Prostate radiotherapy with carbogen and nicotinamide. Final results of the phase 1b/II PROCON trial

Abstract

Purpose or Objective Prostate tumour hypoxia is associated with resistance to radiotherapy (RT) and increased likelihood of relapse post treatment. The concurrent administration of carbogen and nicotinamide (CON) with RT improves overall survival in patients with bladder cancer and regional control rates following laryngeal RT. We evaluated the safety, toxicity of this approach for patients with high risk prostate cancer. Material and Methods 50 patients (with 1 of: T3, Gleason ≥8, PSA ≥20) were recruited into the single arm phase 1b/II PROCON trial between Dec 2011 and Sept 2013. They breathed carbogen via a tight-fitting face mask during RT and took 60mg/kg of nicotinamide daily prior to the delivery of RT (74Gy/37# to the prostate and 60Gy/37# to the pelvic nodes). Twenty men also underwent functional MRI imaging; correction of tumour hypoxia was evaluated by comparing tumour R2* values before and after carbogen administration. Patients were assessed during treatment and 2, 4 and 12 weeks after they had completed RT. The primary endpoints were prevalence of grade 3 (G3) or worse lower gastrointestinal (GI) or genitourinary (GU) toxicities during this period. Secondary end points include PSA progression free survival (PFS) and overall survival (OS) rates at five years as calculated by the Kaplan Meier method. Results The median duration of follow up was 60 months. All patients completed the prescribed 37 fraction schedule of RT over 50 to 56 days (median duration: 52 days). 56% patients experienced grade 1 nausea (CTCAE v 4.0), and 52% patients received anti-emetic treatment. 22% patients had a nicotinamide dose adjustment, 20% patients had a break from nicotinamide and 6% patients discontinued nicotinamide. 96% patients received carbogen with every RT fraction. One patient had an interruption of treatment and received carbogen for 33 of 37 fractions. One patient discontinued carbogen treatment after 7 fractions. No one developed G3 or worse lower GI or GU toxicities; prevalence of G1/G2 toxicities are shown in table 1. The 5 year OS and PSA-PFS rates were 92% and 87% respectively. Six patients experienced biochemical progression. Five patients have died but None had biochemical relapse prior to their death. The functional MRI analysis showed a mean decrease of 5.8% in tumour R2* after the application of carbogen, measured in 72 pairs of pre and post carbogen measurements, indicating that the carbogen exposure resulted in an immediate reduction in tumour hypoxia. Conclusion The prevalence of acute lower GI and GU toxicities among our cohort, together with their 5 year PSA PFS and OS rates, are comparable, or superior to, those reported for patients with high risk prostate cancer receiving RT in other contemporary trials. The concurrent administration of CON with RT is safe and effective. It should be further explored in a phase III setting.