these results will influence our practice.

[Chest diseases in elderly: role of imaging and clinical features]. / Pathologie pulmonaire du sujet âgé: rôle de l'imagerie et aspects cliniques.

Chest x-ray is the most useful examination in the elderly as community acquired pneumonia is very frequent in this high risk population. Technical details have to be considered due to the clinical status of elderly patients. Raising arms above the head may help in the radiographic diagnosis of pneumonia. Guidelines for good radiological practice indicate that a chest x-ray should be done in patients with acute respiratory illness and dementia. Clinical and biological findings of pneumonia may be misleading in the elderly and treatment should be instituted rapidly to avoid complications. Lung cancer of elderly patients has to be investigated and treated without consideration for age. Surgery should be done whenever the tumor is removable by lobectomy. Chemotherapy may be safe even in patients older than 80 with an acceptable quality of life.

[Bone mineral density in patients with chronic lung diseases]. / Etude de la densité minérale osseuse chez des patients insuffisants respiratoires chroniques.

PURPOSE: We evaluated bone mineral density and phosphorus calcium status in patients with chronic lung diseases. PATIENTS AND METHODS: A prospective study was conducted in 58 patients (43 men and 15 women, mean age 44 years, age range 16-68 years) who were classed in three groups: chronic obstructive diseases (25 patients), cystic fibrosis (19 patients), and other lung diseases (14 patients). Fifteen percent of the patients were receiving corticosteroid therapy. Bone mineral density of the lumbar spin and the femoral neck was measured. RESULTS: Serum calcium, phosphate, creatinine, osteocalcin and parathyroid hormone were normal. The 25-hydroxyvitamin D (normal=9-40 ng/ml) level was in the lower limits of normal (12 ng/ml) and was severely decreased in 12 patients (<7 ng/ml). CONCLUSION: Chronic lung disease can lead to osteoporosis. Corticosteroids, low vitamin D level, sedentary lifestyle, smoking, and in cystic fibrosis nutritional deficiencies, delayed puberty and hypogonadism are risk factors. Bone density must be measured in order to prevent and treat osteoporosis.

Nebulized cyclosporine in the rat: assessment of regional lung and extrapulmonary deposition.

BACKGROUND: Nebulized cyclosporine (CsA) has been shown to limit lung allograft rejection as well as intramuscular (IM) CsA, with limited blood diffusion. The present study determined the pharmacokinetic parameters of nebulized CsA, by the assessment of regional lung deposition and extrapulmonary diffusion of CsA. METHODS: CsA was given either by IM injection (10 mg/kg) or by aerosol (at 10 and 25 mg/kg doses); 70 rats were killed at 25 and 50 min, and at 2, 4, 6, 8, 12, 24, or 48 hr after CsA administration. CsA levels were measured in the whole lung, in central and peripheral parts of the lung, in whole blood, kidney, and heart. The areas under the concentration time curves (AUCs) were determined. RESULTS: In blood, kidney, and heart, CsA levels were significantly higher for IM than for aerosol administrations at 10 and 25 mg/kg doses. In the whole lung, the AUC was greater for the aerosol route at 25 mg/kg doses (588 ng x hr/mg) than for the low-dose (200 ng x hr/mg) or IM administration (200 ng x hr/mg). The central to peripheral index of CsA (ratio of AUC central/peripheral part of the lung) was not significantly different for both aerosol administrations (0.63 and 0.69, respectively) and for the IM route (0.81). CONCLUSIONS: Nebulized CsA allows better pulmonary concentration than IM administration, with equivalent central and peripheral deposition whatever the mode of administration, and results in lower levels in blood, kidney, and heart.

Predictive value of cytomegalovirus DNA detection by polymerase chain reaction in blood and bronchoalveolar lavage in lung transplant patients.

BACKGROUND: Despite promising results, the efficacy of polymerase chain reaction (PCR) for clinical management of cytomegalovirus (CMV) infection in transplanted patients is still controversial. METHODS: A prospective study of CMV detection, with concurrent shell vial cultures and PCR in blood and bronchoalveolar lavage (BAL), was conducted in 13 lung transplant recipients, monitored for 15 months (range: 1-42 months). CMV DNA was detected by PCR amplification of a 406-bp fragment in the Us region and a 290-bp fragment in the immediate early region of the viral genome. RESULTS: When comparing PCR to viral culture, the sensitivity and specificity of CMV DNA detection were 100% and 65.7% in blood (n=122) and 100% and 75% in BAL (n=104). The positive and negative predictive values of PCR for a forthcoming diagnosis of CMV infection were 50% and 97% in blood, and 67% and 85% in BAL. Seventeen CMV infections were evaluated at the end of treatment: when PCR was still positive either in blood or BAL, CMV infection relapsed within 35+/-5 days; when PCR was negative, CMV infection relapsed after 142+/-57 days (P=0.01). CONCLUSIONS: Negative CMV detection by PCR strongly advocates against a forthcoming CMV infection. PCR assay seems to be a good predictor for early recurrence of CMV infection, and would be useful for monitoring the response to antiviral therapy.

[Cytomegalovirus pneumopathies. What role should be given to cytomegaloviruses isolated from blood and bronchoalveolar lavage fluid in AIDS and from organ and bone marrow grafts?]. / Pneumopathies à cytomégalovirus. Quelle place accorder à l'isolement du cytomégalovirus dans le sang et le liquide de lavage broncho-alvéolaire au cours du sida, des greffes d'organe et de moelle osseuse?

Cytomegalovirus (CMV) is often suspected as the causal agent in lung disease occurring in various immunodepressive states: AIDS, organ transplantation, bone marrow graft. The mechanisms involved in these three situations is however quite different. The role played by the cytopathogenic effect of the virus and the immune reaction of the host vary considerably depending on the underlying immunodepression. Thus, the criteria allowing to distinguish between CMV infection (presence of the virus or anti-CMV antibodies, no clinical signs) and CMV disease (generalized or organ specific disease resulting from the pathogenic effect of CMV replication) lack precision. The aim of this review of the literature is to assess the implicated immunovirology mechanism and thus the diagnostic (and thus therapeutic) criteria of CMV lung diseases. There is a graduation scale from AIDS, to organ transplantation and bone marrow allograft in the degree of immune reaction implicated in the lung disease and thus the need and timing of antiviral treatment. In AIDS, an interstitial pneumonia, associated with an isolation of CMV (whatever the sample origin, blood, bronchoalveolar lavage or the isolation technique) does not usually implicate treatment. Treatment may be indicated in rare cases (advanced stage immunodepression, high virus titre, endothelial involvement) or in cases in which the infection is also located in other organs. For organ transplantation, observation of CMV in blood or lavage samples in a patient with clinical or radiological signs would justify treatment. For lung transplantation, more so than for any other organ, treatment should be started early whenever respiratory signs are associated with evidence of CMV infection. Finally, in bone marrow allografts, the high rate of failure when pneumonitis has become patent implicates starting treatment immediately upon diagnosis of CMV infection. The strategy proposed here is based on a certain rationale but can be open to discussion. Controlled clinical trials are required to determine the most rigorous and coherent attitude. Finally, within the framework of the diseases examined here, search for lung disease caused by cytomegalovirus should not mask other organ localizations in, for example, the retina, the digestive tract.

[Role of thoracic x-ray computed tomography in the pretherapeutic evaluation of bronchial cancer. A prospective study of 60 patients]. / La place de la tomodensitométrie thoracique dans le bilan préthérapeutique du cancer bronchique. Etude prospective de 60 malades.

The value of computerized tomography (CT) was compared with that of conventional exploratory methods (standard radiology, bronchial tomography and endoscopy) in 60 patients with non-anaplastic bronchial cancer evaluated preoperatively. After CT examination thoracotomy was avoided in 14 (23%) patients with local or distal extension. CT proved more sensitive than conventional methods in the assessment of pleural and/or parietal extension, and of direct or lymph-node mediastinal invasion (67% vs 33%, 50% vs 33%, 64% vs 45% respectively). Similar results (75%) were obtained in cases with hilar lymph-node involvement. However, caution must be exerted before excluding thoracotomy, since CT may give false-positive results.