Long survival of patients with metastatic clear cell renal cell carcinoma. Results of real life study of 344 patients.

The treatment landscape in metastatic renal cell carcinoma has changed fundamentally over the last decade by the development of antiangiogenic agents, mammalian target of rapamycin inhibitors and immunotherapy. Outside of the context of a clinical trial, the treatments are used sequentially. We describe results under real-life conditions of a sequential treatment strategy, before the era of immunotherapy. All patients were treated according to their prognostic score (either Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium) for advanced renal cell carcinoma. A treatment strategy involving 1 to 4 lines was determined including a rechallenge criterion for the repeat use of a treatment class. Three hundred forty-four patients were included over 3 years. Overall survival was 57 months in patients with good or intermediate prognosis and 19 months in patients with poor prognosis. In the former group, the proportions of patients treated with 2 to 4 treatment lines were 70%, 38% and 16%, respectively. The best objective response rates for lines 1 to 4 were 46%, 36%, 16% and 17%, respectively. Grade III/IV toxicity did not appear to be cumulative. The recommended strategy was followed in 68% of patients. A large proportion of patients with good or intermediate prognosis who progress after two lines of treatment still have a performance status good enough to receive a systemic treatment, which justifies such a strategy. Overall survival of patients with good and intermediate prognosis was long, suggesting a benefit from the applied approach. These results might be used as selection criterion for the treatment of patients in the era of immune checkpoint inhibitors.

Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial.

BACKGROUND: There is no recommended therapy for malignant pleural mesothelioma that has progressed after first-line pemetrexed and platinum-based chemotherapy. Disease control has been less than 30% in all previous studies of second-line drugs. Preliminary results have suggested that anti-programmed cell death 1 (PD-1) monoclonal antibody could be efficacious in these patients. We thus aimed to prospectively assess the anti-PD-1 monoclonal antibody alone or in combination with anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody in patients with malignant pleural mesothelioma. METHODS: This multicentre randomised, non-comparative, open-label, phase 2 trial was done at 21 hospitals in France. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, histologically proven malignant pleural mesothelioma progressing after first-line or second-line pemetrexed and platinum-based treatments, measurable disease by CT, and life expectancy greater than 12 weeks. Patients were randomly allocated (1:1) to receive intravenous nivolumab (3 mg/kg bodyweight) every 2 weeks, or intravenous nivolumab (3 mg/kg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks), given until progression or unacceptable toxicity. Central randomisation was stratified by histology (epithelioid vs non-epithelioid), treatment line (second line vs third line), and chemosensitivity to previous treatment (progression ≥3 months vs <3 months after pemetrexed treatment) and used a minimisation method with a 0·8 random factor. The primary outcome was the proportion of patients who achieved 12-week disease control, assessed by masked independent central review; the primary endpoint would be met if disease control was achieved in at least 40% of patients. The primary endpoint was assessed in the first 108 eligible patients. Efficacy analyses were also done in the intention-to-treat population and safety analyses were done in all patients who received at least one dose of their assigned treatment. This trial is registered at ClinicalTrials.gov, number NCT02716272. FINDINGS: Between March 24 and August 25, 2016, 125 eligible patients were recruited and assigned to either nivolumab (n=63) or nivolumab plus ipilimumab (n=62). In the first 108 eligible patients, 12-week disease control was achieved by 24 (44%; 95% CI 31-58) of 54 patients in the nivolumab group and 27 (50%; 37-63) of 54 patients in the nivolumab plus ipilimumab group. In the intention-to-treat population, 12-week disease control was achieved by 25 (40%; 28-52) of 63 patients in the nivolumab group and 32 (52%; 39-64) of 62 patients in the combination group. Nine (14%) of 63 patients in the nivolumab group and 16 (26%) of 61 patients in the combination group had grade 3-4 toxicities. The most frequent grade 3 adverse events were asthenia (one [2%] in the nivolumab group vs three [5%] in the combination group), asymptomatic increase in aspartate aminotransferase or alanine aminotransferase (none vs four [7%] of each), and asymptomatic lipase increase (two [3%] vs one [2%]). No patients had toxicities leading to death in the nivolumab group, whereas three (5%) of 62 in the combination group did (one fulminant hepatitis, one encephalitis, and one acute kidney failure). INTERPRETATION: Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4 ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials. FUNDING: French Cooperative Thoracic Intergroup.

PROPERTY: study protocol for a randomized, double-blind, multicenter placebo-controlled trial assessing neurotoxicity in patients with metastatic gastrointestinal cancer taking PHYCOCARE® during oxaliplatin-based chemotherapy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common adverse effects of antineoplastic agents, ranging in prevalence from 19% to over 85%. Clinically, CIPN is a predominantly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. The high prevalence of CIPN among cancer patients makes it a major problem for both patients and survivors, as well as for their health care providers, especially because there is currently no single effective method of preventing CIPN; moreover, the options for treating this syndrome are very limited. Phycocyanin, a biliprotein pigment and an important constituent of the blue-green algae Spirulina platensis, has been reported to possess significant antioxidant and radical-scavenging properties, offering protection against oxidative stress, which is one of the hypothetic mechanisms, between others, of CIPN occurrence. METHODS: Our hypothesis is that phycocyanin may give protection against oxaliplatin-induced neuropathy in the treatment of gastrointestinal cancers. Our trial will be a randomized double-blind placebo-controlled study with 110 randomized patients suffering from metastatic gastrointestinal adenocarcinoma including esogastric, colorectal, and pancreatic cancers. Patients are being followed up in the gastroenterology or oncology departments of seven French hospitals. DISCUSSION: Due to the neuropathy, patients need to avoid injury by paying careful attention to home safety; patients' physicians often prescribe over-the-counter pain medications. If validated, our hypothesis should help to limit neurotoxicity without the need to discontinue chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT05025826. First published on August 27, 2021.

Can we predict chemo-induced hematotoxicity in elderly patients treated with pegylated liposomal doxorubicin? Results of a population-based model derived from the DOGMES phase II trial of the GINECO.

INTRODUCTION: Use of anthracyclines is often limited in older patients due to cardiac and hematologic toxicities. Thanks to its reduced toxicity profile, Pegylated Liposomal Doxorubicin (PLD) allows an extended use of doxorubicin to this population. We aimed at modeling PLD-induced hematotoxicity in patients with metastatic breast cancer ≥70 years old and at finding predictive factors of neutrophil nadir value. METHODS: Sixty patients, enrolled in the DOGMES prospective multicentric phase II trial, were treated with PLD at 40mg/m(2) every 28days during six cycles. Trial design included geriatric covariates assessment at inclusion and monitoring of cells count every week for three cycles. A population model was developed to describe hematopoiesis and hematopoietic reserve in these patients. The effect of co-administered G-CSF (granulocyte colony-stimulating factor) was also examined. RESULTS: A pharmacodynamic model was built using data from 53 patients not receiving G-CSF. This model assumed an instantaneous effect of PLD on the system. Based on this model, exact neutrophil nadir value was computed and ranged between 0.069K/mm(3) and 2.63K/mm(3) confirming the weak hematotoxicity of PLD. The same model was then applied to the 7 patients receiving G-CSF and showed that basal neutrophil count was higher for these patients. No other difference was found between both cohorts. Among the covariates collected, three were predictive of neutrophil nadir value: diabetes, frailty syndrome and assistance at home. CONCLUSION: This developed model allowed the identification of predictive factors of nadir ANC and the identification of patients that are more likely to develop hematotoxicity that should be monitored with attention.

Cytotoxic T cell responses against mesothelioma by apoptotic cell-pulsed dendritic cells.

Malignant pleural mesothelioma is an uncommon tumor largely confined to the thoracic cavity, which is resistant to conventional therapies, therefore prompting an intensive search for effective treatment alternatives. This study focuses on dendritic cell (DC) vaccination for malignant pleural mesothelioma and evaluates the in vitro efficacy of antigen-loaded DC-based vaccines for the induction of major histocompatibility complex Class I-restricted antimesothelioma cytotoxic T lymphocyte responses. The source of tumor-associated antigens for HLA-A2(+) DCs from healthy donors was apoptotic HLA-A2(-) mesothelioma cells either lacking or expressing heat shock protein 70 according to whether tumor cells were heat shocked or not before ultraviolet-mediated apoptosis. Our results show that both apoptotic preparations were equivalent regarding the responsiveness of DCs to combined treatment with tumor necrosis factor-alpha and poly(inosinic-cytidylic) acid, as determined by similar increased expression of costimulatory molecules and interleukin-12 production. However, only DCs loaded with apoptotic heat shock protein 70-expressing cells were found to be potent in vitro inducers of cytotoxic T lymphocyte activity against HLA-A2(+) mesothelioma cells. Such elicited cytotoxic T lymphocytes also exhibit cytotoxic activity against an HLA-A2(+) melanoma cell line, suggesting recognition of shared antigens. These findings therefore carry the potential of offering an alternative, promising approach for the therapy of patients with malignant pleural mesothelioma.