PMID- 35312941
OWN - NLM
STAT- MEDLINE
DCOM- 20220517
LR  - 20230602
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 40
IP  - 3
DP  - 2022 Jun
TI  - Phase II study of dichloroacetate, an inhibitor of pyruvate dehydrogenase, in 
      combination with chemoradiotherapy for unresected, locally advanced head and neck 
      squamous cell carcinoma.
PG  - 622-633
LID - 10.1007/s10637-022-01235-5 [doi]
AB  - 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.
CI  - (c) 2022. The Author(s), under exclusive licence to Springer Science+Business 
      Media, LLC, part of Springer Nature.
FAU - Powell, Steven F
AU  - Powell SF
AUID- ORCID: 0000-0002-5029-0048
AD  - Sanford Cancer Center, 1309 W. 17th Street, Suite 101, Sioux Falls, SD, 57104, 
      USA. Steven.Powell@sanfordhealth.org.
AD  - Sanford Research, 301 East 60th St N, Sioux Falls, SD, 57104, USA. 
      Steven.Powell@sanfordhealth.org.
AD  - University of South Dakota Sanford School of Medicine, 414 E. Clark St., 
      Vermillion, SD, 57069, USA. Steven.Powell@sanfordhealth.org.
FAU - Mazurczak, Miroslaw
AU  - Mazurczak M
AD  - Sanford Cancer Center, 1309 W. 17th Street, Suite 101, Sioux Falls, SD, 57104, 
      USA.
AD  - Sanford Research, 301 East 60th St N, Sioux Falls, SD, 57104, USA.
AD  - University of South Dakota Sanford School of Medicine, 414 E. Clark St., 
      Vermillion, SD, 57069, USA.
FAU - Dib, Elie G
AU  - Dib EG
AD  - St. Joseph Mercy Cancer Center, 5301 Elliott Dr. Ste 210, Ypsilanti, MI, 48197, 
      USA.
FAU - Bleeker, Jonathon S
AU  - Bleeker JS
AD  - Sanford Cancer Center, 1309 W. 17th Street, Suite 101, Sioux Falls, SD, 57104, 
      USA.
AD  - Sanford Research, 301 East 60th St N, Sioux Falls, SD, 57104, USA.
AD  - University of South Dakota Sanford School of Medicine, 414 E. Clark St., 
      Vermillion, SD, 57069, USA.
FAU - Geeraerts, Louis H
AU  - Geeraerts LH
AD  - Sanford Roger Maris Cancer Center, 820 4th St N, Fargo, ND, 58102, USA.
FAU - Tinguely, Matthew
AU  - Tinguely M
AD  - Sanford Roger Maris Cancer Center, 820 4th St N, Fargo, ND, 58102, USA.
FAU - Lohr, Michele M
AU  - Lohr MM
AD  - Sanford Cancer Center, 1309 W. 17th Street, Suite 101, Sioux Falls, SD, 57104, 
      USA.
AD  - University of South Dakota Sanford School of Medicine, 414 E. Clark St., 
      Vermillion, SD, 57069, USA.
FAU - McGraw, Steven C
AU  - McGraw SC
AD  - Sanford Cancer Center, 1309 W. 17th Street, Suite 101, Sioux Falls, SD, 57104, 
      USA.
AD  - University of South Dakota Sanford School of Medicine, 414 E. Clark St., 
      Vermillion, SD, 57069, USA.
FAU - Jensen, Ashley W
AU  - Jensen AW
AD  - Sanford Roger Maris Cancer Center, 820 4th St N, Fargo, ND, 58102, USA.
FAU - Ellison, Christie A
AU  - Ellison CA
AD  - Sanford Research, 301 East 60th St N, Sioux Falls, SD, 57104, USA.
FAU - Black, Lora J
AU  - Black LJ
AD  - Sanford Research, 301 East 60th St N, Sioux Falls, SD, 57104, USA.
AD  - University of South Dakota Sanford School of Medicine, 414 E. Clark St., 
      Vermillion, SD, 57069, USA.
FAU - Puumala, Susan E
AU  - Puumala SE
AD  - University of South Dakota School of Health Sciences, 414 E. Clark St., 
      Vermillion, SD, 57069, USA.
FAU - Reed, Valerie J
AU  - Reed VJ
AD  - Sanford Research, 301 East 60th St N, Sioux Falls, SD, 57104, USA.
FAU - Miskimins, W Keith
AU  - Miskimins WK
AD  - Sanford Research, 301 East 60th St N, Sioux Falls, SD, 57104, USA.
FAU - Lee, John H
AU  - Lee JH
AD  - University of South Dakota Sanford School of Medicine, 414 E. Clark St., 
      Vermillion, SD, 57069, USA.
AD  - Avera Cancer Institute, 1000 E 23rd St, Sioux Falls, SD, 57105, USA.
FAU - Spanos, William C
AU  - Spanos WC
AD  - Sanford Cancer Center, 1309 W. 17th Street, Suite 101, Sioux Falls, SD, 57104, 
      USA.
AD  - Sanford Research, 301 East 60th St N, Sioux Falls, SD, 57104, USA.
AD  - University of South Dakota Sanford School of Medicine, 414 E. Clark St., 
      Vermillion, SD, 57069, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01386632
GR  - P20 GM103548/GM/NIGMS NIH HHS/United States
GR  - R01 DE026125/DE/NIDCR NIH HHS/United States
GR  - R01 DE029524/DE/NIDCR NIH HHS/United States
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220321
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Pyruvates)
RN  - 9LSH52S3LQ (Dichloroacetic Acid)
RN  - EC 1.- (Oxidoreductases)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - *Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse 
      effects
MH  - Chemoradiotherapy/adverse effects
MH  - Cisplatin/administration & dosage/adverse effects
MH  - Dichloroacetic Acid/administration & dosage/adverse effects
MH  - *Head and Neck Neoplasms/drug therapy/enzymology/radiotherapy
MH  - Humans
MH  - *Oxidoreductases/antagonists & inhibitors/metabolism
MH  - Pyruvates/metabolism
MH  - *Squamous Cell Carcinoma of Head and Neck/drug therapy/enzymology/radiotherapy
PMC - PMC9106928
MID - NIHMS1798469
OTO - NOTNLM
OT  - Chemoradiotherapy
OT  - Dichloroacetate
OT  - Head and neck cancer
OT  - Tumor microenvironment
COIS- 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.
EDAT- 2022/03/22 06:00
MHDA- 2022/05/18 06:00
PMCR- 2023/06/01
CRDT- 2022/03/21 17:19
PHST- 2021/12/07 00:00 [received]
PHST- 2022/03/11 00:00 [accepted]
PHST- 2022/03/22 06:00 [pubmed]
PHST- 2022/05/18 06:00 [medline]
PHST- 2022/03/21 17:19 [entrez]
PHST- 2023/06/01 00:00 [pmc-release]
AID - 10.1007/s10637-022-01235-5 [pii]
AID - 10.1007/s10637-022-01235-5 [doi]
PST - ppublish
SO  - Invest New Drugs. 2022 Jun;40(3):622-633. doi: 10.1007/s10637-022-01235-5. Epub 
      2022 Mar 21.