Phase 1/2 Study on Stereotactic Hypofractionated Once-Weekly Radiation Therapy for Nonmetastatic Prostate Cancer

Abstract

Stereotactic radiotherapy has shown promising results in Phase II studies, but has been investigated predominantly in patients with low-intermediate risk disease. We conducted a clinical trial of stereotactic hypofractionated radiotherapy delivered in once-weekly fractions on patients with non-metastatic disease to test feasibility, acute toxicities, patient reported outcomes, and biochemical control in a cohort with predominantly high-risk disease. Patients with prostatic adenocarcinoma, Gleason 6-10, T1-4N0 (staged with multiparametric MRI and bone scans) and PSA <=60 ng/ml were eligible for enrolment into this Phase I/II trial. A planned sample of 30 patients were treated with volumetric intensity modulated arc radiation therapy to a dose of 35 Gy in 5 fractions delivered once-weekly with an overall treatment time of 29 days. Patients with high-risk disease also received elective nodal irradiation to a dose of 25 Gy in 5 fractions simultaneously. Androgen deprivation was offered to intermediate and high risk patients. Trial specific dose constraints were ensured. The primary outcome was acute toxicity with NCI CTC v4. Secondary outcome measures included biochemical control and late toxicity. Patient reported outcomes were measured with the IPSS score and EORTC QLQ-C30 and PR25 questionnaires. Clinically meaningful worsening of quality of life scores was defined as a 10 point reduction (out of 100) in any scale. All 30 patients completed treatment per-protocol. The majority of patients had T3 (60%) and Gleason 7 (50%) tumors. The median PSA was 17 ng/ml. High risk disease was present in 20 patients (66.7%). There was low incidence of acute toxicities (Grade 2+ urinary toxicities in 1 -3.3%, and grade 2+ rectal toxicities in none). The mean IPSS scores increased from baseline 8.6 to 14.6 at the end of treatment (P < 0.001) but reduced to 10.9 at 6 months (P = 0.05). Of the 21 parameters studied in the EORTC QLQ framework, only the urinary symptom score showed a clinically meaningful worsening from a mean of 20/100 at baseline to 34/100 at end of treatment (P < 0.001), but reduced to 24/100 at 6 months (P = 0.08). Other functional or symptomatic scales did not show any clinically meaningful worsening. There was 1 patient each with late grade 2 rectal bleeding and grade 2 urinary toxicity. With a median follow-up of 25 months, 1 patient developed a distant failure at 10 months, with a 2 year biochemical control rate of 96.7%. In a cohort of mainly high risk cancers in a developing country, stereotactic once-weekly radiation therapy was easy to implement, safe and well tolerated with a low incidence of acute toxicity. Preliminary biochemical control and late toxicity profiles are encouraging. This paves the way for further prospective evaluation in a larger cohort of patients with high-risk disease.