Abstract
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. NCT01386632.
Keywords: Dichloroacetate, chemoradiotherapy, head and neck cancer, tumor microenvironment
Introduction
Chemoradiotherapy (CRT) is the standard-of-care for management of locally-advanced head and neck squamous cell carcinoma (LA-HNSCC) when surgical resection is not feasible or organ preservation is desired [1]. High-dose cisplatin (100 mg/m2 on days 1, 22, and 43 of radiation) has led this treatment paradigm since the Intergroup trial and RTOG 91-11 were reported in 2003 [2, 3]. Despite the approval of novel therapies in this setting, cisplatin-based therapy is still the most widely utilized [4]. Unfortunately, 5-year disease-free survival remains stagnant at 50% [4]. Prior treatment intensification strategies adding novel agents failed to improve survival and caused worse toxicity[5]. Newer therapeutics that limit additive toxicity with cisplatin-based CRT are needed.
The tumor microenvironment (TME) is an important therapeutic target in head and neck cancer[6]. HNSCC consistently undergoes “metabolic reprogramming” which plays a key role in tumor progression by promoting growth, survival, and metastasis[7]. This reprogramming allows a switch from oxidative phosphorylation to glycolysis as a major source of ATP production. The subsequent shift towards anaerobic glycolysis allows for high glycolytic flux and subsequent lactate production in the TME. Previous research demonstrates that this high lactate environment is associated with an unfavorable response to therapy [8-10]. While numerous hypotheses exist around the exact mechanism, data suggest an impaired immune response in the setting of high lactate. High lactate in the TME alters dendritic cell function, inhibits adaptive anti-tumor response, causes a shift towards an immune-suppressive phenotype, and impairs infiltrating CD8+ cytotoxic T lymphocytes [11-14]. Inhibitors of the programmed death-1 (PD-1) receptor and its ligands (PD-L1/L2) on effector immune cells are active agents in recurrent HNSCC [15, 16]. As the field moves to investigate these agents in combination with CRT in LA- HNSCC [17, 18], there is increasing interest in modulating the TME to promote immune response.
Inhibitors of these metabolic derangements may provide a therapeutic approach to combat high lactate production in the TME. Dichloroacetate (DCA) is a metabolic inhibitor that binds and inhibits all 4 isoenzymes of pyruvate dehydrogenase kinase (PDK)[19, 20]. PDK actively contributes to anaerobic glycolysis by limiting entry of pyruvate into oxidative metabolic pathways in mitochondria and is overexpressed in many types of cancer, including HNSCC [21, 22]. By inhibiting PDK, DCA promotes oxidative metabolism of pyruvate rather than its conversion to lactate. In human subjects with metabolic disorders, active dose levels of DCA are defined. Prior studies using DCA as monotherapy at a dose of 6.25 mg/kg to 12.5 mg/kg twice daily (BID) in advanced cancers demonstrated safety and a favorable pharmacokinetic profile [23, 24]. However due to limited efficacy, combination therapeutic approaches should be considered.
Based on this rationale, we performed a randomized phase II study to compare the safety and efficacy of adding DCA vs. placebo to standard HD cisplatin-based CRT in patients with LA-HNSCC. We sought to establish the toxicity profile of adding a metabolic inhibitor to CRT and explore any impact this may have on efficacy.
Materials and Methods
Patient Eligibility
Inclusion criteria included those who were 18 years or older and had histologically, cytologically confirmed and previously untreated American Joint Committee on Cancer (AJCC) 7th edition[25] stage III, IVA or IVB HNSCC eligible for concurrent CRT. Eligible tumor sites included: hypopharynx, oropharynx, oral cavity, and larynx. Patients had measurable disease based on RECIST 1.1 criteria[26] and an ECOG PS of 0- 2. Additionally, they had normal organ and marrow function as defined by, absolute neutrophil count ≥1,500/mL, hemoglobin ≥9.0 g/L, platelets ≥100,000/mL, total bilirubin ≤1.5 X upper limit of normal (ULN), AST(SGOT) and ALT(SGPT) ≤2.5 X ULN, and Creatinine ≤1.5 X institutional ULN. Due to the potential for DCA and cisplatin to be teratogenic, women of child-bearing potential and men must have agreed to use adequate contraception prior to and for the duration of study participation. All patients had the ability to understand and were willing to sign a written informed consent, approved by the Sanford Research Institutional Review Board (IRB).
Exclusion criteria included those with active, invasive malignancies that had not undergone curative treatment >5 years prior to study entry or those with any prior treatment for HNSCC. Subjects were not permitted to be on any additional concomitant anti-cancer therapies outside of the study protocol. Due to drug interactions and the risk of hypoglycemia with DCA, anyone with a prior history of diabetes mellitus requiring oral hypoglycemics and insulin were not eligible. Additionally, anyone with a prior history of grade ≥2 peripheral sensory neuropathy, malabsorptive syndromes, or those with a known allergy to compounds of similar chemical or biologic composition to DCA were excluded. Due to interest in immune response, patients with human immunodeficiency virus and/or any other disease that required chronic immunosuppression were excluded. Pregnant or breast-feeding women were excluded due to risks of the study treatment.
Study Design
This double blind, randomized, placebo-controlled phase II trial took place at 2 centers within the Sanford Health network. Fifty subjects were planned to be enrolled and stratified by disease stage (III, IVA, & IVB), then randomly assigned on a 1:1 ratio to DCA or matching placebo given with CRT. The primary objective was to evaluate safety of the addition of DCA to standard treatment. Key secondary objectives focused on the efficacy of adding DCA by evaluating EOT response to therapy after 3 months, as well as two and five-year PFS and OS.
The first 6 DCA treated patients in the total study population were included in a safety lead-in cohort. The results of the safety lead-in of DCA were evaluated by an independent data safety monitoring board (DSMB) after the 6th subject completed therapy. Recruitment continued during this review period to ensure study staff remained blinded. The study continued to full accrual by the DSMB if no aberrant safety signal was identified compared to historical controls in the DCA treatment group.
Study Protocol Treatment
CRT was started on day 1 with radiation delivered (either 3D or IMRT planning) at standard dosing of 70 Gy fractionated at 2 Gy once daily over 35 fractions. Cisplatin was dosed at 100 mg/m2 as an IV infusion in normal saline over 60-120 minutes on days 1, 22, and 43 with standard hydration, mannitol infusion and high-risk antiemetic therapy as per local guidelines. Cisplatin was held until the ANC exceeded 1000/mL, platelet count exceeded 75,000/mL, and creatinine was less ≤to 1.6 mg/dl. Granulocyte colony stimulating factor or pegfilgrastim was allowed during therapy per investigator discretion. Dose reductions and omissions were allowed per institutional guidelines. Substitution to carboplatin AUC 5 was allowed if cisplatin was contraindicated after the initial dose.
DCA or matching placebo (a lyophilized powder supplied in 500mg and 125 mg capsules) was given by mouth or feeding tube at a dose of 12.5 mg/kg (rounded to the nearest 10 kg) twice daily starting on day 1 until completion of the final dose of radiation. Doses were calculated on baseline weight and not adjusted for change in weight during therapy. Dose modifications (50% dose) for DCA/placebo were mandated for persistent (more than 7 day) grade 2 or grade ≥3 peripheral sensory neuropathy. Prior to dose modification, therapy was held until recovery to Grade 0-1. If there was no recovery, DCA/placebo was permanently discontinued after discussion with the study chair.
Safety and Efficacy Evaluations
All participants went through baseline screening visit with laboratory assessment, imaging, dental, surgical, and clinical evaluation by the multidisciplinary team to determine eligibility. Eligible participants were evaluated weekly during the study treatment to evaluate the primary objective of safety. Laboratory studies and toxicity were collected at these visits to assess AEs and serious AEs. History and physical exam with vital signs were also required prior to each cisplatin dose. Treatment compliance to each therapy was evaluated during this period. Following treatment completion, toxicity assessments were performed 30- and 90-days, then thereafter every 6-months for up 18-months.
Secondary objective disease and survival assessments occurred at 1-week, 3 months, and every 6 months post-treatment completion based on CT imaging of the head and neck. The 1-week assessment evaluated for persistent or progressive disease that may require salvage surgery. The 3-month assessment determined the EOT response. PFS and OS was based on post-treatment every 6-month imaging and clinic visits for up to 5-years. Assessments were performed by a radiology subinvestigator at each center and confirmed by the site investigator.
Tumor Assessments
All participants were required to submit a paraffin embedded or fresh tumor biopsy at baseline. Tumors were assessed for HPV status. HPV status was determined based on immunohistochemical (IHC) staining for p16. Positivity was based on ≥70% of tumor cell staining positive for p16 expression.
Serum Metabolomic Analysis
Serum was collected for evaluating metabolic response to therapy. Samples were collected in EDTA tubes at baseline and mid-treatment and stored in a −80°C freezer. After study completion, batched, viable samples that were from matched time points at baseline and mid-treatment were sent for metabolite analysis using ultrahigh-performance liquid chromatography/tandem mass spectrometry (LC–MS/MS) at Metabolon Inc., as previously described[27]. A total of 867 biochemical compounds were evaluating using this metabolomic analysis with a focus on metabolites involved in glycolysis, the tricarboxylic acid cycle (TCA) cycle and other metabolic changes of clinical interest.
Statistical Analysis
The primary objective of safety was evaluated by AE recording using the CTCAE scale, Version 4.0. Difference in toxicity was determined by comparing the overall frequency of AEs between conditions (DCA vs placebo in combination with CRT) using chi-square tests of equality of proportions. Additionally, due to the high rate of toxicities seen with standard CRT, treatment compliance was evaluated as an additional measure to determine toxicity. Completion of all planned cisplatin doses, dose reductions, and omissions were recorded and compared between groups using Fisher’s exact test. Median cumulative cisplatin dose, radiation dose, and compliance to median DCA/Placebo treatment course was compared between groups using Mann-Whitney U Test. Final radiation dose and fractions completed were compared using Fisher’s exact test. Mean days of radiation treatment duration were compared using Welch's t-test.
EOT response was determined based on RECIST 1.1 criteria [26] at the 12-week post-treatment CT imaging assessment and compared between groups using Fisher’s exact test. Survival outcomes were estimated by the Kaplan-Meier method. Patients with missing PFS or OS data were censored to the time of their last visit. Comparison between groups was performed using the log-rank method. Analysis of metabolomic data (comparison of mean treatment/baseline change) was performed using two-way analysis of variance (ANOVA). To examine the role of covariates in survival, proportional hazards regression models were used. Given the small numbers, each covariate was included with treatment group along with their interaction in a separate model. Hazard ratios and 95% confidence intervals are provided for each subgroup. Statistical analysis was performed using R software.
Results
Patient Characteristics
Patients were enrolled from 5/20/2011 to 4/25/2014. The data safety monitoring board (DSMB) met on 6/15/2012 to review the first 6 DCA treated participants and identified no aberrant safety signal, so the study was allowed to accrue to full enrollment. Data analysis presented here was performed after all subjects reached 5-years of follow-up. Fifty participants were enrolled and 45 (21 DCA, 24 Placebo) were evaluable for the safety and efficacy endpoints. In total, 5 participants were excluded due to global deterioration (n=1), personal reasons (n=3), and inclusion criteria-concomitant medication (n=1). Demographic and disease characteristics are outlined in Table 1. The groups were well-balanced except for the placebo group having significantly more female participants.
Table 1:
Patient Demographics and Disease Characteristics
| Characteristic | All | DCA | Placebo | p-value |
|---|---|---|---|---|
| (N=45) | (N=21) | (N=24) | ||
| Median age, years | 58 | 61 | 58 | 0.3388 |
| Range | (35-80) | (35-80) | (41-78) | |
| Sex | 0.0232 | |||
| Male | 39 (86.7%) | 21 (100%) | 18 (75.0%) | |
| Female | 6 (13.3%) | 0 (0%) | 6 (25.0%) | |
| Race | 0.7212 | |||
| White | 43 (95.6%) | 20 (95.2%) | 23 (95.8%) | |
| Native American | 1 (2.2%) | 1 (4.8%) | 0 (0.0%) | |
| Asian | 1 (2.2%) | 0 (0%) | 1 (4.2%) | |
| Ethnicity | 0.3442 | |||
| Non-Hispanic | 44 (97.8%) | 21 (100%) | 23 (95.8%) | |
| Hispanic/Latino | 1 (2.2%) | 0 (0%) | 1 (4.2%) | |
| HPV Status | 0.2796 | |||
| Positive | 33 (73.3%) | 17 (81.0%) | 16 (66.7%) | |
| Negative | 12 (26.7%) | 4 (19.0%) | 8 (33.3%) | |
| Tumor types | 0.1763 | |||
| Oral cavity | 0 (0%) | 0 (0%) | 0 (0%) | |
| Larynx | 11 (24.4%) | 7 (33.3%) | 4 (16.7%) | |
| Oropharynx | 33 (73.3%) | 13 (61.9%) | 20 (83.3%) | |
| Hypopharynx | 0 (0%) | 0 (0%) | 0 (0%) | |
| Other | 1 (2.2%) | 1 (4.8%) | 0 (0%) | |
| Stage | 0.8485 | |||
| III | 9 (20.0%) | 5 (23.8%) | 4 (16.7%) | |
| IVa | 35 (77.8%) | 16 (76.2%) | 19 (79.2%) | |
| IVb | 1 (2.2%) | 0 (0%) | 1 (4.2%) | |
| Smoking Status (n missing=2) | 0.336 | |||
| Never smoked | 13 (30.2%) | 5 (25.0%) | 8 (34.8%) | |
| Pipe or cigar smoker only | 1 (2.3%) | 1 (5.0%) | 0 (0%) | |
| Cigarette, < 10 pk-yr | 2 (4.7%) | 2 (10.0%) | 0 (0%) | |
| Cigarette, ≥ 10 pk-yr | 27 (62.8%) | 12 (60.0%) | 15 (65.2) |
based on p16 IHC positivity
not available for 2 participants (1 DCA, 1 placebo)
Toxicity and Treatment Compliance
Treatment group-specific and pooled toxicity data attributed (possibly, probably, and definitely) to the study drugs (DCA or placebo) are outlined in table 2 with corresponding p-values (p). Full adverse event (AE) data, regardless of attribution to the study drug, are outlined in table S1.
Table 2:
AEs possibly, probably, or definitely due to study agent occurring in ≥ 33%
| All Grades | Grade 3 | Grade 4 | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AE | DCA (n=21) | Placebo (n=24) | p | DCA (n=21) | Placebo (n=24) | p | DCA (n=21) | Placebo (n=24) | p | ||||||
| N | % | N | % | N | % | N | % | N | % | N | % | ||||
| Anemia | 19 | 90% | 22 | 92% | 0.89 | 1 | 5% | 1 | 4% | 0.92 | 0 | 0% | 1 | 4% | 0.34 |
| Anorexia | 19 | 90% | 22 | 92% | 0.89 | 14 | 67% | 19 | 79% | 0.34 | 0 | 0% | 0 | 0% | |
| Dry mouth | 19 | 90% | 22 | 92% | 0.89 | 2 | 10% | 5 | 21% | 0.3 | 0 | 0% | 0 | 0% | |
| Fatigue | 19 | 90% | 22 | 92% | 0.89 | 5 | 24% | 3 | 13% | 0.32 | 0 | 0% | 0 | 0% | |
| Dysgeusia | 18 | 86% | 22 | 92% | 0.53 | 0 | 0% | 0 | 0% | 0 | 0% | 0 | 0% | ||
| Dysphagia | 18 | 86% | 22 | 92% | 0.53 | 14 | 67% | 20 | 83% | 0.19 | 0 | 0% | 0 | 0% | |
| Mucositis oral | 18 | 86% | 22 | 92% | 0.52 | 8 | 38% | 15 | 63% | 0.10 | 0 | 0% | 0 | 0% | |
| Weight loss | 17 | 81% | 21 | 88% | 0.54 | 4 | 19% | 1 | 4% | 0.11 | 0 | 0% | 0 | 0% | |
| White blood cell decreased | 17 | 81% | 17 | 71% | 0.43 | 8 | 38% | 8 | 33% | 0.74 | 2 | 10% | 1 | 4% | 0.47 |
| Tinnitus | 16 | 76% | 21 | 88% | 0.32 | 1 | 5% | 0 | 0% | 0.28 | 0 | 0% | 0 | 0% | |
| Nausea | 16 | 76% | 20 | 83% | 0.55 | 8 | 38% | 10 | 42% | 0.81 | 0 | 0% | 0 | 0% | |
| Insomnia | 16 | 76% | 16 | 67% | 0.48 | 2 | 10% | 3 | 13% | 0.75 | 0 | 0% | 0 | 0% | |
| Neutrophil count decreased | 16 | 76% | 14 | 58% | 0.20 | 10 | 48% | 7 | 29% | 0.20 | 2 | 10% | 1 | 4% | 0.47 |
| Hyponatremia | 15 | 71% | 17 | 71% | 0.96 | 3 | 14% | 3 | 13% | 0.86 | 0 | 0% | 0 | 0% | |
| Constipation | 15 | 71% | 16 | 67% | 0.73 | 0 | 0% | 1 | 4% | 0.34 | 0 | 0% | 0 | 0% | |
| Lymphocyte count decreased | 15 | 71% | 16 | 67% | 0.73 | 12 | 57% | 14 | 58% | 0.93 | 5 | 24% | 1 | 4% | 0.05 |
| Vomiting | 14 | 67% | 20 | 83% | 0.19 | 2 | 10% | 6 | 25% | 0.17 | 0 | 0% | 0 | 0% | |
| Peripheral sensory neuropathy | 14 | 67% | 15 | 63% | 0.77 | 0 | 0% | 0 | 0% | 0 | 0% | 0 | 0% | ||
| Platelet count decreased | 14 | 67% | 8 | 33% | 0.02* | 1 | 5% | 0 | 0% | 0.28 | 0 | 0% | 0 | 0% | |
| Sore throat | 13 | 62% | 14 | 58% | 0.81 | 2 | 10% | 5 | 21% | 0.3 | 0 | 0% | 0 | 0% | |
| Dermatitis radiation | 12 | 57% | 15 | 63% | 0.71 | 0 | 0% | 0 | 0% | 0 | 0% | 0 | 0% | ||
| Hypoalbuminemia | 9 | 43% | 10 | 42% | 0.93 | 0 | 0% | 0 | 0% | 0 | 0% | 0 | 0% | ||
| Hypertension | 9 | 43% | 8 | 33% | 0.52 | 0 | 0% | 1 | 4% | 0.34 | 0 | 0% | 0 | 0% | |
| Fever | 9 | 43% | 2 | 8% | 0.01* | 0 | 0% | 0 | 0% | 0 | 0% | 0 | 0% | ||
| Hypocalcemia | 8 | 38% | 8 | 33% | 0.74 | 1 | 5% | 0 | 0% | 0.28 | 0 | 0% | 0 | 0% | |
| Dyspepsia | 7 | 33% | 11 | 46% | 0.39 | 0 | 0% | 0 | 0% | 0 | 0% | 0 | 0% | ||
| Generalized muscle weakness | 7 | 33% | 9 | 38% | 0.77 | 0 | 0% | 0 | 0% | 0 | 0% | 0 | 0% | ||
| Hearing impaired | 7 | 33% | 8 | 33% | 0.99 | 2 | 10% | 5 | 21% | 0.30 | 0 | 0% | 0 | 0% | |
| Hypokalemia | 7 | 33% | 7 | 29% | 0.76 | 0 | 0% | 1 | 4% | 0.34 | 0 | 0% | 0 | 0% | |
| Dyspnea | 7 | 33% | 6 | 25% | 0.54 | 3 | 14% | 2 | 8% | 0.53 | 0 | 0% | 0 | 0% | |
| Oral pain | 7 | 33% | 6 | 25% | 0.54 | 0 | 0% | 2 | 8% | 0.18 | 0 | 0% | 0 | 0% | |
| Dizziness | 7 | 33% | 5 | 21% | 0.34 | 3 | 14% | 0 | 0% | 0.05 | 0 | 0% | 0 | 0% | |
p<0.05
100% of participants experienced an AE, with 90% experiencing an AE attributed to the study agent. Common CRT related toxicities (anorexia, dry mouth, dysgeusia, dysphagia, mucositis oral, weight loss, radiation dermatitis) were seen in most participants and were balanced between the treatment groups regardless of attribution.
Grade 4 AEs were limited to hematologic toxicities, with the only exception being one participant each developing sepsis, respiratory failure, and laryngeal edema, all in the DCA group. Common (>33% of participants) grade 3 non-laboratory AEs included anorexia, dysgeusia, fatigue, dysphagia, oral mucositis, and nausea. Significantly higher rates of study drug related fevers (43% vs 8%, p = 0.01) and decreased platelet count (67% vs 33%, p = 0.02) were seen in DCA vs placebo; however, none of these were grade 3 or 4 events. Other attributable events were balanced between groups. Due to prior data suggesting higher rates of peripheral neuropathy with DCA[28], this specific AE was investigated and found to be similar between groups (All-grade in 67% DCA vs 63% placebo, p =0.7708 ) with no grade 3 or higher events.
Table 3 outlines treatment compliance with each modality. In summary, no significant differences in treatment compliance with cumulative cisplatin dose or radiation dose were seen between the groups. 61.9% of DCA and 75.0% of placebo (p = 0.5197) treated participants received the full planned cisplatin course. There were no significant differences in radiation treatment duration or dose completion. 90.5% of DCA-treated and 95.8% of placebo treated participants completed the full planned radiation dose of 70 Gy (p =0.5915). Study drug (DCA or placebo) treatment compliance was available from pill diaries in 42 of 45 participants. Of these 42 participants, study drug compliance (median percentage of therapy completed, interquartile range [IQR]) was 95.5% (IQR 86.75-98) in the DCA group and 95.5% (IQR 83.75-98) in the placebo group. Only 3 participants (15%) in the DCA and 4 participants (18.2%) in the placebo group completed all planned study drug doses (p = 0.99). No participants discontinued DCA or placebo due to an attributed AE, rather they largely discontinued due to CRT related toxicities.
Table 3:
Treatment Compliance
| All (n=45) | DCA (n=21) | Placebo (n=24) | p-value | ||||
|---|---|---|---|---|---|---|---|
| Cisplatin (100 mg/m2 x 3 doses) | Dose reductions (<300 mg/m2) | 7 (15.6%) | Dose reductions (<300 mg/m2) | 4 (19.0%) | Dose reductions (<300 mg/m2) | 3 (12.5%) | 0.69 |
| Dose omission (<3 doses) | 8 (17.8%) | Dose omission (<3 doses) | 5 (23.8%) | Dose omission (<3 doses) | 3 (12.5%) | 0.44 | |
| Completed all doses | 31 (68.9%) | Completed all doses | 13 (61.9%) | Completed all doses | 18 (75.0%) | 0.52 | |
| Median Cumulative Dose (IQR), mg/m2 | 300 [280, 300] | Median Cumulative Dose (IQR), mg/m2 | 300 [260, 300] | Median Cumulative Dose (IQR), mg/m2 | 300 [295, 300] | 0.28 | |
| Radiation (35 fractions: 70 Gy planned) | Treatment delay > 5 days | 0 | Treatment delay > 5 days | 0 | Treatment delay > 5 days | 0 | |
| Treatment delay ≤ 5 days | 10‡ | Treatment delay ≤ 5 days | 4 | Treatment delay ≤ 5 days | 6 | ||
| Mean Days Duration | 48.9 (2.47) | Mean Days Duration | 48.8 (2.41) | Mean Days Duration | 49.1 (2.57) | 0.67 | |
| Range | 45-58 days | Range | 45-53 days | Range | 45-58 days | ||
| 70 Gy RT Completed | 42 (93.3%) | 70 Gy RT Completed | 19 (90.5%) | 70 Gy RT Completed | 23§ (95.8%) | 0.59 | |
| Median Study Drug Compliance Percentage % [IQR] | N=42* | 95.5[86, 98] | N = 20 | 95.5[86.8, 98] | N = 22 | 95.5[83.8, 98] | 0.90 |
| Compliance 100% of Study Drug Doses N (%) | N =42* | 7 (16.7) | N = 20 | 3 (15.0) | N = 22 | 4 (18.2) | 0.99 |
Dose reductions due to neutropenia (n =6), acute renal failure (n =1) and dose omissions due to neutropenia (n = 3), neutropenic fever (n =1), elevated creatinine (n= 1), hearing loss (n =2), and tremors with mental confusion (n = 1)
Delays due to equipment malfunction (n =7), neutropenia (n=1), fever (n=1), copious secretions (n=1)
1 patient refused 1 fraction of radiation
Pill diary unavailable for 3 participants
Efficacy
45 participants were included in the efficacy analysis. Figure 1 shows overall and progression-free survival (OS and PFS) estimates. Outcomes are broken down based on HPV status and study agent, due to the known survival differences in HPV+ and HPV− disease. Regardless of HPV status, PFS at 5-years was 80.4% (95% CI 55.8-92.2%) in the DCA group and 78.3% (95% CI 55.4-90.4%) in the placebo group. 5-year OS was 80.4% (95% CI 55.8-92.2%) in the DCA group and 81.9% (95% CI 58.4-92.8%) in the placebo group. Subgroup analysis (Figure 1c) did not show any significant differences in risk for death across known risk factors.
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.
As shown in Figure S2, participants in the DCA group had a significantly higher CR rate than those treated with placebo (DCA 71.4%; n =15 vs Placebo 37.5%; n = 9, p = 0.0362). However, this may have been impacted by non-evaluable (NE) cases in each group (DCA n = 3;14.3% vs Placebo n = 5; 20.8%, p =0.705). Those with partial response (PR), stable disease (SD), and progressive disease (PD) were similar between groups.
Serum Metabolomic Analysis
Baseline and mid-treatment blood specimens from 10 participants each from the DCA and placebo groups were evaluable for serum metabolite analysis. The population was similar to the overall treatment cohort, however there was only one HPV− case included in the DCA group (Supplementary table S3). This analysis demonstrated changes in key glycolytic and TCA cycle related metabolites during treatment as outlined in Fig. 2. Compared to placebo, the ratio of treatment/baseline demonstrated a significant drop in pyruvate (0.47, p <0.005) and lactate (0.61, p <0.005) levels in the DCA group, while acetylcarnitine (in equilibrium with acetyl-CoA) significantly rose (1.68, p = 0.0136), consistent with on-target effect of DCA on PDK. Evaluation of TCA cycle-related metabolites demonstrated a decrease in citrate (0.81, p = 0.0028) and citraconate/glutaconate (0.40, p = 0.0455) (detected as an isobar) and accumulation of 2-methylcitrate/homocitrate (1.84, p = 0.0001) in the DCA-treated group. There were no differences seen based on HPV status, however limited by low numbers. These, in total, demonstrate expected systemic pharmacodynamic changes of DCA, but based on the assay we cannot say they are reflective of TME changes. Additional exploratory analysis of the effect of DCA on lipid metabolism, redox homeostasis, microbiome-associated compounds, and branched-chain amino acid metabolism were performed on serum metabolomics and are reported in supplementary figures S1-S5. In total, these findings supported that compared to the placebo group, DCA treated patients had enhanced fatty acid oxidation, and increased mitochondrial oxidation that may contribute to unique microbiome-related changes.
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<p<0.10 (light red indicates that the mean values trend higher for that comparison; light green values trend lower).
Abbreviations: Phosphoenolpyruvate (PEP), Lactate dehydrogenase (LDH), Alanine Transaminase (ALT), Pyruvate Dehydrogenase (PDH), pyruvate dehydrogenase kinase (PDK), Citrate Synthase (CS), isocitrate dehydrogenase (IDH1), Succinate Dehydrogenase (SDH), Malate Dehydrogenase (MDH), Nicotinamide adenine dinucleotide (NAD), flavin adenine dinucleotide (FAD), hydrogen (H), Fatty Acid (FA), Branched Chain Amino Acid (BCAA)
Discussion
This randomized, double blinded, placebo-controlled study demonstrated that the addition of DCA is safe during definitive CRT in HNSCC, with no aberrant safety signal of DCA compared to placebo. Treatment compliance with the oral therapy was challenging in this treatment setting; however median study drug completion was similar in both groups, with >95% of doses completed. Grade 3 and 4 toxicity rates were similar between groups with no significant differences. In addition to the safety and tolerability of the study agent, treatment compliance to standard chemotherapy and radiation was not significantly impaired. Furthermore, over 90% of participants completed the full planned radiation dose, which is in line with large clinical trials using radiation in this setting[1, 2]. Finally, even with concurrent use of a chemotherapy agent that causes peripheral neuropathy, there was not a statistically significant increase in toxicity or severity seen in the DCA group. This is important as prior studies in brain and advanced solid tumors demonstrated both central and peripheral neurotoxicity[23, 24]. However, it is possible disease-type and prior treatment related toxicities played some role in their findings. As our study was randomized and, in a treatment-naïve population, it adds additional insight into these toxicities.
As with safety, our efficacy and survival data showed no major differences between the DCA and placebo group. While CR rates at the EOT (71.4% in DCA and 37.5% in placebo, p = 0.0362) were significantly higher, survival findings showed excellent survival in both groups, regardless of HPV status. HPV+ participants had similar 5-year overall (75.6% DCA vs 92.9% placebo, p =0.1828) and progression-free (75.6% DCA and 87.1% placebo, p = 0.4166) survival findings, thus supporting no significant detrimental effect by adding DCA therapy. While 5-year OS was outstanding (100% DCA vs 60% placebo, p = 0.1727), but not significantly different in the DCA treated HPV− participants, it is challenging to draw comparisons due to the very small sample size. It is notable that 5-year survival rates in HPV− disease with both treatments exceeded the 50% survival rates seen in historical controls. In total, the high survival rates could be attributed to higher rate of favorable risk factors including non- and light-smokers (<10 pack year)[29, 30] and no patients with hypopharyngeal primaries[31]. This may have contributed to lack of clear improvement in PFS or OS from adding DCA.
Findings from serum metabolite analysis further supports the mechanistic effect of adding DCA to treatment. There was a significant shift in TCA serum metabolites during treatment with DCA. Expected drops in pyruvate and lactic acid support direct on target effect of PDK inhibition[20]. Additional analysis of key glycolytic and TCA related metabolites support the mechanism of action of this drug. As these were compared to placebo-controlled cases, this suggests the effect was related to DCA and not standard-of-care therapy. This data adds to previous reported data demonstrating pharmacodynamic effect of DCA using the pyruvate breath test [23]. While serum analysis cannot confirm these changes were due to TME effect of the drug, they do confirm pharmacodynamic effect of DCA in this treatment setting.
There are several important limitations to our findings. First, the study was primarily designed to evaluate for differences in safety between DCA and placebo, so it is difficult to make definitive conclusions regarding efficacy. Additionally, there was a significant imbalance in the placebo group having the only female participants, which could have biased results. The prognostic role of gender has conflicting findings in the literature[32, 33], however one large study demonstrated that female patients with oropharyngeal cancers do have a significantly decreased risk of death [34]. Also a high number of participants could not complete or had non-evaluable EOT response on post-treatment CT scan, which further limits our efficacy analysis. RECIST 1.1 is a challenging endpoint in this treatment setting and in the current era is supplemented with positron emission tomography (PET) imaging [35, 36]. At the time this study was developed, this was not the standard-of-care and was optional. Despite our translational findings from peripheral blood, we do not have any on-treatment biopsy data to support the mechanism of action of DCA in this setting. While biopsies were optional in the protocol, none were obtained, as these biopsies are exceedingly difficult in this treatment setting due to radiation toxicity. While serum correlates did demonstrate physiologic effect of the drug, confirmation of direct TME effect is needed with future research.
In conclusion, our study demonstrated the safety of adding DCA during cisplatin-based CRT in LA-HNSCC. The findings are important as this treatment approach already has high toxicity, and DCA did not impair the delivery of curative therapy. Translational research highlights how DCA may play a role in modulating the metabolic TME. A major limitation of our study was the inability to demonstrate an efficacy signal of adding DCA. However, as safety with the combination is confirmed, our findings support future clinical trials evaluating the efficacy of DCA in this treatment setting. In total, this study highlights the potential for metabolic inhibitors as cancer therapies.
Supplementary Material
Acknowledgments:
The authors would like to acknowledge the patients and families who participated in this research. Additionally, they would like to acknowledge the Sanford Research Clinical Research Coordinators, Histology and Imaging Core, and Research Design and Biostatistics Core.
Funding:
Translational metabolite analysis was supported by Center of Biology Research Excellence Award No. 5P20-GM103548-09, sponsored by the National Institute of General Medical Science. Funding for the clinical trial was provided by Sanford Research.
Footnotes
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.
Trial registration number: NCT01386632, Date of Registration: July 1, 2011.
Ethics approval and consent to participate: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Sanford Research (protocol code 03-11-028 and date of approval March 24th, 2011). Informed consent was obtained from all subjects involved in the study.
Consent for publication: Applicable, obtained through informed consent.
Availability of data and materials: The data presented in this study are available on request from the corresponding author. The data are not publicly available due to patient privacy.
Competing Interests: 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 competing interests.
Research involving Human Participants and/or Animals: The study involved human participants and was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Sanford Research (protocol code 03-11-028 and date of approval March 24th, 2011).
Informed consent: Written informed consent was obtained from all subjects involved in the study.
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