The individualisation of treatment for patients with head and neck squamous cell carcinoma with a special interest in induction chemotherapy

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) survival rates showed little improvement in recent decades with some subsites having increased mortality. There is a need to improve understanding of patient heterogeneity to better tailor treatments to suit individual needs. Methods: A homogenous cohort of 132 stage IV neck node positive HNSCC patients treated with induction chemotherapy (ICT: docetaxel, cisplatin and 5-FU [TPF]) followed by concurrent chemoradiotherapy (CRT: cisplatin and IMRT) between 1st January 2009 and 31st December 2013 was identified from The Christie NHS Foundation Trust database. Side effects were reviewed and clinicopathological features were compared to survival outcomes (overall survival [OS], disease specific survival [DSS] and locoregional control [LRC]) to determine tolerability and efficacy of the regimen and identify which patients benefited most. A sub-set of the patients underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) before (42 patients) and after two cycles of ICT (37 patients) to measure tumour plasma perfusion (Fp) and RECIST response compared to long term outcomes. Pre-treatment tumour specimens from the cohort were stained for p16 (n = 109) and the proliferation-related biomarkers EGFR (n = 90) and Ki67 (n = 85). Results: When given with prophylactic medication against predicted side effects, TPF ICT was well tolerated and produced good long-term survival outcomes (3yr OS: 67.2%; DSS: 78.7%; LRC: 78.3%). Patients with a WHO performance status (PS) of 0 and those with poorly differentiated tumours benefitted most whilst those with well and moderately differentiated tumours had poor OS (HR 3.28; 95% CI 1.35 - 7.97, p = 0.009). Fp (stratified by median) was not prognostic for OS (p = 0.42), DSS (p = 0.20) or LRC (p = 0.64). Neither change in tumour Fp nor RECIST response post two cycles of ICT was prognostic for any outcome. Ki67 was not associated with survival, however, high levels of EGFR (top quartile) and tumours with any 3+ (very high) intensity staining had poor outcomes (any 3+ versus no 3+ staining: OS: HR 3.00; 95% CI 1.47 - 6.10, p = 0.002; DSS: HR 3.62; 95% CI 1.48 - 8.89, p = 0.005; LRC: HR 3.63; 95% CI 1.55 - 8.51, p = 0.003). P16 positivity was associated with a good prognosis across all survival measures. Conclusion: TPF should be considered in those with a high risk of distant metastases who have a PS of 0. Pre-treatment tumour Fp and change in tumour Fp post two cycles of ICT were not prognostic for any outcome which may reflect the intra-tumour heterogeneity. ICT acts primarily on distant micro-metastases and only produces a complete locoregional response in 0 - 40% of cases. It may be the genetics of the remaining tumour immediately post ICT that determines long term outcomes. Concordantly, RECIST response to ICT was not prognostic for survival and may not be an appropriate endpoint to determine early efficacy of a treatment in HNSCC patients. The long protracted regimen does not appear suited to those with tumours that have a propensity for accelerated repopulation post injury. Hence, ICT should not be offered to those with well and moderately differentiated tumours or those with high or intensely stained EGFR tumours which may benefit from accelerated treatment. Further larger trials are required to validate these findings.  

Date of Award	1 Aug 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Nalin Thakkar (Supervisor), Catharine West (Supervisor) & Jarrod Homer (Supervisor)