Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2022 Jun;40(3):622-633.
doi: 10.1007/s10637-022-01235-5. Epub 2022 Mar 21.

Phase II study of dichloroacetate, an inhibitor of pyruvate dehydrogenase, in combination with chemoradiotherapy for unresected, locally advanced head and neck squamous cell carcinoma

Steven F Powell  1   2   3 , Miroslaw Mazurczak  4   5   6 , Elie G Dib  7 , Jonathon S Bleeker  4   5   6 , Louis H Geeraerts  8 , Matthew Tinguely  8 , Michele M Lohr  4   6 , Steven C McGraw  4   6 , Ashley W Jensen  8 , Christie A Ellison  5 , Lora J Black  5   6 , Susan E Puumala  9 , Valerie J Reed  5 , W Keith Miskimins  5 , John H Lee  6   10 , William C Spanos  4   5   6
Affiliations
Clinical Trial

Phase II study of dichloroacetate, an inhibitor of pyruvate dehydrogenase, in combination with chemoradiotherapy for unresected, locally advanced head and neck squamous cell carcinoma

Steven F Powell et al. Invest New Drugs. 2022 Jun.

Abstract

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. 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. 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. 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.

Keywords: Chemoradiotherapy; Dichloroacetate; Head and neck cancer; Tumor microenvironment.

PubMed Disclaimer

Conflict of interest statement

Disclosure of potential conflicts of interest: Steven Powell has received research grant support to the institution from Merck, Bristol Myers Squib, Pfizer, Vyriad, Incyte, Actuate, Genentech, Seattle Genetics anded consulting support to the institution from Bristol Myers Squibb. William Spanos received consulting support for Bristol Myers Squibb, Regeneron, and Merck. The other authors declare no conflict of interest.

Figures

Fig. 1:
Fig. 1:. Kaplan-Meier Estimates of Survival with Subgroup Analysis of Overall Survival.
(a) 5-year Overall Survival based on HPV status and treatment group (b) 5-year Progression-Free Survival based on HPV status and treatment group (c) Hazard Ratios from Proportional Hazards Regression. Each covariate subgroup was included in a model with treatment group and interaction. Hazard ratios and 95% confidence intervals are presented for the interaction. For sex, only males could be assessed since there were no females in the DCA group.
Fig. 1:
Fig. 1:. Kaplan-Meier Estimates of Survival with Subgroup Analysis of Overall Survival.
(a) 5-year Overall Survival based on HPV status and treatment group (b) 5-year Progression-Free Survival based on HPV status and treatment group (c) Hazard Ratios from Proportional Hazards Regression. Each covariate subgroup was included in a model with treatment group and interaction. Hazard ratios and 95% confidence intervals are presented for the interaction. For sex, only males could be assessed since there were no females in the DCA group.
Fig. 2:
Fig. 2:. Changes in Glycolysis and TCA Cycle.
Representative changes in metabolite ratio based on key points in TCA cycle and glycolysis were evaluated based on key points in the pathway as shown (a). Results are reported descriptively as outlined in box plot (b) and tabular format (c) with statistical comparison using ANOVA. Briefly, change in serum treatment vs baseline levels of key glycolytic and TCA cycle metabolites were more apparent in the DCA group. Levels of pyruvate and lactate were decreased in the treatment vs baseline comparison of the DCA-exposed group. Levels of acetylcarnitine (in equilibrium with acetyl-CoA) were also elevated. Changes related to the DCA administration were also detected in the TCA cycle intermediates, manifesting as lower levels of citrate and citraconate/glutaconate (detected as an isobar) and accumulation of 2-methylcitrate/homocitrate (DCA-treatment vs DCA-baseline). Statistical legend for metabolites: Red and green shaded cells indicate p≤0.05 (red indicates that the mean values are significantly higher for that comparison; green values significantly lower). Light red and light green shaded cells indicate 0.05
See this image and copyright information in PMC

References

    1. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, Glisson B, Trotti A, Ridge JA, Chao C, Peters G, Lee D-J, Leaf A, Ensley J, Cooper J: Concurrent Chemotherapy and Radiotherapy for Organ Preservation in Advanced Laryngeal Cancer. N. Engl. J. Med 349, 2091–2098 (2003). 10.1056/NEJMoa031317 - DOI - PubMed
    1. Adelstein DJ, Li Y, Adams GL, Wagner H, Kish JA, Ensley JF, Schuller DE, Forastiere AA: An Intergroup Phase III Comparison of Standard Radiation Therapy and Two Schedules of Concurrent Chemoradiotherapy in Patients With Unresectable Squamous Cell Head and Neck Cancer. J. Clin. Oncol 21, 92–98 (2003). 10.1200/JCO.2003.01.008 - DOI - PubMed
    1. Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, Morrison W, Glisson B, Trotti A, Ridge JA, Thorstad W, Wagner H, Ensley JF, Cooper JS: Long-Term Results of RTOG 91-11: A Comparison of Three Nonsurgical Treatment Strategies to Preserve the Larynx in Patients With Locally Advanced Larynx Cancer. J. Clin. Oncol 8 (2013) - PMC - PubMed
    1. Jean-Pierre Pignon E, Aurélie le Maître: 1.Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. 10.1016/j.radonc.2009.04.014 - DOI - PubMed
    1. Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, Galvin JM, Bonner JA, Harris J, El-Naggar AK, Gillison ML, Jordan RC, Konski AA, Thorstad WL, Trotti A, Beitler JJ, Garden AS, Spanos WJ, Yom SS, Axelrod RS: Randomized Phase III Trial of Concurrent Accelerated Radiation Plus Cisplatin With or Without Cetuximab for Stage III to IV Head and Neck Carcinoma: RTOG 0522. J. Clin. Oncol 32, 2940–2950 (2014). 10.1200/JCO.2013.53.5633 - DOI - PMC - PubMed

Publication types

MeSH terms

Associated data