Safety of Off-Label Use of Anticancer Drugs in Oncology

Safety is recognized as a crucial issue of off-label use of anticancer drugs. The potential benefits of such prescriptions in oncology are associated with prevailing the expected clinical benefits over the risks of complications. However, in certain clinical situations with uncertain benefit/risk ratio, an off-label use of drugs may threaten the life and health of the patient. The present paper explores the safety of off-label anticancer drug therapy in real clinical practice. Health care and routine clinical practice are given particular emphasis on systematic recording and careful monitoring of adverse events associated with the off-label use of medicinal products. The creation of a unified registration system for off-label use of drug therapy in oncology along with the creation of large databases (on the sites of institutions with an option to combine the data obtained at the level of districts, regions and the country) enables a significant amount of information on the safety and effectiveness of this approach to be gathered. As a result, a predictable nature of treatment and manageable toxic effects are potentially provided. The study into reasons behind off-label use of drugs in oncology, as well as the study into spectrum and severity of adverse events resulting from the implementation of these prescriptions, will provide detailed information on the safety of off-label use of anticancer agents in patients with malignant neoplasms at different stages of oncological treatment.

1. Scher K.S., Hurria A. Under-representation of older adults in cancer registration trials: known problem, little progress. J Clin Oncol. 2012;30(17):2036–8. DOI: 10.1200/JCO.2012.41.6727

2. 2 Martsevich S.Y., Navasardjan A.R., Komkova N.A. Off-Label Prescribing. Possible Causes, Types and Consequences. Legal Regulation in the Russian Federation. Rational Pharmacotherapy in Cardiology. 2017;13(5):667–74 (In Russ.). DOI: 10.20996/1819-6446-2017-13-5-667-674

3. Pereverzev A.P., Lepakhin V.K. Violation of prescription instructions: a viewpoint of a contemporary. Meditsinskiy sovet = Medical Council. 2013;(4-1):110–9 (In Russ.). DOI: 10.21518/2079-701X-2013-4-110-111

4. Lim M., Shulman D.S., Roberts H., Li A., Clymer J., Bona K., et al. Offlabel prescribing of targeted anticancer therapy at a large pediatric cancer center. Cancer Med. 2020;9(18):6658–66. DOI: 10.1002/cam4.3349

5. Lee D.P., Skolnik J.M., Adamson P.C. Pediatric phase I trials in oncology: an analysis of study conduct efficiency. J Clin Oncol. 2005;23(33):8431–41. DOI: 10.1200/JCO.2005.02.1568

6. Aguilera D., Mazewski C., Fangusaro J., MacDonald T.J., McNallKnapp R.Y., Hayes L.L., et al. Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: a multiinstitutional experience. Childs Nerv Syst. 2013;29(4):589–96. DOI: 10.1007/s00381-012-2013-4

7. Spini A., Ciccone V., Rosellini P., Ziche M., Lucenteforte E., Salvo F., et al. Safety of anti-angiogenic drugs in pediatric patients with solid tumors: a systematic review and meta-analysis. Cancers (Basel). 2022;14(21):5315. DOI: 10.3390/cancers14215315

8. Kalra M., Heath J.A., Kellie S.J., Dalla Pozza L., Stevens M.M., Swamy S., et al. Confirmation of bevacizumab activity, and maintenance of efficacy in retreatment after subsequent relapse, in pediatric low-grade glioma. J Pediatr Hematol Oncol. 2015;37(6):e341–6. DOI: 10.1097/MPH.0000000000000371

9. Calò P., Pianton N., Basle A., Vasiljevic A., Barritault M., Beuriat P.A., et al. Bevacizumab as single agent in children and teenagers with optic pathway glioma. Cancers (Basel). 2023;15(4):1036. DOI: 10.3390/cancers15041036

10. Green K., Panagopoulou P., D’Arco F., O’Hare P., Bowman R., Walters B., et al. A nationwide evaluation of bevacizumab-based treatments in pediatric low-grade glioma in the UK: Safety, efficacy, visual morbidity, and outcomes. Neuro Oncol. 2023;25(4):774–85. DOI: 10.1093/neuonc/noac223

11. Bennebroek C.A.M., van Zwol J., Porro G.L., Oostenbrink R., Dittrich A.T.M., Groot A.L.W., et al. Impact of bevacizumab on visual function, tumor size, and toxicity in pediatric progressive optic pathway glioma: a retrospective nationwide multicentre study. Cancers (Basel). 2022;14(24):6087. DOI: 10.3390/cancers14246087

12. Cenna R., Basiricò M., Berchialla P., Bertorello N., Cagnazzo C., et al. Off-label and compassionate use of targeted anticancer therapies: The experience of an Italian pediatric cancer center. Pediatr Blood Cancer. 2023;70(3):e30148. DOI: 10.1002/pbc.30148

13. de Marcellus C., Tauziède-Espariat A., Cuinet A., Pasqualini C., Robert M.P., Beccaria K., et al. The role of irinotecan-bevacizumab as rescue regimen in children with low-grade gliomas: a retrospective nationwide study in 72 patients. J Neurooncol. 2022;157(2):355–64. DOI: 10.1007/s11060-022-03970-4

14. El-Khouly F.E., Veldhuijzen van Zanten S.E.M., Jansen M.H.A., Bakker D.P., Sanchez Aliaga E., Hendrikse N.H., et al. A phase I/II study of bevacizumab, irinotecan and erlotinib in children with progressive diffuse intrinsic pontine glioma. J Neurooncol. 2021;153(2):263–71. DOI: 10.1007/s11060-021-03763-1

15. Su J.M., Murray J.C., McNall-Knapp R.Y., Bowers D.C., Shah S., Adesina A.M., et al. A phase 2 study of valproic acid and radiation, followed by maintenance valproic acid and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma or high-grade glioma. Pediatr Blood Cancer. 2020;67(6):e28283. DOI: 10.1002/pbc.28283

16. Crotty E.E., Leary S.E.S., Geyer J.R., Olson J.M., Millard N.E., Sato A.A., et al. Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children’s Hospital experience. J Neurooncol. 2020;148(3):607–17. DOI: 10.1007/s11060-020-03558-w

17. Zhukova N., Rajagopal R., Lam A., Coleman L., Shipman P., Walwyn T., et al. Use of bevacizumab as a single agent or in adjunct with traditional chemotherapy regimens in children with unresectable or progressive low-grade glioma. Cancer Med. 2019;8(1):40–50. DOI: 10.1002/cam4.1799

18. Metts J., Harrington B., Salman E., Bradfield S.M., Flanary J., Mosha M., et al. A phase I study of irinotecan and temozolomide with bevacizumab in children with recurrent/refractory central nervous system tumors. Childs Nerv Syst. 2022;38(5):919–28. DOI: 10.1007/s00381-022-05479-7

19. Schiavetti A., Varrasso G., Mollace M.G., Dominici C., Ferrara E., Papoff P., et al. Bevacizumab-containing regimen in relapsed/progressed brain tumors: a single-institution experience. Childs Nerv Syst. 2019;35(6):1007–12. DOI: 10.1007/s00381-019-04117-z

20. Levy A.S., Krailo M., Chi S., Villaluna D., Springer L., WilliamsHughes C., et al. Temozolomide with irinotecan versus temozolomide, irinotecan plus bevacizumab for recurrent medulloblastoma of childhood: Report of a COG randomized Phase II screening trial. Pediatr Blood Cancer. 2021;68(8):e29031. DOI: 10.1002/pbc.29031

21. Gaspar N., Campbell-Hewson Q., Gallego Melcon S., Locatelli F., Venkatramani R., Hecker-Nolting S., et al. Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)☆. ESMO Open. 2021;6(5):100250. DOI: 10.1016/j.esmoop.2021.100250

22. Gaspar N., Venkatramani R., Hecker-Nolting S., Melcon S.G., Locatelli F., Bautista F., et al. Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study. Lancet Oncol. 2021;22(9):1312–21. DOI: 10.1016/S1470-2045(21)00387-9

23. Mascarenhas L., Chi Y.Y., Hingorani P., Anderson J.R., Lyden E.R., Rodeberg D.A., et al. Randomized phase II trial of bevacizumab or temsirolimus in combination with chemotherapy for first relapse rhabdomyosarcoma: a report from the children’s oncology group. J Clin Oncol. 2019;37(31):2866–74. DOI: 10.1200/JCO.19.00576

24. Russo I., Di Paolo V., Crocoli A., Mastronuzzi A., Serra A., Di Paolo P.L., et al. A chart review on the feasibility and safety of the vincristine irinotecan pazopanib (VIPaz) association in children and adolescents with resistant or relapsed sarcomas. Front Oncol. 2020;10:1228. DOI: 10.3389/fonc.2020.01228

25. Weiss A.R., Chen Y.L., Scharschmidt T.J., Chi Y.Y., Tian J., Black J.O., et al. Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2020;21(8):1110–22. DOI: 10.1016/S1470-2045(20)30325-9

26. Federico S.M., Caldwell K.J., McCarville M.B., Daryani V.M., Stewart C.F., Mao S., et al. Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours. Eur J Cancer. 2020;132:35–42. DOI: 10.1016/j.ejca.2020.03.010

27. Geoerger B., Morland B., Jiménez I., Frappaz D., Pearson A.D.J., Vassal G., et al. Phase 1 dose-escalation and pharmacokinetic study of regorafenib in paediatric patients with recurrent or refractory solid malignancies. Eur J Cancer. 2021;153:142–52. DOI: 10.1016/j.ejca.2021.05.023

28. Meany H.J., Widemann B.C., Hinds P.S., Bagatell R., Shusterman S., Stern E., et al. Phase 1 study of sorafenib and irinotecan in pediatric patients with relapsed or refractory solid tumors. Pediatr Blood Cancer. 2021;68(11):e29282. DOI: 10.1002/pbc.29282

29. Santana V.M., Sahr N., Tatevossian R.G., Jia S., Campagne O., Sykes A., et al. A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors. Cancer. 2020;126(8):1749–57. DOI: 10.1002/cncr.32722

30. Inaba H., Panetta J.C., Pounds S.B., Wang L., Li L., Navid F., et al. Sorafenib population pharmacokinetics and skin toxicities in children and adolescents with refractory/relapsed leukemia or solid tumor malignancies. Clin Cancer Res. 2019;25(24):7320–30. DOI: 10.1158/1078-0432.CCR-19-0470

31. Glod J., Arnaldez F.I., Wiener L., Spencer M., Killian J.K., Meltzer P., et al. A phase II trial of vandetanib in children and adults with succinate dehydrogenase-deficient gastrointestinal stromal tumor. Clin Cancer Res. 2019;25(21):6302–8. DOI: 10.1158/1078-0432.CCR-19-0986

32. Verschuur A.C., Bajčiová V., Mascarenhas L., Khosravan R., Lin X., Ingrosso A., et al. Sunitinib in pediatric patients with advanced gastrointestinal stromal tumor: results from a phase I/II trial. Cancer Chemother Pharmacol. 2019;84(1):41–50. DOI: 10.1007/s00280-019-03814-5

33. Keino D., Yokosuka T., Hirose A., Sakurai Y., Nakamura W., Fujita S., et al. Pilot study of the combination of sorafenib and fractionated irinotecan in pediatric relapse/refractory hepatic cancer (FINEX pilot study). Pediatr Blood Cancer. 2020;67(11):e28655. DOI: 10.1002/pbc.28655

34. Kraft I.L., Akshintala S., Zhu Y., Lei H., Derse-Anthony C., Dombi E., et al. Outcomes of children and adolescents with advanced hereditary medullary thyroid carcinoma treated with vandetanib. clin cancer res. 2018;24(4):753–65. DOI: 10.1158/1078-0432.CCR-17-2101

35. Raciborska A., Bilska K. Sorafenib in patients with progressed and refractory bone tumors. Med Oncol. 2018;35(10):126. DOI: 10.1007/s12032-018-1180-x

36. Modak S., Kushner B.H., Basu E., Roberts S.S., Cheung N.K. Combination of bevacizumab, irinotecan, and temozolomide for refractory or relapsed neuroblastoma: Results of a phase II study. Pediatr Blood Cancer. 2017;64(8):10.1002/pbc.26448. DOI: 10.1002/pbc.26448

37. Wetmore C., Daryani V.M., Billups C.A., Boyett J.M., Leary S., Tanos R., et al. Phase II evaluation of sunitinib in the treatment of recurrent or refractory high-grade glioma or ependymoma in children: a children’s Oncology Group Study ACNS1021. Cancer Med. 2016;5(7):1416–24. DOI: 10.1002/cam4.713

38. Mascolo A., Scavone C., Bertini M., Brusco S., Punzo F., Pota E., et al. Safety of anticancer agents used in children: a focus on their off-label use through data from the spontaneous reporting system. Front Pharmacol. 2020;11:621. DOI: 10.3389/fphar.2020.00621

39. Eaton A.A., Sima C.S., Panageas K.S. Prevalence and safety of off-label use of chemotherapeutic agents in older patients with breast cancer: estimates from SEER-Medicare Data. J Natl Compr Canc Netw. 2016;14(1):57–65. DOI: 10.6004/jnccn.2016.0007

40. Dal Pan G.J. Monitoring the safety of medicines used off-label. Clin Pharmacol Ther. 2012;91:787–95. DOI: 10.1038/clpt.2012.24

41. Rusz C.M., Ősz B.E., Jîtcă G., Miklos A., Bătrînu M.G., Imre S. Offlabel medication: from a simple concept to complex practical aspects. Int J Environ Res Public Health. 2021;18(19):10447. DOI: 10.3390/ijerph181910447

42. Eguale T., Buckeridge D.L., Verma A., Winslade N.E., Benedetti A., Hanley J.A., et al. Association of off-label drug use and adverse drug events in an adult population. JAMA Intern Med. 2016;176(1):55–63. DOI: 10.1001/jamainternmed.2015.6058