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Quality of life outcomes from a dose-per-fraction escalation trial of hypofractionation in prostate cancer.

ABSTRACT: OBJECTIVE:This multi-institutional phase I/II trial explored patient-assessed tolerance of increasingly hypofractionated (HPFX) radiation for low/intermediate risk prostate cancer. METHODS:347 patients enrolled from 2002 to 2010. Three increasing dose-per-fraction schedules of 64.7 Gy/22 fx, 58.08 Gy/16 fx and 51.6 Gy/12 fx were each designed to yield equivalent predicted late toxicity. Three quality of life (QoL) surveys were administered prior to treatment and annually upto 3 years. RESULTS:Bowel QoL data at 3years revealed no significant difference among regimens (p=0.469). Bowel QoL for all regimens declined transiently, largely recovering by three years, with only the 22 fraction decrement reaching significance. Bladder outcomes at 3 years were comparable (p=0.343) although, for all patients combined, a significant decline was observed from the baseline (p=0.008). Spitzer quality of life data revealed similarly excellent, 3-year means (p=0.188). International erectile function data also revealed no significant differences at 3 years although all measures except intercourse satisfaction worsened post-treatment. CONCLUSIONS:Three-year QoL changes for bowel, bladder and SQLI were modest and similar for 3 HPFX regimens spanning 2.94-4.3 Gy per fraction. These favorable patient-scored outcomes demonstrate the safety and tolerability of such regimens and may be leveraged to support further implementation of mild to moderately hypofractionated radiotherapy in the setting of low and intermediate-risk prostate cancer.

SUBMITTER: Brower JV

PROVIDER: S-EPMC4764419 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Quality of life outcomes from a dose-per-fraction escalation trial of hypofractionation in prostate cancer.

Brower Jeffrey V JV Forman Jeffrey D JD Kupelian Patrick A PA Petereit Daniel G DG Gondi Vinai V Lawton Colleen A CA Anger Nick N Saha Sandeep S Chappell Rick R Ritter Mark A MA

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 20160102 1

<h4>Objective</h4>This multi-institutional phase I/II trial explored patient-assessed tolerance of increasingly hypofractionated (HPFX) radiation for low/intermediate risk prostate cancer.<h4>Methods</h4>347 patients enrolled from 2002 to 2010. Three increasing dose-per-fraction schedules of 64.7 Gy/22 fx, 58.08 Gy/16 fx and 51.6 Gy/12 fx were each designed to yield equivalent predicted late toxicity. Three quality of life (QoL) surveys were administered prior to treatment and annually upto 3 ye ...[more]

PMID: 26755165

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Project description:PurposeThis phase I/II, multi-institutional trial explored the tolerance and efficacy of stepwise increasing hypofractionation (HPFX) radiation therapy regimens for fraction sizes up to 4.3 Gy in localized prostate cancer.Methods and materialsThree escalating dose-per-fraction schedules were designed to yield similar predicted tumor control while maintaining equivalent predicted late toxicity. HPFX levels I, II, and III were carried out sequentially and delivered schedules of 64.7 Gy/22 fx/2.94 Gy, 58.08 Gy/16 fx/3.63 Gy, and 51.6 Gy/12 fx/4.3 Gy, respectively with next level escalations contingent upon acceptable gastrointestinal (GI) toxicity. The primary endpoints were biochemical control and toxicity.ResultsA total of 347 patients were recruited by 5 institutions with 101, 111, and 135 patients treated on HPFX levels I, II, and III with median follow-ups of 100, 85.5, and 61.7 months, respectively (83.2 months combined). The National Comprehensive Cancer Network low- or intermediate-risk group distribution was 46% and 54%, respectively. Sixteen percent of patients, primarily intermediate risk, received 6 months of androgen deprivation therapy. The 8-year nadir + 2 actuarial biochemical control rates for HPFX levels I, II, and III were 91.1% ± 3.0%, 92.7% ± 2.7%, and 88.5% ± 4.6%, respectively (Kaplan-Meier log rank, 0.903). Among clinical covariates, only Gleason score reached near significance in multivariate analysis (P = .054). Twenty-six patients failed biochemically (crude incidence of 7.5%), and there were 5 cause-specific deaths. GI and genitourinary toxicities were acceptable and similar across the 3 HPFX levels. The combined actuarial cumulative incidence of grade 2+ GI and genitourinary toxicities at 7 years were 16.3% ± 2.1% and 22.1% ± 2.4%, respectively.ConclusionsHPFX employing fraction sizes extending into the 3.6 to 4.3 Gy/fraction range can be delivered with excellent oncologic outcomes. Such schedules, positioned between moderate and ultra-HPFX, may provide additional options for patients wishing to avoid prolonged treatment schedules associated with conventionally fractionated radiation therapy for prostate cancer.

Project description:PURPOSE:To determine the long-term outcomes for prostate adenocarcinoma when escalating radiation dose from 70 Gy to 78 Gy. METHODS AND MATERIALS:Between 1993 and 1998, 301 patients with biopsy-proven clinical stage T1b-T3 prostate adenocarcinoma, any prostate-specific antigen level, and any Gleason score were randomized to 70 Gy in 35 fractions versus 78 Gy in 39 fractions of photon radiation therapy using a 4-field box technique without hormone deprivation therapy. The primary outcome was powered to detect a 15% difference in biochemical or clinical failure. Secondary outcomes included survival, prostate cancer mortality, biochemical failure, local failure, nodal failure, distant failure, and secondary malignancy rates. RESULTS:With a median follow-up of 14.3 years, the cumulative incidence of 15-year biochemical or clinical failure was 18.9% versus 12.0% in the 70 Gy versus 78 Gy arms, respectively (subhazard ratio [sHR], 0.61; 95% confidence interval [CI], 0.38-0.98; Fine-Gray P = .042). The 15-year cumulative incidence of distant metastasis was 3.4% versus 1.1%, respectively (sHR, 0.33; 95% CI, 0.13-0.82; Fine-Gray P = .018). The 15-year cumulative incidence of prostate cancer-specific mortality was 6.2% versus 3.2%, respectively, (sHR, 0.52; 95% CI, 0.27-0.98; Fine-Gray P = .045). There were no differences in overall survival (HR, 1.10; 95% CI, 0.84-1.45; log rank P = .469) or other-cause survival (sHR, 1.33; 95% CI, 0.99-1.79; Fine-Gray P = .061). Salvage therapy was more common in the 70 Gy arm, at 38.7% versus 21.9% in the 78 Gy arm (P = .002). There was a 2.3% secondary solid malignancy rate (1 bladder, 6 rectal) within the radiation treatment field, which was not significantly different between treatment arms. CONCLUSIONS:Dose escalation by 8 Gy (78 Gy vs 70 Gy) provided a sustained improvement in biochemical and clinical failure, which translated into lower salvage rates and improved prostate cancer-specific mortality, but not overall survival. Long-term follow-up demonstrated a low incidence of potential solid tumor secondary malignancies.

Project description:PurposeRadiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa.Methods and materialsThis phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate <33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events.ResultsFifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively.ConclusionsSABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity.

Project description:BackgroundTherapeutic cancer vaccines have shown activity in metastatic castration-resistant prostate cancer (mCRPC), and methods are being assessed to enhance their efficacy. Ipilimumab is an antagonistic monoclonal antibody that binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed to assess the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80.MethodsWe did a phase 1 dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC received 2×10(8) plaque-forming units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1×10(9) plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. This study is registered with ClinicalTrials.gov, number NCT00113984.FindingsWe completed enrolment with 30 patients (24 of whom had not been previously treated with chemotherapy) and we did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient). Only one of the six patients previously treated with chemotherapy had a PSA decline from baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which six were greater than 50%.InterpretationThe use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC.FundingUS National Institutes of Health.

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Quality of life outcomes from a dose-per-fraction escalation trial of hypofractionation in prostate cancer.

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Quality of life outcomes from a dose-per-fraction escalation trial of hypofractionation in prostate cancer.

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