Chest CT scan plus x-ray versus chest x-ray for the follow-up of completely resected non-small-cell lung cancer (IFCT-0302): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC. METHODS: In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I-IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Procedures were repeated every 6 months for the first 2 years and yearly until 5 years. The primary endpoint was overall survival analysed in the intention-to-treat population. Secondary endpoints, also analysed in the intention-to-treat population, included disease-free survival. This trial is registered with ClinicalTrials.gov, NCT00198341, and is active, but not enrolling. FINDINGS: Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and randomly assigned to a follow-up group (888 patients to the minimal follow-up group; 887 patients to the CT-based follow-up group). Median overall survival was not significantly different between follow-up groups (8·5 years [95% CI 7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable-not estimable] in the minimal follow-up group vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events related to the trial procedures were reported. INTERPRETATION: The addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures. FUNDING: French Health Ministry, French National Cancer Institute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Neurological complications induced by immune checkpoint inhibitors: a comprehensive descriptive case-series unravelling high risk of long-term sequelae.

Neurological immune-related adverse events are complications of programmed-cell death 1 or programmed-cell death 1 ligand immunotherapies that can be life threatening and often lead to anticancer immunotherapy withdrawal. Scant clinical data are available that integrate the clinical presentation, therapeutic management and long-term outcome. All consecutive adult patients treated by programmed-cell death 1 or programmed-cell death 1 ligand immunotherapies, given alone or in combination with other treatment, who experienced a neurological immune-related adverse event with a severity grade ≥2 in Paris Saclay-University hospitals were investigated from June 2014 to February 2019. The frequency of neurological immune-related adverse events was calculated from the prospective Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie cohort. Forty patients presenting with 51 distinct neurological immune-related adverse events were included. The prevalence of grade ≥2 neurological immune-related adverse events was estimated to be 1.22% in the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie cohort. Among 40 patients with neurological immune-related adverse events, 65% received programmed-cell death 1 or programmed-cell death 1 ligand monotherapy and 35% received a combination of programmed-cell death 1 plus anti-CTLA4 (Common Terminology Criteria for Adverse Events). Clinical neurological presentations were peripheral (48%), central (35%), or mixed (18%). The severity of neurological immune-related adverse events was grade 2 for 14 (35%) and ≥grade 3 for 26 patients (65%). The mortality rate related to neurological immune-related adverse events was 8%. Corticosteroid treatment led to neurological recovery in 74%. Long-term follow-up highlighted that 53% of patients experienced long-term neurological sequelae. Five patients were rechallenged by programmed-cell death 1 monotherapy without recurrence of their neurological immune-related adverse event(s). Neurological immune-related adverse events induced by programmed-cell death 1 or programmed-cell death 1 ligand are rare but are severe with a mortality rate of 8% and long-term sequelae for 53% of patients. Corticosteroids should be started when neurological immunological complications are identified to avoid long-term sequelae.

Anti-tumour effect of low molecular weight heparin in localised lung cancer: a phase III clinical trial.

The anti-tumour and anti-metastatic properties of heparins have not been tested in patients with early stage cancer. Whether adjuvant low molecular weight heparin (LMWH) tinzaparin impacts the survival of patients with resected non-small cell lung cancer (NSCLC) was investigated.Patients with completely resected stage I, II or IIIA NSCLC were randomly allocated to receive subcutaneous tinzaparin 100 IU·kg-1 once a day for 12 weeks or no treatment in addition to standard of care. The trial was open-label with blinded central adjudication of study outcomes. The primary outcome was overall survival.In 549 patients randomised to tinzaparin (n=269) or control (n=280), mean±sd age was 61.6±8.9 years, 190 (34.6%) patients had stage II-III disease, and 220 (40.1%) patients received adjuvant chemotherapy. Median follow-up was 5.7 years. There was no significant difference in overall survival between groups (hazard ratio (HR) 1.24, 95% CI 0.92-1.68; p=0.17). There was no difference in the cumulative incidence of recurrence between groups (subdistribution HR 0.94, 95% CI 0.68-1.30; p=0.70).Adjuvant tinzaparin had no detectable impact on overall and recurrence-free survival of patients with completely resected stage I-IIIA NSCLC. These results do not support further clinical evaluation of LMWHs as anti-tumour agents.

A phase II study of cisplatin with intravenous and oral vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy with oral vinorelbine and cisplatin for locally advanced non-small cell lung cancer.

BACKGROUND: Concomitant platinum-based chemotherapy and radiotherapy (CT-RT) is the recommended treatment for unresectable locally advanced stage III non-small cell lung cancer (NSCLC). We conducted a phase II study to evaluate the efficacy and safety of fractionated oral vinorelbine with cisplatin as induction CT followed by CT-RT. METHODS: Patients with stage III NSCLC received 2 induction cycles of intravenous vinorelbine 25 mg/m2 and cisplatin 80 mg/m2 on day 1 and oral vinorelbine 60 mg/m2 on day 8. Responding patients received 2 more cycles of cisplatin 80 mg/m2 on day 1 and oral vinorelbine 20 mg on days 1, 3 and 5 concomitantly with radiotherapy 2 Gy daily, 5 days/week for a total of 66 Gy. RESULTS: Seventy patients, median age 61 years, were enrolled. Overall response rate (ORR) was 50.0%; Disease Control Rate was 81.42%. Median PFS was 14.58 months [95% CI, 10.97-18.75]. Median OS was 17.08 months [95% CI, 13.57-29.57]. One-year and 2-year survival rates were 68.6% [95% CI, 57.7-79.4] and 37%. One patient had a grade 3 pulmonary radiation injury and 26.5% had graded 1/2 esophagitis. CONCLUSION: In non-operable IIIA-IIIB NSCLC, the combination oral vinorelbine (fractionated fixed dose) plus cisplatin, during concomitant CT-RT, could offer a well-tolerated option, with comparable activity to I.V. vinorelbine-based chemoradiotherapy regimens. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01839032.