A hypothesis for the pathogenesis of radiation-induced oral mucositis: when biological challenges exceed physiologic protective mechanisms. Implications for pharmacological prevention and treatment

Oral mucositis (OM) remains a significant unmet need for patients being treated with standard concomitant chemoradiation (CRT) regimens for head and neck cancers (HNC). OM’s pathogenesis is complex and includes both direct and indirect damage pathways. In this paper, the field is reviewed with emphasis on the initiating and sustaining role of oxidative stress on OM’s pathobiology. A hypothesis is presented which suggests that based on OM’s clinical and biological trajectory, mucosal damage is largely the consequence of cumulative CRT-induced biological changes overwhelming physiologic self-protective mechanisms. Furthermore, an individual’s ability to mount and maintain a protective response is dependent on interacting pathways which are primarily determined by a multiplex consisting of genomics, epigenomics, and microbiomics. Effective biologic or pharmacologic OM interventions are likely to supplement or stimulate existing physiologic damage-control mechanisms.

Role of Chemoradiation (CRT) in the Adjuvant Treatment of Radically Resected Pancreatic Cancer (PC) Patients: A Mono-Institutional Retrospective Analysis.

BackgroundPancreatic cancer (PC) represents an unfavorable prognosis disease, even in patients with resectable disease. The aim of this series was to investigate the role of treatment intensification with adjuvant chemoradiation (CRT) in radically resected PC patients. MethodsData from PC patients undergone radical surgery, adjuvant chemotherapy (CT) and CRT throughout a 20-year period were retrospectively collected. Actuarial local control (LC) and the overall survival (OS) were the primary endpoints, while secondary end-points were the disease-free-survival (DFS) and metastases-free-survival (MFS). ResultsThe analysis included 108 PC patients treated with adjuvant CRT and CT from January 2000 to August 2019. Median age was 66 years (range: 40-83), all patients underwent radical surgical resection with adjuvant chemotherapy (88, 81,5%) plus concomitant chemoradiation (101, 93,5%) or radiotherapy alone (7, 6,5%). The median dose delivered on tumor bed was 50,4 Gy (range: 45-50,6 Gy), while median dose on regional lymphatic drainage stations was 39,6 Gy (range 39,6-45 Gy. Concomitant CT was gemcitabine-based regimen in the vast majority of patients (87, 80.6%). Median follow-up time was 21 months; the 2- and 5-years LC rate were 75,8% and 59,1%, respectively. Perineural invasion (PNI) at pathological assessment was found significantly associated to LC (p=0.028). Median OS was 40 months with 2- and 5-years OS rate of 73.9% and 41,6 % respectively.ConclusionsThe outcomes of this series strongly suggest that the impact of adjuvant CRT should be deeply investigated in PC patients. Timing, combination of modern CRT with new systemic therapies need to be further investigated to personalize therapy and optimize clinical advantages.

Concomitant Chemoradiation Therapy with Gold Nanoparticles and Platinum Drugs Co-Encapsulated in Liposomes

A liposomal formulation of gold nanoparticles (GNPs) and carboplatin, named LipoGold, was produced with the staggered herringbone microfluidic method. The radiosensitizing potential of LipoGold and similar concentrations of non-liposomal GNPs, carboplatin and oxaliplatin was evaluated in vitro with the human colorectal cancer cell line HCT116 in a clonogenic assay. Progression of HCT116 tumor implanted subcutaneously in NU/NU mice was monitored after an irradiation of 10 Gy combined with either LipoGold, GNPs or carboplatin injected directly into the tumor by convection-enhanced delivery. Radiosensitization by GNPs alone or carboplatin alone was observed only at high concentrations of these compounds. Furthermore, low doses of carboplatin alone or a combination of carboplatin and GNPs did not engender radiosensitization. However, the same low doses of carboplatin and GNPs administered simultaneously by encapsulation in liposomal nanocarriers (LipoGold) led to radiosensitization and efficient control of cell proliferation. Our study shows that the radiosensitizing effect of a combination of carboplatin and GNPs is remarkably more efficient when both compounds are simultaneously delivered to the tumor cells using a liposomal carrier.

Effect of cumulative dexamethasone dose during concomitant chemoradiation on lymphopenia in patients with newly diagnosed glioblastoma.

e14533 Background: Lymphopenia frequently occurs after concomitant chemoradiation (CCRT) in patients with glioblastoma (GBM) and is associated with worse overall survival (OS). A few studies have tried to identify risk factors for lymphopenia; however, the results were not clear. We aimed to identify potential risk factors for lymphopenia, focusing on the use of dexamethasone to control cerebral edema in patients with GBM. Methods: The electronic medical records of 180 patients with newly diagnosed GBM treated at our institution between 2009 and 2017 were retrospectively examined. Acute lymphopenia was defined as TLC (total lymphocyte count) less than 1,000 cells/mm3 at 4 weeks after completion of CCRT. Multivariate logistic regression analysis was used to identify independent risk factors for lymphopenia, and Cox regression analysis was used to identify independent risk factors for OS. Results: Of the 125 eligible patients, 40 patients (32.0%) developed acute lymphopenia. Female sex and median daily dexamethasone dose > 2mg after initiation of CCRT were independent risk factors for acute lymphopenia on multivariate analysis. Acute lymphopenia, extent of surgical resection, and performance status were associated with OS; however, dexamethasone use itself was not an independent risk factor for poor OS. Conclusions: Female sex, median daily dexamethasone dose > 2 mg after initiation of CCRT until four weeks after completion of CCRT may be associated with acute lymphopenia. However, dexamethasone use itself did not affect OS in patients newly diagnosed with GBM. These results should be validated by further prospective studies controlling for other confounding factors.

TO COMPARE THE EFFICACY OF CONCOMITANT BOOST RADIOTHERAPY AGAINST CONCURRENT CHEMORADIATION IN LOCALLY ADVANCED HEAD AND NECK CANCER (OROPHARYNX/LARYNX/ HYPOPHARYNX)

Background: Most head and neck cancers, indeed 95% or more, are squamous cell carcinomas (SCC) and variants thereof, originating from the epithelium of the mucosal lining of the upper aerodigestive tract (UADT), and adenocarcinomas from associated secretory glands. Methods: This prospective randomized study was conducted in the Department of Radiation Therapy & Oncology, Regional Cancer Centre, IGMC, Shimla and patients were enrolled for a period of one year, from July 2012 to July 2013.It included all the eligible, previously untreated patients of squamous cell carcinoma of Head and Neck with histologically confirmed diagnosis and no evidence of distant metastasis. The sites included were oro-pharynx, hypo-pharynx and larynx with stages III, IV A and IV B. Results: On first follow up, overall there was complete response at nodal site in 50 patients(69.4%) 26 in CRT arm (70.3%) and 24 in ART arm(68.6%), however the difference was not statistically significant (p=0.875). Conclusion: There was comparable locoregional disease control with the use of accelerated six fractions a week radiation therapy compared to concomitant chemoradiation with conventional fractionation. Keywords: Six fraction, Concomitant chemoradiation, Conventional fractionation.