Accepted Manuscript. Tetsuo Saito, Ryo Toya, Natsuo Oya. S (18) DOI: Reference: PRRO 984

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1 Accepted Manuscript Pain response rates after conventional radiation therapy for bone metastases in prospective non-randomized studies: A systematic review Tetsuo Saito, Ryo Toya, Natsuo Oya PII: S (18) DOI: Reference: PRRO 984 To appear in: Practical Radiation Oncology Received Date: 6 October 2018 Revised Date: 13 November 2018 Accepted Date: 16 November 2018 Please cite this article as: Saito T, Toya R, Oya N, Pain response rates after conventional radiation therapy for bone metastases in prospective non-randomized studies: A systematic review, Practical Radiation Oncology (2018), doi: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Pain response rates after conventional radiation therapy for bone metastases in prospective non-randomized studies: A systematic review Tetsuo Saito a, Ryo Toya a, Natsuo Oya a a Department of Radiation Oncology, Kumamoto University Hospital, Kumamoto, Japan Corresponding author: Tetsuo Saito, MD, PhD. Department of Radiation Oncology Kumamoto University Hospital 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto, , Japan Phone: Fax: tsaito@kumamoto-u.ac.jp Author responsible for statistical analyses: Tetsuo Saito, MD, PhD. Running title: Pain response rates in non-randomized studies Conflict of interest: none.

3 2 We do not have a source of financial support or funding. Acknowledgement: none.

4 1 Pain response rates after conventional radiation therapy for bone metastases in prospective non-randomized studies: A systematic review

5 2 Abstract Purpose: To determine pain response rates following conventional radiation therapy for painful bone metastases in prospective non-randomized studies, which better reflect daily practice than randomized controlled trials. Methods: A literature search was conducted in PubMed and Scopus for articles published from 2002 to We only included articles in which pain response following radiation therapy was assessed using the International Consensus Endpoint initially published in 2002, or that updated in Additionally, to be included in this review, the study design was required to be prospective or based on prospectively collected data. Our primary outcomes of interest were the overall and complete response rates following conventional radiation therapy for bone metastases. Results: Of 2863 articles identified in the database search, 12 met our inclusion criteria. Six studies excluded patients with features of complicated bone metastases. Only two papers reported exclusion criteria regarding analgesic use. Radiation schedules frequently used were 1 x 8 Gy, 5 x 4 Gy, and 10 x 3 Gy. The overall response rate in evaluable patients was 55%; 754 of the evaluable 1379 patients experienced a complete or partial response. The complete response rate was 15% (196/1348 evaluable patients). In the intention-to-treat patients, the overall response rate was 29% (754/2559 enrolled patients) and the complete response rate was 8% (196/2528 enrolled patients). Conclusions: We determined pain response rates following conventional radiation therapy for

6 3 painful bone metastases in prospective non-randomized studies. The present review may provide benchmarks for future non-randomized studies investigating palliative radiation therapy for bone metastases.

7 4 Introduction Radiation therapy (RT) is a standard treatment for painful bone metastases. 1 In previous randomized controlled trials (RCTs), 72 75% of evaluable patients and 61 62% of intention-to-treat patients were reported to have experienced pain response following RT. 2 Compared with those found in RCTs, the pain response rates following RT for bone metastases found in non-randomized studies are less well known. Patients enrolled in RCTs and non-randomized studies are from different populations, and RCTs and non-randomized studies yield differing conclusions regarding treatment efficacy, even after adjusting for known prognostic factors. 3 In RCTs, specific criteria are used to ensure that the treatment and control groups are similar regarding the distribution of factors affecting response to treatment, and all participants are selected for their performance status and ability to tolerate potentially toxic exposures. 4 In this review, we sought to determine the pain response rates following conventional RT for bone metastases in prospective non-randomized studies, which better reflect daily practice than RCTs. To reduce heterogeneity between studies in the quantitative synthesis, we only included studies in which pain response was evaluated using the International Consensus Endpoint. 5,6

8 5 Methods and materials Search strategy and study selection This study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 7 No formalized review protocol was created in the present study. A literature search was conducted in PubMed and Scopus for articles published from 2002 (year of publication of the original International Consensus Endpoint) to The last search was performed on August 14, Search terms included synonyms and lists of related words for bone, metastasis, radiation therapy, response, and pain. The detailed search strategy is reported in the Appendix (Supplementary Material). For this review, we only included articles in which pain response following RT was assessed using the International Consensus Endpoint initially published in 2002, 5 or that updated in Additionally, to be included in this review, the study design was required to be prospective or based on prospectively collected data so that an intention-to-treat assessment of the responses could be performed for all enrolled patients. The exclusion criteria for our abstract screening were as follows: editorials, reviews, or case reports; publications in languages other than English; reirradiation; and use of radiopharmaceuticals, particle RT, brachytherapy, intraoperative RT, stereotactic body radiation therapy, intensity modulated radiation therapy, concurrent chemotherapy and RT, or half-body irradiation (Figure 1). We only included studies in which most of the patients were treated with conventional RT; conventional RT

9 6 was defined to be two- or three-dimensional RT which was not stereotactic body radiation therapy or intensity modulated radiation therapy. We then assessed the screened full-text papers for eligibility in accordance with the following exclusion criteria: retrospective or randomized studies; studies in which pain response was not assessed using the International Consensus Endpoint; and studies in which response rates were calculated based on the number of painful irradiated lesions instead of the number of patients. At this stage, some studies were excluded based on the abstract screening exclusion criteria. To avoid counting the same patients more than once, for studies in which the Rapid Response Radiotherapy Program 8 database was used, we selected studies according to the following policy: for studies that shared, at least part of, the same enrollment period, only one study, the largest, was selected for this review. Data extraction Our primary outcomes of interest were the overall and complete response rates following conventional RT for bone metastases in prospective non-randomized studies. Overall response includes complete response and partial response. A complete response was defined as an index pain score of zero (0) with no concomitant increase in daily oral morphine equivalent dose (OMED). 6 A partial response was defined as a reduction in the index pain score of 2 without an increase in analgesic use, or a 25% reduction in analgesic use from baseline without an increase in pain score. 6 Pain progression was defined as an increase in the index pain score of 2

10 7 without a reduction in OMED, or a 25% increase in OMED without a decrease in pain score. 6 An indeterminate response was defined as any response that was not captured by the complete response, partial response, or pain progression definitions. 6 For the International Consensus Endpoint originally published in 2002, an indeterminate response was not defined. 5 Therefore, in studies in which responses were assessed using the 2002 consensus endpoint, patients who had responses that were not captured by the complete response, partial response, or pain progression definitions were treated as those with indeterminate responses in this review. For the present study, the response rates were recalculated based on the number of patients reported in the original studies because in some studies, the percentages of responses were not always reported. When more than one assessment of responses was performed, the latest assessment completed within two months after RT was recorded. Additional information compiled included the name of the first author, publication year, journal name, study design, characteristics of bone metastases, eligibility criteria, dose fractionation of RT, definition of the pain response, and the time when the response was measured.

11 8 Results Characteristics of included studies Of the 2863 articles identified in our database search, 12 met our inclusion criteria (Figure 1). The characteristics of the included studies are presented in Table 1. Ten were prospective studies and two were studies based on prospectively collected data. Six studies excluded patients with some features of complicated bone metastases; in the other six studies, there were no eligibility criteria regarding complicated metastases. Only two papers reported exclusion criteria regarding analgesic use. 11,20 No studies reported the run-in period for analgesic adjustment before RT, nor the presence or absence of pain other than the index pain caused by the irradiated tumors at baseline. In 10 studies, there were no eligibility criteria regarding systemic therapy, including chemotherapy; in one study, patients with a history of receiving chemotherapy in the past 4 weeks were not eligible, 17 and one study s exclusion criteria included the start or change of bisphosphonate-use or systemic therapy (or both) during RT and the 10 days following completion of RT. 10 Radiation schedules frequently used were 1 x 8 Gy, 5 x 4 Gy, and 10 x 3 Gy. In a phase II study investigating the effects of dexamethasone for preventing pain flare, all patients took dexamethasone just prior to RT and for three consecutive days following treatment. 11 Pain response rates

12 9 The overall response was evaluable in 1379 (54%) of 2559 enrolled patients (Table 2). The overall response rate in evaluable patients was determined to be 55%; 754 patients of the evaluable 1379 patients experienced a complete or partial response (Table 2). The complete response rate was 15% (196/1348 evaluable patients). In the intention-to-treat patients, the overall response rate was 29% (754/2559 enrolled patients) and the complete response rate was 8% (196/2528 enrolled patients).

13 10 Discussion We found that relatively lower pain response rates following conventional RT for painful bone metastases were reported in prospective non-randomized studies compared with RCTs. In evaluable patients, the overall response rate was 55% and the complete response rate was 15%. These values are lower than the overall response rates of 72 75% and the complete response rates of 28-29% reported in RCTs. 2 Four factors that may have contributed to the differences in response rates in evaluable patients between RCTs and non-randomized studies are discussed in the following paragraphs. First, the differing definitions of the pain responses may partially explain the results of the present review. The studies included in this review used the International Consensus Endpoint for assessment of pain response. 5,6 According to this endpoint definition, patients with alleviated pain and increased opioid analgesic use were diagnosed as nonresponders (patients with an indeterminate response). In many RCTs, the response definition only included pain intensity and did not include analgesic use. 2, This difference in the definition of pain response may, at least in part, explain the differences in response rates between RCTs and the non-randomized studies included in the present review. The second factor is the run-in period before RT. In clinical trials, for patients whose analgesic use is sub-optimal and who require titration of or changes in pain medications, a run-in period of no more than 1 2 weeks for analgesic adjustment is recommended. 5,6 No papers included in the present review included information regarding a run-in period. When a run-in period is not set, some patients, whose pain is palliated after RT, tend to be diagnosed

14 11 with an indeterminate response and accordingly, as nonresponders. To enable more valid comparisons of response rates between studies, future papers on palliative RT should report whether they set a run-in period or not. The third factor that might have influenced the response rates is the presence of complicated bone metastases. Most RCTs evaluating RT for bone metastases excluded patients with features of complicated bone metastases; these features included impending or existing pathologic fracture and existing spinal cord or cauda equina compression. 2, In contrast, six of the 12 non-randomized studies included in the present review did not exclude patients with complicated bone metastases. Little is known regarding the differences in response rates between patients with complicated and uncomplicated bone metastases; in one population-based cohort study, there seems to have been no clear differences in the overall response rates between patients with complicated and uncomplicated bone metastases (statistical analysis not shown). 26 The effects of the presence of complicated bone metastases on pain response need to be further studied. Finally, the fourth factor that may have contributed to the differences in response rates between RCTs and non-randomized studies is the presence of pain other than the index pain caused by the irradiated tumors. Even when RT palliates pain at one site, unmasked pain at other sites may negatively influence quality of life. A secondary analysis of an observational study revealed that in patients with a predominance of non-index pain after RT, opioid analgesic use tended to increase, which may lower response rates. 27 This study also demonstrated that predictors of such a predominance of non-index pain were younger age, the presence of non-index pain due to a malignant or unknown origin at baseline, and no opioid analgesic use at baseline. 27 A few RCTs excluded patients with more than one site of pain, 28

15 12 more than one painful bone metastasis, 29 and those with earlier entry into the same trial for pain at a different site; 30 these eligibility criteria may have excluded some patients who were likely to experience a predominance of non-index pain after RT. In the present review, no studies reported information regarding non-index pain. The presence or absence of non-index pain at baseline and after RT should be recorded and reported in future studies investigating pain palliation by RT. In intention-to-treat patients, we also found low response rates in the studies we reviewed. In the 12 non-randomized studies analyzed, attrition rates were high. These high attrition rates may have contributed to the low response rates observed in the intention-to-treat patients. Bias in study selection may be a limitation of this review. We only included prospective studies in which pain response was evaluated using the International Consensus Endpoint. However, this selection of studies may have reduced heterogeneity between studies and contributed to high quality in quantitative synthesis.

16 13 Conclusions Pain response rates following conventional RT reported in prospective non-randomized studies were reviewed and summarized. The present review may provide benchmarks for future non-randomized studies investigating palliative RT for bone metastases. Future reports on palliative RT for bone metastases should include information regarding the run-in period for analgesic adjustment before RT, complicated/uncomplicated bone metastases, and pain other than the index pain caused by the irradiated tumors.

17 14 References 1. Lutz S, Balboni T, Jones J, Lo S, Petit J, Rich SE, et al. Palliative radiation therapy for bone metastases: Update of an ASTRO Evidence-Based Guideline. Pract Radiat Oncol 2017;7: Rich SE, Chow R, Raman S, Liang Zeng K, Lutz S, Lam H, et al. Update of the systematic review of palliative radiation therapy fractionation for bone metastases. Radiother Oncol 2018;126: Antman K, Amato D, Wood W, Carson J, Suit H, Proppe K, et al. Selection bias in clinical trials. J Clin Oncol 1985;3: Hershman DL, Wright JD. Comparative effectiveness research in oncology methodology: observational data. J Clin Oncol 2012;30: /JCO Chow E, Wu JS, Hoskin P, Coia LR, Bentzen SM, Blitzer PH. International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases. Radiother Oncol 2002;64: Chow E, Hoskin P, Mitera G, Zeng L, Lutz S, Roos D, et al. Update of the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases. Int J Radiat Oncol Biol Phys 2012;82: /j.ijrobp Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b

18 15 8. Fairchild A, Pituskin E, Rose B, Ghosh S, Dutka J, Driga A, et al. The rapid access palliative radiotherapy program: blueprint for initiation of a one-stop multidisciplinary bone metastases clinic. Support Care Cancer 2009;17: Kirou-Mauro A, Hird A, Wong J, Sinclair E, Barnes EA, Tsao M, et al. Is response to radiotherapy in patients related to the severity of pretreatment pain? Int J Radiat Oncol Biol Phys 2008;71: Hird A, Chow E, Zhang L, Wong R, Wu J, Sinclair E, et al. Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: results from three Canadian cancer centers. Int J Radiat Oncol Biol Phys 2009;75: Hird A, Zhang L, Holt T, Fairchild A, DeAngelis C, Loblaw A, et al. Dexamethasone for the prophylaxis of radiation-induced pain flare after palliative radiotherapy for symptomatic bone metastases: a phase II study. Clin Oncol (R Coll Radiol) 2009;21: Zaikova O, Fossa SD, Kongsgaard U, Kvaloy S, Giercksky KE, Skjeldal S. Pain after palliative radiotherapy for spine metastases. Clin Oncol (R Coll Radiol) 2010;22: Caissie A, Zeng L, Nguyen J, Zhang L, Jon F, Dennis K, et al. Assessment of health-related quality of life with the European Organization for Research and Treatment of Cancer QLQ-C15-PAL after palliative radiotherapy of bone metastases. Clin Oncol (R Coll Radiol) 2012;24: Zeng L, Chow E, Bedard G, Zhang L, Fairchild A, Vassiliou V, et al. Quality of life after palliative radiation therapy for patients with painful bone metastases: results of an

19 16 international study validating the EORTC QLQ-BM22. Int J Radiat Oncol Biol Phys 2012;84:e Truntzer P, Atlani D, Pop M, Clavier JB, Guihard S, Schumacher C, et al. Early evaluation predicts pain relief of irradiated bone metastases: a single-center prospective study. BMC Palliat Care 2013;12: Gomez-Iturriaga A, Cacicedo J, Navarro A, Morillo V, Willisch P, Carvajal C, et al. Incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: multicenter prospective observational study. BMC Palliat Care 2015;14: Tahara T, Fujii S, Ogawa T, Michimoto K, Fukunaga T, Tanino T, et al. Fluorodeoxyglucose uptake on positron emission tomography is a useful predictor of long-term pain control after palliative radiation therapy in patients with painful bone metastases: results of a single-institute prospective study. Int J Radiat Oncol Biol Phys 2016;94: Nakamura N, Takahashi O, Zenda S, Kawamori J, Ogita M, Onozawa M, et al. Neuropathic pain features in patients with bone metastases. Clin Oncol (R Coll Radiol) 2016;28: van der Velden JM, Versteeg AL, Verkooijen HM, Fisher CG, Chow E, Oner FC, et al. Prospective evaluation of the relationship between mechanical stability and response to palliative radiotherapy for symptomatic spinal metastases. Oncologist 2017;22: Cacicedo J, Gomez-Iturriaga A, Navarro A, Morillo V, Willisch P, Lopez-Guerra JL, et al. Analysis of predictors of pain response in patients with bone metastasis undergoing

20 17 palliative radiotherapy: does age matter? J Med Imaging Radiat Oncol Wu JS, Bezjak A, Chow E, Kirkbride P. Primary treatment endpoint following palliative radiotherapy for painful bone metastases: need for a consensus definition? Clin Oncol (R Coll Radiol) 2002;14: Wu JS, Wong R, Johnston M, Bezjak A, Whelan T; Cancer Care Ontario Practice Guidelines Initiative Supportive Care Group. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 2003;55: Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 2007;25: Chow E, Zeng L, Salvo N, Dennis K, Tsao M, Lutz S. Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol) 2012;24: Cheon PM, Wong E, Thavarajah N, Dennis K, Lutz S, Zeng L, et al. A definition of "uncomplicated bone metastases" based on previous bone metastases radiation trials comparing single-fraction and multi-fraction radiation therapy. J Bone Oncol 2015;4: Conway JL, Yurkowski E, Glazier J, Gentles Q, Walter A, Bowering G, et al. Comparison of patient-reported outcomes with single versus multiple fraction palliative radiotherapy for bone metastasis in a population-based cohort. Radiother Oncol 2016;119:

21 Saito T, Toya R, Tomitaka E, Matsuyama T, Ninomura S, Watakabe T, et al. Predictors of the Predominance of Non-Index Pain after Palliative Radiation Therapy for Painful Tumors. Adv Radiat Oncol, in press (2018) Foro Arnalot P, Fontanals AV, Galceran JC, Lynd F, Latiesas XS, de Dios NR, et al. Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction. Radiother Oncol 2008;89: Nielsen OS, Bentzen SM, Sandberg E, Gadeberg CC, Timothy AR. Randomized trial of single dose versus fractionated palliative radiotherapy of bone metastases. Radiother Oncol 1998;47: Bone Pain Trial Working Party. 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. Bone Pain Trial Working Party. Radiother Oncol 1999;52:

22 19 Figure caption Figure 1 Flow chart of the study selection procedure.

23 Table 1 Study characteristics First author Year Study design BM characteristics BM mainly from Kirou-Mauro A Based on prospectively collected data Hird A 10 Three-center, 2009 prospective breast, lung, prostate, or gastrointestinal cancer BM mainly from breast, lung, or prostate cancer Eligibility criteria regarding complicated BM None Without a pathologic fracture, or spinal cord or cauda equina Eligibility criteria regarding analgesic use None None Radiation schedule 1 x 8 Gy (47.9%); 5 x 4 Gy (40.0%) 1 x 8 Gy (63%); 5 x 4 Gy (25%) Response definition publication year When response was measured 2 months post-rt 6 weeks after start of RT compression

24 Hird A Three-center, phase II Zaikova 12 Single-institute, 2010 prospective Based on Caissie A prospectively collected data BM mainly from prostate, lung, or breast cancer Spine metastases mainly from prostate, breast, or lung cancer; includes myeloma/lymphoma BM mainly from prostate, breast, lung, or kidney cancer Without a pathologic fracture or spinal cord compression None Without neurological signs or symptoms (e.g., Without an immediate plan to change regular analgesic medication None spinal cord None compression or cauda equina syndrome); 1 x 8 Gy (100%) 10 x 3 Gy (78%) Single fractionation (57%); multiple fractionation (43%) weeks after completion of RT 2 months after start of RT 2 months after first day of RT

25 includes patients with pathological Zeng L Truntzer P Gomez-Iturri aga A Tahara T International prospective (secondary analysis) Single-center, prospective Multicenter, prospective observational Single-institute, prospective BM mainly from breast, prostate, or lung cancer BM mainly from lung/pleura, breast, breast cancer fractures or soft tissue components None None NR x 3 Gy kidney/prostate, or gastrointestinal cancer None None (55.4%); 5 x 4 Gy (18.9%) 2002 BM mainly from 5 x 4 Gy lung, prostate, or None None (61.5%); 1 x 2002 BM mainly from Without lung, breast, or indications for 8 Gy (31.1%) 10 x 3 Gy None 2012 (100%) 1 month after treatment Day 30 after treatment completiont 4 weeks after completion of RT 4 weeks after completion of

26 prostate cancer surgery, pathologic RT fracture, or spinal Nakamura van der Velden JM Cacicedo J Single-institute, prospective Two-center, prospective observational Multicenter, prospective BM mainly from breast, lung, or prostate cancer Spine metastases mainly from breast, prostate, lung, or kidney cancer cord compression None Without invalidating neurological deficits (American Spinal Injury Association E or D without progression) None None BM from lung, Without a No analgesic prostate, or breast pathologic medication 1 x 8 Gy (48%); 10 x 3 Gy (34%); 5 x 4 Gy (17%) 1 x 8 Gy (61%); 5 x 4 Gy (19%); 10 x 3 Gy (17%) 5 x 4 Gy (86.8%); 1 x months after start of RT 4 8 weeks after RT 4 weeks after completion of

27 observational cancer fracture, spinal changes 8 Gy RT (secondary analysis) cord compression or cauda equina syndrome BM, bone metastases; NR, not reported; RT, radiation therapy. immediately before RT (22.4%); 4 x 5 Gy (13.2%)

28 Table 2 Pain response rates Evaluable patients Intention-to-treat patients Study Overall response Complete response Partial response Pain progression Indeterminate response Overall response Complete response Kirou-Mauro A 9 213/412 (52%) 95/412 (23%) 118/412 (29%) 43/412 (10%) 156/412 (38%) 213/1053 (20%) 95/1053 (9%) Hird A 10 48/72 (67%) 1/72 (1%) 47/72 (65%) 6/72 (8%) 18/72 (25%) 48/111 (43%) 1/111 (1%) Hird A 11 22/33 (67%) 0/33 (0%) 22/33 (67%) 1/33 (3%) 10/33 (30%) 22/41 (54%) 0/41 (0%) Zaikova 12 85/229 (37%) 28/229 (12%) 57/229 (25%) 67/229 (29%) 77/229 (34%) 85/355 (24%) 28/355 (8%) Caissie A 13 38/58 (66%) 3/58 (5%) 35/58 (60%) 6/58 (10%) 14/58 (24%) 38/178 (21%) 3/178 (2%) Zeng L 14 22/59 (37%) 0/59 (0%) 22/59 (37%) 8/59 (14%) 29/59 (49%) 22/79 (28%) 0/79 (0%) Truntzer P 15 24/42 (57%) 7/42 (17%) 17/42 (40%) 7/42 (17%) 11/42 (26%) 24/61 (39%) 7/61 (11%) Gomez-Iturri 79/127 (62%) 15/127 (12%) 64/127 (50%) 14/127 (11%) 34/127 (27%) 79/204 (39%) 15/204 (7%)

29 aga A 16 Tahara T 17 27/31 (87%) NR NR NR NR 27/31 (87%) NR Nakamura 18 36/64 (56%) 16/64 (25%) 20/64 (31%) 9/64 (14%) 19/64 (30%) 36/87 (41%) 16/87 (18%) van der Velden JM 19 81/124 (65%) 16/124 (13%) 65/124 (52%) NR NR 81/155 (52%) 16/155 (10%) Cacicedo J 20 79/128 (62%) 15/128 (12%) 64/128 (50%) 14/128 (11%) 35/128 (27%) 79/204 (39%) 15/204 (7%) Number of studies Total 754/1379 (55%) 196/1348 (15%) 531/1348 (39%) 175/1224 (14%) 403/1224 (33%) 754/2559 (29%) 196/2528 (8%) NR, not reported. Response rates are presented as the number of patients who experienced the response divided by the total number of patients (%). Overall response includes complete response and partial response.

30 Included Eligibility Screening Identification Articles identified through database search (n = 3741) Articles after duplicates removed (n = 2863) Full-text articles assessed for eligibility (n = 91) Articles excluded after abstract screening (n = 2772) Full-text articles excluded (n = 79) ACCEP TED MANUS CRIP T Studies included in quantitative synthesis (n = 12)