Stereotactic body radiotherapy for localized prostate cancer: Pooled analysis from a multi-institutional consortium of prospective phase II trials
TL;DR: PSA relapse-free survival rates after SBRT compare favorably with other definitive treatments for low and intermediate risk patients, and the current evidence supports consideration of S BRT among the therapeutic options for these patients.
About: This article is published in Radiotherapy and Oncology.The article was published on 2013-11-01 and is currently open access. It has received 394 citations till now. The article focuses on the topics: PSA Failure & Androgen deprivation therapy.
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University of Alabama at Birmingham1, University of South Florida2, Vanderbilt University3, City of Hope National Medical Center4, Fox Chase Cancer Center5, University Of Tennessee System6, Brigham and Women's Hospital7, Seattle Cancer Care Alliance8, Case Western Reserve University9, Roswell Park Cancer Institute10, Northwestern University11, Harvard University12, University of Nebraska Medical Center13, University of Utah14, Memorial Sloan Kettering Cancer Center15
TL;DR: This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.
Abstract: Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.
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TL;DR: There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy, consistent with the physician-evaluated toxicity.
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The Royal Marsden NHS Foundation Trust1, Institute of Cancer Research2, Northwood University3, James Cook University Hospital4, Sunnybrook Health Sciences Centre5, Clatterbridge Cancer Centre NHS Foundation Trust6, Queen's University Belfast7, Cambridge University Hospitals NHS Foundation Trust8, Cardiff University9, Churchill Hospital10, University of Leicester11, Freeman Hospital12, Coventry Health Care13, McMaster University14, Beatson West of Scotland Cancer Centre15
TL;DR: The results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity.
Abstract: Summary Background Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer. Methods PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0–2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1–2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov , NCT01584258 . PACE-B recruitment is complete and follow-up is ongoing. Findings Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference −1·9 percentage points, 95% CI −6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference −4·2 percentage points, 95% CI −10·0 to 1·7; p=0·16). No treatment-related deaths occurred. Interpretation Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity. Funding Accuray and National Institute of Health Research.
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TL;DR: The benefit of a hydrogel spacer in reducing the rectal dose, toxicity, and QOL declines after image guided intensity modulated radiation therapy for prostate cancer was maintained or increased with a longer follow-up period, providing stronger evidence for the benefit of hydrogels spacer use in prostate radiation therapy.
Abstract: Purpose SpaceOAR, a Food and Drug Administration–approved hydrogel intended to create a rectal–prostate space, was evaluated in a single-blind phase III trial of image guided intensity modulated radiation therapy. A total of 222 men were randomized 2:1 to the spacer or control group and received 79.2 Gy in 1.8-Gy fractions to the prostate with or without the seminal vesicles. The present study reports the final results with a median follow-up period of 3 years. Methods and Materials Cumulative (Common Terminology Criteria for Adverse Events, version 4.0) toxicity was evaluated using the log-rank test. Quality of life (QOL) was examined using the Expanded Prostate Cancer Index Composite (EPIC), and the mean changes from baseline in the EPIC domains were tested using repeated measures models. The proportions of men with minimally important differences (MIDs) in each domain were tested using repeated measures logistic models with prespecified thresholds. Results The 3-year incidence of grade ≥1 (9.2% vs 2.0%; P =.028) and grade ≥2 (5.7% vs 0%; P =.012) rectal toxicity favored the spacer arm. Grade ≥1 urinary incontinence was also lower in the spacer arm (15% vs 4%; P =.046), with no difference in grade ≥2 urinary toxicity (7% vs 7%; P =0.7). From 6 months onward, bowel QOL consistently favored the spacer group ( P =.002), with the difference at 3 years (5.8 points; P P P =.002) and urinary QOL (30% vs 17%; P =.04). Furthermore, the control group were also more likely to have experienced large declines (twice the MID) in bowel QOL (21% vs 5%; P =.02) and urinary QOL (23% vs 8%; P =.02). Conclusions The benefit of a hydrogel spacer in reducing the rectal dose, toxicity, and QOL declines after image guided intensity modulated radiation therapy for prostate cancer was maintained or increased with a longer follow-up period, providing stronger evidence for the benefit of hydrogel spacer use in prostate radiation therapy.
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TL;DR: SBRT appears to be a safe and effective treatment for high-risk prostate carcinoma and the data suggests that SBRT alone may be the optimal approach.
Abstract: Stereotactic Body Radiotherapy (SBRT) has excellent control rates for low- and intermediate-risk prostate carcinoma.The role of SBRT for high-risk disease remains less studied. We present long-term results on a cohort of patients with NCCN-defined high-risk disease treated with SBRT. We retrospectively studied 97 patients treated as part of prospective trial from 2006–2010 with SBRT alone (n = 52) to dose of 35–36.25 Gy in 5 fractions, or pelvic radiation to 45 Gy followed by SBRT boost of 19–21 Gy in 3 fractions (n = 45). 46 patients received Androgen Deprivation Therapy. Quality of life and bladder/bowel toxicity was assessed using the Expanded Prostate Index Composite (EPIC) and RTOG toxicity scale. Median followup was 60 months. 6-year biochemical disease-free survival (bDFS) was 69%. On multivariate analysis, only PSA remained significant (P < 0.01) for bDFS. Overall toxicity was mild, with 5% Grade 2–3 urinary and 7% Grade 2 bowel toxicity. Use of pelvic radiotherapy was associated with significantly higher bowel toxicity (P = .001). EPIC scores declined for the first six months and then returned towards baseline. SBRT appears to be a safe and effective treatment for high-risk prostate carcinoma. Our data suggests that SBRT alone may be the optimal approach. Further followup and additional studies is required to corroborate our results.
202 citations
Cites background from "Stereotactic body radiotherapy for ..."
...Such studies include patients who received SBRT alone and patients who received SBRT as boost to pelvic radiotherapy [17-20]....
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TL;DR: Significant late bladder and rectal toxicities from SBRT for prostate cancer are infrequent and the current evidence supports consideration of stereotactic body radiotherapy among the therapeutic options for localized prostate cancer.
Abstract: Purpose Hypofractionated radiotherapy has an intrinsically different normal tissue and tumor radiobiology. The results of a prospective trial of stereotactic body radiotherapy (SBRT) for prostate cancer with long-term patient-reported toxicity and tumor control rates are presented. Methods and Materials From 2003 through 2009, 67 patients with clinically localized low-risk prostate cancer were enrolled. Treatment consisted of 36.25 Gy in 5 fractions using SBRT with the CyberKnife as the delivery technology. No patient received hormone therapy. Patient self-reported bladder and rectal toxicities were graded on the Radiation Therapy Oncology Group scale (RTOG). Results Median follow-up was 2.7 years. There were no grade 4 toxicities. Radiation Therapy Oncology Group Grade 3, 2, and 1 bladder toxicities were seen in 3% (2 patients), 5% (3 patients), and 23% (13 patients) respectively. Dysuria exacerbated by urologic instrumentation accounted for both patients with Grade 3 toxicity. Urinary incontinence, complete obstruction, or persistent hematuria was not observed. Rectal Grade 3, 2, and 1 toxicities were seen in 0, 2% (1 patient), and 12.5% (7 patients), respectively. Persistent rectal bleeding was not observed. Low-grade toxicities were substantially less frequent with QOD vs. QD dose regimen ( p = 0.001 for gastrointestinal and p = 0.007 for genitourinary). There were two prostate-specific antigen (PSA), biopsy-proven failures with negative metastatic workup. Median PSA at follow-up was 0.5 ± 0.72 ng/mL. The 4-year Kaplan-Meier PSA relapse-free survival was 94% (95% confidence interval, 85%–102%). Conclusion Significant late bladder and rectal toxicities from SBRT for prostate cancer are infrequent. PSA relapse-free survival compares favorably with other definitive treatments. The current evidence supports consideration of stereotactic body radiotherapy among the therapeutic options for localized prostate cancer.
360 citations
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TL;DR: The outcomes after high-dose hypofractionation were acceptable in the entire cohort of patients treated with the schedule of 70 at 2.5 Gy/fraction and the 5-year nadir + 2 ng/mL rate was 83% (95% confidence interval, 79–86%).
Abstract: Purpose: To study the outcomes in patients treated for localized prostate cancer with 70 Gy delivered at 2.5-Gy/fraction within 5 weeks. Methods and Materials: The study sample included all 770 consecutive patients with localized prostate cancer treated with hypofractionated intensity-modulated radiotherapy at the Cleveland Clinic between 1998 and 2005. The median follow-up was 45 months (maximum, 86). Both the American Society for Therapeutic Radiology and Oncology (ASTRO) biochemical failure definition and the alternate nadir + 2 ng/mL definition were used. Results: The overall 5-year ASTRO biochemical relapse-free survival rate was 82% (95% confidence interval, 79–85%), and the 5-year nadir + 2 ng/mL rate was 83% (95% confidence interval, 79–86%). For patients with low-risk, intermediate-risk, and high-risk disease, the 5-year ASTRO rate was 95%, 85%, and 68%, respectively. The 5-year nadir + 2 ng/mL rate for patients with low-, intermediate-, and high-risk disease was 94%, 83%, and 72%, respectively. The Radiation Therapy Oncology Group acute rectal toxicity scores were 0 in 51%, 1 in 40%, and 2 in 9% of patients. The acute urinary toxicity scores were 0 in 33%, 1 in 48%, 2 in 18%, and 3 in 1% of patients. The late rectal toxicity scores were 0 in 89.6%, 1 in 5.9%, 2 in 3.1%, 3 in 1.3%, and 4 in 0.1% (1 patient). The late urinary toxicity scores were 0 in 90.5%, 1 in 4.3%, 2 in 5.1%, and 3 in 0.1% (1 patient). Conclusion: The outcomes after high-dose hypofractionation were acceptable in the entire cohort of patients treated with the schedule of 70 at 2.5 Gy/fraction.
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TL;DR: In this paper, the feasibility and toxicity of stereotactic hypofractionated accurate radiotherapy (SHARP) for localized prostate cancer were evaluated in a Phase I/II trial with 40 patients.
Abstract: Purpose: To evaluate the feasibility and toxicity of stereotactic hypofractionated accurate radiotherapy (SHARP) for localized prostate cancer. Methods and Materials: A Phase I/II trial of SHARP performed for localized prostate cancer using 33.5 Gy in 5 fractions, calculated to be biologically equivalent to 78 Gy in 2 Gy fractions (α/β ratio of 1.5 Gy). Noncoplanar conformal fields and daily stereotactic localization of implanted fiducials were used for treatment. Genitourinary (GU) and gastrointestinal (GI) toxicity were evaluated by American Urologic Association (AUA) score and Common Toxicity Criteria (CTC). Prostate-specific antigen (PSA) values and self-reported sexual function were recorded at specified follow-up intervals. Results: The study includes 40 patients. The median follow-up is 41 months (range, 21–60 months). Acute toxicity Grade 1–2 was 48.5% (GU) and 39% (GI); 1 acute Grade 3 GU toxicity. Late Grade 1–2 toxicity was 45% (GU) and 37% (GI). No late Grade 3 or higher toxicity was reported. Twenty-six patients reported potency before therapy; 6 (23%) have developed impotence. Median time to PSA nadir was 18 months with the majority of nadirs less than 1.0 ng/mL. The actuarial 48-month biochemical freedom from relapse is 70% for the American Society for Therapeutic Radiology and Oncology definition and 90% by the alternative nadir + 2 ng/mL failure definition. Conclusions: SHARP for localized prostate cancer is feasible with minimal acute or late toxicity. Dose escalation should be possible.
338 citations
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TL;DR: This study was designed as a noninferiority investigation with a predefined tolerance of −7.5%.
Abstract: Purpose The optimal radiation dose fractionation schedule for localized prostate cancer is unclear. This study was designed to compare two dose fractionation schemes (a shorter 4-week radiation schedule v a longer 6.5-week schedule). Patients and Methods Patients with early-stage (T1 or T2) prostate cancer were randomly assigned to 66 Gy in 33 fractions over 45 days (long arm) or 52.5 Gy in 20 fractions over 28 days (short arm). The study was designed as a noninferiority investigation with a predefined tolerance of −7.5%. The primary outcome was a composite of biochemical or clinical failure (BCF). Secondary outcomes included presence of tumor on prostate biopsy at 2 years, survival, and toxicity. Results From March 1995 to December 1998, 936 men were randomly assigned to treatment; 470 were assigned to the long arm, and 466 were assigned to the short arm. The median follow-up time was 5.7 years. At 5 years, the BCF probability was 52.95% in the long arm and 59.95% in the short arm (difference = −7.0%; 90...
324 citations
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TL;DR: A pre-planned preliminary safety analysis of side-effects in stages 1 and 2 of a randomised trial comparing standard and hypofractionated radiotherapy seems equally well tolerated as conventionally fractionated treatment at 2 years.
Abstract: Summary Background Prostate cancer might have high radiation-fraction sensitivity, implying a therapeutic advantage of hypofractionated treatment. We present a pre-planned preliminary safety analysis of side-effects in stages 1 and 2 of a randomised trial comparing standard and hypofractionated radiotherapy. Methods We did a multicentre, randomised study and recruited men with localised prostate cancer between Oct 18, 2002, and Aug 12, 2006, at 11 UK centres. Patients were randomly assigned in a 1:1:1 ratio to receive conventional or hypofractionated high-dose intensity-modulated radiotherapy, and all were given with 3–6 months of neoadjuvant androgen suppression. Computer-generated random permuted blocks were used, with risk of seminal vesicle involvement and radiotherapy-treatment centre as stratification factors. The conventional schedule was 37 fractions of 2 Gy to a total of 74 Gy. The two hypofractionated schedules involved 3 Gy treatments given in either 20 fractions to a total of 60 Gy, or 19 fractions to a total of 57 Gy. The primary endpoint was proportion of patients with grade 2 or worse toxicity at 2 years on the Radiation Therapy Oncology Group (RTOG) scale. The primary analysis included all patients who had received at least one fraction of radiotherapy and completed a 2 year assessment. Treatment allocation was not masked and clinicians were not blinded. Stage 3 of this trial completed the planned recruitment in June, 2011. This study is registered, number ISRCTN97182923. Findings 153 men recruited to stages 1 and 2 were randomly assigned to receive conventional treatment of 74 Gy, 153 to receive 60 Gy, and 151 to receive 57 Gy. With 50·5 months median follow-up (IQR 43·5–61·3), six (4·3%; 95% CI 1·6–9·2) of 138 men in the 74 Gy group had bowel toxicity of grade 2 or worse on the RTOG scale at 2 years, as did five (3·6%; 1·2–8·3) of 137 men in the 60 Gy group, and two (1·4%; 0·2–5·0) of 143 men in the 57 Gy group. For bladder toxicities, three (2·2%; 0·5–6·2) of 138 men, three (2·2%; 0·5–6·3) of 137, and none (0·0%; 97·5% CI 0·0–2·6) of 143 had scores of grade 2 or worse on the RTOG scale at 2 years. Interpretation Hypofractionated high-dose radiotherapy seems equally well tolerated as conventionally fractionated treatment at 2 years. Funding Stage 1 was funded by the Academic Radiotherapy Unit, Cancer Research UK programme grant; stage 2 was funded by the Department of Health and Cancer Research UK.
288 citations