FOLFIRI in advanced platinum-resistant/refractory small-cell lung cancer: a retrospective study.

BACKGROUND: Small-cell lung cancer (SCLC) accounts for approximately 15% of lung cancer and is associated with poor prognosis. In platinum-refractory or -resistant SCLC patients, few treatment options are available. Topotecan is one of the standards of care for these patients, however, due to its high toxicity, several different approaches are employed. FOLFIRI (folinate, 5-fluorouracil and irinotecan) is a chemotherapy regimen used in digestive neuroendocrine carcinoma, which shares pathological similarities with SCLC. In this retrospective study, we evaluated the efficacy and safety of FOLFIRI in patients with platinum-resistant/refractory SCLC. METHODS: Medical records from all consecutive SCLC patients treated with FOLFIRI in a French University Hospital from 2013 to 2021 were analyzed retrospectively. The primary endpoint was the objective response rate according to RECIST v1.1 or EORTC criteria (ORR); secondary endpoints included duration of response, disease control rate, progression-free survival (PFS), overall survival (OS) and safety profile. RESULTS: Thirty-four patients with metastatic platinum-resistant (n = 14) or -refractory (n = 20) SCLC were included. Twenty-eight were evaluable for response, with a partial response observed in 5 patients for an overall ORR in the evaluable population of 17.9% (5/28) and 14.7% (5/34) in the overall population. The disease control rate was 50% (14/28) in the evaluable population. The median PFS and OS were 2.8 months (95%CI, 2.0-5.2 months) and 5.3 months (95%CI, 3.5-8.9 months), respectively. All patients were included in the safety analysis. Grade 3 or 4 adverse events occurred in 13 (38.2%) patients. The most common grade 3 or 4 adverse events were asthenia, neutropenia, thrombopenia and diarrhea. There was no adverse event leading to discontinuation or death. CONCLUSION: FOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response and had an acceptable safety profile. However, caution is needed in interpreting this result. FOLFIRI could represent a potential new treatment for platinum-resistant/refractory SCLC patients. Further prospective studies are needed to assess the benefits of this chemotherapy regimen.HIGHLIGHTSFOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response.FOLFIRI was well-tolerated in platinum resistant/refractory SLCL patients.FOLFIRI could represent a potential new treatment for SCLC, prospective studies are needed.

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.

Efficacy of next treatment received after nivolumab progression in patients with advanced nonsmall cell lung cancer.

Nivolumab for the treatment of advanced nonsmall cell lung cancer (NSCLC) evaluated in phase III trials showed 50% progression at first evaluation, but better overall survival (OS), suggesting regained efficacy of treatments given thereafter. We aimed to evaluate the efficacy of nivolumab and of next treatment received after nivolumab progression in patients with advanced NSCLC. Our multicentre retrospective study included all patients receiving nivolumab between January and December 2015. The primary end-point was progression-free survival (PFS) of treatment given after nivolumab. The 303 patients had the following characteristics: median age 63 years, 69% males, 92% smokers, 67% performance status 0-1 and 61% adenocarcinoma. Nivolumab was given as second-line treatment in 40% of patients. With 13.7 months of median follow-up, nivolumab PFS and OS were 2.6 and 11.3 months, respectively. At the cut-off analysis 18% were controlled under nivolumab, 14% were deceased and 5% were lost to follow-up under nivolumab. Among the 191 (63%) patients eligible for post-nivolumab (PN) treatment, 115 (38%) received further treatment and were characterised by better performance status (p=0.028) and by receiving more injections of nivolumab (p=0.001). Global PN-OS and PN-PFS were 5.2 and 2.8 months, respectively. Drugs most frequently used after nivolumab were gemcitabine (23%), docetaxel (22%) and erlotinib (16%), with median PFS of 2.8, 2.7 and 2.0 months, respectively. Nivolumab produced similar efficacy as in phase III trials, although patients received nivolumab later and had worse performance status. 38% received treatment after nivolumab progression with efficacy comparable to historical second-line trials.

Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease.

OBJECTIVE: Patients with autoimmune or inflammatory disease (AID) are susceptible to immune-related adverse events (irAEs) when treated with immune check-point inhibitors (ICIs). We decided to analyse the safety and effectiveness of anti-PD-1 antibodies in AID patients and look for an association between the presence of pre-existing AID and the clinical outcome. METHODS: In a prospective study of the REISAMIC registry of grade ≥2 irAEs occurring in ICI-treated patients, we studied the associations between pre-existing AID on one hand and irAE-free survival, overall survival and best objective response rate on the other. RESULTS: We identified 45 patients with 53 AIDs in REISAMIC. The cancer diagnoses included melanoma (n = 36), non-small-cell lung cancer (n = 6) and others (n = 3). The most frequent pre-existing AIDs were vitiligo (n = 17), psoriasis (n = 12), thyroiditis (n = 7), Sjögren syndrome (n = 4) and rheumatoid arthritis (n = 2). Twenty patients (44.4%) presented with at least one irAE: eleven of these were associated with a pre-existing AID ('AID flare'). Treatment with anti-PD-1 antibodies was maintained in 15 of the 20 patients with an irAE. The IrAE-free survival time was significantly shorter in AID patients (median: 5.4 months) than in AID-free patients (median: 13 months, p = 2.1 × 10-4). The AID and AID-free groups did not differ significantly with regard to the overall survival time and objective response rate (p = 0.38 and 0.098, respectively). CONCLUSION: In patients treated with anti-PD-1 antibody, pre-existing AID was associated with a significantly increased risk of irAEs. Our results indicate that cancer treatments with anti-PD-1 antibodies are just as effective in AID patients as they are in AID-free patients.

Phase 2 study of frontline bortezomib in patients with advanced non-small cell lung cancer.

BACKGROUND: Preliminary results indicated that bortezomib (B) (Velcade*) as a single agent may have activity in pretreated NSCLC patients with similar or lesser toxicity compared to chemotherapy. This phase II study was initiated to determine the efficacy of single-agent B in chemonaïve patients with advanced NSCLC. An early tumor assessment (after 6 weeks of therapy) was performed to allow for rapid and appropriate management of non-responding patients. METHODS: Patients received B (1.5 mg/m2) twice a week for 2 consecutive weeks (days 1, 4, 8, and 11) followed by a 10-day rest period. The primary endpoint was non-progression rate (NPR) after 6 weeks of treatment. Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses included FDG-PET response at 6 weeks and circulating tumors cell (CTC) assessment at day 1 of each cycle in a subset of patients. RESULTS: 18 patients were enrolled from 06/06 to 02/07 from 3 French institutions. DEMOGRAPHICS: male/female 15/3; median age 66 (54-79); PS 0/1/2, 3/12/3; pathology: adenocarcinoma 11, squamous cell carcinoma 5, large-cell carcinoma 2; smoking status never/former/current 1/10/7; stage IIIB/IV 2/16. Seventeen patients received B and 16 were assessable (1 early withdrawal and 1 progression at D26). The most frequent toxicity was fatigue (17 patients). Twelve patients (71%) had at least one grade 3 toxicity: 4 haematological, 1 infection, 5 gastro-intestinal toxicity, 9 fatigue, 1 neuropathy. The non-progression rate was 59% [33-82%] at 6 weeks (10/17 patients). No objective response was seen. With a median follow-up of 12.3 months, the median PFS and OS were 2.4 and 9.8 months respectively. Eleven deaths occurred. No PET response was observed, and CTC were detected only in 1 out of 8 patients evaluated. CONCLUSIONS: Although according to the protocol rules the trial should not be stopped, the lack of any objective response either by CT-scan or PET-CT, along with substantial toxicity, did not argue in favor of the current strategy of B as a single agent in the front-line setting of NSCLC.

Pulmonary toxicity related to systemic treatment of nonsmall cell lung cancer.

Physicians who are responsible for the delivery of systemic treatment in lung cancer should be aware of the potential risk of drug-induced pulmonary toxicity (DIPT), because such toxicity may develop in the context of a multifactorial clinical condition. First, most patients with lung cancer may suffer from other non-neoplastic, smoking-related lung diseases, such as emphysema and chronic obstructive lung disease, which may generate pathologic changes in lung parenchyma. In addition, lung cancer itself may worsen the respiratory function, inducing atelectasis and lymphangitic carcinomatosis. The superimposed iatrogenic damage may lead to respiratory failure and, sometimes, death. The risk of DIPT from chemotherapeutic agents has been widely examined in the past; and, currently, the potential for lung toxicity has been extended by the introduction of molecular targeted therapies. Because there are no univocal criteria with which to recognize DIPT, the diagnosis often is made by exclusion; consequently, it is hard to establish an early diagnosis. The objective of this review was to describe the major DIPTs associated with antineoplastic agents against nonsmall cell lung cancer to help physicians with this difficult diagnostic challenge.

Noninvasive contrast-enhanced US quantitative assessment of tumor microcirculation in a murine model: effect of discontinuing anti-VEGF therapy.

PURPOSE: To determine, by using contrast material-enhanced ultrasonography (US), how quickly renal tumors grafted in mice begin to revascularize after stopping bevacizumab treatment. MATERIALS AND METHODS: All experiments were approved by the regional ethics committee. A human tumor cell line SK-NEP-1 was grafted at day 0 in the left kidney of 50 nude mice. Forty-two mice developed tumors and longitudinal follow-up was performed on 32 surviving mice. From day 13, 14 controls received biweekly saline; 11 mice received biweekly bevacizumab until day 35 (continuous); and seven received biweekly bevacizumab until day 22, then biweekly placebo until day 35 (discontinued). Contrast-enhanced US was performed on days 13, 14, 22, 27, and 35. Once the injected contrast material distribution reached an equilibrium phase, high-acoustic pressure pulses were applied to destroy microbubbles in the capillary bed in the imaged plane. Reperfusion was monitored, and time-signal intensity (SI) curves were obtained from the linear average of SIs in intratumoral and matched-depth renal cortex regions of interest. A kinetic parameter calculated from reperfusion curves reflects local perfusion, normalized with respect to adjacent renal cortex perfusion. Normalized perfusion obtained from each group was compared with that from the other groups and with necrosis percentages and microvascular density assessed histologically at day 35. Comparisons were made by using analyses of variance and Tukey-Kramer tests. RESULTS: The lowest excised mean tumor weights (+/- standard deviation) corresponded to the longest bevacizumab-treatment duration: 1.4 g +/- 1.1 (continuous-treatment) compared with 2.3 g +/- 2.1 (discontinued) and 3.7 g +/- 1.9 (control) (P = .01). On day 35, the respective control and continuously treated groups had comparable and significantly larger necrotic areas: 37% +/- 14 and 32% +/- 17 larger than the discontinued-treatment group (15% +/- 9; P < .05). Normalized perfusion increased significantly with time (P = .02) in the discontinued-treatment group after therapy ceased (day 22). CONCLUSION: Noninvasively measured contrast-enhanced US parameters demonstrated tumor revascularization after stopping antiangiogenic therapy in this murine tumor model.

[Angiogenesis and renal cell carcinoma]. / Angiogenèse et cancer du rein.

Developments in the knowledge of molecular biology of renal cell carcinoma (RCC) over the past 20 years have been identified. Angiogenesis is playing a key role in the physiopathology of RCC. Von Hippel-Lindau (VHL) alterations, HIFalpha accumulation and vascular endothelial growth factor (VEGF) overexpression are important mediators of this process. Several stategies have been developped to target angiogenesis for the treatment of metastatic RCC. These include inhibition of VEGF receptors (inhibition of the tyrosine kinase activity) or binding to the VEGF protein. Several additional kinases inhibitions including PDGF receptors are also targeted. Sunitinib (SU11248) is an orally biovailable small molecule that has demonstrated superiority over interferon-alpha for the treatment of metastatic RCC. In a recent randomized phase III study conducted in 750 patients, the response rate to sunitinib was 31% and to interferon 6%. The median of progression free survival (PFS) was 11 months for sunitinib and 5 months for interferon (p < 0.001). Sorafenib (BAY43-9006) was found to inhibit Raf1, but also VEGFR2 and 3, Flt3, PDGFR-a and b and c-kit, has been tested in a phase III study against placebo after one prior systemic therapy. The median of the time to progression (TTP) for sorafenib was 24 weeks versus 12 weeks for patients in the placebo arm (p = 0,01). Other molecules tested in metastatic RCC will be presented including axitinib, pazopanib and bevacizumab.

[Adjuvant chemotherapy in non-small cell lung cancer]. / Chimiothérapie adjuvante dans le cancer bronchique non à petites cellules.

Lung cancer is the leading cause of cancer death in France. Nearly 80% of lung tumors are non-small cell lung cancers (NSCLC). Surgery is the best curative approach, but it only concerns 30% of NSCLC, since the diagnosis is frequently made in patients with locally advanced or metastatic disease. Even when surgery is performed relapse occurs in up to 50% of patients. Several adjuvant trials have been led in the late 90's after an individual data-based meta-analysis suggested a 5% survival benefit at 5 years. Among those, the IALT study, with 1 867 patients included, confirms the benefit of post-operative chemotherapy in resected NSCLC. In this article, the current status of adjuvant chemotherapy is reviewed, and future prospects are discussed.