Yip, Kent; (2019) Hypoxic modification in the radiotherapeutic treatment for prostate cancer. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Introduction: Tumour hypoxia exists among patients with prostate cancer. It is associated with resistance to radiotherapy and increased likelihood of relapse post treatment. The concurrent administration of carbogen and nicotinamide with radiotherapy has been shown to improve survival in patients with bladder cancer and selected patients with head and neck cancer, but this approach has not been attempted previously in patients with prostate cancer. Inhalation of carbogen alone can improve the oxygenation status of prostate cancer as evaluated by functional MR imaging. However, androgen deprivation therapy (ADT) causes collapse in the tumour vasculature, and patients with high risk prostate cancer routinely receive three months of androgen deprivation therapy prior to the start of their course of radical radiotherapy. The ability of carbogen administration to reverse tumour hypoxia during radiotherapy may thus be compromised. / Methods: Fifty patients with high risk prostate cancer were recruited into the single arm phase 1b/II PROCON (PROstate CarbOgen and Nicotinamide) clinical trial. They received carbogen and nicotinamide during their course of radiotherapy after they had undergone three months of neoadjuvant hormone treatment. Prevalence of urinary and gastrointestinal toxicities at two, four and twelve weeks of completing radiotherapy were recorded. PSA progression free and overall survival were calculated using the Kaplan Meier method. Twenty patients among them also underwent functional MR imaging (BOLD, diffusion weighted and dynamic contrast enhanced sequences) before and during their radiotherapy to assess the oxygenation status of their prostate cancer in response to carbogen and the state of their vasculature. / Results: None of the patients developed grade 3 or worse acute urinary or gastrointestinal toxicity, and the side effect profile is comparable to contemporary clinical trials. Despite the antivascular effect of prior hormone treatment, as confirmed by the drop in the mean Ktrans value (18-25%) following three months of ADT, the application of carbogen remained effective in reversing tumour hypoxia as demonstrated by the mean reduction in R2* value of 5.8% following the administration of carbogen. The 5 year overall survival for the entire cohort was 92%, and the 5 year PSA progression free survival was 87%. / Conclusion: The concurrent administration of carbogen and nictotinamide in patients receiving a course of radical radiotherapy for their prostate cancer is safe, and can improve tumour hypoxia despite the antivascular effect of prior hormone treatment. The 5 year PSA progression free and overall survival rates are comparable to those reported by other contemporary trials for patients with high risk prostate cancer. Future randomised clinical trials involving the use of carbogen and nicotinamide alone, or in combination with other systemic treatments, should focus on patients with hypoxic prostate cancer.

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