Phase II Study of Dichloroacetate (DCA) in Combination with Chemoradiotherapy for Unresected, Locally Advanced Head and Neck Squamous Cell Carcinoma

Background: Chemoradiotherapy (CRT) for locally-advanced head and neck squamous cell carcinoma (LA-HSNCC) yields 5-year survival rates near 50% despite causing significant toxicity. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase metabolic inhibitor, reduces tumor lactate production and has been used in cancer therapy previously. The safety of adding this agent to CRT is unknown. Methods: Our randomized, placebo-controlled, double-blind phase II study added DCA to cisplatin-based CRT in patients with LA-HNSCC. The primary endpoint was safety by adverse events (AEs). Secondary endpoints compared efficacy via 3-month end-of-treatment response, 5-year progression-free and overall survival. Translational research evaluated pharmacodynamics of serum metabolite response. Results: 45 participants (21 DCA, 24 Placebo) were enrolled from May 2011-April 2014. Higher rates of all-grade drug related fevers (43% vs 8%, p = 0.01) and decreased platelet count (67% vs 33%, p = 0.02) were seen in DCA versus placebo. However, there were no significant differences in grade 3/4 AE rates. Treatment compliance to DCA/placebo, radiation therapy, and cisplatin showed no significant difference between groups. While end-of-treatment complete response rates were significantly higher in the DCA group compared to placebo (71.4% vs 37.5%, p = 0.0362), survival outcomes were not significantly different between groups. Treatment to baseline metabolites demonstrated a significant drop in pyruvate (0.47, p <0.005) and lactate (0.61, p <0.005) in the DCA group. Conclusions: Adding DCA to cisplatin-based CRT appears safe with no detrimental effect on survival and expected metabolite changes compared to placebo. This supports further investigation into combining metabolic agents to CRT.Trial registration number: NCT01386632, Date of Registration: July 1, 2011.

DOSIMETRIC ANALYSIS OF ADAPTIVE RADIOTHERAPY(ART) IN LOCALLY ADVANCED HEAD AND NECK CANCER

PURPOSE/OBJECTIVE: The objective of this study is to evaluate the dosimetric parameters in adaptive radiotherapy for locally advanced head and neck cancers METHODS AND MATERIALS: This is a Hospital-based Prospective study conducted in the period from Dec 2020 to March 2021. Histologically proven Head and Neck Carcinoma patients with Stage III to IV (locally advanced) were selected for the study. A total of 10 patients receiving denitive, conformal radiation therapy to the head and neck region were evaluated for the study. After the acquisition of CT images, target volumes, OARs were contoured in the planning CT. Images were again acquired midway during the planned course of radiation therapy. Body contours, target volumes, and organs at risk were redrawn on the new set of images. Two sets of additional treatment plans were generated: 1) a non-optimized plan (plan 2), which is an overlay of the original plan (plan 1) on the new set of contours, and 2) an optimized plan(plan 3) with the new set of contours. These 3 sets of plans were then compared for dosimetric differences. RESULTS: Four patients had locally advanced nasopharyngeal cancers, 4 patients had locally advanced oropharyngeal cancers, 2 patients had locally advanced hypopharyngeal cancer. The average reduction in gross tumour volume was 37.1 ml. The average changes in right and left parotid volume were 5.94 and 5.49 ml, respectively. With the non-optimized plan, the average increase in the maximum dose to the spinal cord was 9.8% (58.96-68.76; p= 0.156). With reoptimization, the maximum dose to the spinal cord decreased from 68.76% to 54.97% (mean difference, -13.79%, p=0.03). The average D99 for the planning target volume( dose received by 99% of the target volume) was 98.68% and 98.65% with the original and reoptimized plans, respectively. Most of the patients during radiation had Grade 2 skin toxicity and Grade 2 mucositis which was managed conservatively. CONCLUSIONS: This study demonstrates that during radiation there is gross changes of volumes in locally advanced head and neck cancers and thus adaptive radiation therapy plays a pivotal role in locally advanced head and neck cancer