Nutritional Status, Body Surface, and Low Lean Body Mass/Body Mass Index Are Related to Dose Reduction and Severe Gastrointestinal Toxicity Induced by Afatinib in Patients With Non-Small Cell Lung Cancer.

BACKGROUND: The main reason for dose reduction of afatinib is gastrointestinal toxicity (GT). In a phase II study, we analyzed anthropometrical, nutritional, and biochemical factors associated with GT induced by afatinib. MATERIALS AND METHODS: Patients diagnosed with non-small cell lung cancer who progressed to prior chemotherapy received 40 mg of afatinib. Malnutrition was determined by Subjective Global Assessment, and lean body mass (LBM) was determined by computed tomography scan analysis using a pre-established Hounsfield unit threshold. Toxicity was obtained during four cycles by Common Terminology Criteria for Adverse Events. RESULTS: Eighty-four patients were enrolled. Afatinib was administered as the second, third, and fourth line of treatment in 54.8%, 38.1%, and 7.12% of patients, respectively. Severe diarrhea, mucositis, and overall severe GT were present in 38.9%, 28.8%, and 57.5%, respectively. Of the patients, 50% developed dose-limiting toxicity (DLT). Patients with malnutrition have higher risk for severe GT. Patients with lower LBM and body mass index developed more DLT (71.4% vs. 18.8%). CONCLUSION: Malnutrition is associated with a higher risk of severe GT induced by afatinib. Determination of nutritional status and body composition are helpful in identifying patients at higher risk of severe GT and could allow initiating treatment with lower doses according to tolerance.

Nitroglycerin Plus Whole Intracranial Radiation Therapy for Brain Metastases in Patients With Non-Small Cell Lung Cancer: A Randomized, Open-Label, Phase 2 Clinical Trial.

PURPOSE: Hypoxia has been associated with chemoradioresistance secondary to vascular endothelial growth factor receptor induced by hypoxia-induced factor (HIF). Nitroglycerin (NTG) can reduce HIF-1 in tissues, and this may have antiangiogenic, proapoptotic, and antiefflux effects. Particularly, epidermal growth factor-mutated (EGFRm) tumor cell lines have been shown to overexpress both vascular endothelial growth factor and HIF. In this phase 2 study, we evaluated the effect of transdermal NTG plus whole brain radiation therapy (WBRT) in patients with non-small cell lung cancer (NSCLC) with brain metastases (BM). METHODS: This was an open-label, phase 2 clinical trial with 96 patients with NSCLC and BM. Patients were randomized 1:1 to receive NTG plus WBRT (30 Gy in 10 fractions) or WBRT alone. The primary endpoint was intracranial objective response rate (iORR) evaluated 3 months posttreatment. NTG was administered using a transdermal 36-mg patch from Monday through Friday throughout WBRT administration (10 days). The protocol was retrospectively registered at ClinicalTrials.gov (NCT04338867). RESULTS: Fifty patients were allocated to the control group, and 46 were allocated to the experimental group (NTG); among these, 26 (52%) had EGFRm in the control group and 21 (45.7%) had EGFRm in the NTG arm. In terms of the iORR, patients in the NTG group had a significantly higher response compared with controls (56.5% [n = 26/46 evaluable patients] vs 32.7% [n = 16/49 evaluable patients]; relative risk, 1.73; 95% confidence interval [CI], 1.08-2.78; P = .024). Additionally, patients who received NTG + WBRT had an independently prolonged intracranial progression-free survival (ICPFS) compared with those who received WBRT alone (27.7 vs 9.6; hazard ratio [HR], 0.5; 95% CI, 0.2-0.9; P = .020); this positively affected overall progression-free survival among patients who received systemic therapy (n = 88; HR, 0.5; 95% CI, 0.2-0.9; P = .043). The benefit of ICPFS (HR, 0.4; 95% CI, 0.2-0.9; P = .030) was significant in the EGFRm patient subgroup. No differences were observed in overall survival. A significantly higher rate of vomiting presented in the NTG arm of the study (P = .016). CONCLUSIONS: The concurrent administration of NTG and radiation therapy improves iORR and ICPFS among patients with NSCLC with BM. The benefit in ICPFS is significant in the EGFRm patient subgroup.

Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients.

BACKGROUND: Afatinib has shown long progression free survival and improvement in quality of life in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Although afatinib causes acneiform rash, it can be manageable. Tetracyclines are usually used to treat it; nonetheless, there is no trial that evaluates their prophylactic efficacy on afatinib induced-skin toxicities (AIST). PATIENTS AND METHODS: This open-label, randomized, controlled trial assessed the preventive effect of tetracycline for reducing afatinib-skin toxicities in NSCLC patients receiving afatinib 40 mg/day. Patients were randomly assigned to receive pre-emptive treatment with tetracycline 250 mg every 12h for 4 weeks or not. Reactive treatment in both groups included general dermatological recommendations such as use of skin moisturizers, sunscreen and topical steroids, according to toxicity severity. All patients were blindly monitored for skin toxicities by an expert dermatologist at the start of treatment with afatinib (day 0), weeks 2 and 4 of treatment. The protocol is registered on clinicaltrials.gov (NCT01880515). RESULTS: We included 90 patients, no differences were found in clinical and dermatological baseline characteristics. Rash incidence of any grade, and grade ≥2 was less frequent in the pre-emptive arm vs. the control arm (44.5 vs. 75.6%, RR 0.4 [95% CI 0.17-0.99], p=0.046 and 15.6 vs. 35.6%, RR 0.35 [95% CI, 0.12-0.91], p=0.030, respectively). No difference was found in paronychia, xerosis, mucositis, folliculitis, and skin fissure. No adverse event was associated with tetracycline. Neither rash nor pre-emptive tetracycline impacted on response rate, progression-free or overall survivals. CONCLUSION: Pre-emptive tetracycline was well tolerated and reduced the rash incidence and severity associated with afatinib in more than 60%.

A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma.

PURPOSE: Low-dose, prolonged infusion of gemcitabine has effects similar to standard doses in several cancers. We evaluated the toxicity and efficacy of low-dose gemcitabine in prolonged infusion plus cisplatin in patients with advanced pleural mesothelioma. METHODS: Patients with mesothelioma received gemcitabine (250 mg/m(2)) in a 6-h infusion plus cisplatin (35 mg/m(2)) on days 1 and 8 every three weeks. We used the modified response evaluation criteria in solid tumours. This study is registered in clinical trials (NCT01869023). RESULTS: We included 39 patients; 82.1 % were low risk according to the European Organisation for Research and Treatment of Cancer prognostic group. Partial response was observed in 53.8 % (21/39), stable disease in 33.3 % (13/39) and progression in 12.8 % (5/39). The median progression-free survival was 6.9 months (95 % CI 3.2-10.6 months), and the associated factors were the EORTC risk and histology. The median overall survival was 20.7 months (95 % CI 10.7-30.8 months). The functional, physical and emotional roles and dyspnoea, insomnia and pain symptom scales improved. The most commonly graded 3/4 side effects were neutropenia (24.4 %), lymphopenia (14.6 %), thrombocytopenia (14.7 %) and anaemia (12.2 %). CONCLUSIONS: Low-dose, prolonged gemcitabine infusion plus cisplatin has acceptable toxicity and high efficacy with improved quality of life, representing an affordable regimen for the low-income population.