Intensity Modulated Radiation Therapy

Transcription

1 [Year] Health Technology Assessment Intensity Modulated Radiation Therapy Final Evidence Report September 6, 2012 Health Technology Assessment Program (HTA) Washington State Health Care Authority PO Box Olympia, WA (360)

2 Intensity Modulated Radiation Therapy September 6, 2012 Center for Evidence-based Policy Oregon Health & Science University 3455 SW US Veterans Hospital Road Mailstop SN-4N, Portland, OR Phone: Fax:

3 About the Center for Evidence-based Policy The Center for Evidence-based Policy (Center) is recognized as a national leader in evidencebased decision making and policy design. The Center understands the needs of policymakers and supports public organizations by providing reliable information to guide decisions, maximize existing resources, improve health outcomes, and reduce unnecessary costs. The Center specializes in ensuring diverse and relevant perspectives are considered, and appropriate resources are leveraged to strategically address complex policy issues with highquality evidence and collaboration. The Center is based at Oregon Health & Science University in Portland, Oregon. Nature and Purpose of Technology Assessments This technology assessment report is based on research conducted by a contracted technology assessment center, with updates as contracted by the Washington State Health Care Authority. This report is an independent assessment of the technology question(s) described based on accepted methodological principles. The findings and conclusions contained herein are those of the investigators and authors who are responsible for the content. These findings and conclusions may not necessarily represent the views of the HCA/Agency and thus, no statement in this report shall be construed as an official position or policy of the HCA/Agency. The information in this assessment is intended to assist health care decision makers, clinicians, patients and policy makers in making sound evidence-based decisions that may improve the quality and cost-effectiveness of health care services. Information in this report is not a substitute for sound clinical judgment. Those making decisions regarding the provision of health care services should consider this report in a manner similar to any other medical reference, integrating the information with all other pertinent information to make decisions within the context of individual patient circumstances and resource availability. This document was prepared by the Center for Evidence-based Policy at Oregon Health & Science University (the Center). This document is intended to support organizations and their constituent decision-making bodies to make informed decisions about the provision of health care services. The document is intended as a reference and is provided with the understanding that the Center is not engaged in rendering any clinical, legal, business or other professional advice. The statements in this document do not represent official policy positions of the Center. Researchers and authors involved in preparing this document have no affiliations or financial involvement that conflict with material presented in this document.

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5 Acknowledgements This report was prepared by: Edgar E. Clark, MD, MHA Aasta Thielke, MPH Heidi Kriz, RD, MPH Kendra Bunker, MPH Katharine Ryan, MPH Robyn Liu, MD, MPH Valerie King, MD, MPH Center for Evidence-based Policy Oregon Health and Science University The tables of evidence were completed with assistance from: Martha Gerrity, MD, MPH, PhD Jennifer Gilbert, MD, MPH Heidi Gullett, MD, MPH Catherine Pettenari, PhD Shannon Vandegriff, BA Hayes, Inc. Suggested Citation: Clark, E.E., Thielke, A., Kriz, H., Bunker, K., Ryan, K., & King, V. (2012). Intensity modulated radiation therapy. Portland, OR: Center for Evidence-based Policy, Oregon Health and Science University.

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7 Table of Contents Executive Summary... 1 Background Washington State Data PICO and Key Questions Methods Findings Abdomen Brain Breast Female Pelvis Head & Neck Lung Prostate Sarcoma Other Cancers MAUDE Database Guidelines Policy Considerations Overall Summary Limitations of the Evidence Appendix A. Database Search Strategies Appendix B. Excluded Studies... see separate appendix Appendix C. MEDLINE Search Dates by Malignancy Appendix D. Quality Assessment Tools Appendix E. Summary of Findings Tables by Malignancy Appendix F. Evidence Tables by Malignancy Appendix G. Guideline Summary Table Appendix H. Quality Assessment of Guidelines Appendix I. Summary of Federal and Private Payer Policies Appendix J. Peer Review Comments and Disposition... see separate appendix Appendix K. Public Comments and Disposition... see separate appendix

8 Appendix L. MAUDE Database Search Results References

9 List of Abbreviations bdfs biochemical disease-free survival BRT brachytherapy CBTR contralateral breast tumor recurrence CRT conventional radiation therapy also referred to as EBRT 2DCRT two dimensional conventional radiation therapy 3DCRT three dimensional conventional radiation therapy DFS disease-free survival DSS disease-specific survival EBRT external beam radiation therapy GI gastrointestinal GU gastrourinary HR hazard risk IBTR ipsilateral breast tumor recurrence IGRT Image-guided radiation therapy IMRT intensity-modulated radiation therapy MA meta-analysis NSCLC non-small cell lung cancer OR odds ratio OS overall survival PFS progression-free survival QoL quality of life RCT randomized controlled trial RFS recurrence-free survival RR relative risk SCLC small-cell lung cancer SR systematic review

10 TA technology assessment VMAT volumetric-modulated arc therapy

11 Executive Summary Background Clinical and epidemiological overview Over the past ten years, significant advances have been made in the techniques available to deliver external beam radiation therapy (EBRT) as a treatment modality for certain cancers. The goal of these newer techniques is two-fold: to improve the targeting of radiation to the tumor to minimize damage to normal tissue and increase the dose of radiation delivered to the tumor. One of these newer techniques is intensity modulated radiation therapy (IMRT). Intensity modulated radiation therapy, like other forms of EBRT is used as primary treatment or in conjunction with surgery, hormonal therapy and/or chemotherapy; it is used in treatment in primary, recurrent and metastatic cancer. Intensity modulated radiation therapy has been used for treatment of tumors of the central nervous system, head and neck, breast, prostate, gastrointestinal tract, and gynecologic system. It can be used to treat sites previously treated with radiation and areas in close proximity to organs and vulnerable tissue (American College of Radiology & American Society for Radiation Oncology [ACR-ASTRO] 2011). Technology overview Typically, conventional EBRT (also called 2-dimensional conventional radiation therapy (2DCRT) or 3-dimentional conventional radiation therapy (3DCRT)) 1 is delivered in 25 to 50 fractions (doses) delivered five days per week for 5 to 10 weeks. Intensity modulated radiation therapy uses hundreds of radiation beam-shaping devices (collimators) to deliver external beam radiation (Tipton 2011b). The collimators allow the intensity of the radiation to vary during a treatment session thus different doses of radiation can be directed at different areas of the tumor and nearby tissues. The goal of IMRT is to increase radiation to the tumor while reducing radiation exposure to normal tissue. Treatment planning for IMRT involves additional steps to contour the radiation dose to the tumor and to reduce radiation to surrounding tissues; these additional steps and the additional time required to administer each treatment fraction during the course of therapy result in considerably more cost for IMRT than EBRT. Cost information Intensity modulated radiation therapy typically costs approximately twice as much as EBRT. The following approximate charges for IMRT were identified for this report: Non-small cell lung cancer: EBRT$55,000, IMRT $146,000 (Tipton 2011a); Breast cancer (whole breast irradiation): EBRT $9,500, IMRT $17,900 (Suh 2005); Breast cancer (partial breast irradiation): EBRT $7,200, IMRT $9,200 (Suh 2005); and Prostate cancer: EBRT ranging from $10,000 to $27,000, IMRT ranging from $33,000 to $52,000 (Hummel 2010). 1 In this report 2DCRT and 3DCRT are grouped together as conventional radiation therapy (CRT) except where individual studies compare IMRT to either 2DCRT or 3DCRT. Current conventional EBRT is also referred to as CRT. Washington State Health Care Authority HCA 1

12 Policy context Use of new radiation technologies has grown dramatically in the last decade. Among men with prostate cancer receiving external beam radiation, the use of IMRT increased from 29% in 2002 to 82% in 2005 to 96% in 2008 (Jacobs 2012; Sheets 2012). Among women with breast cancer, the likelihood of IMRT use for breast cancer rose from 0.9% in 2001 to 11.2% in 2005 (Smith 2011). Despite this rapid adoption of IMRT, the Federal Food and Drug Administration (FDA) process for approving new radiation therapies does not require a review of safety and efficacy, which has resulted in limited information about efficacy and comparative effectiveness of IMRT. Methods Key Questions KQ 1: What is the evidence of effectiveness for intensity modulated radiation therapy compared to conventional external beam radiation therapy (EBRT) for patients with cancer by site and type of cancer? KQ 2: What are the potential harms of IMRT compared to conventional external beam radiation therapy (EBRT)? What is the incidence of these harms? Include consideration of progression of treatment in unnecessary or inappropriate ways. KQ 3: What is the evidence that IMRT has differential efficacy or safety issues in subpopulations? Including consideration of: a. Gender; b. Age; c. Site and type of cancer; d. Stage and grade of cancer; and e. Setting, provider characteristics, equipment, quality assurance standards and procedures. KQ 4: What is the evidence of cost and cost-effectiveness of IMRT compared to EBRT? Methods Evidence For this WA HTA report, a search was conducted to identify published systematic reviews (SRs), meta-analyses (MAs), technology assessments (TAs) and individual studies (from April 2002 to April 2012) in the MEDLINE and Cochrane databases. General inclusion criteria: Published, peer reviewed, English-language articles; SRs, TAs, RCTs, and observational comparative study designs (prospective, retrospective, and controlled clinical trials); For KQ 2 (harms), all study designs with a minimum sample size of 50 participants; and 2 Health Technology Assessment HTA

13 o For pediatric populations and/or reports of serious harms (i.e., surgery, hospitalization, mortality), all study designs with a sample size of 20 participants. Specific inclusion criteria malignancy: Breast, Head and Neck, Prostate Minimum sample size of 50 participants; Less prevalent malignancies (abdomen, brain, female pelvis, lung, sarcoma, skin, thyroid, spinal metastases) SRs, TAs, RCTs, observational comparative study designs (prospective, retrospective, and controlled clinical trials) and case series; Minimum sample size of 20 participants; Exclusions included studies published in a non-english language, commentaries, letters, editorials, narrative reviews, and news articles. Studies that focused on aspects of treatment planning, including different dosing regimens, and/or included patients who were concurrently receiving chemotherapy (with the exception of head and neck cancers) were excluded. The methodological quality of the included studies was assessed using standard instruments developed and adapted by the Center for Evidence-based Policy and the MED Project that are modifications of the systems used by National Institute for Health and Clinical Excellence (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN) (NICE 2009; SIGN 2009). Each study was assigned a rating of good, fair, poor, based on its adherence to recommended methods and potential for biases. The methodological quality of the economic studies was rated (good, fair, poor) using a standard instrument developed and adapted by the Center for Evidence-based Policy and the MED Project that are modifications of the British Medical Journal (Drummond 1996), the Consensus on Health Economic Criteria list (Evers 2005), and the NICE economic evaluation checklist (NICE 2009). The overall strength of evidence was rated (high, moderate, low, very low) using a modified version of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (Guyatt 2008). A systematic review using best evidence methodology was used to search and summarize evidence for Key Questions #1 through #3 as outlined below: A complete search of the Medicaid Evidence-based Decisions (MED) Project primary evidence sources was conducted; Existing high quality SRs and TAs summarized for each Key Question; If there were two or more comparable SRs or TAs identified and one was more recent, of better quality, or more comprehensive, then the other review(s) were excluded; Additional search of the MEDLINE and Cochrane databases completed to identify subsequently published studies. Individual studies published after the search dates of the last high quality review were appraised and synthesized with the results of the high quality SR; and Washington State Health Care Authority HCA 3

14 If there were no high quality reviews identified, a search, appraisal, and summary of primary individual studies was completed for the last 10 years (April 2002 to April 2012). For Key Question #4, all relevant economic evaluations were included. Methods Guidelines A search for relevant clinical practice guidelines was conducted using a list of predetermined high quality sources from the MED Project and additional relevant specialty organizations and associations. Guidelines included were limited to those published after The methodological quality of the guidelines was assessed using an instrument adapted from the Appraisal of Guidelines Research and Evaluation (AGREE) Collaboration (AGREE Next Steps Consortium 2009). Each guideline was assigned a rating of good, fair, poor, based on the adherence to recommended methods and the potential for biases. Methods Policies At the direction of the WA HTA program, select payer policies were searched and summarized. Aetna, Blue Cross Blue Shield, GroupHealth, and Medicare National and Local Coverage Determinations were searched using the payers websites. Methods MAUDE Database The Manufacturer and User Facility Device Experience (MAUDE) Database, hosted by the US Food and Drug Administration (FDA), was searched using the terms intensity modulated, intensity modulated radiation therapy, intensity modulated radiotherapy, and imrt. The search was limited to adverse events reports submitted between 2002 and Two reports of serious adverse events were identified and are summarized in Appendix L. Public Comment and Peer Review The topic nomination, draft key questions, and draft version of this report were open to public comment. All comments and references received from the public were reviewed and taken into account in the drafting of the final report. In addition, the draft report was reviewed by two peer reviewers and their comments were also considered in drafting the final report. The full peer reviews and disposition are available in Appendix J. Full comments submitted by the public with disposition are available in Appendix K. Findings This report provides the best available evidence for multiple cancer types. The most completely evaluated cancers are cancers of the head and neck, breast and prostate. For these cancers there are large TAs and several SRs. For many of the other cancers, there are as few as one case series. The evidence consists mostly of case series of which some are designed to compare IMRT with EBRT but many are non-comparative studies that give outcomes or harms results for IMRT without comparison with EBRT. Because of the absence of randomized trials and comparative studies, the strength of the evidence is very low or low for most of the findings. 4 Health Technology Assessment HTA

15 Abdomen (Anus, Esophagus, Liver, Pancreas, Rectum, Stomach, Whole Pelvis Radiation) In this section, tumors of the anus, liver, pancreas, rectum, and stomach and treatments involving whole pelvis radiation are summarized. One study on cancer of the esophagus is included in this section even though the esophagus is not technically in the abdomen. Anal Cancer KQ 1: What is the evidence of effectiveness for intensity modulated radiation therapy compared to conventional external beam radiation therapy (EBRT) for patients with cancer by site and type of cancer? The overall strength of evidence is very low that IMRT is associated with better 3-year OS, 3- year locoregional control, and 3-year PFS when compared to EBRT for treatment of anal cancer. KQ 2: What are the potential harms of IMRT compared to conventional external beam radiation therapy (EBRT)? What is the incidence of these harms? There is very low overall strength of evidence that IMRT had significant reductions in acute greater than Grade 2 nonhematologic toxicity, skin, and mucosal eruptions in the female genital area, and acute Grade 2 diarrhea after treatment compared with EBRT. When treatment is a combination of chemotherapy and IMRT, there is a very low overall strength of evidence that toxicity may be related more to chemotherapy based on one small case series. KQ 3: What is the evidence that IMRT has differential efficacy or safety issues in subpopulations? Based on one fair quality case series, the overall strength of evidence is very low that there is no difference in 3-year local control and 3-year OS for IMRT compared to EBRT for the treatment of HIV-positive patients with anal cancer. KQ 4: What is the evidence of cost and cost-effectiveness of IMRT compared to EBRT? No studies on costs or cost-effectiveness were identified. Esophagus KQ 1: What is the evidence of effectiveness for intensity modulated radiation therapy compared to conventional external beam radiation therapy (EBRT) for patients with cancer by site and type of cancer? The overall strength of evidence is very low. One small, poor quality case series reported 1-year OS (79%), 2-year OS (38%), and 2-year actuarial loco-regional control of 64%. Due to the lack of a comparative data, no conclusions can be reached regarding clinical effectiveness. Washington State Health Care Authority HCA 5

16 KQ 2: What are the potential harms of IMRT compared to conventional external beam radiation therapy (EBRT)? What is the incidence of these harms? The overall strength evidence is very low. One poor quality case series reported moderate levels of acute and chronic complications. KQ 3: What is the evidence that IMRT has differential efficacy or safety issues in subpopulations? No studies on subpopulations were identified. KQ 4: What is the evidence of cost and cost-effectiveness of IMRT compared to EBRT? No studies on costs or cost-effectiveness were identified. Liver KQ 1: What is the evidence of effectiveness for intensity modulated radiation therapy compared to conventional external beam radiation therapy (EBRT) for patients with cancer by site and type of cancer? The overall strength of evidence is very low. Three poor quality case series reported mean of 5 to 16 months. Due to the lack of a comparative data, no conclusions can be reached regarding clinical effectiveness. KQ 2: What are the potential harms of IMRT compared to conventional external beam radiation therapy (EBRT)? What is the incidence of these harms? The overall strength of evidence is very low. Among patients treated with IMRT in one poor quality case series for hepatocellular cancer, approximately 28% of patients experienced less than or equal to Grade 2 hepatic toxicity. Two poor quality case series reported moderate levels of nausea, vomiting and changes in hepatic function. Due to the lack of comparative data, no conclusions can be reached regarding relative harms. KQ 3: What is the evidence that IMRT has differential efficacy or safety issues in subpopulations? No studies on subpopulations were identified. KQ 4: What is the evidence of cost and cost-effectiveness of IMRT compared to EBRT? No studies on costs or cost-effectiveness were identified. Pancreas KQ 1: What is the evidence of effectiveness for intensity modulated radiation therapy compared to conventional external beam radiation therapy (EBRT) for patients with cancer by site and type of cancer? 6 Health Technology Assessment HTA

17 The overall strength of evidence is very low. One poor quality case series reported 1- and 2-year OS rates of 79% and 40%, respectively. Due to the lack of comparative data, no conclusions can be reached regarding the clinical effectiveness. KQ 2: What are the potential harms of IMRT compared to conventional external beam radiation therapy (EBRT)? What is the incidence of these harms? The overall strength of evidence is very low. One poor quality case series reported acute and chronic toxicity GI in 9% of patients. Due to the lack of comparative data, no conclusions can be reached regarding relative harms. KQ 3: What is the evidence that IMRT has differential efficacy or safety issues in subpopulations? No studies on subpopulations were identified. KQ 4: What is the evidence of cost and cost-effectiveness of IMRT compared to EBRT? The overall strength of evidence is low. One poor quality cost-effectiveness modeling study calculated that IMRT had an ICER of $1,584,100/QALY compared to EBRT. Rectum KQ 1: What is the evidence of effectiveness for intensity modulated radiation therapy compared to conventional external beam radiation therapy (EBRT) for patients with cancer by site and type of cancer? The overall strength of evidence is very low. One poor quality case series of 63 patients reported 2-year PFS and OS rates of 90% and 96%, respectively. Due to the lack of comparative data, no conclusions can be reached regarding the clinical effectiveness. KQ 2: What are the potential harms of IMRT compared to conventional external beam radiation therapy (EBRT)? What is the incidence of these harms? The overall strength of evidence is very low. One poor quality case series reported relatively low levels of complications. Due to the lack of comparative data, no conclusions can be reached regarding the relative harms. KQ 3: What is the evidence that IMRT has differential efficacy or safety issues in subpopulations? No studies on subpopulations were identified. KQ 4: What is the evidence of cost and cost-effectiveness of IMRT compared to EBRT? No studies on costs or cost-effectiveness were identified. Washington State Health Care Authority HCA 7

18 Stomach KQ 1: What is the evidence of effectiveness for intensity modulated radiation therapy compared to conventional external beam radiation therapy (EBRT) for patients with cancer by site and type of cancer? The overall strength of evidence is very low. Based on two small, poor quality cohort studies, there is inconsistent evidence on whether IMRT improves 2-year OS compared with 3DCRT. KQ 2: What are the potential harms of IMRT compared to conventional external beam radiation therapy (EBRT)? What is the incidence of these harms? The overall strength of evidence is very low. The two poor quality cohort studies report decrease in renal function measured by creatinine levels for 3DCRT compared to IMRT; the difference was significant in one study but not the other study. The effect of chemotherapy on renal toxicity is not investigated in either study. KQ 3: What is the evidence that IMRT has differential efficacy or safety issues in subpopulations? No studies on subpopulations were identified. KQ 4: What is the evidence of cost and cost-effectiveness of IMRT compared to EBRT? No studies on costs or cost-effectiveness were identified. Whole Pelvis Radiation KQ 1: What is the evidence of effectiveness for intensity modulated radiation therapy compared to conventional external beam radiation therapy (EBRT) for patients with cancer by site and type of cancer? No studies on effectiveness were identified. KQ 2: What are the potential harms of IMRT compared to conventional external beam radiation therapy (EBRT)? What is the incidence of these harms? Among patients treated with IMRT for whole pelvis radiation 2, there is very low overall strength of evidence that there were no significant differences in toxicity frequency for IMRT compared to EBRT. KQ 3: What is the evidence that IMRT has differential efficacy or safety issues in subpopulations? No studies on subpopulations were identified. KQ 4: What is the evidence of cost and cost-effectiveness of IMRT compared to EBRT? 2 Study included patients with endometrium, cervical, rectum, anal canal, and bladder cancers. 8 Health Technology Assessment HTA

19 No studies on costs or cost-effectiveness were identified. Brain In this section, evidence on intracranial tumors is summarized. There is limited evidence for all tumor types. No other cancers were identified for this section. The sections are divided up by intracranial malignancy and include the following: astrocytomas, brain metastases, glioblastomas, high-grade gliomas, medulloblastomas, meningiomas, pituitary adenomas, and sacral chodomas. Malignancies are discussed as they were reported in literature. For instance, although astrocytomas and glioblastoma multiforme are types of gliomas, they are discussed in separate sections as they were reported by individual studies. Astrocytoma KQ 1: What is the evidence of effectiveness for intensity modulated radiation therapy compared to conventional external beam radiation therapy (EBRT) for patients with cancer by site and type of cancer? There is very low overall strength of evidence that patients treated by IMRT had significantly greater 1-year OS and PFS than EBRT. There is very low overall strength of evidence that the IMRT group had greater 2-year OS and PFS compared to EBRT. KQ 2: What are the potential harms of IMRT compared to conventional external beam radiation therapy (EBRT)? What is the incidence of these harms? There is very low overall strength of evidence. One fair quality cohort study reported that patients undergoing treatment with IMRT for astrocytoma had fewer Grade 1 toxicities, but more Grade 2 and 3 toxicities than patients undergoing EBRT. Due to the limitations of small sample size, no conclusions can be reached regarding relative harms. KQ 3: What is the evidence that IMRT has differential efficacy or safety issues in subpopulations? No studies on subpopulations were identified. KQ 4: What is the evidence of cost and cost-effectiveness of IMRT compared to EBRT? No studies on costs or cost-effectiveness were identified. Brain metastases KQ 1: What is the evidence of effectiveness for intensity modulated radiation therapy compared to conventional external beam radiation therapy (EBRT) for patients with cancer by site and type of cancer? The overall strength of evidence is very low. The sole study identified did not compare treatment groups, which precluded any conclusions about the relative effectiveness of volumemodulated arc therapy (VMAT) treatment for patients with brain metastases. Patients treated Washington State Health Care Authority HCA 9

20 solely by VMAT had six-month OS of 55.1%, while patients treated by surgery and VMAT had six-month OS of 72.0%. Further, individuals undergoing VMAT treatment had significantly decreased physical functioning and role functioning scores on self-assessments of QOL. KQ 2: What are the potential harms of IMRT compared to conventional external beam radiation therapy (EBRT)? What is the incidence of these harms? The overall strength of evidence is very low. Given the lack of a comparator, no conclusions can be reached regarding the relative harms of VMAT treatment. As reported by one fair quality case series, patients treated by VMAT with brain metastases experienced Grade 1 and 2 alopecia. KQ 3: What is the evidence that IMRT has differential efficacy or safety issues in subpopulations? No studies on subpopulations were identified. KQ 4: What is the evidence of cost and cost-effectiveness of IMRT compared to EBRT? No studies on costs or cost-effectiveness were identified. Glioblastoma multiforme KQ 1: What is the evidence of effectiveness for intensity modulated radiation therapy compared to conventional external beam radiation therapy (EBRT) for patients with cancer by site and type of cancer? The overall strength of evidence is very low. As reported by three case series, the 2-year OS ranged from 0% to 55.6%, 2-year PFS ranged from 0% to 53.6%, median PFS was 9.0 months (95% CI, ), and median OS ranged from 14.4 to 20.1 months. Due to the lack of a comparator, no conclusions can be drawn. KQ 2: What are the potential harms of IMRT compared to conventional external beam radiation therapy (EBRT)? What is the incidence of these harms? The overall strength of evidence for all harms is very low. One fair quality case series reports on IMRT alone; two additional case series (one fair quality, one poor quality) report on IMRT plus chemotherapy. Results from the case series are inconsistent. One case series reported Grade 3 or higher toxicity in 38% (8 patients); one case series reported Grade 3 neurotoxicity in 16% (6 patients); and one case series reported no Grade 3 or higher toxicity. Due to the lack of comparative data, no conclusions can be reached regarding relative harms. KQ 3: What is the evidence that IMRT has differential efficacy or safety issues in subpopulations? No studies on subpopulations were identified. 10 Health Technology Assessment HTA