Ultrahypofractionated Radiation Therapy Research Articles

Ultrahypofractionated versus hypofractionated and conventionally fractionated radiation therapy for localized prostate cancer: A systematic review and meta-analysis of phase III randomized trials

IntroductionTo characterize the efficacy (5-year disease-free survival [DFS]) and safety (incidence of grade 2+ late gastrointestinal or genitourinary toxicity) of ultrahypofractionated radiation therapy (UHRT) versus hypofractionated radiation therapy (HFRT) and conventionally fractionated radiation therapy (CFRT) by comparing patients treated on phase III protocols. MethodsA PICOS/PRISMA/MOOSE protocol was used to identify eligible studies. Weighted random effects meta-analyses were conducted using the DerSimonian and Laird method. Wald-type tests were used to compare treatment modalities for each outcome, where the null hypothesis was rejected for p < 0.05. ResultsSeven studies were included that consisted of 6795 patients (2849 CFRT, 3357 HFRT, and 589 UHRT). Median age was 68 years. Summary effect sizes for 5-year DFS were 85.1% (95% CI: 82.1%–87.8%) for CFRT, 86% (95% CI: 83%–88.7%) for HFRT, and 85% (95% CI: 80%–87%) for UHRT (p = 0.66 and p = 0.8 for CFRT vs. HFRT and CFRT versus UHRT, respectively). Summary effect sizes for late grade 2+ gastrointestinal toxicity were 12.1% (95% CI: 9.2%–15.4%) for CFRT, 14.6% (95% CI: 9.9%–20%) for HFRT, and 10% (95% CI: 7%–13%) for UHRT (p = 0.41 and p = 0.09 for CFRT versus HFRT and CFRT versusus UHRT, respectively). Summary effect sizes for late grade 2+ genitourinary toxicity were 19.4% (95% CI: 10.7–29.9%) for CFRT, 20.4% (95% CI: 10.2%–32.9%) for HFRT, and 18% (95% CI: 15%–22%) for UHRT (p = 0.89 and p = 0.92 for CFRT versus HFRT and CFRT versus UHRT, respectively). ConclusionUltrahypofrationated regimens appear to offer similar levels of safety and efficacy to CFRT and HFRT. These findings are hypothesis-generating and require further validation by ongoing prospective trials.

Erectile Dysfunction and Absorbed Dose to Penile Base Structures in a Randomized Trial Comparing Ultrahypofractionated and Conventionally Fractionated Radiation Therapy for Prostate Cancer

To study the relationships between absorbed dose to penile base structures and erectile dysfunction (ED) in patients treated with ultrahypofractionated (UHF) radiation therapy (RT) or conventionally fractionated (CF) RT for prostate cancer. This dose-response study comprises 673 patients (57%) of the 1180 per-protocol patients included in the HYPO-RT-PC trial (median follow-up 5, years), where patients were randomized to CF (39 × 2.0 Gy, 8 weeks) or UHF (7 × 6.1 Gy, 2.5 weeks). No androgen deprivation therapy was allowed. Only patients with erectile function sufficient for intercourse at baseline and complete RT data were included in this study. Erectile function was assessed by physician at regular follow-ups. The main endpoint was severe ED (EDs). The penile bulb (PB) and crus were retrospectively delineated on the treatment planning computed tomography scans. Dose-volume descriptors were derived from EQD2 converted dose matrices (α/β = 3 Gy). Univariable and multivariable Cox proportional hazard regression and logistic regression were used to find predictors for EDS. No significant difference in EDs was found between CF and UHF. During the follow-up period, EDs occurred in 27% of the patients in both treatment groups. Average (median) PB mean dose, Dmean, was 24.5 (20.2) in CF and 18.7 (13.1) Gy3 in UHF. Age was the only significant predictor for EDs in Cox analyses. All dose-volume variables contributed significantly in univariable logistic regression at 2-year follow-up. Age and near maximum dose (D2%) were significant predictors for EDs in multivariable logistic regression analyses at both 1 and 2 years. The frequency of EDS was similar in the CF and UHF treatment groups. Age at radiation therapy was the strongest predictor for EDs, followed by dose to PB, and was most evident for younger patients. We propose D2 % <50 Gy3 and Dmean <20 Gy3 to the PB as the primary objectives to be applied in the treatment planning process.

Diminishing Returns From Ultrahypofractionated Radiation Therapy for Prostate Cancer

More than a decade of randomized controlled trials in prostate cancer has established a positive radiation dose response at moderate doses and a consistently low α/β ratio in the linear quadratic model for moderate hypofractionation. The recently published large randomized trial of ultrahypofractionated prostate cancer radiation therapy adds substantially to our current knowledge of dose response and fractionation sensitivity. Randomized trials of dose escalation and hypofractionation of radiation therapy were meta-analyzed to yield the overall best estimate of the α/β ratio. Additionally, a putative saturation of dose effect previously reported at approximately 80 Gy EQD2 was investigated by mapping the relative effectiveness assessed at 5 years onto a single reference dose-response curve. Meta-analysis of 14 randomized trials including 13,384 patients yielded a best estimate of α/β = 1.6 Gy (95% confidence interval, 1.3-2.0 Gy) but with highly significant heterogeneity (I2 = 70%, P = .0005). Further analysis indicated an association between increasing dose per fraction in the experimental arm and increasing α/β ratio (slope, 0.6 Gy increase in α/β per Gy increase in fraction size; P = .017). This deviation from the linear quadratic model could, however, also be explained by biochemical control maxing out at doses above approximately 80 Gy. Biochemical control data from randomized controlled trials of dose-per-fraction escalation in prostate cancer radiation therapy are inconsistent with the presence of a constant fractionation sensitivity in the linear-quadratic model and/or a monotonic dose response for biochemical control beyond 80 Gy equivalent dose. These observations have a potential effect on the optimal doses in future trials and the interpretation of ongoing trials of ultrahypofractionation.

Early Tolerance and Tumor Control Outcomes with High-dose Ultrahypofractionated Radiation Therapy for Prostate Cancer

BackgroundStudies using stereotactic body radiotherapy (SBRT) dose escalation in in low- and intermediate-risk prostate cancer patients have indicated favorable outcomes. ObjectiveTo evaluate tolerance and tumor control outcomes in low- and intermediate-risk prostate cancer patients treated with high-dose SBRT following our phase 1 trial. Design, setting, and participantsA total of 551 patients with low- or intermediate-risk prostate cancer were treated with SBRT. InterventionTreatment with 37.5–40Gy SBRT in five fractions directed to the prostate and seminal vesicles. Outcome measurements and statistical analysisOutcome measurements included acute toxicities (<3 mo after radiotherapy [RT]) and late toxicities (>3 mo after RT) and tumor control evaluation (prostate-specific antigen [PSA] levels at 3–6-mo intervals and post-treatment prostate biopsy at 2yr). Results and limitationsAcute grade 2 gastrointestinal (GI) toxicities occurred in 1.8% of patients, and late grade 2 and 3 GI toxicities were observed in 3.4% and 0.4% of patients, respectively. Acute grade 2 genitourinary (GU) toxicities occurred in 10% of patients, and grade 3 acute GU toxicities were observed in 0.7% of patients. Late grade 2 and 3 GU toxicities were observed in 21.1% and 2.5% of patients, respectively. The use of a hydrogel rectal spacer was significantly associated with reduced late GI toxicity and lower odds of developing late GU toxicity. The median follow-up was 17 mo, and 53% of those with at least 2yr of follow-up (103/193) had a biopsy performed. The 5-yr cumulative incidence of PSA failure was 2.1%, and the incidence of a positive 2-yr treatment biopsy was 12%. Limitations to this report include its retrospective nature and short follow-up time. ConclusionsFavorable short-term outcomes were achieved with high-dose SBRT for low- and intermediate-risk disease. Severe late toxicities were observed and favorable tumor control was found. Patient summaryWe utilized stereotactic body radiotherapy, a form of external beam radiotherapy that delivers highly targeted high-dose treatment to the prostate, to treat over 500 localized prostate cancer patients in five sessions over 1.5 wk. Treatments were well tolerated without significant urinary or rectal side effects. Nearly 90% of those who underwent biopsies after treatment did not demonstrate residual active disease.

Current status of intensity-modulated radiation therapy for prostate cancer: History, clinical results and future directions.

External beam radiotherapy has changed dramatically over several decades with the improvement of computer hardware and software, and machinery developments. Intensity-modulated radiation therapy is the most sophisticated technique for all cancer treatment with radiation therapy, and is widely disseminated and available for daily use in many countries. Several retrospective and prospective studies have shown that intensity-modulated radiation therapy reduces the radiation dose in the organs at risk with diminished rates of acute and late toxicity, even with higher doses (>74Gy). An important technique for the clinical use of intensity-modulated radiation therapy is image-guided radiation therapy. The clinical benefit for prostate image-guided radiation therapy has been assessed by comparing the outcomes of patients with either the image-guided radiation therapy or non-image-guided radiation therapy technique. These studies have shown that image-guided radiation therapy significantly decreases acute and late rectal and bladder toxicities. Randomized trials and meta-analysis have shown that higher doses result in better biochemical control. More recently, hypofractionated radiation therapy comparing hypofractionated radiation therapy versus conventional fractionated radiation therapy have shown that hypofractionated radiation therapy produces biochemical control and toxicity rated similar to those produced by conventional fractionated radiation therapy. The clinical use of ultrahypofractionated radiation therapy and simultaneous integrated boost technique is necessary to evaluate its further safety and benefits. Intensity-modulated radiation therapy is also widely accepted in the field of salvage therapy and for the patients with distant oligometastases. The purpose of the present review is to summarize the history of intensity-modulated radiation therapy, new techniques for intensity-modulated radiation therapy, hypofractionation and future directions for prostate cancer.

Baseline genomic and circulating tumor cell (CTC) correlative data from very high-risk (VHR), localized, node-negative prostate cancer patients.

e16563 Background: Few data exist on CTC frequency and number, genetic landscape, and tumor mutational burden (TMB) in VHR, node negative, localized prostate cancer (PCa). Methods: We are conducting a single-arm phase 2 trial of ultra-hypofractionated radiation (RT) with 6 months of abiraterone, apalutamide and leuprolide in VHR PCa, defined as: Gleason (Gl) 9-10 or 2 high risk features (including radiographic (r) T3/T4 disease) or &gt; 4 cores of Gl8. We report baseline correlatives in the first 38 screened patients (pts). CTCs were isolated using a non-selection based platform (EPIC Sciences). Additional analyses were conducted using MSK IMPACT, a next generation sequencing assay. Results: Median PSA was 14.8 ng/mL (IQR, 7.7-28.1); Gl7 was present in 5% (n = 2), Gl8 in 32% (n = 12), Gl9 in 61% (n = 23) and Gl10 in 2% (n = 1) of pts; on MR, 42% of pts were rT2 (n = 16), 39% had rT3a disease (n = 15) and 18% had rT3b disease (n = 7). CTC data were available on 31 pts; 74% (n = 23) had ≥1 detectable CTC (range, 0.8-14.6 cells per mL); 29% (n = 9) had CK+ clusters (range, 0.8-7.1 clusters per mL). IMPACT was available for 20 pts: KMT2D/C mutations were present in 25% (n = 4), TP53 missense mutations in 20% (n = 4), FOXA1 mutations in 20% (n = 4), PTEN truncating or missense mutations in 15% (n = 3), SPOP missense mutations in 15% (n = 3), PIK3CA activating mutations in 15% (n = 3), APC deletions in 15% (n = 3); 85% (17/20) had alterations in one of these genes. No clinically significant germline mutations were present. Median TMB was 2.63 mutations/mB (range, 0.87-60.56); the TMB-highest pt had an in-frame deletion in MSH2. Among IMPACTed pts with normalized testosterone post-protocol treatment (n = 16), there was a trend towards an association with SPOP/FOXA1 mutations and undetectable ( &lt; 0.05 ng/mL) PSA; 5/6 pts with mutations had undetectable PSA (83.3%) vs 3/10 without (30%) (p = 0.12). The trial is managed by the PCCTC and funded by Janssen. Conclusions: The genetic profile and TMB of VHR, localized PCa resembles non-castrate, metastatic disease. The frequency of detectable CTCs is high with implications for post-treatment surveillance. SPOP/FOXA1 mutations may predict initial response to RT with total androgen blockade. Clinical trial information: NCT02772588.

Hypofractionated Radiation Therapy for Localized Prostate Cancer: Executive Summary of an ASTRO, ASCO and AUA Evidence-Based Guideline.

The aim of this guideline is to present recommendations regarding moderately hypofractionated (240-340 cGy per fraction) and ultrahypofractionated (500 cGy or more per fraction) radiation therapy for localized prostate cancer. The American Society for Radiation Oncology convened a task force to address 8 key questions on appropriate indications and dose-fractionation for moderately and ultrahypofractionated radiation therapy, as well as technical issues, including normal tissue dose constraints, treatment volumes, and use of image guided and intensity modulated radiation therapy. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and Society-approved tools for grading evidence quality and recommendation strength. Based on high-quality evidence, strong consensus was reached for offering moderate hypofractionation across risk groups to patients choosing external beam radiation therapy. The task force conditionally recommends ultrahypofractionated radiation may be offered for low- and intermediate-risk prostate cancer but strongly encourages treatment of intermediate-risk patients on a clinical trial or multi-institutional registry. For high-risk patients, the task force conditionally recommends against routine use of ultrahypofractionated external beam radiation therapy. With any hypofractionated approach, the task force strongly recommends image guided radiation therapy and avoidance of nonmodulated 3-dimensional conformal techniques. Hypofractionated radiation therapy provides important potential advantages in cost and convenience for patients, and these recommendations are intended to provide guidance on moderate hypofractionation and ultrahypofractionation for localized prostate cancer. The limits in the current evidentiary base-especially for ultrahypofractionation-highlight the imperative to support large-scale randomized clinical trials and underscore the importance of shared decision making between clinicians and patients.

Hypofractionated Radiation Therapy for Localized Prostate Cancer: Executive Summary of an ASTRO, ASCO, and AUA Evidence-Based Guideline

PurposeThe aim of this guideline is to present recommendations regarding moderately hypofractionated (240-340 cGy per fraction) and ultrahypofractionated (500 cGy or more per fraction) radiation therapy for localized prostate cancer. Methods and MaterialsThe American Society for Radiation Oncology convened a task force to address 8 key questions on appropriate indications and dose-fractionation for moderately and ultrahypofractionated radiation therapy, as well as technical issues, including normal tissue dose constraints, treatment volumes, and use of image guided and intensity modulated radiation therapy. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and Society-approved tools for grading evidence quality and recommendation strength. ResultsBased on high-quality evidence, strong consensus was reached for offering moderate hypofractionation across risk groups to patients choosing external beam radiation therapy. The task force conditionally recommends ultrahypofractionated radiation may be offered for low- and intermediate-risk prostate cancer but strongly encourages treatment of intermediate-risk patients on a clinical trial or multi-institutional registry. For high-risk patients, the task force conditionally recommends against routine use of ultrahypofractionated external beam radiation therapy. With any hypofractionated approach, the task force strongly recommends image guided radiation therapy and avoidance of nonmodulated 3-dimensional conformal techniques. ConclusionsHypofractionated radiation therapy provides important potential advantages in cost and convenience for patients, and these recommendations are intended to provide guidance on moderate hypofractionation and ultrahypofractionation for localized prostate cancer. The limits in the current evidentiary base—especially for ultrahypofractionation—highlight the imperative to support large-scale randomized clinical trials and underscore the importance of shared decision making between clinicians and patients.

Apalutamide + abiraterone + leuprolide with stereotactic, ultra-hypofractionated radiation (AASUR) in very high risk prostate cancer (PCa).

TPS5100Background: Radiotherapy and long course (18-28 months) androgen deprivation therapy (ADT) is a current standard of care in very high risk PCa; however, biochemical failure remains frequent....

Patient-Reported Sexual Aid Utilization and Efficacy After Radiation Therapy for Localized Prostate Cancer

Toreport sexual health-related quality of life outcomes and utilization and efficacy of sexual aids in a contemporary cohort of patients treated for localized prostate cancer. Between 2008 and 2013, 471 consecutive men with localized prostate cancer were treated on 2 institutional protocols (NCT01766492, NCT01618851) or on a prospective institutional registry with patient-reported health-related quality of life. All patients were treated with ultra-hypofractionated radiation therapy. Erectile function (EF) was defined as "firm enough for intercourse" with or without aids per Expanded Prostate Cancer Index Composite-26 (n = 222 at baseline); results apply to this cohort unless specifically noted. Sexual aid utilization and efficacy were patient reported. Multivariable analysis of EF was performed. Median follow-up was 60months, median age was 67years, and 70% had intermediate- or high-risk disease per National Comprehensive Cancer Network guidelines. At 24 and 60months, questionnaire response rates were 86% and 67%, and EF was retained in 53% and 41%, respectively. Baseline sexual aid utilization was 37% (n=82) and was associated with lower 24-month EF preservation on multivariable analysis (adjusted odds ratio 0.49, 95% confidence interval 0.26-0.92). By 60months, 70% of men had tried aids. Of those who found aids helpful at baseline, 84% to 89% reported continued benefit at 24 to 60months. Among aid-naïve patients, efficacy was 80% with first-time use within 12months and 70% more than 12months after radiation therapy (P=.02). Among men who developed erectile dysfunction but found sexual aids helpful, 25% were not current users at 60months. One-third of men used sexual aids at baseline, which doubled by 5years after radiation therapy. Self-reported efficacy was high and sustained. Despite significant declines in EF, a number of men reported helpfulness of aids but were not active users. Future study is required to understand drivers of aid utilization to optimize posttreatment sexual function.

Stereotactic body radiation therapy for prostate cancer-a review.

Prostate cancer can be managed with external beam radiation therapy, delivered with either protons or photons, brachytherapy, surgery, or active surveillance. Advances in imaging and radiation therapy delivery have allowed treatment of prostate cancer using ultra-hypofractionated radiation therapy with a high dose per fraction using a technique called stereotactic body radiation therapy (SBRT). While no randomized trials have compared the efficacy of SBRT to conventionally fractionated radiation therapy (CFRT), numerous prospective trials and retrospective reviews have demonstrated the safety and efficacy of SBRT for localized prostate cancer, used either definitively or as a boost along with CFRT. Prostate cancer SBRT may be more cost effective than CFRT using intensity modulated radiation therapy (IMRT) or proton based radiation therapy.