Postoperative Radiotherapy and the Role of Regional Lymph Node Irradiation in Localized Merkel Cell Carcinoma: A Single-Center Retrospective Analysis.

The aim of this study was to analyze the pattern of relapse of patients with Merkel cell carcinoma (MCC) that underwent resection of the primary tumor site and postoperative radiotherapy at the Department of Radiation Oncology of Heidelberg University and to determine the role of the elective radiotherapy of regional lymph nodes with respect to SLNB results. A total of 57 patients were included in the present retrospective analysis. A total of 33 patients had additional lymph node irradiation (LNI); 24 had postoperative radiotherapy of the tumor bed only. Median follow-up was 43 months. Recurrence rate of the total cohort was 22.8%. Most relapses (69%) occurred in the regional nodes. Cumulative infield-tumor recurrence rate was low with 5.3%. Regional recurrence was more frequent in the cohort without LNI with 85.7% versus 37.5% with LNI. These results were similar for patients with negative sentinel lymph node (SLN) only with 80% regional relapses for those without LNI versus 33% with LNI. In conclusion, our data show that regional recurrence is the most frequent site of relapse in stage I-III MCC treated with curative intended postoperative radiotherapy and that elective irradiation of the regional lymph nodes reduces the risk of regional relapse even if the SLN was negative.

High-risk patients with locally advanced non-small cell lung cancer treated with stereotactic body radiation therapy to the peripheral primary combined with conventionally fractionated volumetric arc therapy to the mediastinal lymph nodes.

Introduction: A very narrow therapeutic window exists when delivering curative chemoradiotherapy for inoperable locally advanced non-small cell lung cancer (NSCLC), particularly when large distances exist between areas of gross disease in the thorax. In the present study, we hypothesize that a novel technique of stereotactic body radiation therapy (SBRT) to the primary tumor in combination with volumetric arc therapy (VMAT) to the mediastinal lymph nodes (MLN) is a suitable approach for high-risk patients with large volume geographically distant locally advanced NSCLC. Patients and methods: In this single institutional review, we identified high-risk patients treated between 2014 and 2017 with SBRT to the parenchymal lung primary as well as VMAT to the involved MLN using conventional fractionation. Dosimetrically, comparative plans utilizing VMAT conventionally fractionated delivered to both the primary and MLN were analyzed. Clinically, toxicity (CTCAE version 5.0) and oncologic outcomes were analyzed in detail. Results: A total of 21 patients were identified, 86% (n=18) of which received chemotherapy as a portion of their treatment. As treatment phase was between 2014 and 2017, none of the patients received consolidation immunotherapy. Target volume (PTV) dose coverage (99 vs. 87%) and CTV volume (307 vs. 441 ml) were significantly improved with SBRT+MLN vs. for VMAT alone (p<0.0001). Moreover, low-dose lung (median V5Gy [%]: 71 vs. 77, p<0.0001), heart (median V5Gy [%]: 41 vs. 49, p<0.0001) and esophagus (median V30Gy [%]: 54 vs. 55, p=0.03) dose exposure were all significantly reduced with SBRT+MLN. In contrast, there was no difference observed in high-dose exposure of lungs, heart, and spinal cord. Following SBRT+MLN treatment, we identified only one case of high-grade pneumonitis. As expected, we observed a higher rate of esophagitis with a total of seven patients experience grade 2+ toxicity. Overall, there were no grade 4+ toxicities identified. After a median 3 years follow up, disease progression was observed in 70% of patients irradiated using SBRT+MLN, but never in the spared 'bridging' tissue between pulmonary SBRT and mediastinal VMAT. Conclusion: For high risk patients, SBRT+MLN is dosimetrically feasible and can provide an alternative to dose reductions necessitated by otherwise very large target volumes.

Safety and Efficacy of Stereotactic Body Radiotherapy in Ultracentral Lung Tumors Using a Risk-optimized Fractionation Scheme.

BACKGROUND: Delivery of stereotactic body radiotherapy (SBRT) to ultracentral lung tumors remains a major challenge, with potentially excessive SBRT-related toxicity. This study investigates a risk-optimized approach to ultracentral SBRT in an elderly and comorbid patient cohort. PATIENTS AND METHODS: Analysis encompassed 129 patients (mean age: 70 ± 11 years, median Charlson comorbidity index: 4 [range, 3-5]) following risk-adapted SBRT to central or ultracentral primary and secondary lung tumors between 2012 and 2019 (78 central, 51 ultracentral). Ultracentral tumors were defined by planning target volume overlap with the proximal bronchial tree. Whereas ultracentral tumors were treated with a risk-optimized fractionation scheme of 50 Gy in 10 fractions, central tumors received higher-fractionated 60 Gy in 8 fractions. Outcome parameters and toxicity for ultracentral and central tumors were assessed using Kaplan-Meier and competing risk analyses. RESULTS: Local failure rate was not significantly increased in ultracentral tumors compared with central tumors (2-year local failure rate ultracentral, 26.9%; 95% confidence interval [CI], 12.2%-44.2%; central, 14.6%; 95% CI, 6.6%-25.5%; P = .17). Overall survival was similar in both groups (2-year overall survival central, 55.4%; 95% CI, 44.5%-68.9%; ultracentral, 54.9%; 95% CI, 40.8%-73.9%; P = .6). Toxicity was moderate, with toxicity ≥ grade 3 rates of 15.3% (95% CI, 5.9%-28.9%) for ultracentral and 7.3% (95% CI, 2.7%-15.0%) for central tumors after 2 years (P = .27). No grade 4 toxicity and only 1 potential grade 5 toxicity were observed in the ultracentral cohort. CONCLUSION: Risk-optimized SBRT to ultracentral lung tumors is a reasonably effective and safe treatment alternative in frail patients.

Impact of the Monocarboxylate Transporter-1 (MCT1)-Mediated Cellular Import of Lactate on Stemness Properties of Human Pancreatic Adenocarcinoma Cells †.

Metabolite exchange between stromal and tumor cells or among tumor cells themselves accompanies metabolic reprogramming in cancer including pancreatic adenocarcinoma (PDAC). Some tumor cells import and utilize lactate for oxidative energy production (reverse Warburg-metabolism) and the presence of these "reverse Warburg" cells associates with a more aggressive phenotype and worse prognosis, though the underlying mechanisms are poorly understood. We now show that PDAC cells (BxPc3, A818-6, T3M4) expressing the lactate-importer monocarboxylate transporter-1 (MCT1) are protected by lactate against gemcitabine-induced apoptosis in a MCT1-dependent fashion, contrary to MCT1-negative PDAC cells (Panc1, Capan2). Moreover, lactate administration under glucose starvation, resembling reverse Warburg co a phenotype of BxPc3 and T3M4 cells that confers greater potential of clonal growth upon re-exposure to glucose, along with drug resistance and elevated expression of the stemness marker Nestin and reprogramming factors (Oct4, KLF4, Nanog). These lactate dependent effects on stemness properties are abrogated by the MCT1/lactate-uptake inhibitor 7ACC2 or MCT1 knock-down. Furthermore, the clinical relevance of these observations was supported by detecting co-expression of MCT1 and reprogramming factors in human PDAC tissues. In conclusion, the MCT1-dependent import of lactate supplies "reverse Warburg "PDAC cells with an efficient driver of metabostemness. This condition may essentially contribute to malignant traits including therapy resistance.

Progression of Pulmonary Function and Correlation with Survival Following Stereotactic Body Radiotherapy of Central and Ultracentral Lung Tumors.

Stereotactic body radiotherapy (SBRT) to central and ultracentral lung tumors carries a risk of excessive toxicity. This study analyzed changes in pulmonary function tests (PFT) and their correlation with overall survival (OS) in 107 patients following central (n = 62) or ultracentral (n = 45) lung SBRT. Ultracentral location was defined as planning target volume overlap with the proximal bronchial tree (PBT). Vital capacity (VC) (-0.3 l, absolute -9.4% of predicted, both p < 0.001) and forced expiratory volume in the first second (FEV1s) (-0.2 l, absolute -7.7% of predicted, both p < 0.001) significantly decreased following SBRT. Higher maximum dose to the PBT significantly correlated with a steeper decline in VC (p = 0.005) and FEV1s (p = 0.03) over time. Pronounced decline in FEV1s between 6 and 12 months (HR = 0.90, p = 0.006) and pronounced decline in VC between baseline and 12 months (HR = 0.95, p = 0.004) independently correlated with worse OS. Consequently, PFT presented a statistically significant albeit clinically mild decrease in lung volumes following central and ultracentral SBRT that correlated moderately with maximum dose to the PBT. Stronger decline in pulmonary function was associated with constrained survival, advocating consequent performance of PFT during follow-up.