50 Gy Stereotactic Body Radiation Therapy to the Dominant Intra-Prostatic Nodule: Results from a Phase Ia/b Trial
Mené sur 9 puis 11 patients atteints d'un cancer de la prostate de stade localisé, cet essai de phase Ia/b évalue la tolérabilité d'une radiothérapie corporelle stéréotaxique hypofractionnée avec escalade de dose jusqu'à 50 Gy
Purpose : Although localized prostate cancer (PCa) is multifocal, the dominant intraprostatic nodule (DIN) is responsible for disease progression after radiation therapy. PCa expresses antigens that could be recognized by the immune system. We therefore hypothesized that stereotactic dose escalation to the DIN is safe, may increase local control and may initiate tumor-specific immune responses. Patients and Methods : patients with localized PCa were treated with stereotactic extreme hypo-fractionated doses of 36.25 Gy in 5 fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image (MRI) visible DIN (45 Gy, 47.5 Gy, and 50 Gy in five fractions). Phase Ia part was designed to determine the recommended phase Ib dose (RP1B) in a “3 + 3” cohort-based dose escalation design. Primary endpoint: Dose-limiting toxicities (DLT) defined as grade 3 or worse gastrointestinal (GI) and/or genitourinary (GU) toxicity by Common Terminology Criteria of Adverse Events (version 4) up to 90 days after the first radiation fraction. Secondary endpoints: PSA kinetics, quality-of-life (QoL), and blood immunological responses. Results : 9 patients were treated in the phase Ia. No DLT was observed at either level and therefore the maximum tolerated dose (MTD) was not reached. Further characterization of tolerability, efficacy and immunological outcomes were conducted in the subsequent 11 patients irradiated at the highest dose level (50 Gy) in the phase Ib expansion cohort. Grade 1 and 2 GU and GI toxicity was 45% and 25%, and 20% and 5%, respectively. No grade 3 or more toxicity was reported. The average (±SEM) of the QoL assessments at baseline and at 3-month post-treatment were 0.8 (±0.8), and 3.5 (±1.5) for the bowel (mean difference, 2.7; 95% CI, 0.1-5), and 6.4 (±0.8) and 7.27 (±0.9) for IPSS (mean difference, 0.87; 95% CI, 0.3-1.9); respectively. A subset of patients developed antigen-specific immune responses against: prostate-specific membrane antigen (N=2), prostatic acid phosphatase (N=1), prostate stem cell antigen (N=4), prostate-specific antigen (N=2). Conclusions : Irradiation of the whole prostate with 36.25 Gy in 5 fractions and dose escalation to 50 Gy to the DIN was tolerable and determined as RP1B. This treatment has promising anti-tumor activity, which will be confirmed by the ongoing phase II part. Preliminary QoL analysis showed minimal impact in GU, GI, and sexual domains. Stereotactic irradiation induced antigen specific immune responses in a subset of patients.
https://www.redjournal.org/article/S0360-3016(18)33803-3/fulltext 2018