سامانه مدیریت نشریات علمی دانشگاه علوم پزشکی مشهد

Rahmanian, Mohsen, Khosropanah, Sarah, Hoseinzadeh Moghaddam, Sepehr, Vatankhah, Abulfazl, Abdi Bastami, Elahe, Roashanzamir, Soheila, Rahmanian Sharifabad, Amir, Ganji, Reza. (1404). A Systematic Review and Meta-Analysis of Regorafenib's Effectiveness and Safety in the Treatment of Bone Sarcoma. , 13(12), 776-787. doi: 10.22038/abjs.2025.87671.3969
Mohsen Rahmanian; Sarah Khosropanah; Sepehr Hoseinzadeh Moghaddam; Abulfazl Vatankhah; Elahe Abdi Bastami; Soheila Roashanzamir; Amir Rahmanian Sharifabad; Reza Ganji. "A Systematic Review and Meta-Analysis of Regorafenib's Effectiveness and Safety in the Treatment of Bone Sarcoma". , 13, 12, 1404, 776-787. doi: 10.22038/abjs.2025.87671.3969
Rahmanian, Mohsen, Khosropanah, Sarah, Hoseinzadeh Moghaddam, Sepehr, Vatankhah, Abulfazl, Abdi Bastami, Elahe, Roashanzamir, Soheila, Rahmanian Sharifabad, Amir, Ganji, Reza. (1404). 'A Systematic Review and Meta-Analysis of Regorafenib's Effectiveness and Safety in the Treatment of Bone Sarcoma', , 13(12), pp. 776-787. doi: 10.22038/abjs.2025.87671.3969
Rahmanian, Mohsen, Khosropanah, Sarah, Hoseinzadeh Moghaddam, Sepehr, Vatankhah, Abulfazl, Abdi Bastami, Elahe, Roashanzamir, Soheila, Rahmanian Sharifabad, Amir, Ganji, Reza. A Systematic Review and Meta-Analysis of Regorafenib's Effectiveness and Safety in the Treatment of Bone Sarcoma. , 1404; 13(12): 776-787. doi: 10.22038/abjs.2025.87671.3969

A Systematic Review and Meta-Analysis of Regorafenib's Effectiveness and Safety in the Treatment of Bone Sarcoma

The Archives of Bone and Joint Surgery
مقاله 3، دوره 13، شماره 12، اسفند 2025، صفحه 776-787    اصل مقاله (1.37 M)
نوع مقاله: SYSTEMATIC REVIEW
شناسه دیجیتال (DOI): 10.22038/abjs.2025.87671.3969
نویسندگان
Mohsen Rahmanian1؛ Sarah Khosropanah1؛ Sepehr Hoseinzadeh Moghaddam1؛ Abulfazl Vatankhah1؛ Elahe Abdi Bastami2؛ Soheila Roashanzamir1؛ Amir Rahmanian Sharifabad1؛ Reza Ganji* 3
1School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
2Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
3Department of Orthopedic Surgery, North Khorasan University of Medical Sciences, Bojnurd, Iran -Orthopedic Research Center, Ghaem Hospital, Mashhad, Iran
چکیده
Objectives: Bone sarcomas are rare, aggressive tumors with poor outcomes and limited systemic options in advanced stages. This systematic review and meta-analysis evaluated its efficacy and safety in bone sarcomas using randomized controlled trials (RCTs).
Methods: We searched PubMed, Scopus, and Web of Science for RCTs published from September 27, 2012, to October 14, 2024. After removing duplicates, 350 records were screened, and five RCTs met the inclusion criteria. Primary outcomes were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Study quality was assessed using the Cochrane Risk of Bias 2 (RoB2) tool. Meta-analyses were performed with a random-effects model, and heterogeneity was evaluated using I² statistics. All analyses were conducted using R version 4.3.1.
Results: A total of 350 records were screened after duplicate removal, of which 339 were excluded based on title and abstract. Eleven full-text articles were assessed for eligibility, and six were excluded for not meeting RCT criteria, resulting in five RCTs being included. Most had metastatic disease at baseline. Regorafenib significantly improved PFS (MD = 9.69 weeks; 95% CI: 4.54–14.84; I² = 0%), with no statistically significant overall survival (OS) benefit (MD = 0.85 weeks; 95% CI: –36.33 to 38.02; I² = 0%). These findings were consistent across studies and histological subtypes. All pooled analyses demonstrated zero or near-zero heterogeneity (I² = 0%), indicating highly consistent treatment effects among trials. No significant between-group heterogeneity was observed in subgroup analyses, confirming that regorafenib’s benefit on progression-free survival was stable across different bone sarcoma types. Common regorafenib-related AEs included hand–foot skin reaction, hypertension, fatigue, and diarrhea. Grade 3–5 events were mostly hypertension and pain, generally manageable with dose modifications. Safety results were also consistent across studies, showing zero or near-zero heterogeneity (I² = 0%) and no significant subgroup differences, indicating a homogeneous safety profile across sarcoma subtypes.
Conclusion: Regorafenib significantly improves progression-free survival in bone sarcomas across multiple subtypes, with a manageable toxicity profile. These results support its use as a novel therapy and highlight the need for future trials focused on optimizing dosing and patient selection. 
        Level of evidence: I
کلیدواژه‌ها
Bone sarcoma؛ Meta-analysis؛ Oncology؛ PFS؛ RCT؛ Regorafenib؛ Tyrosine kinase inhibitor
مراجع
  1. Gutowski CJ, Basu-Mallick A, Abraham JA. Management of bone sarcoma. Surg Clin North Am. 2016;96(5):1077-1106. doi:10.1016/j.suc.2016.06.002.
  2. Lin PP, Patel S, eds. Bone Sarcoma. New York, NY: Springer; 2013.
  3. DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Vol 2. Philadelphia, PA: Lippincott; 1985.
  4. Gosheger G, Gebert C, Ahrens H, Streitbuerger A, Winkelmann W, Hardes J. Endoprosthetic reconstruction in 250 patients with sarcoma. Clin Orthop Relat Res. 2006;450:164-171. doi:10.1097/01.blo.0000223978.36831.39.
  5. Eilber FR, Eckhardt J, Morton DL. Advances in the treatment of sarcomas of the extremity: current status of limb salvage. Cancer. 1984;54(S2):2695-2701. doi: 10.1002/1097-0142(19841201)54:2+<2695::aid-cncr2820541415>3.0.co;2-o.
  6. Biermann JS, Adkins DR, Agulnik M, et al. Bone cancer. J Natl Compr Canc Netw. 2013;11(6):688-723. doi:10.6004/jnccn.2013.0088.
  7. Wagner MJ, Livingston JA, Patel SR, Benjamin RS. Chemotherapy for bone sarcoma in adults. J Oncol Pract. 2016;12(3):208-216. doi:10.1200/JOP.2015.009944.
  8. Harris MA, Hawkins CJ. Recent and ongoing research into metastatic osteosarcoma treatments. Int J Mol Sci. 2022;23(7):3817. doi:10.3390/ijms23073817.
  9. Altun I, Sonkaya A. The most common side effects experienced by patients receiving the first cycle of chemotherapy. Iran J Public Health. 2018;47(8):1218-1219. doi:10.15171/ijph.2018.14306.
  10. Tian Z, Niu X, Yao W. Receptor tyrosine kinases in osteosarcoma treatment: which is the key target? Front Oncol. 2020;10:1642. doi:10.3389/fonc.2020.01642.
  11. Duffaud F. Role of TKI for metastatic osteogenic sarcoma. Curr Treat Options Oncol. 2020;21(8):60. doi:10.1007/s11864-020-00760-w.
  12. Skårderud MR, Polk A, Vistisen KK, Larsen FO, Nielsen DL. Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: a systematic review. Cancer Treat Rev. 2018;62:61-73. doi:10.1016/j.ctrv.2017.11.010.
  13. Khachatryan V, Muazzam A, Hamal C, et al. The role of regorafenib in the management of advanced gastrointestinal stromal tumors: a systematic review. Cureus. 2022;14(9):e28665. doi: 10.7759/cureus.28665.
  14. Facciorusso A, Abd El Aziz MA, Sacco R. Efficacy of regorafenib in hepatocellular carcinoma patients: a systematic review and meta-analysis. Cancers (Basel). 2019;12(1):79. doi:10.3390/cancers12010036.
  15. Mercier J, Voutsadakis IA. A systematic review and meta-analysis of retrospective series of regorafenib for treatment of metastatic colorectal cancer. Anticancer Res. 2017;37(11):5925-5934. doi:10.21873/anticanres.12039.
  16. Cochrane Methods Bias.Eldridge S, Campbell MK, Campbell MJ, Drahota AK, Giraudeau B, Reeves BC, Siegfried N, Higgins JP. Revised Cochrane risk of bias tool for randomized trials (RoB 2). Available at: https://methods.cochrane.org/bias/resources/rob-2-revised-cochrane-risk-bias-tool-randomized-trials. Cochrane Handbook for Systematic Reviews of Interventions;2019.
  17. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-1558. doi:10.1002/sim.1186.
  18. Duffaud F, Mir O, Boudou-Rouquette P, et al. Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2019;20(1):120-133. doi:10.1016/S1470-2045(18)30742-3.
  19. Duffaud F, Italiano A, Bompas E, et al. Efficacy and safety of regorafenib in patients with metastatic or locally advanced chondrosarcoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre phase II study. Eur J Cancer. 2021;150:108-118. doi: 10.1016/j.ejca.2021.03.039.
  20. Duffaud F, Blay JY, Le Cesne A, et al. Regorafenib in patients with advanced Ewing sarcoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre phase II study. Br J Cancer. 2023;129(12):1940-1948. doi: 10.1038/s41416-023-02413-9.
  21. Le Cesne A, Chevreau C, Perrin C, et al. Regorafenib in patients with relapsed advanced or metastatic chordoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre phase II study. ESMO Open. 2023;8(3):101569. doi:10.1016/j.esmoop.2023.101569.
  22. Davis L, Bolejack V, Ryan C, et al. Randomized double-blind phase II study of regorafenib in patients with metastatic osteosarcoma. J Clin Oncol. 2019;37(16):1424-1431. doi:10.1200/JCO.18.02374.
  23. Blay JY, Duffaud F, George S, Maki RG, Penel N. Regorafenib for the treatment of sarcoma. Curr Treat Options Oncol. 2022;23(11):1477-1502. doi: 10.1007/s11864-022-00990-0.
  24. Longhi A, Paioli A, Palmerini E, et al. Pazopanib in relapsed osteosarcoma patients: report on 15 cases. Acta Oncol. 2019;58(1):124-128. doi:10.1080/0284186X.2018.1503714.
  25. Xie L, Xu J, Sun X, et al. Apatinib for advanced osteosarcoma after failure of standard multimodal therapy: an open-label phase II clinical trial. Oncologist. 2019;24(7):e542-e550. doi:10.1634/theoncologist.2018-0246.
  26. Gaspar N, Casanova M, Sirvent FJ, et al. Single-agent expansion cohort of lenvatinib (LEN) and combination dose-finding cohort of LEN+ etoposide (ETP)+ ifosfamide (IFM) in patients (pts) aged 2 to≤ 25 years with relapsed/refractory osteosarcoma (OS). Lancet Oncol. 2018. doi:10.1016/S1470-2045(21)00387-9.
  27. Italiano A, Penel N, Toulmonde M, et al. Cabozantinib in patients with advanced osteosarcomas and Ewing sarcomas: a French Sarcoma Group/US National Cancer Institute phase II collaborative study. Ann Oncol. 2018;29(suppl 8):viii753. doi:10.1016/S1470-2045(19)30825-3.
  28. Ott PA, Hodi FS, Buchbinder EI. Inhibition of immune checkpoints and vascular endothelial growth factor as combination therapy for metastatic melanoma: an overview of rationale, preclinical evidence, and initial clinical data. Front Oncol. 2015;5:202. doi:10.3389/fonc.2015.00202.
  29. Atkins MB, Plimack ER, Puzanov I, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018;19(3):405-415. doi:10.1016/S1470-2045(18)30081-0.
  30. Kim SY, Kim SM, Chang H, et al. Safety of tyrosine kinase inhibitors in patients with differentiated thyroid cancer: real-world use of lenvatinib and sorafenib in Korea. Front Endocrinol (Lausanne). 2019;10:384. doi:10.3389/fendo.2019.00384.
  31. Zhang L, Zhou Q, Ma L, Wu Z, Wang Y. Meta-analysis of dermatological toxicities associated with sorafenib. Clin Exp Dermatol. 2011;36(4):344-350. doi:10.1111/j.1365-2230.2011.04060.x.
  32. Sternberg CN, Hawkins RE, Wagstaff J, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;49(6):1287-1296. doi:10.1016/j.ejca.2012.12.010.
  33. McCormack PL. Pazopanib: a review of its use in the management of advanced renal cell carcinoma. Drugs. 2014;74:1111-1125. doi:10.1007/s40265-014-0243-3.
  34. Small HY, Montezano AC, Rios FJ, Savoia C, Touyz RM. Hypertension due to antiangiogenic cancer therapy with vascular endothelial growth factor inhibitors: understanding and managing a new syndrome. Can J Cardiol. 2014;30(5):534-543. doi:10.1016/j.cjca.2014.02.011.
  35. Robinson ES, Khankin EV, Karumanchi SA, Humphreys BD. Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: mechanisms and potential use as a biomarker. InSeminars in nephrology 2010 (Vol. 30, No. 6, pp. 591-601). WB Saunders.
  36. Fojo T. Commentary: novel therapies for cancer: why dirty might be better. Oncologist. 2008;13(3):277-283. doi:10.1634/theoncologist.2007-0090.
  37. Ghazanfary S, Rahmanian M, Vatanchian M, Haghbin A, Shakeri F, Oroojalian F. Characterization and Efficacy Evaluation of mPEG-PLGA/Taraxasterol Acetate Nanoparticles as Nano-Therapeutic Agents in Asthma Management. BioNanoScience. 2025;15(1):124.
  38. Rahmanian M, Oroojalian F, Kesharwani P, Sahebkar A. Liposome-mediated anticancer drug delivery strategies for advancing brain tumor therapy. Eur Polym J. 2025;114001. doi:10.1016/j.eurpolymj.2025.114001.
  39. Sanna V, Pala N, Sechi M. Targeted therapy using nanotechnology: focus on cancer. Int J Nanomedicine. 2014;9:467-483. doi:10.2147/IJN.S36654.
  40. Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther. 2022;7(1):93. doi:10.1038/s41392-022-00947-7.
  41. Sadek WS, Ahmed AG, Abou Senna WG, Ebeid WA. Does Unplanned Excision of Soft Tissue Sarcomas Affect the Oncological Outcome: A retrospective study. Arch Bone Jt Surg. 2025 Oct 4. In Press
 

 

 

 

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