Abstract
BackgroundCisplatin-based chemoradiation (CCRT) offers locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients high local control rate, however, relapses are frequent. Our goal was to evaluate if association of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, with CCRT improved response rate (RR) and associated biomarkers.MethodsThis phase II trial included patients with unresectable locally advanced (LA) oropharynx (OP) squamous cell carcinoma. CCRT began after 2 weeks of VPA (P1). Primary goal was RR at 8 weeks after chemoradiation (CRT)+VPA (P2). Biomarkers included microRNA (miR) polymerase chain reaction (PCR)-array profiling in plasma compared to healthy controls by two-sample t-test. Distribution of p-values was analysed by beta-uniform mixture. Findings were validated by real-time PCR quantitative polymerase chain reaction (qPCR) for selected miRs in plasma and saliva. p16, HDAC2 and RAD23 Homolog B, Nucleotide Excision Repair Protein (HR23B) tumour immunohistochemistry were evaluated.ResultsGiven significant toxicities, accrual was interrupted after inclusion of ten LA p16 negative OP patients. All were male, smokers/ex-smokers, aged 41–65 and with previous moderate/high alcohol intake. Nine evaluable patients yielded a RR of 88%. At false discovery rate of 5%, 169 miRs were differentially expressed between patients and controls, including lower expression of tumour suppressors (TSs) such as miR-31, -222, -let-7a/b/e and -145. miR-let-7a/e expression was validated by qPCR using saliva. A HDAC2 H-score above 170 was 90% accurate in predicting 6-month disease-free survival.ConclusionsVPA and CRT offered high RR; however, with prohibitive toxicities, which led to early trial termination. Patients and controls had a distinct pattern of miR expression, mainly with low levels of TS miRs targeting Tumor protein P53 (TP53). miR-let-7a/e levels were lower in patients compared to controls, which reinforces the aggressive nature of such tumours (NCT01695122).
Highlights
Cisplatin-based chemoradiation (CCRT) offers locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients high local control rate, relapses are frequent
valproic acid (VPA) and CRT offered high response rate (RR); with prohibitive toxicities, which led to early trial termination
Patients and controls had a distinct pattern of miR expression, mainly with low levels of tumour suppressors (TSs) miRs targeting Tumor protein P53 (TP53). miR-let-7a/e levels were lower in patients compared to controls, which reinforces the aggressive nature of such tumours (NCT01695122)
Summary
Cisplatin-based chemoradiation (CCRT) offers locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients high local control rate, relapses are frequent. The mainstay treatment for inoperable locally advanced head and neck squamous cell carcinoma (LAHNSCC) has been cisplatin-based chemoradiation (CCRT) for decades [1]. It provides adequate local control, relapses are frequent, especially in human papillomavirusIcesp: Instituto do Cancer do Estado de Sao Paulo (HPV)-negative oropharynx (OP) squamous cell carcinoma and with burdensome acute and late toxicities [2]. Valproic acid (VPA) has long been used as an anti-epileptic drug and mood stabilizer and has a well-known toxicity profile [9] It is widely available and with an accessible cost, which makes it attractive to study as therapeutic repurposing. Numerous small clinical trials have evaluated VPA in combination with other epigenetic regulators such as 2′-deoxy-5-azacytidine (AZA) or standard treatment as chemotherapy or radiation both in haematological and solid tumours, with conflicting results (Table 1) [14,15,16,17,18,19,20,21,22]
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