Hypoxia Modification during Prostate Radiation Therapy Using Carbogen and Nicotinamide: Toxicity Results from a Phase 2 Study (PROCON)

Abstract

To evaluate treatment related acute and late urinary (GU) and gastrointestinal (GI) toxicity in men with high risk prostate cancer treated with hypoxia modification using carbogen gas (98% O2/2% CO2) and nicotinamide (CON) during external beam radiotherapy (EBRT). Fifty men with high risk prostate cancer were recruited to a prospective single-arm phase II clinical trial. They received standard treatment with androgen deprivation and intensity-modulated radiation therapy (IMRT) of 74Gy in 37 fractions to the prostate and seminal vesicles and 60Gy in 37 fractions to the pelvic nodes. Hypoxia modification with CON was administered daily during radiation treatment. Carbogen gas was administered before and during each fraction of radiotherapy along with daily oral nicotinamide at 60mg/kg. The primary endpoint was treatment related toxicity as measured by CTCAE v4. Secondary endpoints include PSA progression-free survival, overall survival and quality of life assessment. A total of 48 patients completed PROCON treatment. Two patients discontinued nicotinamide within the first 10 fractions of treatment due to nausea and continued RT with carbogen alone. A total of 12% of patients reported grade 3 nausea with 50% requiring an oral anti-emetic. Protocol defined dose adjustment to 40mg/kg occurred for reduced tolerance in 22% of patients. A total of 9 (18%) pts had a nicotinamide break of 1-2 days due to nausea. Carbogen was tolerated by all patients but with one unable to tolerate the tight-fitting face mask and ceased carbogen following 9 fractions. No grade 3 GU or GI toxicity was recorded. One patient developed jaundice 4-5 weeks after treatment which resolved without further intervention and was thought to be unrelated to the study medications. Acute grade ≤ 1 GU toxicity at 2 and 4 weeks was 84% and 88% respectively. Acute grade 2 toxicity rates were 16% and 12% at 2 and 4 weeks. GI toxicity at the same time points were 10% and 2 %. GU and GI toxicity at the primary endpoint of 12 weeks was 92% for ≤ grade 1 and 4 % grade 2. CON can be safely administered with EBRT in high risk prostate cancer patients without a significant increase in treatment related toxicities. Nausea was the most significant acute toxicity. Phase III testing is now warranted.