serval:BIB_8A5A6B3310C5
50-Gy Stereotactic Body Radiation Therapy to the Dominant Intraprostatic Nodule: Results From a Phase 1a/b Trial.
10.1016/j.ijrobp.2018.09.023
000455220100011
30267761
Herrera
F.G.
author
Valerio
M.
author
Berthold
D.
author
Tawadros
T.
author
Meuwly
J.Y.
author
Vallet
V.
author
Baumgartner
P.
author
Thierry
A.C.
author
De Bari
B.
author
Jichlinski
P.
author
Kandalaft
L.
author
Coukos
G.
author
Harari
A.
author
Bourhis
J.
author
article
2019-02-01
International journal of radiation oncology, biology, physics
1879-355X
0360-3016
journal
103
2
320-334
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 with localized PCa were treated with stereotactic extreme hypofractionated doses of 36.25 Gy in 5 fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image-visible DIN (45 Gy, 47.5 Gy, and 50 Gy in 5 fractions). The phase 1a part was designed to determine the recommended phase 1b dose in a "3 + 3" cohort-based, dose-escalation design. The primary endpoint was dose-limiting toxicities defined as ≥grade 3 gastrointestinal (GI) or genitourinary (GU) toxicity (or both) by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) up to 90 days after the first radiation fraction. The secondary endpoints were prostate-specific antigen kinetics, quality of life (QoL), and blood immunologic responses.
Nine patients were treated in phase 1a. No dose-limiting toxicities were observed at either level, and therefore the maximum tolerated dose was not reached. Further characterization of tolerability, efficacy, and immunologic outcomes was conducted in the subsequent 11 patients irradiated at the highest dose level (50 Gy) in the phase 1b expansion cohort. Toxicity was 45% and 25% for grades 1 and 2 GU, and 20% and 5% for grades 1 and 2 GI, respectively. No grade 3 or worse toxicity was reported. The average (±standard error of the mean) of the QoL assessments at baseline and at 3-month posttreatment were 0.8 (±0.8) and 3.5 (±1.5) for the bowel (mean difference, 2.7; 95% confidence interval, 0.1-5), and 6.4 (±0.8) and 7.27 (±0.9) for the International Prostate Symptom Score (mean difference, 0.87; 95% confidence interval, 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), and prostate-specific antigen (n = 2).
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 the recommended phase 1b dose. This treatment has promising antitumor activity, which will be confirmed by the ongoing phase 2 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.
Aged
Aged, 80 and over
Disease Progression
Dose Fractionation, Radiation
Humans
Immune System
Magnetic Resonance Imaging
Male
Maximum Tolerated Dose
Middle Aged
Prostate/radiation effects
Prostate-Specific Antigen
Prostatic Neoplasms/radiotherapy
Quality of Life
Radiometry
Radiosurgery
Radiotherapy Dosage
Radiotherapy Planning, Computer-Assisted
Radiotherapy, Intensity-Modulated
T-Lymphocytes/immunology
eng
60_published
true
peer-reviewed
Publication types: Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
University of Lausanne
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