Prostate adenocarcinoma definitive EBRT intermediate-risk

Acute: Short term side effects during or within a few weeks post radiation therapy (usually temporary)
Fatigue	Read more about fatigue.
Proctitis	Including diarrhoea, increased bowel frequency, rectal urgency, pain and bleeding. Read more about proctitis. Read more about treatment induced diarrhoea.
Enteritis	Abdominal discomfort.
Irritative or obstructive urinary symptoms	Bladder spasms, dysuria, nocturia, frequency, incontinence, urgency, retention.
Cystitis	Read more about cystitis.

Late: Long term side effects - months to years post radiation therapy (may be permanent)
Proctitis	Read more about proctitis.
Small bowel toxicity	Including obstruction and perforation.
Urethral stricture
Cystitis/urethritis	Includes haematuria. Read more about cystitis.
Sexual dysfunction	Including erectile dysfunction, impotence, dry and/or painful ejaculation, haematospermia and reduction in ejaculate. Patients should be offered sexual counselling to manage potential late effects related to sexual function.
Impaired fertility or infertility	Fertility preservation should be discussed prior to commencement of treatment. Read more about fertility preservation for people with cancer opens in a new tab or window.
Insufficiency fracture
Second malignancy

Source	Study & year published	Supports use Yes/No/NA	Is the radiation dose and fractionation consistent with the protocol?	Comments
Meta-analysis	Zaorsky et al. 201819	Yes	Yes	Supports use of dose escalated radiation therapy to prevent biochemical failure in low and intermediate-risk prostate cancer patients.
	Viani et al. 200920	Yes	Yes	Supports use of high dose radiation therapy to prevent biochemical failure in low, intermediate and high-risk prostate cancer patients.
Phase III trials	Bolla et al. 201621	Yes	Range of doses: 70 Gy/74 Gy/78 Gy
	Denham et al. 201422  (TROG 03.04 RADAR)	Yes	Range of doses: 66 Gy/ 70 Gy/ 74 Gy
	Denham et al. 201123 (TROG 96.10)	Yes	No 66 Gy to prostate/SV
	Kuban et al. 200824 and 201125	Yes	Yes 70 Gy vs 78 Gy	Modest escalation in radiation therapy dose improved freedom from biochemical and clinical failure, with the largest benefit in prostate cancer patients with PSA >10 ng/ml (78% for 78 Gy vs 39% for 70 Gy; p = 0.001).
	Zelefsky et al. 200826	Yes	Yes Dose range: 66-86 Gy	Significant improvements were observed with higher doses for patients with intermediate and high-risk features. For intermediate-risk features, multivariate analysis showed that radiation dose was an important predictor for improved PSA relapse-free survival (p <0.0001) and improved distant metastases-free survival (p = 0.04).
	D'Amico et al. 200827 (Dana Faber Trial)	Yes	Yes 70 Gy vs 80 Gy
	Peeters et al. 200628	Yes	Yes 68 Gy vs 78 Gy
	Roach et al. 200329 (RTOG 94.13)	Yes	Yes 68 Gy vs 78 Gy
	Catton et al. 201730 (PROFIT)	Yes	60 Gy/20 fx  (3 Gy/fx)
	Dearnaley et al. 201611 (CHHiP)	Yes	60 Gy/20 fx  (3 Gy/fx)
	Hoffman et al. 201831	Yes	72 Gy/30 fx (2.4 Gy/fx)
	Incrocci et al. 201632 (HYPRO)	No	64.6 Gy/19 fx (3.4 Gy/fx)
Guidelines	Date published/revised	Supports use	Is the dose and regimen consistent with the protocol?	Comments
NCCN	V4.20241	Yes	Yes
EAU	20242	Yes	Yes	Offer intensity-modulated radiotherapy (IMRT)/volumetric modulated arc therapy (VMAT) plus image-guided radiotherapy (IGRT), with a total dose of 76–78 Gy or moderate hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks), in combination with short-term androgen deprivation therapy (ADT) (four to six months).
AUA-ASTRO	20223	Yes	Yes	Clinicians should offer moderate hypofractionated external beam radiation therapy (EBRT) for patients with low- or intermediate-risk prostate cancer who elect EBRT. (Strong Recommendation; Evidence Level: Grade A)

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NCCN Clinical Practice Guidelines in Oncology - Prostate Cancer - Version 4. 2024 www.nccn.org

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Cornford, P., R. C. N. van den Bergh, E. Briers, et al. 2024. "EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer-2024 Update. Part I: Screening, Diagnosis, and Local Treatment with Curative Intent." Eur Urol 86(2):148-163.

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BACKGROUND AND OBJECTIVE: The European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) guidelines provide recommendations for the management of clinically localised prostate cancer (PCa). This paper aims to present a summary of the 2024 version of the EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on the screening, diagnosis, and treatment of clinically localised PCa. METHODS: The panel performed a literature review of all new data published in English, covering the time frame between May 2020 and 2023. The guidelines were updated, and a strength rating for each recommendation was added based on a systematic review of the evidence. KEY FINDINGS AND LIMITATIONS: A risk-adapted strategy for identifying men who may develop PCa is advised, generally commencing at 50 yr of age and based on individualised life expectancy. The use of multiparametric magnetic resonance imaging in order to avoid unnecessary biopsies is recommended. When a biopsy is considered, a combination of targeted and regional biopsies should be performed. Prostate-specific membrane antigen positron emission tomography imaging is the most sensitive technique for identifying metastatic spread. Active surveillance is the appropriate management for men with low-risk PCa, as well as for selected favourable intermediate-risk patients with International Society of Urological Pathology grade group 2 lesions. Local therapies are addressed, as well as the management of persistent prostate-specific antigen after surgery. A recommendation to consider hypofractionation in intermediate-risk patients is provided. Patients with cN1 PCa should be offered a local treatment combined with long-term intensified hormonal treatment. CONCLUSIONS AND CLINICAL IMPLICATIONS: The evidence in the field of diagnosis, staging, and treatment of localised PCa is evolving rapidly. These PCa guidelines reflect the multidisciplinary nature of PCa management. PATIENT SUMMARY: This article is the summary of the guidelines for "curable" prostate cancer. Prostate cancer is "found" through a multistep risk-based screening process. The objective is to find as many men as possible with a curable cancer. Prostate cancer is curable if it resides in the prostate; it is then classified into low-, intermediary-, and high-risk localised and locally advanced prostate cancer. These risk classes are the basis of the treatments. Low-risk prostate cancer is treated with "active surveillance", a treatment with excellent prognosis. For low-intermediary-risk active surveillance should also be discussed as an option. In other cases, active treatments, surgery, or radiation treatment should be discussed along with the potential side effects to allow shared decision-making.

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Eastham, J. A., G. B. Auffenberg, D. A. Barocas, et al. 2022. "Clinically Localized Prostate Cancer: AUA/ASTRO Guideline. Part III: Principles of Radiation and Future Directions." J Urol 208(1):26-33.

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Abstract

Purpose: The summary presented herein represents Part III of the three-part series dedicated to Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, discussing principles of radiation and offering several future directions of further relevant study in patients diagnosed with clinically localized prostate cancer. Please refer to Parts I and II for discussion of risk assessment, staging, and risk-based management (Part I), and principles of active surveillance and surgery and follow-up (Part II).

Materials and methods: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles.

Results: The Clinically Localized Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with clinically localized prostate cancer. Statements regarding management of patients using radiation therapy as well as important future directions of research are detailed herein.

Conclusions: This guideline aims to inform clinicians treating patients with clinically localized prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to further improve care for these men.

Keywords: Active surveillance; Prostate cancer; Radiation therapy for prostate cancer; Radical prostatectomy; Shared decision making.

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Hamstra, D. A., N. Mariados, J. Sylvester, et al. 2017. "Continued Benefit to Rectal Separation for Prostate Radiation Therapy: Final Results of a Phase III Trial." Int J Radiat Oncol Biol Phys 97(5):976-985.

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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<.05) meeting the threshold for a MID. The control group had a 3.9-point greater decline in urinary QOL compared with the spacer group at 3 years (P<.05), but the difference did not meet the MID threshold. At 3 years, more men in the control group than in the spacer group had experienced a MID decline in bowel QOL (41% vs 14%; 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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Kerkmeijer, L. G. W., V. H. Groen, F. J. Pos, et al. 2021. "Focal Boost to the Intraprostatic Tumor in External Beam Radiotherapy for Patients With Localized Prostate Cancer: Results From the FLAME Randomized Phase III Trial." J Clin Oncol 39(7):787-796.

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Abstract

Purpose: This study investigates whether focal boosting of the macroscopic visible tumor with external beam radiotherapy increases biochemical disease-free survival (bDFS) in patients with localized prostate cancer.

Patients and methods: In the phase III, multicenter, randomized controlled Focal Lesion Ablative Microboost in Prostate Cancer trial, 571 patients with intermediate- and high-risk prostate cancer were enrolled between 2009 and 2015. Patients assigned to standard treatment received 77 Gy (fractions of 2.2 Gy) to the entire prostate. The focal boost arm received an additional simultaneous integrated focal boost up to 95 Gy (fractions up to 2.7 Gy) to the intraprostatic lesion visible on multiparametric magnetic resonance imaging. Organ at risk constraints were prioritized over the focal boost dose. The primary end point was 5-year bDFS. Secondary end points were disease-free survival (DFS), distant metastases-free survival, prostate cancer-specific survival, overall survival, toxicity, and health-related quality of life.

Results: Median follow-up was 72 months. Biochemical DFS was significantly higher in the focal boost compared with the standard arm (hazard ratio 0.45, 95% CI, 0.28 to 0.71, P < .001). At 5-year follow-up bDFS was 92% and 85%, respectively. We did not observe differences in prostate cancer-specific survival (P = .49) and overall survival (P = .50). The cumulative incidence of late genitourinary and GI toxicity grade ≥ 2 was 23% and 12% in the standard arm versus 28% and 13% in the focal boost arm, respectively. Both for late toxicity as health-related quality of life, differences were small and not statistically significant.

Conclusion: The addition of a focal boost to the intraprostatic lesion improved bDFS for patients with localized intermediate- and high-risk prostate cancer without impacting toxicity and quality of life. The Focal Lesion Ablative Microboost in Prostate Cancer study shows that a high focal boost strategy to improve tumor control while respecting organ at risk dose constraints is effective and safe.

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Tree, A. C., L. Satchwell, E. Alexander, et al. 2023. "Standard and Hypofractionated Dose Escalation to Intraprostatic Tumor Nodules in Localized Prostate Cancer: 5-Year Efficacy and Toxicity in the DELINEATE Trial." Int J Radiat Oncol Biol Phys 115(2):305-316.

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Abstract

Purpose: Our purpose was to report 5-year efficacy and toxicity of intraprostatic lesion boosting using standard and hypofractionated radiation therapy.

Methods and materials: DELINEATE (ISRCTN 04483921) is a single center phase 2 multicohort study including standardly fractionated (cohort A: 74 Gy/37F to prostate and seminal vesicles [PSV]; cohort C 74 Gy/37F to PSV plus 60 Gy/37F to pelvic lymph nodes) and moderately hypofractionated (cohort B: 60 Gy/20F to PSV) prostate intensity-modulated radiation therapy patients with National Comprehensive Cancer Network intermediate/high-risk disease. Patients received an integrated boost of 82 Gy (cohorts A and C) or 67 Gy (cohort B) to multiparametric magnetic resonance imaging identified lesion(s). Primary endpoint was late Radiation Therapy Oncology Group (RTOG) gastrointestinal (GI) toxicity at 1 year. Secondary endpoints were acute and late toxicity (clinician and patient reported) and freedom from biochemical/clinical failure at 5 years.

Results: Two hundred and sixty-five men were recruited and 256 were treated (55 cohort A, 153 cohort B, and 48 cohort C). Median follow-up for each cohort was >5 years. Cumulative late RTOG grade 2+ GI toxicity at 1 year was 3.6% (95% confidence interval [CI], 0.9%-13.8%) (cohort A), 7.2% (95% CI, 4%-12.6%) (cohort B), and 8.4% (95% CI, 3.2%-20.8%) (cohort C). Cumulative late RTOG grade 2+ GI toxicity to 5 years was 12.8% (95% CI, 6.3%-25.1%) (cohort A), 14.6% (95% CI, 9.9%-21.4%) (cohort B), and 20.7% (95% CI, 11.2%-36.2%) (cohort C). Cumulative RTOG grade 2+ genitourinary toxicity to 5 years was 12.9% (95% CI, 6.4%-25.2%) (cohort A), 18.2% (95% CI, 12.8%-25.4%) (cohort B), and 18.2% (95% CI, 9.5%-33.2%) (cohort C). Five-year freedom from biochemical/clinical failure was 98.2% (95% CI, 87.8%-99.7%) (cohort A), 96.7% (95% CI, 91.3%- 98.8%) (cohort B), and 95.1% (95% CI, 81.6-98.7%) (cohort C).

Conclusions: The DELINEATE trial has shown safety, tolerability, and feasibility of focal boosting in 20 or 37 fractions. Efficacy results indicate a low chance of prostate cancer recurrence 5 years after radiation therapy. Evidence from ongoing phase 3 randomized trials is awaited.

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Hayden, A. J., J. M. Martin, A. B. Kneebone, et al. 2010. "Australian & New Zealand Faculty of Radiation Oncology Genito-Urinary Group: 2010 consensus guidelines for definitive external beam radiotherapy for prostate carcinoma." J Med Imaging Radiat Oncol 54(6):513-525.

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External beam radiotherapy for prostate cancer has undergone substantial technological and clinical advances in the recent years. The Australian & New Zealand Faculty of Radiation Oncology Genito-Urinary Group undertook a process to develop consensus clinical practice guidelines for external beam radiotherapy for prostate carcinoma delivered with curative intent, aiming to provide guidance for clinicians on the appropriate integration of clinical evidence and newer technologies. Draft guidelines were presented and discussed at a consensus workshop in May 2009 attended by radiation oncologists, radiation therapists and medical physicists. Amended guidelines were distributed to radiation oncologists in Australia, New Zealand and Singapore for comment, and modifications were incorporated where appropriate. Evidence based recommendations for risk stratification, the role of image-guided and intensity-modulated radiation therapy, prescribed dose, simulation and treatment planning, the role and duration of neo-adjuvant/adjuvant androgen deprivation therapy and outcome reporting are presented. Central to the guidelines is the recommendation that image-guided radiation therapy should be used when definitive external beam radiotherapy for prostate cancer is prescribed. The consensus guidelines provide a co-operatively developed, evidence-based framework for contemporary treatment of prostate cancer with external beam radiotherapy.

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McLaughlin, P. W., C. Evans, M. Feng, et al. 2010. "Radiographic and anatomic basis for prostate contouring errors and methods to improve prostate contouring accuracy." Int J Radiat Oncol Biol Phys 76(2):369-378.

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PURPOSE: Use of highly conformal radiation for prostate cancer can lead to both overtreatment of surrounding normal tissues and undertreatment of the prostate itself. In this retrospective study we analyzed the radiographic and anatomic basis of common errors in computed tomography (CT) contouring and suggest methods to correct them. METHODS AND MATERIALS: Three hundred patients with prostate cancer underwent CT and magnetic resonance imaging (MRI). The prostate was delineated independently on the data sets. CT and MRI contours were compared by use of deformable registration. Errors in target delineation were analyzed and methods to avoid such errors detailed. RESULTS: Contouring errors were identified at the prostatic apex, mid gland, and base on CT. At the apex, the genitourinary diaphragm, rectum, and anterior fascia contribute to overestimation. At the mid prostate, the anterior and lateral fasciae contribute to overestimation. At the base, the bladder and anterior fascia contribute to anterior overestimation. Transition zone hypertrophy and bladder neck variability contribute to errors of overestimation and underestimation at the superior base, whereas variable prostate-to-seminal vesicle relationships with prostate hypertrophy contribute to contouring errors at the posterior base. CONCLUSIONS: Most CT contouring errors can be detected by (1) inspection of a lateral view of prostate contours to detect projection from the expected globular form and (2) recognition of anatomic structures (genitourinary diaphragm) on the CT scans that are clearly visible on MRI. This study shows that many CT prostate contouring errors can be improved without direct incorporation of MRI data.

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Salembier, C., G. Villeirs, B. De Bari, et al. 2018. "ESTRO ACROP consensus guideline on CT- and MRI-based target volume delineation for primary radiation therapy of localized prostate cancer." Radiother Oncol 127(1):49-61.

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BACKGROUND AND PURPOSE: Delineation of clinical target volumes (CTVs) remains a weak link in radiation therapy (RT), and large inter-observer variation is seen. Guidelines for target and organs at risk delineation for prostate cancer in the primary setting are scarce. The aim was to develop a delineation guideline obtained by consensus between a broad European group of radiation oncologists. MATERIAL AND METHODS: An ESTRO contouring consensus panel consisting of leading radiation oncologists and one radiologist with known subspecialty expertise in prostate cancer was asked to delineate the prostate, seminal vesicles and rectum on co-registered CT and MRI scans. After evaluation of the different contours, literature review and multiple informal discussions by electronic mail a CTV definition was defined and a guide for contouring the CTV of the prostate and the rectum was developed. RESULTS: The panel achieved consensus CTV contouring definitions to be used as guideline for primary RT of localized prostate cancer. CONCLUSION: The ESTRO consensus on CT/MRI based CTV delineation for primary RT of localized prostate cancer, endorsed by a broad base of the radiation oncology community, is presented to improve consistency and reliability.

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Wilkins, A., O. Naismith, D Brand, et al. 2020. “Derivation of Dose/Volume Constraints for the anorectum from clinician and patient reported outcomes in the CHHiP trial of radiation therapy fractionation” Int J Radiation Oncol Biol Phys 106(5): 928-938

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PURPOSE: The CHHiP trial randomized 3216 men with localized prostate cancer (1:1:1) to 3 radiation therapy fractionation schedules: 74 Gy in 37 fractions over 7.4 weeks; 60 Gy in 20 fractions over 4 weeks; and 57 Gy in 19 fractions over 3.8 weeks. Literature-based dose constraints were applied with arithmetic adjustment for the hypofractionated arms. This study aimed to derive anorectal dose constraints using prospectively collected clinician-reported outcomes (CROs) and patient-reported outcomes (PROs) and to assess the added predictive value of spatial dose metrics. METHODS AND MATERIALS: A case-control study design was used; 7 CRO and 5 PRO bowel symptoms were evaluated. Cases experienced a moderate or worse symptom 1 to 5 years after-radiation therapy and did not have the symptom before radiation therapy. Controls did not experience the symptom at baseline or between 1 to 5 years after radiation therapy. The anorectum was recontoured from the anal verge to the rectosigmoid junction; dose/volume parameters were extracted. Univariate logistic regression, atlases of complication indices, and bootstrapped receiver-operating-characteristic analysis (1000 replicates, balanced outcomes) were used to derive dose constraints for the whole cohort (hypofractionated schedules were converted to 2-Gy equivalent schedules using α/β = 3 Gy) and separate hypofractionated/conventional fractionation cohorts. Only areas under the curve with 95% confidence interval lower limits >0.5 were considered statistically significant. Any constraint derived in <95% to 99% of bootstraps was excluded. RESULTS: Statistically significant dose constraints were derived for CROs but not PROs. Intermediate to high doses were important for rectal bleeding, whereas intermediate doses were important for increased bowel frequency, fecal incontinence, and rectal pain. Spatial dose metrics did not improve prediction of CROs or PROs. A new panel of dose constraints for hypofractionated schedules to 60 Gy or 57 Gy are V20Gy <85%, V30Gy <57%, V40Gy <38%, V50Gy <22%, and V60Gy <0.01%. CONCLUSION: Dose constraints differed among symptoms, indicating potentially different pathogenesis of radiation-induced side effects. Derived dose constraints were stricter than those used in CHHiP and may reduce bowel symptoms after radiation therapy.

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Dearnaley, D., I. Syndikus, H. Mossop, et al. 2016. "Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial." Lancet Oncol 17(8):1047-1060.

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BACKGROUND: Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up. METHODS: CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b-T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7.4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3.8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1.208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923. FINDINGS: Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62.4 months (IQR 53.9-77.0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88.3% (95% CI 86.0-90.2) in the 74 Gy group, 90.6% (88.5-92.3) in the 60 Gy group, and 85.9% (83.4-88.0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0.84 [90% CI 0.68-1.03], pNI=0.0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1.20 [0.99-1.46], pNI=0.48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13.7% (111 events) and 9.1% (66 events) in the 74 Gy group, 11.9% (105 events) and 11.7% (88 events) in the 60 Gy group, 11.3% (95 events) and 6.6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported. INTERPRETATION: Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer. FUNDING: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

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Wilkins, A., H. Mossop, I. Syndikus, et al. 2015. “Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2 year patient reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial”. Lancet Oncol 16(16):1605-16.

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BACKGROUND: Patient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial. METHODS: The CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b-T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923. FINDINGS: 2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50·0 months (IQR 38·4-64·2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59). We saw no differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months. INTERPRETATION: The incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer.

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Pollack, A., A. L. Hanlon, E. M. Horwitz, et al. 2006. "Dosimetry and preliminary acute toxicity in the first 100 men treated for prostate cancer on a randomized hypofractionation dose escalation trial." Int J Radiat Oncol Biol Phys 64(2):518-526.

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PURPOSE: The alpha/beta ratio for prostate cancer is postulated to be between 1 and 3, giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation. The dosimetry and acute toxicity are described in the first 100 men enrolled in a randomized trial. PATIENTS AND METHODS: The trial compares 76 Gy in 38 fractions (Arm I) to 70.2 Gy in 26 fractions (Arm II) using intensity modulated radiotherapy. The planning target volume (PTV) margins in Arms I and II were 5 mm and 3 mm posteriorly and 8 mm and 7 mm in all other dimensions. The PTV D95% was at least the prescription dose. RESULTS: The mean PTV doses for Arms I and II were 81.1 and 73.8 Gy. There were no differences in overall maximum acute gastrointestinal (GI) or genitourinary (GU) toxicity acutely. However, there was a slight but significant increase in Arm II GI toxicity during Weeks 2, 3, and 4. In multivariate analyses, only the combined rectal DVH parameter of V65 Gy/V50 Gy was significant for GI toxicity and the bladder volume for GU toxicity. CONCLUSION: Hypofractionation at 2.7 Gy per fraction to 70.2 Gy was well tolerated acutely using the planning conditions described.

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ENZARAD/ ANZUP 1303 Trial. 2015. "A randomised phase 3 trial of enzalutamide in androgen deprivation therapy with radiation therapy for high risk, clinically localised, prostate cancer: ENZARAD."

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Patient Population:
The target population is men with localised prostate cancer at high risk for recurrence deemed suitable for external beam radiation therapy
Intervention:
Enzalutamide 160mg daily by mouth combined with LHRHA and external beam radiation therapy
Primary Outcome:
Overall survival (death from any cause)
Secondary Outcomes:
To determine effects on:
2) Cause-specific survival (prostate cancer, and other causes)
3) PSA progression free survival (Phoenix criteria)
4) Clinical progression free survival
5) Time to subsequent hormonal therapy (restarting ADT)
6) Adverse events (CTCAE v4.03)
7) Health related quality of life (EORTC QLQC-30,PR-25 & EQ-5D-5L)
8) Health outcomes relative to costs (incremental cost effectiveness ratio)

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QUANTEC 2010 "Quantitative Analyses of Normal Tissue Effects in the Clinic." Int J Radiat Oncol Biol Phys 76(3):S1-S160.

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RTOG 0126 (2014) A Phase III Randomized Study of High Dose 3DCRT/IMRT versus Standard Dose 3DCRT/IMRT in Patients Treated for Localized Prostate Cancer

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Determine whether 3D-CRT/IMRT to 79.2 Gy in 44 fractions will lead to improved overall survival in patients treated for prostate cancer compared to a group of patients treated with 3D-CRT/ IMRT to 70.2 Gy in 39 fractions. https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0126

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Richardson, M., K. Skehan, L. Wilton, et al. 2021. "Visualising the urethra for prostate radiotherapy planning." J Med Radiat Sci 68(3):282-288.

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Abstract

Introduction

The prostatic urethra is an organ at risk for prostate radiotherapy with genitourinary toxicities a common side effect. Many external beam radiation therapy protocols call for urethral sparing, and with modulated radiotherapy techniques, the radiation dose distribution can be controlled so that maximum doses do not fall within the prostatic urethral volume. Whilst traditional diagnostic MRI sequences provide excellent delineation of the prostate, uncertainty often remains as to the true path of the urethra within the gland. This study aims to assess if a high-resolution isotropic 3D T2 MRI series can reduce inter-observer variability in urethral delineation for radiotherapy planning.

Methods

Five independent observers contoured the prostatic urethra for ten patients on three data sets; a 2 mm axial CT, a diagnostic 3 mm axial T2 TSE MRI and a 0.9 mm isotropic 3D T2 SPACE MRI. The observers were blinded from each other’s contours. A Dice Similarity Coefficient (DSC) score was calculated using the intersection and union of the five observer contours vs an expert reference contour for each data set.

Results

The mean DSC of the observer vs reference contours was 0.47 for CT, 0.62 for T2 TSE and 0.78 for T2 SPACE (P < 0.001).

Conclusions

The introduction of a 0.9 mm isotropic 3D T2 SPACE MRI for treatment planning provides improved urethral visualisation and can lead to a significant reduction in inter-observer variation in prostatic urethral contouring.

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Gay, H. A., H. J. Barthold, E. O'Meara, et al. 2012. "Pelvic normal tissue contouring guidelines for radiation therapy: a Radiation Therapy Oncology Group consensus panel atlas." Int J Radiat Oncol Biol Phys 83(3):e353-362.

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PURPOSE: To define a male and female pelvic normal tissue contouring atlas for Radiation Therapy Oncology Group (RTOG) trials. METHODS AND MATERIALS: One male pelvis computed tomography (CT) data set and one female pelvis CT data set were shared via the Image-Guided Therapy QA Center. A total of 16 radiation oncologists participated. The following organs at risk were contoured in both CT sets: anus, anorectum, rectum (gastrointestinal and genitourinary definitions), bowel NOS (not otherwise specified), small bowel, large bowel, and proximal femurs. The following were contoured in the male set only: bladder, prostate, seminal vesicles, and penile bulb. The following were contoured in the female set only: uterus, cervix, and ovaries. A computer program used the binomial distribution to generate 95% group consensus contours. These contours and definitions were then reviewed by the group and modified. RESULTS: The panel achieved consensus definitions for pelvic normal tissue contouring in RTOG trials with these standardized names: Rectum, AnoRectum, SmallBowel, Colon, BowelBag, Bladder, UteroCervix, Adnexa_R, Adnexa_L, Prostate, SeminalVesc, PenileBulb, Femur_R, and Femur_L. Two additional normal structures whose purpose is to serve as targets in anal and rectal cancer were defined: AnoRectumSig and Mesorectum. Detailed target volume contouring guidelines and images are discussed. CONCLUSIONS: Consensus guidelines for pelvic normal tissue contouring were reached and are available as a CT image atlas on the RTOG Web site. This will allow uniformity in defining normal tissues for clinical trials delivering pelvic radiation and will facilitate future normal tissue complication research.

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Zaorsky, N. G., S. W. Keith, T. Shaikh, et al. 2018. "Impact of Radiation Therapy Dose Escalation on Prostate Cancer Outcomes and Toxicities." Am J Clin Oncol 41(4):409-415.

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Objectives: Freedom from biochemical failure (FFBF) is a common primary outcome of randomized-controlled trials of prostate cancer (PCa). We aimed to determine how increasing the PCa biologically equivalent dose (BED) of external radiation therapy (RT) is correlated with FFBF and overall patient outcomes: overall survival (OS), distant metastasis (DM), and cancer-specific mortality (CSM); as well as genitourinary (GU), and gastrointestinal toxicities. Materials and Methods: We performed a meta-analysis of 6884 PCa patients from 12 randomized-controlled trials of external beam RT. Mixed effects regression models were used to estimate weighted linear relationships between BED and observed percentages of 5- and 10-year outcomes. For toxicities, a subset analysis of using 3-dimensional conformal RT (3D-CRT) versus intensity-modulated RT (IMRT) was performed. Results: Increasing BED correlated with improved FFBF: 10-year absolute improvement of 9.6% and 7.2% for low-risk and intermediate-risk patients, respectively (P<0.05); but not with improvement of OS, DM, or CSM at either time point. BED escalation was not correlated with increased acute toxicities; it was correlated with increased late gastrointestinal toxicities in patients treated with 3D-CRT (1.5% increase over BED range, P<0.01). IMRT patients had significantly fewer late toxicities, despite being treated at higher BED. Conclusions: RT BED escalation has resulted in significantly improved PCa FFBF at up to 10 years; but not with improvement in OS, DM, or CSM. Thus, FFBF is a poor surrogate of overall patient outcomes for trials of RT. Late toxicities were less frequent with IMRT than with 3D-CRT, even at higher BED. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Viani, G. A., E. J. Stefano and S. L. Afonso. 2009. "Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials." Int J Radiat Oncol Biol Phys 74(5):1405-1418.

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PURPOSE: To determine in a meta-analysis whether the outcomes in men with localized prostate cancer treated with high-dose radiotherapy (HDRT) are better than those in men treated with conventional-dose radiotherapy (CDRT), by quantifying the effect of the total dose of radiotherapy on biochemical control (BC). METHODS AND MATERIALS: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as the proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing HDRT with CDRT for localized prostate cancer. To evaluate the dose-response relationship, we conducted a meta-regression analysis of BC ratios by means of weighted linear regression. RESULTS: Seven RCTs with a total patient population of 2812 were identified that met the study criteria. Pooled results from these RCTs showed a significant reduction in the incidence of biochemical failure in those patients with prostate cancer treated with HDRT (p < 0.0001). However, there was no difference in the mortality rate (p = 0.38) and specific prostate cancer mortality rates (p = 0.45) between the groups receiving HDRT and CDRT. However, there were more cases of late Grade >2 gastrointestinal toxicity after HDRT than after CDRT. In the subgroup analysis, patients classified as being at low (p = 0.007), intermediate (p < 0.0001), and high risk (p < 0.0001) of biochemical failure all showed a benefit from HDRT. The meta-regression analysis also detected a linear correlation between the total dose of radiotherapy and biochemical failure (BC = -67.3 + [1.8 x radiotherapy total dose in Gy]; p = 0.04). CONCLUSIONS: Our meta-analysis showed that HDRT is superior to CDRT in preventing biochemical failure in low-, intermediate-, and high-risk prostate cancer patients, suggesting that this should be offered as a treatment for all patients, regardless of their risk status.

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Bolla, M., P. Maingon, C. Carrie, et al. 2016. "Short Androgen Suppression and Radiation Dose Escalation for Intermediate- and High-Risk Localized Prostate Cancer: Results of EORTC Trial 22991." J Clin Oncol 34(15):1748-1756.

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PURPOSE: Up to 30% of patients who undergo radiation for intermediate- or high-risk localized prostate cancer relapse biochemically within 5 years. We assessed if biochemical disease-free survival (DFS) is improved by adding 6 months of androgen suppression (AS; two injections of every-3-months depot of luteinizing hormone-releasing hormone agonist) to primary radiotherapy (RT) for intermediate- or high-risk localized prostate cancer. PATIENTS AND METHODS: A total of 819 patients staged: (1) cT1b-c, with prostate-specific antigen (PSA) >/= 10 ng/mL or Gleason >/= 7, or (2) cT2a (International Union Against Cancer TNM 1997), with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread, with PSA </= 50 ng/mL, were centrally randomized 1:1 to either RT or RT plus AS started on day 1 of RT. Centers opted for one dose (70, 74, or 78 Gy). Biochemical DFS, the primary end point, was defined from entry until PSA relapse (Phoenix criteria) and clinical relapse by imaging or death of any cause. The trial had 80% power to detect hazard ratio (HR), 0.714 by intent-to-treat analysis stratified by dose of RT at the two-sided alpha = 5%. RESULTS: The median patient age was 70 years. Among patients, 74.8% were intermediate risk and 24.8% were high risk. In the RT arm, 407 of 409 patients received RT; in the RT plus AS arm, 403 patients received RT plus AS and three patients received RT only. At 7.2 years median follow-up, RT plus AS significantly improved biochemical DFS (HR, 0.52; 95% CI, 0.41 to 0.66; P < .001, with 319 events), as well as clinical progression-free survival (205 events, HR, 0.63; 95% CI, 0.48 to 0.84; P = .001). In exploratory analysis, no statistically significant interaction between treatment effect and dose of RT could be evidenced (heterogeneity P = .79 and P = .66, for biochemical DFS and progression-free survival, respectively). Overall survival data are not mature yet. CONCLUSION: Six months of concomitant and adjuvant AS improves biochemical and clinical DFS of intermediate- and high-risk cT1b-c to cT2a (with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread) prostatic carcinoma, treated by radiation.

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Denham, J. W., D. Joseph, D. S. Lamb, et al. 2014. "Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial." Lancet Oncol 15(10):1076-1089.

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SummaryBackground We investigated whether 18 months of androgen suppression plus radiotherapy, with or without 18 months of zoledronic acid, is more effective than 6 months of neoadjuvant androgen suppression plus radiotherapy with or without zoledronic acid. Methods We did an open-label, randomised, 2 × 2 factorial trial in men with locally advanced prostate cancer (either T2a N0 M0 prostatic adenocarcinomas with prostate-specific antigen [PSA] ≥10 μg/L and a Gleason score of ≥7, or T2b–4 N0 M0 tumours regardless of PSA and Gleason score). We randomly allocated patients by computer-generated minimisation—stratified by centre, baseline PSA, tumour stage, Gleason score, and use of a brachytherapy boost—to one of four groups in a 1:1:1:1 ratio. Patients in the control group were treated with neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) for 6 months (short-term) and radiotherapy alone (designated STAS); this procedure was either followed by another 12 months of androgen suppression with leuprorelin (intermediate-term; ITAS) or accompanied by 18 months of zoledronic acid (4 mg every 3 months for 18 months, intravenously; STAS plus zoledronic acid) or by both (ITAS plus zoledronic acid). The primary endpoint was prostate cancer-specific mortality. This analysis represents the first, preplanned assessment of oncological endpoints, 5 years after treatment. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00193856. Findings Between Oct 20, 2003, and Aug 15, 2007, 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 7·4 years (IQR 6·5–8·4). Cumulative incidences of prostate cancer-specific mortality were 4·1% (95% CI 2·2–7·0) in the STAS group, 7·8% (4·9–11·5) in the STAS plus zoledronic acid group, 7·4% (4·6–11·0) in the ITAS group, and 4·3% (2·3–7·3) in the ITAS plus zoledronic acid group. Cumulative incidence of all-cause mortality was 17·0% (13·0–22·1), 18·9% (14·6–24·2), 19·4% (15·0–24·7), and 13·9% (10·3–18·8), respectively. Neither prostate cancer-specific mortality nor all-cause mortality differed between control and experimental groups. Cumulative incidence of PSA progression was 34·2% (28·6–39·9) in the STAS group, 39·6% (33·6–45·5) in the STAS plus zoledronic acid group, 29·2% (23·8–34·8) in the ITAS group, and 26·0% (20·8–31·4) in the ITAS plus zoledronic acid group. Compared with STAS, no difference was noted in PSA progression with ITAS or STAS plus zoledronic acid; however, ITAS plus zoledronic acid reduced PSA progression (sub-hazard ratio [SHR] 0·71, 95% CI 0·53–0·95; p=0·021). Cumulative incidence of local progression was 4·1% (2·2–7·0) in the STAS group, 6·1% (3·7–9·5) in the STAS plus zoledronic acid group, 1·5% (0·5–3·7) in the ITAS group, and 3·4% (1·7–6·1) in the ITAS plus zoledronic acid group; no differences were noted between groups. Cumulative incidences of bone progression were 7·5% (4·8–11·1), 14·6% (10·6–19·2), 8·4% (5·5–12·2), and 7·6% (4·8–11·2), respectively. Compared with STAS, STAS plus zoledronic acid increased the risk of bone progression (SHR 1·90, 95% CI 1·14–3·17; p=0·012), but no differences were noted with the other two groups. Cumulative incidence of distant progression was 14·7% (10·7–19·2) in the STAS group, 17·3% (13·0–22·1) in the STAS plus zoledronic acid group, 14·2% (10·3–18·7) in the ITAS group, and 11·1% (7·6–15·2) in the ITAS plus zoledronic acid group; no differences were recorded between groups. Cumulative incidence of secondary therapeutic intervention was 25·6% (20·5–30·9), 28·9% (23·5–34·5), 20·7% (16·1–25·9), and 15·3% (11·3–20·0), respectively. Compared with STAS, ITAS plus zoledronic acid reduced the need for secondary therapeutic intervention (SHR 0·67, 95% CI 0·48–0·95; p=0·024); no differences were noted with the other two groups. An interaction between trial factors was recorded for Gleason score; therefore, we did pairwise comparisons between all groups. Post-hoc analyses suggested that the reductions in PSA progression and decreased need for secondary therapeutic intervention with ITAS plus zoledronic acid were restricted to tumours with a Gleason score of 8–10, and that ITAS was better than STAS in tumours with a Gleason score of 7 or lower. Long-term morbidity and quality-of-life scores were not affected adversely by 18 months of androgen suppression or zoledronic acid. Interpretation Compared with STAS, ITAS plus zoledronic acid was more effective for treatment of prostate cancers with a Gleason score of 8–10, and ITAS alone was effective for tumours with a Gleason score of 7 or lower. Nevertheless, these findings are based on secondary endpoint data and post-hoc analyses and must be regarded cautiously. Long- term follow-up is necessary, as is external validation of the interaction between zoledronic acid and Gleason score. STAS plus zoledronic acid can be ruled out as a potential therapeutic option. Funding National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Calvary Health Care (Calvary Mater Newcastle Radiation Oncology Fund), Hunter Medical Research Institute, Maitland Cancer Appeal, Cancer Standards Institute New Zealand.

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Denham, J. W., A. Steigler, D. S. Lamb, et al. 2011. "Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial." Lancet Oncol 12(5):451-459.

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BACKGROUND: The TROG 96.01 trial assessed whether 3-month and 6-month short-term neoadjuvant androgen deprivation therapy (NADT) decreases clinical progression and mortality after radiotherapy for locally advanced prostate cancer. Here we report the 10-year results. METHODS: Between June, 1996, and February, 2000, 818 men with T2b, T2c, T3, and T4 N0 M0 prostate cancers were randomly assigned to receive radiotherapy alone, 3 months of NADT plus radiotherapy, or 6 months of NADT plus radiotherapy. The radiotherapy dose for all groups was 66 Gy, delivered to the prostate and seminal vesicles (excluding pelvic nodes) in 33 fractions of 2 Gy per day (excluding weekends) over 6.5-7.0 weeks. NADT consisted of 3.6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day. NADT began 2 months before radiotherapy for the 3-month NADT group and 5 months before radiotherapy for the 6-month NADT group. Primary endpoints were prostate-cancer-specific mortality and all-cause mortality. Treatment allocation was open label and randomisation was done with a minimisation technique according to age, clinical stage, tumour grade, and initial prostate-specific antigen concentration (PSA). Analysis was by intention-to-treat. The trial has been closed to follow-up and all main endpoint analyses are completed. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000237482. FINDINGS: 802 men were eligible for analysis (270 in the radiotherapy alone group, 265 in the 3-month NADT group, and 267 in the 6-month NADT group) after a median follow-up of 10.6 years (IQR 6.9-11.6). Compared with radiotherapy alone, 3 months of NADT decreased the cumulative incidence of PSA progression (adjusted hazard ratio 0.72, 95% CI 0.57-0.90; p=0.003) and local progression (0.49, 0.33-0.73; p=0.0005), and improved event-free survival (0.63, 0.52-0.77; p<0.0001). 6 months of NADT further reduced PSA progression (0.57, 0.46-0.72; p<0.0001) and local progression (0.45, 0.30-0.66; p=0.0001), and led to a greater improvement in event-free survival (0.51, 0.42-0.61, p<0.0001), compared with radiotherapy alone. 3-month NADT had no effect on distant progression (0.89, 0.60-1.31; p=0.550), prostate cancer-specific mortality (0.86, 0.60-1.23; p=0.398), or all-cause mortality (0.84, 0.65-1.08; p=0.180), compared with radiotherapy alone. By contrast, 6-month NADT decreased distant progression (0.49, 0.31-0.76; p=0.001), prostate cancer-specific mortality (0.49, 0.32-0.74; p=0.0008), and all-cause mortality (0.63, 0.48-0.83; p=0.0008), compared with radiotherapy alone. Treatment-related morbidity was not increased with NADT within the first 5 years after randomisation. INTERPRETATION: 6 months of neoadjuvant androgen deprivation combined radiotherapy is an effective treatment option for locally advanced prostate cancer, particularly in men without nodal metastases or pre-existing metabolic comorbidities that could be exacerbated by prolonged androgen deprivation. FUNDING: Australian Government National Health and Medical Research Council, Hunter Medical Research Institute, AstraZeneca, and Schering-Plough.

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Kuban, D. A., S. L. Tucker, et al. 2008. "Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer." Int.J Radiat.Oncol Biol.Phys. 70(1): 67-74.

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PURPOSE: To report the long-term results of a randomized radiotherapy dose escalation trial for prostate cancer. METHODS AND MATERIALS: From 1993 to 1998, a total of 301 patients with stage T1b to T3 prostate cancer were accrued to a randomized external beam dose escalation trial using 70 Gy versus 78 Gy. The median follow-up is now 8.7 years. Kaplan-Meier analysis was used to compute rates of prostate-specific antigen (PSA) failure (nadir + 2), clinical failure, distant metastasis, disease-specific, and overall survival as well as complication rates at 8 years post-treatment. RESULTS: For all patients, freedom from biochemical or clinical failure (FFF) was superior for the 78-Gy arm, 78%, as compared with 59% for the 70-Gy arm (p = 0.004, and an even greater benefit was seen in patients with initial PSA >10 ng/ml (78% vs. 39%, p = 0.001). The clinical failure rate was significantly reduced in the 78-Gy arm as well (7% vs. 15%, p = 0.014). Twice as many patients either died of prostate cancer or are currently alive with cancer in the 70-Gy arm. Gastrointestinal toxicity of grade 2 or greater occurred twice as often in the high dose patients (26% vs. 13%), although genitourinary toxicity of grade 2 or greater was less (13% vs. 8%) and not statistically significantly different. Dose-volume histogram analysis showed that the complication rate could be significantly decreased by reducing the amount of treated rectum. CONCLUSIONS: Modest escalation in radiotherapy dose improved freedom from biochemical and clinical progression with the largest benefit in prostate cancer patients with PSA >10 ng/ml

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Kuban, D. A., L. B. Levy, M. R. Cheung, et al. 2011. "Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease?" Int J Radiat Oncol Biol Phys 79(5):1310-1317.

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PURPOSE: To report long-term failure patterns and survival in a randomized radiotherapy dose escalation trial for prostate cancer. MATERIALS AND METHODS: A total of 301 patients with Stage T1b-T3 prostate cancer treated to 70 Gy versus 78 Gy now have a median follow-up of 9 years. Failure patterns and survival were compared between dose levels. The cumulative incidence of death from prostate cancer versus other causes was examined and regression analysis was used to establish predictive factors. RESULTS: Patients with pretreatment prostate-specific antigen (PSA) >10 ng/mL or high-risk disease had higher biochemical and clinical failures rates when treated to 70 Gy. These patients also had a significantly higher risk of dying of prostate cancer. Patients <70 years old at treatment died of prostate cancer nearly three times more frequently than of other causes when they were radiated to 70 Gy, whereas those treated to 78 Gy died of other causes more frequently. Patients age 70 or older treated to 70 Gy died of prostate cancer as often as other causes, and those receiving 78 Gy never died of prostate cancer within 10 years of follow-up. In regression analysis, factors predicting for death from prostate cancer were pretreatment PSA >10.5 ng/mL, Gleason score 9 and 10, recurrence within 2.6 years of radiation, and doubling time of <3.6 months at the time of recurrence. CONCLUSIONS: Moderate dose escalation (78 Gy) decreases biochemical and clinical failure as well as prostate cancer death in patients with pretreatment PSA >10 ng/mL or high-risk disease.

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Zelefsky, M. J., Y. Yamada, Z. Fuks, et al. 2008. "Long-term results of conformal radiotherapy for prostate cancer: impact of dose escalation on biochemical tumor control and distant metastases-free survival outcomes." Int J Radiat Oncol Biol Phys 71(4):1028-1033.

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PURPOSE: To report prostate-specific antigen (PSA) relapse-free survival and distant metastases-free survival (DMFS) outcomes for patients with clinically localized prostate cancer treated with high-dose conformal radiotherapy. METHODS AND MATERIALS: Between 1988 and 2004, a total of 2,047 patients with clinically localized prostate cancer were treated with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Prescribed dose levels ranged from 66-86.4 Gy. Median follow-up was 6.6 years (range, 3-18 years). RESULTS: Although no differences were noted among low-risk patients for the various dose groups, significant improvements were observed with higher doses for patients with intermediate- and high-risk features. In patients with intermediate-risk features, multivariate analysis showed that radiation dose was an important predictor for improved PSA relapse-free survival (p < 0.0001) and improved DMFS (p = 0.04). In patients with high-risk features, multivariate analysis showed that the following variables predict for improved PSA relapse-free survival: dose (p < 0.0001); age (p = 0.0005), and neoadjuvant-concurrent androgen deprivation therapy (ADT; p = 0.01). In this risk group, only higher radiation dose was an important predictor for improved DMFS (p = 0.04). CONCLUSIONS: High radiation dose levels were associated with improved biochemical tumor control and decreased risk of distant metastases. For high-risk patients, despite the delivery of high radiation dose levels, the use of ADT conferred an additional benefit for improved tumor control outcomes. We observed a benefit for ADT in high-risk patients who received higher doses.

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D'Amico, A. V., M. H. Chen, A. A. Renshaw, et al. 2008. "Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial." Jama 299(3):289-295.

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CONTEXT: Comorbidities may increase the negative effects of specific anticancer treatments such as androgen suppression therapy (AST). OBJECTIVES: To compare 6 months of AST and radiation therapy (RT) to RT alone and to assess the interaction between level of comorbidity and all-cause mortality. DESIGN, SETTING, AND PATIENTS: At academic and community-based medical centers in Massachusetts, between December 1, 1995, and April 15, 2001, 206 men with localized but unfavorable-risk prostate cancer were randomized to receive RT alone or RT and AST combined. All-cause mortality estimates stratified by randomized treatment group and further stratified in a postrandomization analysis by the Adult Comorbidity Evaluation 27 comorbidity score were compared using a log-rank test. MAIN OUTCOME MEASURE: Time to all-cause mortality. RESULTS: As of January 15, 2007, with a median follow-up of 7.6 (range, 0.5-11.0) years, 74 deaths have occurred. A significant increase in the risk of all-cause mortality (44 vs 30 deaths; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.1-2.9; P = .01) was observed in men randomized to RT compared with RT and AST. However, the increased risk in all-cause mortality appeared to apply only to men randomized to RT with no or minimal comorbidity (31 vs 11 deaths; HR, 4.2; 95% CI, 2.1-8.5; P < .001). Among men with moderate or severe comorbidity, those randomized to RT alone vs RT and AST did not have an increased risk of all-cause mortality (13 vs 19 deaths; HR, 0.54; 95% CI, 0.27-1.10; P = .08). CONCLUSIONS: The addition of 6 months of AST to RT resulted in increased overall survival in men with localized but unfavorable-risk prostate cancer. This result may pertain only to men without moderate or severe comorbidity, but this requires further assessment in a clinical trial specifically designed to assess this interaction. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00116220.

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Peeters, S. T., W. D. Heemsbergen, et al. 2006. "Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy." J Clin Oncol 24(13): 1990-6.

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PURPOSE: To determine whether a dose of 78 Gy improves outcome compared with a conventional dose of 68 Gy for prostate cancer patients treated with three-dimensional conformal radiotherapy. PATIENTS AND METHODS: Between June 1997 and February 2003, stage T1b-4 prostate cancer patients were enrolled onto a multicenter randomized trial comparing 68 Gy with 78 Gy. Patients were stratified by institution, age, (neo)adjuvant hormonal therapy (HT), and treatment group. Four treatment groups (with specific radiation volumes) were defined based on the probability of seminal vesicle involvement. The primary end point was freedom from failure (FFF). Failure was defined as clinical failure or biochemical failure, according to the American Society of Therapeutic Radiation Oncology definition. Other end points were freedom from clinical failure (FFCF), overall survival (OS), and toxicity. RESULTS: Median follow-up time was 51 months. Of the 669 enrolled patients, 664 were included in the analysis. HT was prescribed for 143 patients. FFF was significantly better in the 78-Gy arm compared with the 68-Gy arm (5-year FFF rate, 64% v 54%, respectively), with an adjusted hazard ratio of 0.74 (P = .02). No significant differences in FFCF or OS were seen between the treatment arms. There was no difference in late genitourinary toxicity of Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer grade 2 or more and a slightly higher nonsignificant incidence of late gastrointestinal toxicity of grade 2 or more. CONCLUSION: This multicenter randomized trial shows a significantly improved FFF in prostate cancer patients treated with a higher dose of radiotherapy.

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Roach, M., III, M. DeSilvio, et al. 2003. "Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413." J Clin Oncol. 21(10): 1904-1911.

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PURPOSE: This trial tested the hypothesis that combined androgen suppression (CAS) and whole-pelvic (WP) radiotherapy (RT) followed by a boost to the prostate improves progression-free survival (PFS) by 10% compared with CAS and prostate-only (PO) RT. This trial also tested the hypothesis that neoadjuvant and concurrent hormonal therapy (NCHT) improves PFS compared with adjuvant hormonal therapy (AHT) by 10%. MATERIALS AND METHODS: Eligibility included localized prostate cancer with an elevated prostate-specific antigen (PSA) < or = 100 ng/mL and an estimated risk of lymph node (LN) involvement of 15%. Between April 1, 1995, and June 1, 1999, 1,323 patients were accrued. Patients were randomly assigned to WP + NCHT, PO + NCHT, WP + AHT, or PO + AHT. Failure for PFS was defined as the first occurrence of local, regional, or distant disease; PSA failure; or death for any cause. RESULTS: With a median follow-up of 59.5 months, WP RT was associated with a 4-year PFS of 54% compared with 47% in patients treated with PO RT (P =.022). Patients treated with NCHT experienced a 4-year PFS of 52% versus 49% for AHT (P =.56). When comparing all four arms, there was a progression-free difference among WP RT + NCHT, PO RT + NCHT, WP RT + AHT, and PO RT + AHT (60% v 44% v 49% v 50%, respectively; P =.008). No survival advantage has yet been seen. CONCLUSION: WP RT + NCHT improves PFS compared with PO RT and NCHT or PO RT and AHT, and compared with WP RT + AHT in patients with a risk of LN involvement of 15%

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Catton, C. N., H. Lukka, C. S. Gu, et al. 2017. "Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer." J Clin Oncol 35(17):1884-1890.

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Purpose Men with localized prostate cancer often are treated with external radiotherapy (RT) over 8 to 9 weeks. Hypofractionated RT is given over a shorter time with larger doses per treatment than standard RT. We hypothesized that hypofractionation versus conventional fractionation is similar in efficacy without increased toxicity. Patients and Methods We conducted a multicenter randomized noninferiority trial in intermediate-risk prostate cancer (T1 to 2a, Gleason score </= 6, and prostate-specific antigen [PSA] 10.1 to 20 ng/mL; T2b to 2c, Gleason </= 6, and PSA </= 20 ng/mL; or T1 to 2, Gleason = 7, and PSA </= 20 ng/mL). Patients were allocated to conventional RT of 78 Gy in 39 fractions over 8 weeks or to hypofractionated RT of 60 Gy in 20 fractions over 4 weeks. Androgen deprivation was not permitted with therapy. The primary outcome was biochemical-clinical failure (BCF) defined by any of the following: PSA failure (nadir + 2), hormonal intervention, clinical local or distant failure, or death as a result of prostate cancer. The noninferiority margin was 7.5% (hazard ratio, < 1.32). Results Median follow-up was 6.0 years. One hundred nine of 608 patients in the hypofractionated arm versus 117 of 598 in the standard arm experienced BCF. Most of the events were PSA failures. The 5-year BCF disease-free survival was 85% in both arms (hazard ratio [short v standard], 0.96; 90% CI, 0.77 to 1.2). Ten deaths as a result of prostate cancer occurred in the short arm and 12 in the standard arm. No significant differences were detected between arms for grade >/= 3 late genitourinary and GI toxicity. Conclusion The hypofractionated RT regimen used in this trial was not inferior to conventional RT and was not associated with increased late toxicity. Hypofractionated RT is more convenient for patients and should be considered for intermediate-risk prostate cancer.

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Hoffman, K. E., K. R. Voong, L. B. Levy, et al. 2018. "Randomized Trial of Hypofractionated, Dose-Escalated, Intensity-Modulated Radiation Therapy (IMRT) Versus Conventionally Fractionated IMRT for Localized Prostate Cancer." J Clin Oncol 36(29):2943-2949.

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PURPOSE: Hypofractionated radiotherapy delivers larger daily doses of radiation and may increase the biologically effective dose delivered to the prostate. We conducted a randomized trial testing the hypothesis that dose-escalated, moderately hypofractionated intensity-modulated radiation therapy (HIMRT) improves prostate cancer control compared with conventionally fractionated IMRT (CIMRT) for men with localized prostate cancer. PATIENTS AND METHODS: Men were randomly assigned to 75.6 Gy in 1.8-Gy fractions delivered over 8.4 weeks (CIMRT) or 72 Gy in 2.4 Gy fractions delivered over 6 weeks (HIMRT, biologically equivalent to 85 Gy in 1.8-Gy fractions assuming prostate cancer alpha-to-beta ratio of 1.5). Failure was defined as prostate-specific antigen (PSA) failure (nadir plus 2 ng/mL) or initiation of salvage therapy. Modified Radiation Therapy Oncology Group criteria were used to grade late (>/= 90 days after completion of radiotherapy) GI and genitourinary toxicity. RESULTS: Most of the 206 men (72%) had cT1, Gleason score 6 or 7 (99%), and PSA level </= 10 ng/mL (90%) disease. Androgen deprivation therapy was received by 24%. With a median follow-up of 8.5 years, men treated with HIMRT experienced fewer treatment failures (n = 10) than men treated with CIMRT (n = 21; P = .036). The 8-year failure rate was 10.7% (95% CI, 5.8% to 19.1%) with HIMRT and 15.4% (95% CI, 9.1% to 25.4%) with CIMRT. There was no difference in overall survival ( P = .39). There was a nonsignificant increase in late grade 2 or 3 GI toxicity with HIMRT (8-year 5.0% v 12.6%; P = .08). However, GI toxicity was only 8.6% when rectal volume receiving 65 Gy of HIMRT was </= 15%. Late genitourinary toxicity was similar ( P = .84). There was no grade 4 toxicity. CONCLUSION: The results of this randomized trial demonstrate superior cancer control for men with localized prostate cancer who receive dose-escalated moderately hypofractionation radiotherapy while shortening treatment duration.

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Incrocci, L., R. C. Wortel, W. G. Alemayehu, et al. 2016. "Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial." Lancet Oncol 17(8):1061-1069.

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BACKGROUND: Studies have reported a low alpha/beta ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. In the multicentre phase 3, HYpofractionated irradiation for PROstate cancer (HYPRO) trial, hypofractionated radiotherapy was compared with conventionally fractionated radiotherapy for treatment of prostate cancer. We have previously reported acute and late incidence of genitourinary and gastrointestinal toxicity; here we report protocol-defined 5-year relapse-free survival outcomes. METHODS: We did an open-label, randomised, phase 3 trial at seven Dutch radiotherapy centres. We enrolled patients with intermediate-risk to high-risk T1b-T4NX-N0MX-M0 localised prostate cancer, a prostate-specific antigen concentration of 60 mug/L or less, and a WHO performance status of 0-2. We used a web-based application to randomly assign (1:1) patients to either hypofractionated radiotherapy of 64.6 Gy (19 fractions of 3.4 Gy, three fractions per week) or conventionally fractionated radiotherapy of 78.0 Gy (39 fractions of 2.0 Gy, five fractions per week). Based on an estimated alpha/beta ratio for prostate cancer of 1.5 Gy, the equivalent total dose in fractions of 2.0 Gy was 90.4 Gy for hypofractionation compared with 78.0 Gy for conventional fractionation. The primary endpoint was relapse-free survival. All analyses were done on an intention-to-treat basis in all eligible patients. The HYPRO trial completed recruitment in 2010 and follow-up is ongoing. This trial is registered with ISRCTN, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients were enrolled, of whom 804 were eligible and assessable for intention-to-treat analyses. Of these, 407 were assigned hypofractionated radiotherapy and 397 were allocated conventionally fractionated radiotherapy. 537 (67%) of 804 patients received concomitant androgen deprivation therapy for a median duration of 32 months (IQR 10-44). Median follow-up was 60 months (IQR 51-69). Treatment failure was reported in 169 (21%) of 804 patients, 80 (20%) in the hypofractionation group and 89 (22%) in the conventional fractionation group. 5-year relapse-free survival was 80.5% (95% CI 75.7-84.4) for patients assigned hypofractionation and 77.1% (71.9-81.5) for those allocated conventional fractionation (adjusted hazard radio 0.86, 95% CI 0.63-1.16; log-rank p=0.36). There were no treatment-related deaths. INTERPRETATION: Hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. Our hypofractionated radiotherapy regimen cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer. FUNDING: Dutch Cancer Society.

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Bryant, R. J., J. Oxley, G. J. Young, et al. 2020. "The ProtecT trial: analysis of the patient cohort, baseline risk stratification and disease progression." BJU Int 125(4):506-514.

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Abstract

Objective

To test the hypothesis that the baseline clinico‐pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10‐year median follow‐up were different from those of men with stable disease (n = 1409).

Patients and Methods

We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models.

Results

The findings showed that 34% of participants (n = 505) had intermediate‐ or high‐risk PCa, and 66% (n = 973) had low‐risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low‐ and intermediate‐/high‐risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65–69 vs 50–64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins.

Conclusions

We demonstrate that one‐third of the ProtecT cohort consists of people with intermediate‐/high‐risk disease, and the outcomes data at an average of 10 years' follow‐up are generalizable beyond men with low‐risk PCa.

Keywords: Prostate cancer, pathology, risk stratification

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Hamdy, F. C., J. L. Donovan, J. A. Lane, et al. 2023. "Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer." N Engl J Med 388(17):1547-1558.

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Abstract

Background: Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy.

Methods: At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes).

Results: Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P = 0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis.

Conclusions: After 15 years of follow-up, prostate cancer-specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.).

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Wilt, T. J., K. M. Jones, M. J. Barry, et al. 2017. "Follow-up of Prostatectomy versus Observation for Early Prostate Cancer." N Engl J Med 377(2):132-142.

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Abstract

Background: We previously found no significant differences in mortality between men who underwent surgery for localized prostate cancer and those who were treated with observation only. Uncertainty persists regarding nonfatal health outcomes and long-term mortality.

Methods: From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer to radical prostatectomy or observation. We extended follow-up through August 2014 for our primary outcome, all-cause mortality, and the main secondary outcome, prostate-cancer mortality. We describe disease progression, treatments received, and patient-reported outcomes through January 2010 (original follow-up).

Results: During 19.5 years of follow-up (median, 12.7 years), death occurred in 223 of 364 men (61.3%) assigned to surgery and in 245 of 367 (66.8%) assigned to observation (absolute difference in risk, 5.5 percentage points; 95% confidence interval [CI], -1.5 to 12.4; hazard ratio, 0.84; 95% CI, 0.70 to 1.01; P=0.06). Death attributed to prostate cancer or treatment occurred in 27 men (7.4%) assigned to surgery and in 42 men (11.4%) assigned to observation (absolute difference in risk, 4.0 percentage points; 95% CI, -0.2 to 8.3; hazard ratio, 0.63; 95% CI, 0.39 to 1.02; P=0.06). Surgery may have been associated with lower all-cause mortality than observation among men with intermediate-risk disease (absolute difference, 14.5 percentage points; 95% CI, 2.8 to 25.6) but not among those with low-risk disease (absolute difference, 0.7 percentage points; 95% CI, -10.5 to 11.8) or high-risk disease (absolute difference, 2.3 percentage points; 95% CI, -11.5 to 16.1) (P=0.08 for interaction). Treatment for disease progression was less frequent with surgery than with observation (absolute difference, 26.2 percentage points; 95% CI, 19.0 to 32.9); treatment was primarily for asymptomatic, local, or biochemical (prostate-specific antigen) progression. Urinary incontinence and erectile and sexual dysfunction were each greater with surgery than with observation through 10 years. Disease-related or treatment-related limitations in activities of daily living were greater with surgery than with observation through 2 years.

Conclusions: After nearly 20 years of follow-up among men with localized prostate cancer, surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation. Surgery was associated with a higher frequency of adverse events than observation but a lower frequency of treatment for disease progression, mostly for asymptomatic, local, or biochemical progression. (Funded by the Department of Veterans Affairs and others; PIVOT ClinicalTrials.gov number, NCT00007644 .).

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Pryor, D. I., S. L. Turner, K. H. Tai, et al. 2018. "Moderate hypofractionation for prostate cancer: A user's guide." J Med Imaging Radiat Oncol 62(2):232-239.

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Three large randomised controlled trials have been published in the last year demonstrating the non-inferiority of moderate hypofractionation compared to conventional fractionation for localised prostate cancer with respect to both disease control and late toxicity at 5 years. Furthermore, no clinically significant differences in patient-reported outcomes have emerged. More mature follow-up data are now also available from phase 2 studies confirming that moderate hypofractionation is associated with low rates of significant toxicity at 10 years. Moving forward it is likely that appropriate patient selection, integration of androgen deprivation and attention to optimising technique will play a more important role than modest differences in dose-fractionation schedules. Here we briefly review the evidence, discuss issues of patient selection and provide an approach to implementing moderately hypofractionated radiation therapy for prostate cancer in clinical practice.

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Morgan, S. C., K. Hoffman, D. A. Loblaw, et al. 2018. "Hypofractionated Radiation Therapy for Localized Prostate Cancer: An ASTRO, ASCO, and AUA Evidence-Based Guideline." J Clin Oncol:Jco1801097.

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Martin, J. M., S. Supiot, P. J. Keall, et al. 2018. "Moderately hypofractionated prostate external-beam radiotherapy: an emerging standard." Br J Radiol 91(1086):20170807.

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Research over recent years has demonstrated that curative external-beam radiotherapy can be safely and efficaciously delivered with roughly half the number of treatments which was previously considered standard. We review the data supporting this change in practice, methods for implementation, as well as emerging future directions.

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Arcangeli, G., B. Saracino, S. Arcangeli, et al. 2017. "Moderate Hypofractionation in High-Risk, Organ-Confined Prostate Cancer: Final Results of a Phase III Randomized Trial." J Clin Oncol 35(17):1891-1897.

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Purpose To report the final results on treatment outcomes of a randomized trial comparing conventional and hypofractionated radiotherapy in high-risk, organ-confined prostate cancer (PCa). Patients and Methods This single-institution, randomized clinical trial, conducted from January 2003 to December 2007, enrolled 168 patients with high-risk PCa who were randomly assigned in a 1:1 ratio to conventional (80 Gy in 40 fractions in 8 weeks) or hypofractionated radiotherapy (62 Gy in 20 fractions in 5 weeks) to prostate and seminal vesicles. The primary outcome measure was late toxicity. Additional outcomes were freedom from biochemical failure (FFBF), prostate cancer-specific survival (PCaSS), and overall survival (OS), evaluated on an intention-to-treat basis. Results A total of 85 patients were assigned to conventional and 83 to hypofractionated radiotherapy. At a median follow-up of 9 years (interquartile range, 7.5 to 10.1 years), no differences was observed in physician-assessed late gastro intestinal and genitourinary toxicity greater than or equal to grade 2 ( P = .68 and .57, respectively) were found between the two arms. The 10-year FFBF rate was 72% in the hypofractionation group and 65% in the conventional fractionation group ( P = .148). Ten-year OS rates were 75% in the hypofractionation group and 64% in the conventional group, respectively ( P = .22). The same features for 10-year PCaSS were 95% and 88%, respectively ( P = .066). Hypofractionation, pretreatment prostate-specific antigen level, Gleason score, and clinical tumor stage for FFBF, and hypofractionation and Gleason score for PCaSS were significant prognostic variables on the multivariate analysis. Conclusion Long-term findings showed that hypofractionated radiotherapy failed the intent of either reducing physician-assessed late toxicity or maintaining the same efficacy. A postrandomization analysis, however, revealed that hypofractionation was a significant prognostic factor for FFBF and PCaSS, when adjusted for clinical prognostic variables.

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Bauman, G., M. Haider, U. A. Van der Heide, et al. 2013. "Boosting imaging defined dominant prostatic tumors: a systematic review." Radiother Oncol 107(3):274-281.

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Abstract

Introduction: Dominant cancer foci within the prostate are associated with sites of local recurrence post radiotherapy. In this systematic review we sought to address the question: "what is the clinical evidence to support differential boosting to an imaging defined GTV volume within the prostate when delivered by external beam or brachytherapy".

Materials and methods: A systematic review was conducted to identify clinical series reporting the use of radiation boosts to imaging defined GTVs.

Results: Thirteen papers describing 11 unique patient series and 833 patients in total were identified. Methods and details of GTV definition and treatment varied substantially between series. GTV boosts were on average 8 Gy (range 3-35 Gy) for external beam, or 150% for brachytherapy (range 130-155%) and GTV volumes were small (<10 ml). Reported toxicity rates were low and may reflect the modest boost doses, small volumes and conservative DVH constraints employed in most studies. Variability in patient populations, study methodologies and outcomes reporting precluded conclusions regarding efficacy.

Conclusions: Despite a large cohort of patients treated differential boosts to imaging defined intra-prostatic targets, conclusions regarding optimal techniques and/or efficacy of this approach are elusive, and this approach cannot be considered standard of care. There is a need to build consensus and evidence. Ongoing prospective randomized trials are underway and will help to better define the role of differential prostate boosts based on imaging defined GTVs.

Keywords: Boost; DIL; GTV; MRI; PET; Prostate; SPECT.

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Moore, A., M. A. Kollmeier, S. M. McBride, et al. 2024. "Long-term Outcomes from a Phase 1 Dose Escalation Study Using Stereotactic Body Radiotherapy for Patients with Low- or Intermediate-risk Prostate Cancer." Eur Urol Oncol 7(4):812-820.

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Abstract

Background: Ultrahypofractionated stereotactic body radiation therapy (SBRT) has become a standard treatment intervention for localized prostate cancer.

Objective: To report final long-term tumor control outcomes and late gastrointestinal (GI) and genitourinary (GU) toxicities from a single-center phase 1 dose escalation study using SBRT for patients with low- or intermediate-risk prostate cancer.

Design, setting and participants: Between 2009 and 2012, 136 patients were enrolled and treated. The initial dose level was 32.5 Gy in five fractions. Doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy in five fractions delivered every other day.

Outcome measurements and statistical analysis: The primary endpoint was late treatment-related toxicity. Secondary endpoints included prostate-specific antigen (PSA) failure.

Results and limitations: The median follow-up was 10.5 yr for the 32.5-Gy group, 9.9 yr for the 35-Gy group, 8.2 yr for the 37.5-Gy group, and 7.3 yr for the 40-Gy group. The 8-yr cumulative incidence of PSA failure was 26% for 32.5 Gy, 15% for 35 Gy, 3.4% for 37.5 Gy, and 6.6% for 40 Gy. Higher radiation dose (37.5-40 Gy) and favorable intermediate risk (vs unfavorable intermediate risk) were associated with better PSA recurrence rates (p = 0.011 and 0.002, respectively). The 8-yr actuarial probability rates for survival free from late grade ≥2 toxicity were 94% for GI toxicity and 86% for GU toxicity. No grade 4 events were recorded. Higher dose levels were not associated with higher rates of late grade ≥2 GI (p = 0.2) or GU (p > 0.9) toxicity.

Conclusions: SBRT doses ranging from 32.5 to 40 Gy were associated with low incidence of moderate or severe toxicities. Higher doses resulted in superior disease control outcomes 8 yr after treatment.

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Jones, C. U., D. Hunt, D. G. McGowan, et al. 2011. "Radiotherapy and short-term androgen deprivation for localized prostate cancer." N Engl J Med 365(2):107-118.

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BACKGROUND: It is not known whether short-term androgen-deprivation therapy (ADT) before and during radiotherapy improves cancer control and overall survival among patients with early, localized prostate adenocarcinoma. METHODS: From 1994 through 2001, we randomly assigned 1979 eligible patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostate-specific antigen (PSA) level of 20 ng per milliliter or less to radiotherapy alone (992 patients) or radiotherapy with 4 months of total androgen suppression starting 2 months before radiotherapy (radiotherapy plus short-term ADT, 987 patients). The primary end point was overall survival. Secondary end points included disease-specific mortality, distant metastases, biochemical failure (an increasing level of PSA), and the rate of positive findings on repeat prostate biopsy at 2 years. RESULTS: The median follow-up period was 9.1 years. The 10-year rate of overall survival was 62% among patients receiving radiotherapy plus short-term ADT (the combined-therapy group), as compared with 57% among patients receiving radiotherapy alone (hazard ratio for death with radiotherapy alone, 1.17; P=0.03). The addition of short-term ADT was associated with a decrease in the 10-year disease-specific mortality from 8% to 4% (hazard ratio for radiotherapy alone, 1.87; P=0.001). Biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years were significantly improved with radiotherapy plus short-term ADT. Acute and late radiation-induced toxic effects were similar in the two groups. The incidence of grade 3 or higher hormone-related toxic effects was less than 5%. Reanalysis according to risk showed reductions in overall and disease-specific mortality primarily among intermediate-risk patients, with no significant reductions among low-risk patients. CONCLUSIONS: Among patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a PSA level of 20 ng per milliliter or less, the use of short-term ADT for 4 months before and during radiotherapy was associated with significantly decreased disease-specific mortality and increased overall survival. According to post hoc risk analysis, the benefit was mainly seen in intermediate-risk, but not low-risk, men. (Funded by the National Cancer Institute; RTOG 94-08 ClinicalTrials.gov number, NCT00002597.).

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Jackson, W. C., H. E. Hartman, R. T. Dess, et al. 2020. “Addition of androgen-deprivation therapy or brachytherapy boost to external beam radiotherapy for localized prostate cancer: a network meta-analysis of randomized trials” J Clin Oncol 38(26):3024-3031

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Purpose: In men with localized prostate cancer, the addition of androgen-deprivation therapy (ADT) or a brachytherapy boost (BT) to external beam radiotherapy (EBRT) have been shown to improve various oncologic end points. Practice patterns indicate that those who receive BT are significantly less likely to receive ADT, and thus we sought to perform a network meta-analysis to compare the predicted outcomes of a randomized trial of EBRT plus ADT versus EBRT plus BT.

Materials and methods: A systematic review identified published randomized trials comparing EBRT with or without ADT, or EBRT (with or without ADT) with or without BT, that reported on overall survival (OS). Standard fixed-effects meta-analyses were performed for each comparison, and a meta-regression was conducted to adjust for use and duration of ADT. Network meta-analyses were performed to compare EBRT plus ADT versus EBRT plus BT. Bayesian analyses were also performed, and a rank was assigned to each treatment after Markov Chain Monte Carlo analyses to create a surface under the cumulative ranking curve.

Results: Six trials compared EBRT with or without ADT (n = 4,663), and 3 compared EBRT with or without BT (n = 718). The addition of ADT to EBRT improved OS (hazard ratio [HR], 0.71 [95% CI, 0.62 to 0.81]), whereas the addition of BT did not significantly improve OS (HR, 1.03 [95% CI, 0.78 to 1.36]). In a network meta-analysis, EBRT plus ADT had improved OS compared with EBRT plus BT (HR, 0.68 [95% CI, 0.52 to 0.89]). Bayesian modelling demonstrated an 88% probability that EBRT plus ADT resulted in superior OS compared with EBRT plus BT.

Conclusion: Our findings suggest that current practice patterns of omitting ADT with EBRT plus BT may result in inferior OS compared with EBRT plus ADT in men with intermediate- and high-risk prostate cancer. ADT for these men should remain a critical component of treatment regardless of radiotherapy delivery method until randomized evidence demonstrates otherwise.

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Aluwini, S., F. Pos, E. Schimmel, et al. 2016. "Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial." Lancet Oncol 17(4):464-474.

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BACKGROUND: Several studies have reported a low alpha to beta ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. We tested this theory in the phase 3 HYPRO trial for patients with intermediate-risk and high-risk prostate cancer. We have previously reported acute incidence of genitourinary and gastrointestinal toxicity; here we report data for late genitourinary and gastrointestinal toxicity. METHODS: In this randomised non-inferiority phase 3 trial, done in seven radiotherapy centres in the Netherlands, we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer, a prostate-specific antigen concentration of 60 ng/mL or lower, and WHO performance status of 0-2. A web-based application was used to randomly assign (1:1) patients to receive either standard fractionation with 39 fractions of 2 Gy in 8 weeks (five fractions per week) or hypofractionation with 19 fractions of 3.4 Gy in 6.5 weeks (three fractions per week). Randomisation was done with the minimisation procedure, stratified by treatment centre and risk group. The primary endpoint was to detect a 10% enhancement in 5-year relapse-free survival with hypofractionation. A key additional endpoint was non-inferiority of hypofractionation in cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity. We planned to reject inferiority of hypofractionation for late genitourinary toxicity if the estimated hazard ratio (HR) was less than 1.11 and for gastrointestinal toxicity was less than 1.13. We scored toxicity with the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer (RTOG/EORTC) criteria from both physicians' records (clinical record form) and patients' self-assessment questionnaires. Analyses were done in the intention-to-treat population. Patient recruitment for the HYPRO trial was completed in 2010. The trial was registered with www.controlled-trials.com, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients (410 in both groups) were randomly assigned. Analyses for late toxicity included 387 assessable patients in the standard fractionation group and 395 in the hypofractionation group. The median follow-up was 60 months (IQR 51.2-67.3). The database for all analyses (both groups and both genitourinary and gastrointestinal toxicities) was locked on March 26, 2015. The incidence of grade 2 or worse genitourinary toxicity at 3 years was 39.0% (95% CI 34.2-44.1) in the standard fractionation group and 41.3% (36.6-46.4) in the hypofractionation group. The estimated HR for the cumulative incidence of grade 2 or worse late genitourinary toxicity was 1.16 (90% CI 0.98-1.38), suggesting that non-inferiority could not be shown. The incidence of grade 2 or worse gastrointestinal toxicity at 3 years was 17.7% (14.1-21.9) in standard fractionation and 21.9% (18.1-26.4) hypofractionation. With an estimated HR of 1.19 (90% CI 0.93-1.52) for the cumulative incidence of grade 2 or worse late gastrointestinal toxicity, we could not confirm non-inferiority of hypofractionation for cumulative late gastrointestinal toxicity. Cumulative grade 3 or worse late genitourinary toxicity was significantly higher in the hypofractionation group than in the standard fractionation group (19.0% [95% CI 15.2-23.2] vs 12.9% [9.7-16.7], respectively; p=0.021), but there was no significant difference between cumulative grade 3 or worse late gastrointestinal toxicity (2.6% [95% CI 1.2-4.7]) in the standard fractionation group and 3.3% [1.7-5.6] in the hypofractionation group; p=0.55). INTERPRETATION: Our data could not confirm that hypofractionation was non-inferior for cumulative late genitourinary and gastrointestinal toxicity compared with standard fractionation. Before final conclusions can be made about the utility of hypofractionation, efficacy outcomes need to be reported. FUNDING: The Dutch Cancer Society.

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Pollack, A., G. Walker, E. M. Horwitz, et al. 2013. "Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer." J Clin Oncol 31(31):3860-3868.

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PURPOSE: To determine if escalated radiation dose using hypofractionation significantly reduces biochemical and/or clinical disease failure (BCDF) in men treated primarily for prostate cancer. PATIENTS AND METHODS: Between June 2002 and May 2006, men with favorable- to high-risk prostate cancer were randomly allocated to receive 76 Gy in 38 fractions at 2.0 Gy per fraction (conventional fractionation intensity-modulated radiation therapy [CIMRT]) versus 70.2 Gy in 26 fractions at 2.7 Gy per fraction (hypofractionated IMRT [HIMRT]); the latter was estimated to be equivalent to 84.4 Gy in 2.0 Gy fractions. High-risk patients received long-term androgen deprivation therapy (ADT), and some intermediate-risk patients received short-term ADT. The primary end point was the cumulative incidence of BCDF. Secondarily, toxicity was assessed. RESULTS: There were 303 assessable patients with a median follow-up of 68.4 months. No significant differences were seen between the treatment arms in terms of the distribution of patients by clinicopathologic or treatment-related (ADT use and length) factors. The 5-year rates of BCDF were 21.4% (95% CI, 14.8% to 28.7%) for CIMRT and 23.3% (95% CI, 16.4% to 31.0%) for HIMRT (P = .745). There were no statistically significant differences in late toxicity between the arms; however, in subgroup analysis, patients with compromised urinary function before enrollment had significantly worse urinary function after HIMRT. CONCLUSION: The hypofractionation regimen did not result in a significant reduction in BCDF; however, it is delivered in 2.5 fewer weeks. Men with compromised urinary function before treatment may not be ideal candidates for this approach.

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Shaikh, T., T. Li, E. A. Handorf, et al. 2017. "Long-Term Patient-Reported Outcomes From a Phase 3 Randomized Prospective Trial of Conventional Versus Hypofractionated Radiation Therapy for Localized Prostate Cancer." Int J Radiat Oncol Biol Phys 97(4):722-731.

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PURPOSE: To assess the long-term quality of life (QoL) outcomes from a phase 3 trial comparing 2 modes of intensity modulated radiation therapy (IMRT): conventional IMRT (CIMRT) versus hypofractionated IMRT (HIMRT) in patients with localized prostate cancer. METHODS AND MATERIALS: Between 2002 and 2006, 303 men with low-risk to high-risk prostate cancer were randomized to 76 Gy in 38 fractions (CIMRT) versus 70.2 Gy in 26 fractions (HIMRT). QoL was compared by use of the Expanded Prostate Cancer Index Composite (EPIC), the International Prostate Symptom Score (IPSS), and EuroQoL (EQ5D) questionnaires. The primary outcome of the QoL analysis was a minimum clinically important difference defined as a 0.5 standard deviation change from baseline for each respective QoL parameter. Treatment effects were evaluated with the use of logistic mixed effects regression models. RESULTS: A total of 286, 299, and 218 patients had baseline EPIC, IPSS, or EQ5D data available and were included in the analysis. Overall, there was no statistically significant difference between the 2 treatment arms in terms of EPIC, IPSS, or EQ5D scores over time, although there was a trend toward lower EPIC urinary incontinence scores in the HIMRT arm. More patients in the HIMRT arm had a lower EPIC urinary incontinence score relative to baseline versus patients in the CIMRT arm with long-term follow-up. On multivariable analysis, there was no association between radiation fractionation scheme and any QoL parameter. When other clinical factors were examined, lymph node radiation was associated with worse EPIC hormonal scores versus patients receiving no lymph node radiation. In general, QoL outcomes were generally stable over time, with the exception of EPIC hormonal and EQ5D scores. CONCLUSIONS: In this randomized prospective study, there were stable QoL changes in patients receiving HIMRT or CIMRT. Our results add to the growing body of literature suggesting that HIMRT may be an acceptable treatment modality in clinically localized prostate cancer.

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Version 7

Date	Summary of changes
10/03/2025	Organs at risk "Urethral PRV" D2 constraints corrected. 20 fractions constraints: Previous: Ideal: ≤77 Gy Acceptable:  ≤83 Gy Updated: Ideal: ≤62.4 Gy Acceptable:  ≤67.3 Gy 39-40 fractions constraints: Previous: Ideal: ≤62.4 Gy Acceptable:  ≤67.3 Gy Updated: Ideal: ≤77 Gy Acceptable:  ≤83 Gy.

Version 6

Date

Summary of changes

07/02/2025

Reviewed at the radiation oncology urogenital reference committee meeting on 07/11/2024. Summary of changes: Title: Updated from “Prostate adenocarcinoma definitive EBRT conventional intermediate-risk” to “Prostate adenocarcinoma definitive EBRT intermediate-risk." Indications and patient population: Indications: Included N0 M0. Cautions and exclusions: Transurethral resection of the prostate (TURP) added as a caution. Indication notes: Reworded active surveillance note to read "A subset of patients with favourable intermediate-risk prostate cancer may be offered active surveillance with involvement of a urologist." Removed hypofractionated radiation therapy note. Include statement regarding select low-risk patients treated with this protocol and link to ID 416: Prostate adenocarcinoma definitive brachytherapy permanent seeds LDR as an alternative treatment for this cohort. Clinical information: Update timing of radiation therapy (RT) post-TURP from "8-12 weeks" to "> 3 months." Include statement "Patients should be offered sexual counselling to manage potential late effects related to sexual function." Androgen deprivation therapy (ADT): include "The use of ADT is not recommended for patients in the low-risk group." Simulation table: Other imaging: "Consider" removed from before "MRI" and "hydrogel" changed to "rectal spacer." Dose prescription: Table: Updated format and target area name to PTV. Included hypofractionated dose prescription (60 Gy in 20 fractions). Removed 1.8 Gy per fraction as an option from conventional dose prescription. Prescription notes: Add statement "If treating elective nodes refer to ID 235: Prostate adenocarcinoma definitive EBRT high-risk protocol." Remove hypofractionated radiation therapy note. Include note to "Consider dose escalation to the GTV/dominant intraprostatic lesion (DIL) e.g. 67 Gy/20# or 82-95 Gy for conventionally fractionated prescriptions" and reference DELINEATE and FLAME trials. Include statement " It may be acceptable to decrease the dose to the proximal seminal vesicles." Target volumes: Target volume tables: Updated table formatting. Added footnote to CTV volume “In the low-risk setting, the CTV is the prostate only." Included DIL volumes table. Target volume notes/guidelines: Removed link to NRG pelvic lymph node volumes atlas. Added note “If treating elective nodes, refer to the ID 235 Prostate adenocarcinoma definitive EBRT high-risk protocol.” Organs at risk: OAR table: Remove 1.8 Gy from table heading. Include the hypofractionated OAR constraints from discontinued eviQ protocol  ID 3370; referenced from the CHHiP trial. Include "Urethra" as an OAR with constraints and for when treating DIL include "Urethra PRV" with constraints. Include additional information for contouring urethra from MRI fused with CT and Urethral PRV = Urethra + 0.2-0.3 cm radial expansion. OAR notes/atlases: Remove hypofractionated constraints note. Include the following statements: "The reference committee strongly recommends treating clinicians consider improving on these constraints by taking into account local and patient specific factors" and "When boosting DIL, prioritise OAR tolerance over DIL boost dose coverage." Include the RTOG  Pelvic normal tissue contouring guidelines for radiation therapy and ESTRO ACROP consensus guidelines of localised prostate cancer. Side effects: Remove "male" from sexual dysfunction late side effect. Include link to clinical resource "Radiation-induced cystitis" in "Cystitis/urethritis" section. Include link to clinical resource 'Treatment induced diarrhoea' in "Proctitis" section. Evidence section: Evidence table: Phase III trials to include hypofractionated evidence - PROFIT (2017), CHHiP (2016), Hoffman et al. 2018 and HYPRO (2016). Update guidelines - NCCN to Version 4.2024, EAU 2024 and AUA-ASTRO 2022.   Efficacy: Include section on active surveillance (AS). Include the key evidence supporting hypofractionation: phase 3 multicentre international randomised non-inferiority trials PROFIT and CHHiP and the Dutch open-label phase 3 trial -HYpofractionated irradiation for PROstate cancer (HYPRO) trial. Include sections discussing cancer risk category and IMRT and IGRT use in trials. Dose escalation section, remove link to evidence and efficacy sections of discontinued protocol ID 3370 - Prostate adenocarcinoma definitive EBRT hypofractionation. Include subheading dominant intraprostatic lesion (DIL), suggesting a potential role for dose-escalating the DIL to improve local control, reference to FLAME and DELINEATE trials. Toxicity: Toxicity table updated to include toxicity from key trials supporting hypofractionation: PROFIT, CHHiP and HYPRO. ​​Patient information: Updated treatment duration to include hypofractionated schedules. Review in 2 years.

Version 5

Date	Summary of changes
8/04/2021	Reviewed online and at urogenital RCM 15/10/2020. Approved and published to eviQ. Review in 2 years.

Version 4

Date	Summary of changes
9/06/2009	Approved on CI-SCaT. Previous CI-SCaT ID : 02-1183.
20/08/2009	Reviewed and transferred to eviQ.
15/12/2010	Integrated boost doses added.
30/06/2014	Biennial review and updated with the following changes: Conventional added into the title to distinguish between hypofractionated protocols in the future Review Group 2
30/04/2017	Protocol reviewed at August 2016 RCM. Approved and published to eviQ. Review group 2.
31/05/2017	Transferred to new eviQ website.