Association between Genetic Variants and Peripheral Neuropathy in Patients with NSCLC Treated with First-Line Platinum-Based Therapy.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect in non-small cell lung cancer (NSCLC) patients treated with platinum-based therapy. There is increasing evidence for associations between genetic variants and susceptibility to CIPN. The aim of this study was to further explore genetic risk factors for CIPN by investigating previously reported genetic associations. Methods: A multicenter prospective follow-up study (PGxLUNG, NTR NL5373610015) in NSCLC patients (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy was conducted. Clinical evaluation of neuropathy (CTCAE v4.03) was performed at baseline and before each cycle (four cycles, every three weeks) of chemotherapy and at three and six months after treatment initiation. The relationship between 34 single nucleotide polymorphisms (SNPs) in 26 genes and any grade (grade ≥ 1) and severe (grade ≥ 2) CIPN was assessed by using univariate and multivariate logistic regression modelling. Results: In total, 320 patients were included of which 26.3% (n = 84) and 8.1% (n = 26) experienced any grade and severe CIPN, respectively. The GG-genotype (rs879207, A > G) of TRPV1, a gene expressed in peripheral sensory neurons, was observed in 11.3% (n = 36) of the patients and associated with an increased risk of severe neuropathy (OR 5.2, 95%CI 2.1−12.8, adjusted p-value 0.012). A quarter (25%, n = 9/36) of the patients with the GG-genotype developed severe neuropathy compared to 6% (n = 17/282) of the patients with the AG- or AA-genotype. Multivariate logistic regression analysis showed statistically significant associations between the GG-genotype (ORadj 4.7, 95%CI 1.8−12.3) and between concomitant use of paclitaxel (ORadj 7.2, 95%CI 2.5−21.1) and severe CIPN. Conclusions: Patients with the GG-genotype (rs879207) of TRPV1 have an almost 5-fold higher risk of developing severe neuropathy when treated with platinum-based therapy. Future studies should aim to validate these findings in an independent cohort and to further investigated the individualization of platinum-based chemotherapy in clinical practice.

Adjuvant Treatment Following Irradical Resection of Stage I-III Non-small Cell Lung Cancer: A Population-based Study.

Irradical (R1-2) resection for non-small cell lung cancer (NSCLC) is associated with a dismal prognosis. Adjuvant treatment attempts to improve survival outcomes, but evidence on the optimal strategy is limited. The purpose of this study was to compare overall survival (OS) between different adjuvant treatment strategies in these patients. Out of 8,528 patients with newly diagnosed NSCLC from 2015-2018, those with an R1-2 resection were identified from the Netherlands Cancer Registry. First, OS was compared between adjuvant treatment groups 'no therapy', 'radiotherapy (RT) only', 'chemotherapy only', and 'chemo- and radiotherapy (CRT)' using multinomial propensity score-weighted Cox regression analysis. Second, three 1:1 propensity score-matched sets were created for chemotherapy vs no chemotherapy, RT only vs no therapy, and CRT vs chemotherapy only. Kaplan-Meier and Cox regression analyses for OS were performed in each set. With a median follow-up of 23 months, 427 patients were selected. In the weighted regression analysis, compared to no adjuvant therapy, chemotherapy and CRT were associated with improved OS (HR 0.41, 95%CI: 0.22-0.76; and HR 0.55, 95%CI: 0.37-0.81, respectively), whereas RT was not (HR 1.04, 95%CI: 0.73-1.50). In the matched sets, OS was improved after chemotherapy (+/- RT) compared to no chemotherapy (HR 0.47, 95%CI: 0.32-0.69). No OS difference was observed between matched groups of RT only vs no adjuvant therapy (HR 1.13, 95%CI: 0.74-1.72), nor for CRT vs chemotherapy only (HR 1.37, 95%CI: 0.70-2.71). Adjuvant chemotherapy, but not radiotherapy, improves survival after an R1-2 resection in stage I-III NSCLC.

Feasibility of Concomitant Chemoradiotherapy in Daily Practice for Patients with NSCLC Stage III.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC), approximately 25% have locally advanced disease. For patients with irresectable (N2-3 or T4) or inoperable disease, treatment consists of chemoradiotherapy. Concomitant chemoradiotherapy improves survival compared to sequential chemoradiotherapy in these patients. PATIENTS AND METHODS: Treatment plans and completion of treatment was evaluated for all patients treated at the St. Antonius Hospital from 2008-2011 for NSCLC stage IIIA/B not eligible for surgery. RESULTS: Between 2008 and 2011, 180 patients with NSCLC stage III were treated at our hospital. A total of 152 patients were not eligible for surgery; in 78 (51%) patients, primary treatment was chemoradiotherapy; 31 (20%) were planned for concomitant treatment. The most frequent reasons for refraining from concomitant chemoradiotherapy were limitations of radiotherapy constraints and condition of the patients (87%). CONCLUSION: Although concomitant chemoradiotherapy is the standard-of-care in patients with stage IIIA/B NSCLC ineligible for surgery, the majority (80%) of the patients were treated otherwise.