Systematic vitamin D supplementation is associated with improved outcomes and reduced thyroid adverse events in patients with cancer treated with immune checkpoint inhibitors: results from the prospective PROVIDENCE study.

BACKGROUND: Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs). METHODS: We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion. RESULTS: Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34-0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40-0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03-0.85). CONCLUSION: The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs.

Radiotherapy of non-small-cell lung cancer in the era of EGFR gene mutations and EGF receptor tyrosine kinase inhibitors.

Non-small-cell lung cancer (NSCLC) occurs, approximately, in 80-85% of all cases of lung cancer. The majority of patients present locally advanced or metastatic disease when diagnosed, with poor prognosis. The discovery of activating mutations in the EGFR gene has started a new era of personalized treatment for NSCLC patients. To improve the treatment outcome in patients with unresectable NSCLC and, in particular, EGFR mutated, a combined strategy of radiotherapy and medical treatment can be undertaken. In this review we will discuss preclinical data regarding EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) and radiotherapy, available clinical trials investigating efficacy and toxicity of combined treatment (thoracic or whole brain radiotherapy and EGFR-TKIs) and, also, the role of local radiation in mutated EGFR patients who developed EGFR-TKI resistance.

Granulocyte growth factors in the treatment of non-small cell lung cancer (NSCLC).

Neutropenia and subsequent infections are common events that limit treatment of non-small cell lung cancer (NSCLC). Granulocyte growth factors (G- and GM-CSF) have been introduced in clinical practice and their use has yielded a reduction of the infection risk related to chemotherapy and a dose increase of drug delivery. Randomized clinical trials have shown that granulocyte colony-stimulating factors and, more recently, the longer-acting pegylated granulocyte colony-stimulating factor (pegfilgrastim) effectively reduce the incidence and severity of neutropenia and of its complications. Recommendations for the use of haematopoietic colony-stimulating factors from the American Society of Clinical Oncology (ASCO) have been published in 1994 and updated in 1996, 1997 and 2000. Recently, moreover, National Comprehensive Cancer Network (NCCN) guidelines for the myeloid growth factors in cancer treatment make available. Chemotherapy-associated myelosuppression is a major limitation of anticancer therapy also in early stage, local advanced and metastatic NSCLC. Recently, dose-dense chemotherapy has been shown to improve the outcome in early stage breast cancer and non-Hodgkin's lymphoma. However, few randomized trials have been reported on chemotherapy with or without granulocyte growth factors as primary prophylaxis in NSCLC. Presently, there is no evidence for a benefit in response rate and survival from the use of granulocyte growth factors as support of chemotherapy, in particular, for locally advanced and metastatic NSCLC. In clinical practice, the role of granulocyte growth factors for NSCLC treatment should be limited following the guidelines. An appropriate use of granulocyte growth factors may reduce the overall cost of treatment and improve the quality of life, important aims in the treatment of patients with local advanced or metastatic NSCLC. In the future, we need to identify patients who can benefit from granulocyte growth factors for optimize the schedule and doses, in advanced disease and also, after the recent positive results of adjuvant chemotherapy, in early stages. This review summarizes the present knowledge on the use of granulocyte growth factors in NSCLC.