The Role of IMRT in Prostate Cancer

Evidence-Based Series 21-3-1 EDUCATION AND INFORMATION 2013 The Role of IMRT in Prostate Cancer G. Bauman, R.B. Rumble, J. Chen, A. Loblaw, P. Warde,...
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Evidence-Based Series 21-3-1 EDUCATION AND INFORMATION 2013

The Role of IMRT in Prostate Cancer G. Bauman, R.B. Rumble, J. Chen, A. Loblaw, P. Warde, and members of the IMRT Indications Expert Panel A Quality Initiative of the Program in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO), and the Radiation Treatment Program, CCO

Report Date: October 27, 2010 An assessment conducted in November 2013 put Evidence-based Series (EBS) 21-3-1 in the Education and Information section. This means that the recommendations will no longer be maintained but may still be useful for academic or other information purposes. The PEBC has a formal and standardized process to ensure the currency of each document (PEBC Assessment & Review Protocol). EBS 21-3-1 is comprised of 3 sections and is available on the CCO website (http://www.cancercare.on.ca) PEBC Cancer Screening page at: http://www.cancercare.on.ca/toolbox/qualityguidelines/clin-program/radther/ Section 1: Guideline Recommendations Section 2: Evidentiary Base Section 3: EBS Development Methods and External Review Process For further information about this series, please contact: For information about the PEBC and the most current version of all reports, please visit the CCO website at http://www.cancercare.on.ca/ or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: [email protected] Journal Citation (Vancouver Style): Bauman G, Rumble RB, Chen J, Loblaw A, Warde P; Members of the IMRT Indications Expert Panel. Intensity-modulated radiotherapy in the treatment of prostate cancer. Clin Oncol. 2012;24:461-73. doi:10.1016/j.clon.2012.05.002. Guideline Citation (Vancouver Style): Bauman G, Rumble RB, Chen J, Loblaw A, Warde P; Members of the IMRT Indications Expert Panel. The role of IMRT in prostate cancer. Toronto (ON): Cancer Care Ontario; 2010 Oct 27. Program in Evidence-based Care Evidence-based Series No.: 21-3-1

EBS 21-3-1- EDUCATION AND INFORMATION 2013

Evidence-Based Series 21-3-1: Section 1

The Role of IMRT in Prostate Cancer: Guideline Recommendations G. Bauman, R.B. Rumble, J. Chen, A. Loblaw, P. Warde, and members of the IMRT Indications Expert Panel A Quality Initiative of the Program in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO) and the Radiation Treatment Program, CCO Report Date: October 27, 2010 QUESTIONS 1. When external-beam radiotherapy is selected as the primary modality of choice for adult patients with prostate cancer, what is the role of intensity-modulated radiation therapy (IMRT), compared to three-dimensional conformal radiation therapy (3DCRT), in treating clinically localized or locally advanced prostate cancer? 2. When external-beam radiotherapy is selected as the adjuvant postoperative treatment of choice for adult patients with prostate cancer, what is the role of IMRT (compared to 3DCRT)? TARGET POPULATION The target population is comprised of all adult patients with prostate cancer for whom treatment with radiation is being considered. INTENDED USERS This guideline targets radiation oncologists, physicists, dosimetrists, and therapists involved in the treatment of prostate cancer with radiation. BACKGROUND When radiotherapy is used for the primary treatment of prostate cancer, an escalated radiation dose to the prostate using conventional three-dimensional conformal techniques has been shown to improve outcomes but with a small associated increase in gastrointestinal (GI) and (GU) genitourinary toxicity due radiation effects on the bladder and rectum (1). IMRT is a newer method of delivering radiation to target structures that differs from traditional methods. The basis of IMRT is the use of intensity-modulated beams that can provide two or more intensity levels for any single beam direction and any single source position (2). RECOMMENDATIONS – page 1

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Through this mechanism, IMRT treatment plans are able to generate concave dose distributions and dose gradients with narrower margins than those allowed using traditional methods (2,3). This makes IMRT especially suitable for treating complex treatment volumes and avoiding close-proximity organs at risk (OAR) that might be dose limiting (2). As a consequence, IMRT theoretically may provide benefits in terms of increased tumour control through escalated dose and reduced normal tissue complications through OAR sparing. It must be noted that, as the total radiation dose delivered via IMRT would be the same as the total radiation dose given via any other method of radiation therapy, no difference in diseaserelated outcomes would be expected. The main benefit expected with IMRT is a reduction in adverse event rates, especially those associated with radiation damage to nearby OARs. Given the potential dosimetric advantages of IMRT and the commercial availability of IMRT-enabled treatment planning systems and linear accelerators, IMRT has been introduced clinically for a number of disease sites, including head and neck cancer and prostate cancer. This evidence-based series (EBS) reviews the published experience with IMRT in the treatment of prostate cancer in order to quantify the potential benefits of this new technology and make recommendations for radiation treatment programs considering adopting this technique. RECOMMENDATIONS AND KEY EVIDENCE IMRT is recommended over 3DCRT for the radical treatment of localized prostate cancer where an escalated radiation (>70Gy) dose is required Evidence Where the radiation doses administered are similar, the available evidence suggests there is at a minimum no difference, and in many cases superiority, for IMRT compared with 3DCRT for the radical treatment of localized prostate cancer in terms of acute and late GI and GU side effects in the setting of dose-escalated (>70Gy/2Gy fractions) radiotherapy (4-12). The single study (12) that did not show significant benefits associated with IMRT treatment (compared with 3DCRT) for acute rectal, acute GU, or late GU effects used lower doses in the 3DCRT group compared with the IMRT group (IMRT 81Gy versus compared with 66-81Gy 3DCRT). Given the available evidence supporting dose escalation for improved disease control in prostate cancer (see Related Guidelines, PEBC EBS #3-11), the documented dosimetric advantages for IMRT over 3DCRT, and the published clinical evidence supporting the improved toxicity profile of IMRT in this setting, IMRT rather than 3DCRT should be offered to eligible patients. In the setting of postoperative radiotherapy, there are currently insufficient data to recommend IMRT over 3DCRT. Evidence There is no evidence to support or refute offering IMRT rather than 3DCRT to patients in the postoperative setting. Qualifying Statement The benefits of using IMRT compared with 3DCRT have been demonstrated primarily where radiation doses in the range of 70-80Gy rather than conventional (1.8Gy - 2.0Gy) or mildly hypo-fractionated (≤2.5Gy/day) treatment schedules were used (4-7,9-14).

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Key Evidence Eleven reports (4-14), comprising a total of 4,559 patients and comparing 3DCRT with IMRT or one regimen of IMRT with another IMRT regimen in the treatment of localized prostate cancer, form the basis of this evidence-based review. Of the 11 included papers, nine were retrospective cohort studies (5-7,9-14), and two were randomized controlled trials (RCTs) (4,8). Three (8,10,13) of the 11 reports compared dose-escalated prostate radiotherapy (7480Gy) with IMRT to moderate-dose (65-70Gy) radiotherapy. The remainder (4-7,9,11,12,14) compared similar doses delivered with IMRT or 3DCRT. Two reports, a retrospective cohort study (10) and an RCT (4) comprising 494 patients, compared disease-related outcomes (biochemical control or clinical endpoints). Both demonstrated improved outcomes with IMRT, with one (10) reporting a statistically significant improvement. The RCT (4) did not detect any differences in disease-related outcomes. Nine studies (4-12), comprising 4,253 patients, reported on adverse effects, and a total of six (4-6,9,11,12) detected statistically significant differences in adverse effect rates for at least one comparison. Of these six studies, five (4-6,9,11) favoured treatment with IMRT over 3DCRT at similar dosages. Six studies (n=2561 patients) reported on acute GI effects (4,5,8,10-12). Of these six, four detected significant differences, three in favour of IMRT (4,5,11) (n=454 patients) and one in favour of 3DCRT (12) (n=1571 patients). Six studies (4,5,8,10-12) (n=541 patients) reported on acute GU effects. Of these six, only one (12) (n=1,571 patients) detected a significant difference in favour of treatment with 3DCRT. Six studies (4,6,7,9,11,12), (n=3539 patients) reported on late GI effects. Of these six, four studies (6,9,11,12), (n=3333 patients) detected significant differences in favour of IMRT. Five studies (4,6,10-12) (n=3768 patients) reported on late GU effects. Of these five studies, only one (12) (n=1571) patients detected a significant difference favouring treatment with 3DCRT. Two studies (13,14) (n=60 patients) that reported on quality of life (QOL) outcomes, detected improvements in QoL for patients treated with IMRT over non-IMRT techniques. Qualifying Statement The majority of the available evidence consists of prospective and retrospective cohort and case control studies with few randomized trials of IMRT in prostate cancer reported. The possibility for bias due to an imbalance in clinical factors (such as stage migration, differences in length of follow-up, and differences in radiation dose between cohorts) exists, and the reported studies inconsistently controlled for these biases. Nevertheless, the published data are consistent with improved acute and late toxicity profiles with IMRT, and when considered with the physical dosimetric advantages to IMRT and the benefits of IMRT demonstrated for other disease sites, the Expert Panel felt there was sufficient data to recommend IMRT as a standard treatment for dose-escalated radiotherapy for prostate cancer. While there is a lack of comparative evidence addressing the postoperative or pelvic nodal setting, the emergence of consensus definitions for postoperative and pelvic nodal radiotherapy define volumes at least as challenging as the intact prostate treatment setting. Thus, it is reasonable to expect that the benefits of IMRT in reducing acute and late GU and GI toxicity might be also realized in the postoperative radiation and pelvic nodal radiation settings. For this reason, IMRT may be considered a viable treatment option as determined by the Precautionary Principle (15), which states that it is ethical to recommend a treatment with little known harm over one with greater expected harm prior to scientific proof of the difference in harm being established. The implementation of IMRT requires a significant investment in resources and process change beyond 3DCRT, including the planning process, quality assurance, patient

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immobilization, and daily localization practices. In particular, higher conformality and sharper dose gradients associated with IMRT require careful consideration of patient setup and localization practices to realize the full benefits of IMRT in terms of toxicity and disease outcomes. Specifically, localization practices beyond setup based on surface skin tattoos are recommended and should include in-room imaging (electronic portal imaging device or EPID), fiducial markers, ultrasound, or computed tomography (CT), combined with real time or offline correction protocols. FUTURE RESEARCH Clinical trials are ongoing, examining the use of image-guided IMRT in the treatment of patients in the post-prostatectomy setting (RADICALS, SPORT) and for evaluating altered fractionation schemes (PROFIT, RTOG P0415) and combinations of hormone therapy and chemotherapy for high-risk prostate cancer (RTOG 0521, NCIC PR-12). See Table 8, Section 2 for a list of ongoing trials. RELATED GUIDELINES  PEBC EBS#3-11 The Use of Conformal Radiotherapy and the Selection of Radiation Dose in T1 or T2 Prostate Cancer (16).  PEBC EBS#21-1 Organizational Standards for the Delivery of Intensity Modulated Radiation Therapy (IMRT) in Ontario (17). Funding The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way. Contact Information For further information about this report, please contact: Dr. Glenn Bauman, Associate Professor, Department of Oncology, The University of Western Ontario Phone: 519-685-8500 ext. 53293 Fax: 519-685-8627 E-mail: [email protected] or Dr. Padraig Warde, Provincial Head, Radiation Treatment Program, CCO Phone: 416-971-9800 ext. 3734 Fax: 416-971-6888 E-mail: [email protected] For information about the PEBC and the most current version of all reports, please visit the CCO website at http://www.cancercare.on.ca/ or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: [email protected]

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EBS 21-3-1- EDUCATION AND INFORMATION 2013

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Viani GA, Stefano EJ, Afonso SL. Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys. 2009;74(5):1405-18. Veldeman L, Madani I, Hulstaert F, De Meerleer G, Mareel M, De Neve W. Evidence behind use of intensity-modulated radiotherapy: a systematic review of comparative clinical studies. Lancet Oncol. 2008;9(4):9. Galvin JM, Ezzell G, Eisbrauch A, Yu C, Butler B, Xiao Y, et al. Implementing IMRT in clinical practice: a joint document of the American Society for Therapeutic Radiology and Oncology and the American Association of Physicists in Medicine. Int J Radiat Oncol Biol Phys. 2004;58(5):19. Al-Mamgani A, Heemsbergen WD, Peeters STH, Lebesque JV. Role of intensity-modulated radiotherapy in reducing toxicity in dose escalation for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2009;73(3):685-91. Alongi F, Fiorino C, Cozzarini C, Perna L, Di Muzio NG, Broggi S, et al. Reduction of acute toxicity with IMRT and tomotherapy in the treatment of pelvic nodes during postoperative radiotherapy for high and intermediate risk prostate patients. Int J Radiat Oncol Biol Phys. 2008;72(1, Supplement 1):S293. Kirichenko AV, Ruth K, Horwitz EM, Buyyounouski MK, Feigenberg SJ, Chen DY, et al. Intensity modulated radiation therapy for prostate cancer: preliminary results on treatment morbidity compared to 3-D conformal radiation therapy. Int J Radit Oncol Biol Phys. 2006;66(3, Supplement 1):S326. Kupelian PA, Reddy CA, Carlson TP, Willoughby TR. Dose/volume relationship of late rectal bleeding after external beam radiotherapy for localized prostate cancer: absolute or relative rectal volume? Cancer. 2002;8(1):62-6. Pollack A, Hanlon AL, Horwitz EM, Feigenberg SJ, Konski AA, Movsas B, et al. 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. 2006;64(2):518-26. Sanguineti G, Cavey ML, Endres EJ, Franzone P, Barra S, Parker BC, et al. Does treatment of the pelvic nodes with IMRT increase late rectal toxicity over conformal prostate-only radiotherapy to 76 Gy? Strahlenther Onkol. 2006;182(9):543-9. Vora SA, Wong WW, Schild SE, Ezzell GA, Halyard MY. Analysis of biochemical control and prognostic factors in patients treated with either low-dose three-dimensional conformal radiation therapy or high-dose intensity-modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2007;68(4):1053-8. Zelefsky MJ, Fuks Z, Happersett L, Lee HJ, Ling CC, Burman CM, et al. Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer. Radiother Oncol. 2000;55(3):241-9. Zelefsky MJ, Levin EJ, Hunt M, Yamada Y, Shippy AM, Jackson A, et al. Incidence of Late Rectal and Urinary Toxicities After Three-Dimensional Conformal Radiotherapy and Intensity-Modulated Radiotherapy for Localized Prostate Cancer. Int J Radiat Oncol Biol Phys. 2008;70(4):1124-9. Lips I, Dehnad H, Kruger AB, van Moorselaar J, van der Heide U, Battermann J, et al. Health-related quality of life in patients with locally advanced prostate cancer after 76 Gy intensity-modulated radiotherapy vs. 70 Gy conformal radiotherapy in a prospective and longitudinal study. Int J Radiat Oncol Biol Phys. 2007;69(3):656-61. Yoshimura K, Kamoto T, Nakamura E, Segawa T, Kamba T, Takahashi T, et al. Healthrelated quality-of-life after external beam radiation therapy for localized prostate

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cancer: intensity-modulated radiation therapy versus conformal radiation therapy. Prostate Cancer Prostatic Dis. 2007;10(3):288-92. 15. Andorno R. The Precautionary Principle: A new legal standard for a technological age. J Int Biotechnol Law. 2004;1(1):8. 16. Brundage M, Lukka H, Crook J, Warde P, Bauman G, Catton C, et al. The use of conformal radiotherapy and the selection of radiation dose in T1 or T2 low or intermediate risk prostate cancer - a systematic review. . Radiother Oncol. 2002;64(3):12. 17. Whitton A, Warde P, Sharpe M, Oliver TK, Bak K, Leszczynski K, et al. Organisational standards for the delivery of intensity-modulated radiation therapy in Ontario. Clin Oncol. 2009;21(3):12.

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Evidence-Based Series 21-3-1: Section 2

The Role of IMRT in Prostate Cancer: Evidentiary Base G. Bauman, R.B. Rumble, J. Chen, A. Loblaw, P. Warde, and members of the IMRT Indications Expert Panel A Quality Initiative of the Program in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO), and the Radiation Treatment Program, CCO Report Date: October 27, 2010 QUESTIONS 1. When external-beam radiotherapy is selected as the primary modality of choice for adult patients with prostate cancer, what is the role of intensity-modulated radiation therapy (IMRT), compared to three-dimensional conformal radiation therapy (3DCRT), in treating clinically localized or locally advanced prostate cancer? 2. When external-beam radiotherapy is selected as the adjuvant postoperative treatment of choice for adult patients with prostate cancer, what is the role of IMRT (compared to 3DCRT)? BACKGROUND When radiotherapy is used for the primary treatment of prostate cancer, an escalated radiation dose to the prostate using conventional three-dimensional conformal techniques has been shown to improve outcomes but with a small associated increase in gastrointestinal (GI) and genitourinary (GU) toxicity due to radiation effects on the bladder and rectum (1). IMRT is a newer method of delivering radiation to target structures that differs from traditional methods. The basis of IMRT is the use of intensity-modulated beams that can provide two or more intensity levels for any single beam direction and any single source position (2). Through this mechanism, IMRT treatment plans are able to generate concave dose distributions and dose gradients with narrower margins than those allowed using traditional methods (2,3). This makes IMRT especially suitable for treating complex treatment volumes and avoiding close-proximity organs at risk (OAR) that may be dose limiting (2). As a consequence, IMRT theoretically may provide benefits in terms of increased tumour control through escalated dose and reduced normal tissue complications through OAR sparing. It must be noted that, as the total radiation dose delivered via IMRT would be the same as the total radiation dose given via any other method of radiation therapy, no difference in disease-

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related outcomes would be expected. The main benefit expected with IMRT is a reduction in adverse event rates, especially those associated with radiation damage to nearby OARs. Given the potential dosimetric advantages of IMRT and the commercial availability of IMRT-enabled treatment planning systems and linear accelerators, IMRT has been introduced clinically for a number of disease sites, including head and neck cancer and prostate cancer. This evidence based series reviews the published experience with IMRT in the treatment of prostate cancer in order to quantify the potential benefits of this new technology and make recommendations for radiation treatment programs considering adopting this technique. INTRODUCTION The goal of radical radiotherapy is to obtain tumour control with low rates of acute and late side effects and preservation of long-term QOL. In the case of prostate cancer, prospective Phase I/II and randomized trials have confirmed the safety and efficacy of doseescalated radiotherapy for localized prostate cancer (4-17) (see Appendix 1: Historical evidence). However, the potential for late GI and GU side effects with high-dose radiotherapy remains a concern as rates of late GI and GU toxicity in the range of 10-30% have been reported (5-8,12,14-17). In addition, a dose escalation beyond 78Gy (to further improve disease-related outcomes) and efforts to implement a larger dose per fraction via hypofractionation regimens (to exploit postulated radiobiologic features of prostate cancer and shorten radiation schedules for convenience and resource issues) require a higher dose conformality than is possible with conventional 3DCRT. Thus, technical refinement in the delivery of radiotherapy to keep the risk of acute and late side effects at clinically acceptable levels in these settings is necessary. These refinements have occurred on many fronts: the introduction of computerized tomography (CT)-based simulation for target delineation; computer-controlled beam shaping through multi-leaf collimation on treatment units, and improved techniques for daily alignment for treatment through the use of in-room guidance with portal imaging, ultrasound, and in-room CT guidance. The initial studies of dose-escalated external beam radiotherapy exploited these refinements using 3DCRT (5,8,12-16). In this technique, multiple fields (4-6) are used to deliver beams of uniform intensity, with the field shaped to conform to the target in the beam’s eye view (BEV). Randomized controlled trials (RCTs), large series, and Phase I/II trials have confirmed the benefit of 3DCRT in reducing side effects at conventional doses and permitting dose escalation, although with some increase in side effects (1,5-8,12-17). IMRT represents a further refinement in the delivery of radiotherapy, because the target volumes (i.e., prostate) and OAR (i.e., rectum and bladder) are delineated on the volumetric CT data set used for treatment planning. Dose and volume constraints are assigned to these structures, and an inverse treatment-planning system is used to generate a combination of beams of non-uniform intensity that achieve the treatment objectives specified. IMRT allows the generation of more conformal dose distributions with sharp radiation-dose gradients that potentially facilitate enhanced OAR sparing compared to 3DCRT. One convenient way to deliver these beams with non-uniform intensity involves dynamic adjustment of the multi-leaf collimators during the treatment, and a number of treatment platforms exist for this purpose (18). In the treatment of prostate cancer, IMRT was introduced in the early 1990s at a number of centres, with the largest experience being detailed at the Memorial SloanKettering Cancer Center (MSKCC). In the latest of a series of institutional case series, Zelefsky et al (19) reported on the treatment of 1571 patients with IMRT at doses as high as 81 Gy, with rates of GI and GU toxicity less than that reported from their institution for 3DCRT at similar or lower doses. Likewise, Kupelian et al (11) have reported results on a large study involving 770 patients treated at the Cleveland Clinic with intensity modulated

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techniques at biologically effective doses comparable to those at the MSKCC and with similar low rates of GI and GU toxicity. The movement from non-conformal to 3D-conformal radiotherapy techniques occurred to a large degree in the absence of definitive RCTs where other important variables (i.e., total dose, dose per fraction, and use of hormonal therapy) were held constant. Similarly, given the potential for improved dose conformality with IMRT and the favourable results reported in these large institutional series, IMRT has increasingly been adopted as the standard technique for prostate cancer radiotherapy in the absence of randomized comparisons to 3DCRT. Indeed, in current randomized trials for prostate cancer by cooperative groups throughout North America, IMRT is accepted (or specified) as the standard planning and delivery technique. The adoption of IMRT requires substantial capital investments in IMRT-capable treatment machines and planning systems. In addition, planning and quality assurance processes are more resource intense for IMRT, particularly during the initial implementation of IMRT within a centre, and can have significant impacts on a radiation treatment program. Given these resource implications, it is important to delineate the potential benefits of this technology for those entities responsible for funding these treatments and to assist physicians in making decisions around the adoption of IMRT for various disease scenarios. In this evidence-based systematic review, we examine the available data that compares IMRT with 3DCRT for the treatment of prostate cancer. METHODS The EBS guidelines developed by the CCO Program in Evidence-Based Care (PEBC) use the methods of the Practice Guidelines Development Cycle (20). For this project, the core methodology used to develop the evidentiary base was the systematic review. Evidence was selected and reviewed by one member of the IMRT Indications Expert Panel and one methodologist. The systematic review is a convenient and up-to-date source of the best available evidence on the role of IMRT in prostate cancer. The body of evidence in this review is primarily comprised of published reports of comparative studies between IMRT and 3DCRT. That evidence forms the basis of the recommendations developed by the IMRT Indications Expert Panel and will be published when completed. A listing of the Expert Panel members appears in Appendix 2. The systematic review and companion recommendations are intended to promote evidence-based practice in Ontario, Canada. The PEBC and the Radiation Treatment Program (RTP) are supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Literature Search Strategy The MEDLINE and Embase databases were searched for evidence on prostate cancer and IMRT on March 10, 2009. In both databases keywords for “prostate cancer” were combined with keywords for “intensity-modulated radiotherapy” and the following terms were excluded: “brachytherapy”, “proton therapy”, “biological markers”, “gene therapy”, “children”, “childhood cancer”, “pediatric cancer”, “quality assurance”, “treatment plan comparison”, “aperture optimization”, “independent dose calculation”, “EPID dosimetry”, and “set up errors”. Results were limited to those published in English from the year 2000 to the current date in 2009. The MEDLINE and Embase literature search strategies used appear in Appendix 3. A search for Clinical Practice Guidelines (CPG), Systematic Reviews (SR), and Health Technology Assessments (HTAs) was also performed. A search of the National Guidelines

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Clearinghouse (located at: http://www.guideline.gov) was performed on March 9, 2009. Additionally, a search of the MEDLINE and Embase databases was performed on March 25, 2009 using keywords for IMRT in combination with terms for all disease sites and limited to review articles published after 2000. Finally, the Scottish Collegiate Guidelines Network (SIGN) (located at: http://www.sign.ac.uk), the National Institute for Health & Clinical Evidence (NICE) (located at: http://www.nice.org.uk), and the Agency for Healthcare Research & Quality (AHRQ) (located at: http://www.ahrq.gov) were searched on March 25, 2009 using keywords for “IMRT”, and “radiation” in combination with disease-site specific terms. Study Selection Criteria Inclusion Criteria All the following publication types must include comparative data on IMRT (inverse planned) versus 3DCRT in the primary or adjuvant (post-surgery) treatment of prostate cancer. Studies comparing one IMRT against other IMRT regimens were also considered, in order to answer the third guideline question regarding appropriate IMRT dose and fractionation.  CPGs, SRs, HTAs  Randomized phase II or phase III trials  Dose escalation studies, toxicity reports, QOL reports, case-series, and retrospective studies The studies also must:  Report on 50 or more adult patients  Be published in English  Be published in the year 2000 to current date Exclusion Criteria  IMRT other than inverse planned  IMRT compared with brachytherapy, proton therapy, or gene therapy  IMRT where the focus of the study is on biological markers  IMRT where the focus of the study is on treatment plan comparison, quality assurance, aperture optimization, independent dose calculation, EPID dosimetry, or set-up errors.  Comparative data not provided  Treatment population includes children Synthesizing the Evidence While no statistical analyses were planned in this systematic review, it would be considered if the data would allow. RESULTS Literature Search Results The MEDLINE and Embase search returned 359 and 361 potential articles, respectively. After removing ineligible articles based on title and abstract review, 17 were ordered based on the MEDLINE results, and 13 were ordered based on the Embase results (30 articles in total were ordered for full-text review). Three guidelines were ordered for full-text review as well as three American Society for Therapeutic Radiology and Oncology (ASTRO) Conference Proceedings abstracts. Of the three guidelines, the 30 fully published papers, and the three ASTRO Conference proceedings abstracts ordered for full-text review, only 11 (19,21-30) of the 30 fully published papers were retained, including two ASTRO abstracts (22,23). These 11 papers EVIDENTIARY BASE – page 4

comprise the body of evidence in this systematic review. Of the three guidelines reviewed, all were excluded. A table of the three excluded guidelines, 21 articles, and one abstract along with the reasons for exclusion appears in Appendix 4. Study Design Of the 11 articles retained, nine were retrospective cohort studies (RCS) (19,22-25,2730), and two were RCTs (21,26). One of the RCT reports (21) was a subgroup analysis using data from a larger trial. Table 1 describes the years on study, the total number of included patients, and the funding source where reported by the study design used. Table 1: Study design of included evidence. Author, year Years on study published Retrospective cohort studies Zelefsky MJ et al, 1992-1998 2000 (30) Kupelian PA et al, 1998-1999 2002 (24) Kirichenko AV et 1995-2001 al, 2006 (23) [abstract] Sanguineti G et al, 1995-1999 2006 (27) 2002-2004 Lips I et al, 2007 1997-2001 (25) Vora SY et al, 1993-2000 2007 (28) Yoshimura K et al, 2000-2004 2007 (29) Alongi F et al, 2004-2008 2008 (22) [abstract] Zelefsky MJ et al, 1988-2000 2008 (19) Randomized Controlled Trials Pollack A et al, NR 2006 (26)

Total included N

Sponsorship

232

NCI Grant CA59017

128 1417

General Motors Company NR

113

NR

215

NR

416

NR

145

NR

144

NR

1571

NR

100

Al-Mamgani A et al, 2009 (21)

78

NCI Grant CA101984-01 CA00692 Dutch Cancer Society

NR

Note: RCT, randomized controlled trial; N, number; NCI, National Cancer Institute (U.S.); NR, not reported.

Table 2 describes study details, including the comparison that was made and the dosages used, the number of patients in each group, the disease stages included in the study population, the overall median follow-up, and what outcomes were reported on.

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Table 2: Details of included studies. Author, Comparison and doses year published Retrospective cohort studies Zelefsky MJ IMRT: 81Gy/1.8f et al, 2000 (30) 3DCRT: 72Gy/1.8f +9Gy boost Kupelian IMRT: 70Gy/2.5f PA et al, 2002 (24) 3DCRT: 78Gy/2f Kirichenko IMRT: 74-78Gy AV et al, 2006 (23) 3DCRT: 70-79Gy [abstract] Sanguineti IMRT: 76Gy/2f G et al, 2006 (27) 3DCRT: 76Gy/2f Lips I et al, IMRT: 76Gy/2.17f 2007 (25) 3DCRT: 70Gy/2f Vora SY et IMRT: 75.6Gy al, 2007 (28) 3DCRT: 68.4Gy Yoshimura IMRT: 71.6Gy K et al, 2007 (29) 3DCRT: 70.7-72.6Gy Alongi F et IMRT: 70.3Gy/1.8-2.55f al, 2008 (22) 3DCRT: 72.8Gy/1.8f [abstract] TOMO: 70.3Gy/1.8-2.55f Zelefsky MJ IMRT: 81Gy/1.8f et al, 2008 (19) 3DCRT: 66-81Gy/1.8f Randomized Controlled Trials Pollack A HD-IMRT: 76Gy/2f et al, 2006 (26) IMRT :70.2Gy/2.7f Al-Mamgani IMRT: 78Gy/2f A et al, 2009 (21) 3DCRT: 78Gy/2f

Total N

Disease Stage

Median followup [months]

Outcomes reported

171

T1c-T3

12 [9-32]

AE

52

T1-3

24 [3-34]

AE

76 489

NR

NR

AE

45

T1-3

25.9

AE

68 116

T1-4

NR

QoL

99 145

T1-3

60 [36-120]

TRO AE

271 61

T1-3

NR

QoL

84 19

NR

NR

AE

T1-3

78

AE

61

928

80 44 NR NR

120

50

T1-3

NR

TRO AE

50 41

T1-3

56

TRO AE

37

76

Note: IMRT, intensity modulated radiotherapy; 3DCRT, 3D conformal radiotherapy; Gy, Gray; f, fraction; T, tumour; AE, adverse effects; N, node; M, metastases; NA, not applicable; EBRT, external beam radiotherapy; QoL, quality of life; HD-IMRT, high dose IMRT; TRO, treatment related outcome; tomo, tomotherapy.

Table 3 outlines the technical details of the IMRT regimen, including the planning system used, the type of IMRT administered (e.g., step & shoot, sliding window, volumetric arc), the field arrangement (e.g., 5 field, 7 field), the planned target volume (e.g., whole pelvis with prostate boost, prostate plus seminal vesicles, prostate alone), the planned target volume margin expansion (mm), and the image guidance method used (e.g. none, implanted fiducial markers, EPID, daily ultrasound, in-room CT, other).

EVIDENTIARY BASE – page 6

Table 3: IMRT details of included studies. Author, Planning Type of year system IMRT published Retrospective cohort studies Zelefsky Inverse Sliding MJ et al, window 2000 (30) Kupelian Corvus NR PA et al, 2002 (24)

Field Arrangement

Planned Target Volume

Planned target volume margin expansion (mm)

Image guidance

Isocentric 5field

10* 4 posteriorly, 8 laterally, 5 in all other directions

Permanent localization marks BAT transabdominal US

Kirichenko AV et al, 2006 (23) [abstract] Sanguineti G et al, 2006 (27) Lips I et al, 2007 (25) Vora SY et al, 2007 (28) Yoshimura K et al, 2007 (29) Alongi F et al, 2008 (22) [abstract]

Prostate + seminal vesicles Prostate + seminal vesicles (HR); prostate alone (LR) NR

NR

NR

Prostate seminal vesicles NR

15

NR

NR

NR

Prostate + seminal vesicles Prostate + seminal vesicles Prostatic bed + pelvic lymph nodes

6-10 7 or 15

Daily transabdominal US NR

NR

NR

NR

NR

IMRT: 5 posteriorly, 8 in all other directions HIMRT: 3 posteriorly, 7 in all other directions 0 posteriorly, 10 in all other directions

NR

NR

NR

NR

NR

Pinnacle

NR

8 field

NR

NR

NR

NR

NR

NR

Helios

NR

5 field

IMRT: MLC, Varian TOMOIMRT: Hi-Art II NR

NR

IMRT: 5 field

+

TOMO-IMRT: NR

Zelefsky NR MJ et al, 2008 (19) Randomized Controlled Trials Pollack A Corvus Step & et al, shoot 2006 (26)

NR

NR

NR

Prostate seminal vesicles

+

AlMamgani A et al, 2009 (21)

5 field

Prostate seminal vesicles

+

NR

Step & shoot

NR

Note: NR, not reported; HR, high-risk; LR, low-risk; BAT, B-Mode Acquisition & Targeting; US, ultrasound; IMRT, Intensity Modulated Radiotherapy; MLC, multi leaf collimators; TOMO, IMRT-Tomotherapy. *except around prostate-rectum interface where 6mm was used. An additional 5mm was added around the circumference of the PTV (except superiorly and inferiorly) to account for penumbra.

EVIDENTIARY BASE – page 7

Study Quality Of the 11 included papers, nine were retrospective cohort studies (19,22-25,27-30), and two were RCTs (21,26). The reported quality of the RCT by Pollack et al (5) was acceptable, with all components fully detailed except blinding and length of follow-up. The RCT by Al-Mamgani (21) et al was also well described, except blinding and differences in baseline characteristics were not reported. This same RCT (21) only reported data on a subgroup of patients from within a larger trial (78 out of the 669 included patients). Table 4 describes the components of quality for the RCTs. The retrospective cohort studies were assessed for quality according to criteria such as balance between the treatment groups, identification of prognostic factors, and reporting of differences between baseline prognostic factors. Other variances in study design that could affect the reliability of the study finding were also reported on. Four of the nine studies included comparisons between groups that were imbalanced, Zelefsky et al (30) (61, 3DCRT vs. 171, IMRT), Kirichenko et al (23) (928, 3DCRT vs. 489, IMRT), Vora et al (28) (271, 3DCRT vs. 145, IMRT), Alongi et al (22) (80, 3DCRT vs. 44, IMRT). One of the included studies by Zelefsky et al did not report the number of patients in each group (19). Six of the nine studies identified prognostic factors that were used to determine differences in the baselines characteristics of each group (23,25,27-30). Of these six, only the study by Sanguineti et al reported any differences in baseline characteristics, but significant differences were found in age, race, diabetes, hypertension, disease stage, and Gleason score. One of the retrospective cohort studies (Sanguineti et al (27)) may have an inherent selection bias as the 3DCRT group was comprised of patients from Italy, while the IMRT group was comprised of patients from the United States (U.S.A). Also affecting quality was the fact that only six of the 11 included studies reported any data on length of follow-up (19,21,24,27,28,30). As acute and/or late adverse effects were reported on in nine (19,2124,26-28,30) of the 11 included studies, a minimum follow-up of one year was desired; however, data were unavailable. Table 4: Study quality, RCT. Study Randomization

Blinding Analysis details*

Funding source Expected effect size and power calculation details Length of followup (months) Differences in patient characteristics

Pollack A et al, 2006 (26) Patients were randomized into two groups stratified by initial PSA, Gleason score, and whether long-course androgen deprivation was planned NR

Al-Mamgani A et al (21) Patients were randomized into two groups stratified by age, institution, use of neoadjuvant or adjuvant hormonal therapy NR

Stepwise ordinal logistic regression modelling was used for AE analysis with all coding and covariates fully described NCI Grant CA101984-01 CA00692 15% gain in freedom from biological failure

Outcomes were calculated using the Kaplan-Meier method, and the differences were assessed with the log– rank test. Dutch Cancer Society Grants NKI 98-1830 CKTO 96-10 10% difference in freedom from failure, using a two-sided test (α = 0.05) and power of 80%. 115

NR Reported no significant differences in patient characteristics between the two arms

NR

Note: NCI, National Cancer Institute (U.S.).

EVIDENTIARY BASE – page 8

Outcomes: Disease-Related Only two of the articles obtained reported on any of the disease-related outcomes of interest (21,28). While both the retrospective cohort study by Vora et al (28) and the RCT by Al-Mamgani et al (21) reported on five-year biochemical freedom from failure rates, AlMamgani et al also reported on five-year clinical recurrence-free survival. Neither of the papers obtained reported on disease-free survival. The only statistically significant difference detected was in biochemical freedom from failure in favour of treatment with IMRT over 3DCRT in the paper by Vora et al (28) (74.1% vs. 60.4%; p0.05 (ns) p>0.05 (ns) p>0.05 (ns) -

GU

3DCRT % (n/N) 27 (72/271) 20 (54/271) 54 (145/271) 0

p-value

IMRT % (n/N) p>0.05 0 28 (IMRT vs. (41/145) 3DCRT, 1 23 all (33/145) grades) 2 46 (66/145) 3 3 (5/145) Acute toxicity: RTOG/EORTC Scale

Grade 2-3 GU % 6.3 12.5 p=0.21

Grade

Grade 2-3 upper GI % 4.8 22.5 p=0.0035

EVIDENTIARY BASE – page 10

3DCRT % (n/N) 38 (103/271) 21 (58/271) 40 (107/271) 1 (2/271)

p-value p>0.05 (IMRT vs. 3DCRT, all grades)

Grade 2-3 Rectal % 0 8.8 p=0.05

Zelefsky MJ et al, 2008 (19)

Acute toxicity: NCI-CTC 3.0 IMRT % 3 37

Rectal GU Randomized Controlled Trials Pollack A et al, 2006 (26)

p-value p=0.04 p=0.001

Acute toxicity: 0.05 (ns)

None

p>0.05 (ns)

1

p>0.05 (ns)

2

61 (30/50) 31 (15/50) 8 (4/50) 0

p>0.05 (ns) 3 Acute toxicity

IMRT % (n/N) 64 (32/50) 30 (15/50) 6 (3/50) 0

p-value p>0.05 (ns) p>0.05 (ns) p>0.05 (ns) p>0.05 (ns)

GI, Grade 2+: 20% (8/41) IMRT vs. 61% (23/37) 3DCRT; p=0.001 GI, Grade 3+: 0 IMRT vs. 13% (3/37) 3DCRT; p=0.001 Acute proctitis: 15% (6/41) IMRT vs. 38% (14/37) 3DCRT; p=0.03 GU, Grade 2+: 53% (22/41) IMRT vs. 69% (26/37) 3DCRT; p=0.3 GU, Grade 3+: 15% (6/41) IMRT vs. 22% (8/37) 3DCRT; p>0.05

Note: GI, gastrointestinal; GU, genitourinary; IMRT, intensity modulated radiotherapy; 3DCRT, 3D conformal radiotherapy; ns, not significant; 4F-CRT, 4 field pelvic radiotherapy; HD-IMRT, high dose IMRT; 4F/6F-PRT, 4 field or 6 field PRT; HR, Hazard rate; TOMO, tomotherapy; RTOG, Radiation Therapy Oncology Group; NCI CTC 3.0; National Cancer Institute Common Toxicity Criteria Version 3.0.

Late GI Effects Seven of the nine papers obtained reported on late GI effects (19,21,23,24,27,28,30). Four of the papers (19,23,27,30), all retrospective cohort studies including a total of 3333 patients, detected differences between IMRT and 3DCRT for at least one comparison. The three papers that did not detect any differences between IMRT and 3DCRT for any comparisons were the two retrospective cohort studies by Kupelian et al (24) and Kirichenko et al (23) and the RCT reported by Al-Mamgani et al (21), all together including a total of 622 patients. The study by Zelefsky et al (30), including 232 patients, detected a difference in late Grade 2 GI effects in favour of treatment with IMRT (0.5% vs. 13%; p=0.001) but no difference was detected in Grades 0, 1, or 3. The study reported by Kirichenko et al (23), including 1417 patients, detected a difference in Grade 2 and higher late GI effects in favour of treatment with IMRT (6.2% vs. 10.4%; p=0.009). The study by Sanguineti et al (27), including 113 patients, detected a difference in overall late rectal effects in favour of treatment with IMRT (0.1% vs. 1%; p=0.01). The second report by Zelefsky et al (19), including 1571 patients, detected a difference in overall late GI effects in favour of treatment with IMRT (5% vs. 13%; p120 days p-value

Grade

p=0.09

None

p=0.8

1

p=0.0001

2

p=0.4

3

IMRT % (n/N) 83 (142/171) 8 (13/171) 9 (16/171) 0

-

4

0

GU 3DCRT % (n/N) 82 (50/61) 11 (7/61) 5 (3/61) 2 (1/61) 0

p-value p=0.7 p=0.3 p=0.3 p=0.1 -

3DCRT % (n/N)

p-value

0

p>0.05 (ns)

1.3 (1/76) 1.3 (1/76) 3.9 (3/76) 0

p>0.05 (ns) p>0.05 (ns) p>0.05 (ns) p>0.05 (ns)

24-month actuarial rectal bleeding rate: 8% IMRT (4/52) vs. 8% 3DCRT (6/76); p=0.63 IMRT associated with a reduction in late ≥ grade 2 GI toxicity compared with 3DCRT (3-year actuarial risk, IMRT: 6.2% vs. 3DCRT:10.4%; p=0.009) No difference in adverse event rates were detected for late ≥ grade 2 GU toxicity ((3-year estimated risk, IMRT: 8.4% vs. 3DCRT:5.7%; p>0.05) HR, Late rectal toxicity: IMRT: 0.1 (95% CI, 0.0-0.6) vs. 3DCRT: 1; p=0.01 Late toxicity Grade 0

IMRT % (n/N) 56 (81/145)

GI 3DCRT % (n/N) 57 (154/271)

p-value

Grade

p>0.05 (IMRT vs.

0

EVIDENTIARY BASE – page 12

IMRT % (n/N) 45 (65/145)

GU 3DCRT % (n/N) 66 (177/271)

p-value p>0.05 (IMRT vs.

1 2 3

30 (29/145) 23 (33/145) 1 (2/145)

Zelefsky MJ et al, 2008 (19)

26 (71/271) 14 (39/271) 2 (5/271) IMRT % 5 20

3DCRT, all grades)

1

27 (39/145) 2 23 (33/145) 3 6 (8/145) Late toxicity: NCI CTC 3.0 3DCRT % 13 12

GI GU Randomized Controlled Trial AlLate toxicity: 5 years Mamgani GI, Grade 2+: A et al, 21% (9/41) IMRT vs. 37% (14/37) 3DCRT; p=0.16 2009 (21) GI, Grade 3+: 0 IMRT vs. 7% (3/37) 3DCRT; p=0.1 GU, Grade 2+: 43% (18/41) IMRT vs. 45% (17/37) 3DCRT; p=1.0 GU, Grade 3+: 15% (6/41) IMRT vs. 22% (8/37) 3DCRT; p=0.5

13 (34/271) 17 (45/271) 5 (13/271)

3DCRT, all grades)

p-value p0.05 (ns)

IMRT 7.6 (p0.05 (ns)

-2.3 (ns) IMRT

-4.0 (ns) 3DCRT old new

p>0.05 (ns) P=value

EVIDENTIARY BASE – page 13

2007 (29)

Physical function Role limitation due to physical problems Bodily pain General health perception Mental health Role limitation due to emotional problems Social function Vitality UCLA PCI 12 month Urinary function Urinary bother Bowel function Bowel bother Sexual function

NR NR

NR NR

NR NR

p=ns p=ns

NR NR NR NR

NR NR NR NR

NR NR NR NR

p=ns p=ns p=ns p=ns

NR NR

NR NR

p=ns p=ns

IMRT NR NR NR NR NR

NR NR 3DCRT old NR NR NR NR NR

new NR NR NR NR NR

Sexual bother

NR

NR

NR

p-value p=ns p=ns p=ns p=ns p

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