Abstract
Cholangiocarcinoma is a cancer of the bile duct frequently diagnosed at a late stage with a poor prognosis. Selective fibroblast growth factor receptor (FGFR) inhibitors have demonstrated efficacy in the treatment of cholangiocarcinoma with FGFR2 fusions or rearrangements, but are associated with hyperphosphatemia, fatigue, and ocular, dermatologic, and gastrointestinal adverse events (AEs). Treatment adherence and patient outcomes can be improved by anticipating and effectively managing the AEs associated with FGFR inhibitors and providing appropriate intervention and patient education. The multidisciplinary care team for patients with cholangiocarcinoma can involve optometrists and advanced practice providers, including nurse practitioners, physician assistants, pharmacists. This review provides practical insights for advanced practice providers on the management of these common AEs associated with selective FGFR inhibitors in the real-world setting, focusing on pemigatinib and futibatinib. Impacts of renal or hepatic impairment, drug–drug interactions, and drug–food interactions are discussed. Also presented are practical recommendations for prophylaxis and supportive care measures, and resources for health-care professionals and patients.
References
Abou-Alfa, G. K., Sahai, V., Hollebecque, A., Vaccaro, G., Melisi, D., Al-Rajabi, R.,...Vogel, A. (2020). Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: A multicentre, open-label, phase 2 study. The Lancet Oncology, 21(5), 671–684. https://doi.org/10.1016/S1470-2045(20)30109-1
Aiyer, R., Noori, S. A., Chang, K. V., Jung, B., Rasheed, A., Bansal, N.,...Gulati, A. (2020). Therapeutic ultrasound for chronic pain management in joints: A systematic review. Pain Medicine, 21(7), 1437–1448. https://doi.org/10.1093/pm/pnz102
Aman, M. M., Mahmoud, A., Deer, T., Sayed, D., Hagedorn, J. M., Brogan, S. E.,...Narang, S. (2021). The American Society of Pain and Neuroscience (ASPN) best practices and guidelines for the interventional management of cancer-associated pain. Journal of Pain Research, 14, 2139–2164. https://doi.org/10.2147/JPR.S315585
Babina, I. S., & Turner, N. C. (2017). Advances and challenges in targeting FGFR signalling in cancer. Nature Reviews. Cancer, 17(5), 318–332. https://doi.org/10.1038/nrc.2017.8
Bailey, D. G., Dresser, G., & Arnold, J. M. (2013). Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? Canadian Medical Association Journal, 185(4), 309–316. https://doi.org/10.1503/cmaj.120951
Banales, J. M., Marin, J. J. G., Lamarca, A., Rodrigues, P. M., Khan, S. A., Roberts, L. R.,...Gores, G. J. (2020). Cholangiocarcinoma 2020: The next horizon in mechanisms and management. Nature Reviews. Gastroenterology & Hepatology, 17(9), 557–588. https://doi.org/10.1038/s41575-020-0310-z
Blechacz, B. (2017). Cholangiocarcinoma: Current knowledge and new developments. Gut and Liver, 11(1), 13–26. https://doi.org/10.5009/gnl15568
Bower, J. E., Bak, K., Berger, A., Breitbart, W., Escalante, C. P., Ganz, P. A.,...Jacobsen, P. B. (2014). Screening, assessment, and management of fatigue in adult survivors of cancer: An American Society of Clinical Oncology clinical practice guideline adaptation. Journal of Clinical Oncology, 32(17), 1840–1850. https://doi.org/10.1200/JCO.2013.53.4495
Carroll, M. F., & Schade, D. S. (2003). A practical approach to hypercalcemia. American Family Physician, 67(9), 1959–1966. https://www.ncbi.nlm.nih.gov/pubmed/12751658
Chae, Y. K., Ranganath, K., Hammerman, P. S., Vaklavas, C., Mohindra, N., Kalyan, A.,...Giles, F. J. (2017). Inhibition of the fibroblast growth factor receptor (FGFR) pathway: The current landscape and barriers to clinical application. Oncotarget, 8(9), 16052–16074. https://doi.org/10.18632/oncotarget.14109
Chamberlain, C. X., Faust, E., Goldschmidt, D., Webster, N., Boscoe, A. N., Macaulay, D., & Peters, M. L. (2021). Burden of illness for patients with cholangiocarcinoma in the United States: A retrospective claims analysis. Journal of Gastrointestinal Oncology, 12(2), 658–668. https://doi.org/10.21037/jgo-20-544
Cope, D. G. (2022). Clinical updates in nausea and vomiting. Seminars in Oncology Nursing, 38(1), 151249. https://doi.org/10.1016/j.soncn.2022.151249
D’Alessandro, C., Piccoli, G. B., & Cupisti, A. (2015). The “phosphorus pyramid”: A visual tool for dietary phosphate management in dialysis and CKD patients. BMC Nephrology, 16, 9. https://doi.org/10.1186/1471-2369-16-9
Deng, G. (2019). Integrative medicine therapies for pain management in cancer patients. Cancer Journal, 25(5), 343–348. https://doi.org/10.1097/PPO.0000000000000399
Dev, R., Wong, A., Hui, D., & Bruera, E. (2017). The evolving approach to management of cancer cachexia. Oncology (Williston Park), 31(1), 23–32. https://www.ncbi.nlm.nih.gov/pubmed/28090619
Farrugia, A., & Arasaradnam, R. (2021). Bile acid diarrhoea: Pathophysiology, diagnosis and management. Frontline Gastroenterology, 12, 500–507. https://fg.bmj.com/content/12/6/500.info
Fernández-Ruiz, M., Guerra-Vales, J. M., & Colina-Ruizdelgado, F. (2009). Comorbidity negatively influences prognosis in patients with extrahepatic cholangiocarcinoma. World Journal of Gastroenterology, 15(42), 5279–5286. https://doi.org/10.3748/wjg.15.5279
Gilreath, J. A., & Rodgers, G. M. (2020). How I treat cancer-associated anemia. Blood, 136(7), 801–813. https://doi.org/10.1182/blood.2019004017
Goyal, L., Meric-Bernstam, F., Hollebecque, A., Valle, J. W., Morizane, C., Karasic, T. B.,...Bridgewater, J. A. (2023). Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. New England Journal of Medicine, 388(3), 228–239. https://doi.org/10.1056/NEJMoa2206834
Hariyanto, T. I., & Kurniawan, A. (2021). Appetite problem in cancer patients: Pathophysiology, diagnosis, and treatment. Cancer Treatment and Research Communication, 27, 100336. https://doi.org/10.1016/j.ctarc.2021.100336
Hoy, S. M. (2020). Pemigatinib: first approval. Drugs, 80(9), 923–929. https://doi.org/10.1007/s40265-020-01330-y
Huynh Dagher, S., Blom, A., Chabanol, H., & Funck-Brentano, E. (2021). Cutaneous toxicities from targeted therapies used in oncology: Literature review of clinical presentation and management. International Journal of Women’s Dermatology, 7(5Part A), 615–624. https://doi.org/10.1016/j.ijwd.2021.09.009
Incyte Corporation. (2022). Pemazyre (pemigatinib) tablets, for oral use package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213736s002lbl.pdf
Incyte Corporation. (2023). Pemazyre (pemigatinib) summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/pemazyre-epar-product-information_en.pdf
Jain, A., Borad, M. J., Kelley, R. K., Wang, Y., Abdel-Wahab, R., Meric-Bernstam, F.,...Javle, M. (2018). Cholangiocarcinoma with FGFR genetic aberrations: A unique clinical phenotype. JCO Precision Oncology, 2, 1–12. https://doi.org/10.1200/PO.17.00080
Jain, M., & Wylie, W. P. (2022). Diphenoxylate and atropine. In StatPearls. https://www.ncbi.nlm.nih.gov/pubmed/32644726
Janssen Pharmaceutical Companies. (2019). Balversa (erdafitinib) tablets, for oral use package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212018s000lbl.pdf
Javle, M., Lee, S., Azad, N. S., Borad, M. J., Kate Kelley, R., Sivaraman, S.,...Bekaii-Saab, T. S. (2022). Temporal changes in cholangiocarcinoma incidence and mortality in the United States from 2001 to 2017. Oncologist, 27(10), 874–883. https://doi.org/10.1093/oncolo/oyac150
Ji, T., Rockich, K., Epstein, N., Overholt, H., Wang, P., Chen, X.,...Yeleswaram, S. (2021a). Evaluation of drug-drug interactions of pemigatinib in healthy participants. European Journal of Clinical Pharmacology, 77(12), 1887–1897. https://doi.org/10.1007/s00228-021-03184-z
Ji, T., Rockich, K., Epstein, N., Overholt, H., Wang, P., Chen, X.,...Yeleswaram, S. (2021b). Evaluation of the pharmacokinetics of pemigatinib in patients with impaired hepatic or renal function. British Journal of Clinical Pharmacology, 88(1), 237–247. https://doi.org/10.1111/bcp.14954
Kang, C. (2021). Infigratinib: First approval. Drugs, 81(11), 1355–1360. https://doi.org/10.1007/s40265-021-01567-1
Khan, S. A., Tavolari, S., & Brandi, G. (2019). Cholangiocarcinoma: Epidemiology and risk factors. Liver International, 39(Suppl 1), 19–31. https://doi.org/10.1111/liv.14095
Kommalapati, A., Tella, S. H., Borad, M., Javle, M., & Mahipal, A. (2021). FGFR inhibitors in oncology: Insight on the management of toxicities in clinical practice. Cancers (Basel), 13(12), 2968. https://doi.org/10.3390/cancers13122968
Krook, M. A., Reeser, J. W., Ernst, G., Barker, H., Wilberding, M., Li, G.,...Roychowdhury, S. (2021). Fibroblast growth factor receptors in cancer: Genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance. British Journal of Cancer, 124(5), 880–892. https://doi.org/10.1038/s41416-020-01157-0
Lacouture, M. E., Sibaud, V., Anadkat, M. J., Kaffenberger, B., Leventhal, J., Guindon, K., & Abou-Alfa, G. (2021). Dermatologic adverse events associated with selective fibroblast growth factor receptor inhibitors: Overview, prevention, and management guidelines. Oncologist, 26(2), e316–e326. https://doi.org/10.1002/onco.13552
Lee, D. K., & Lipner, S. R. (2022). Optimal diagnosis and management of common nail disorders. Annals of Medicine, 54(1), 694–712. https://doi.org/10.1080/07853890.2022.2044511
Loriot, Y., Necchi, A., Park, S. H., Garcia-Donas, J., Huddart, R., Burgess, E.,...Siefker-Radtke, A. O. (2019). Erdafitinib in locally advanced or metastatic urothelial carcinoma. New England Journal of Medicine, 381(4), 338–348. https://doi.org/10.1056/NEJMoa1817323
Lowery, M. A., Ptashkin, R., Jordan, E., Berger, M. F., Zehir, A., Capanu, M.,...Abou-Alfa, G. K. (2018). Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: Potential targets for intervention. Clinical Cancer Research, 24(17), 4154–4161. https://doi.org/10.1158/1078-0432.CCR-18-0078
Madeddu, C., Gramignano, G., Astara, G., Demontis, R., Sanna, E., Atzeni, V., & Macciò, A. (2018). Pathogenesis and treatment options of cancer related anemia: Perspective for a targeted mechanism-based approach. Frontiers in Physiology, 9, 1294. https://doi.org/10.3389/fphys.2018.01294
Madeddu, C., Neri, M., Sanna, E., Oppi, S., & Macciò, A. (2021). Experimental drugs for chemotherapy- and cancer-related anemia. Journal of Experimental Pharmacology, 13, 593–611. https://doi.org/10.2147/JEP.S262349
Mahipal, A., Tella, S. H., Kommalapati, A., Yu, J., & Kim, R. (2020). Prevention and treatment of FGFR inhibitor-associated toxicities. Critical Reviews in Oncology/Hematology, 155, 103091. https://doi.org/10.1016/j.critrevonc.2020.103091
National Community Oncology Dispensing Association Inc (NCODA), Oncology Nursing Society (ONS), Association of Community Cancer Centers (ACCC), & Hematology Oncology Pharmacy Association (HOPA). (2020). Oral chemotherapy education: Pemigatinib. http://www.oralchemoedsheets.com/sheets/Pemigatinib_Patient_Education.pdf
National Comprehensive Cancer Network. (2022). NCCN Clinical Practice Guidelines: Cancer-related fatigue. V.2.2024. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1424
Newsome, P. N., Cramb, R., Davison, S. M., Dillon, J. F., Foulerton, M., Godfrey, E. M.,...Yeoman, A. (2018). Guidelines on the management of abnormal liver blood tests. Gut, 67(1), 6–19. https://doi.org/10.1136/gutjnl-2017-314924
Oh, D.-Y., He, A. R., Qin, S., Chen, L.-T., Okusaka, T., Vogel, A.,...Valle, J. W. (2022). A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. Journal of Clinical Oncology, 40(4_Suppl), 378–378. https://doi.org/10.1200/JCO.2022.40.4_suppl.378
Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. T., & Carbone, P. P. (1982). Toxicity and response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology, 5(6), 649–655. https://www.ncbi.nlm.nih.gov/pubmed/7165009
Pfizer. (2017). Lomotil Cv (diphenoxylate hydrochloride and atropine sulfate tablets, USP) tablets: Prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/012462s045lbl.pdf
Qu, W. F., Zhou, P. Y., Liu, W. R., Tian, M. X., Jin, L., Jiang, X. F.,...Shi, Y. H. (2020). Age-adjusted Charlson Comorbidity Index predicts survival in intrahepatic cholangiocarcinoma patients after curative resection. Annals of Translational Medicine, 8(7), 487. https://doi.org/10.21037/atm.2020.03.23
Roila, F., Molassiotis, A., Herrstedt, J., Aapro, M., Gralla, R. J., Bruera, E.,...van der Wetering, M. (2016). 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Annals of Oncology, 27(Suppl 5), v119–v133. https://doi.org/10.1093/annonc/mdw270
Scarborough, B. M., & Smith, C. B. (2018). Optimal pain management for patients with cancer in the modern era. CA: A Cancer Journal for Clinicians, 68(3), 182–196. https://doi.org/10.3322/caac.21453
Shankar, A., Roy, S., Malik, A., Julka, P. K., & Rath, G. K. (2015). Prevention of chemotherapy-induced nausea and vomiting in cancer patients. Asian Pacific Journal of Cancer Prevention, 16(15), 6207–6213. https://doi.org/10.7314/apjcp.2015.16.15.6207
Spencer, A. S., da Silva Dias, D., Capelas, M. L., Pimentel, F., Santos, T., Neves, P. M.,...Ravasco, P. (2021). Managing severe dysgeusia and dysosmia in lung cancer patients: A systematic scoping review. Frontiers in Oncology, 11, 774081. https://doi.org/10.3389/fonc.2021.774081
Spolverato, G., Kim, Y., Alexandrescu, S., Marques, H. P., Lamelas, J., Aldrighetti, L.,...Pawlik, T. M. (2016). Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma following previous curative-intent surgical resection. Annals of Surgical Oncology, 23(1), 235–243. https://doi.org/10.1245/s10434-015-4642-9
Subbiah, V., Iannotti, N. O., Gutierrez, M., Smith, D. C., Feliz, L., Lihou, C. F.,...Saleh, M. (2022). FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies. Annals of Oncology, 33(5), 522–533. https://doi.org/10.1016/j.annonc.2022.02.001
Taiho Pharmaceutical Co., & Ltd. (2022). Lytgobi (futibatinib) tablets, for oral use package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214801s000lbl.pdf
Takashi, Y., Sawatsubashi, S., Endo, I., Ohnishi, Y., Abe, M., Matsuhisa, M.,...Fukumoto, S. (2021). Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span. Biochemistry and Biophysics Reports, 27, 101107. https://doi.org/10.1016/j.bbrep.2021.101107
Togni, L., Mascitti, M., Vignigni, A., Alia, S., Sartini, D., Barlattani, A.,...Santarelli, A. (2021). Treatment-related dysgeusia in oral and oropharyngeal cancer: A comprehensive review. Nutrients, 13(10), 3325. https://doi.org/10.3390/nu13103325
Valle, J., Wasan, H., Palmer, D. H., Cunningham, D., Anthoney, A., Maraveyas, A.,...Bridgewater, J. (2010). Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. New England Journal of Medicine, 362(14), 1273–1281. https://doi.org/10.1056/NEJMoa0908721
Wanat, K. A., Stewart, C. L., Negoianu, D., & Rosenbach, M. (2014). Severe nonuremic calciphylaxis due to hyperphosphatemia resolving with multimodality treatment including phosphate binders. JAMA Dermatology, 150(6), 671–673. https://doi.org/10.1001/jamadermatol.2013.7508
Warrington, L., Absolom, K., Conner, M., Kellar, I., Clayton, B., Ayres, M., & Velikova, G. (2019). Electronic systems for patients to report and manage side effects of cancer treatment: Systematic review. Journal of Medical Internet Research, 21(1), e10875. https://doi.org/10.2196/10875
Wickham, R. J. (2017). Managing constipation in adults with cancer. Journal of the Advanced Practitioner in Oncology, 8(2), 149–161. https://www.ncbi.nlm.nih.gov/pubmed/29900023
Wu, L., Tsilimigras, D. I., Paredes, A. Z., Mehta, R., Hyer, J. M., Merath, K.,...Pawlik, T. M. (2019). Trends in the incidence, treatment and outcomes of patients with intrahepatic cholangiocarcinoma in the USA: Facility type is associated with margin status, use of lymphadenectomy and overall survival. World Journal of Surgery, 43(7), 1777–1787. https://doi.org/10.1007/s00268-019-04966-4
Yamamiya, I., Laabs, J., Hunt, A., Takenaka, T., Sonnichsen, D., Mina, M.,...Benhadji, K. (2021). Evaluation of potential drug-drug interactions (DDIs) between futibatinib and CYP3A inhibitors/inducers, CYP3A substrates, or proton pump inhibitors (PPIs). Cancer Research, 81, Abstract CT125. https://doi.org/10.1158/1538-7445.AM2021-CT125
Yoong, J., & Poon, P. (2018). Principles of cancer pain management: An overview and focus on pharmacological and interventional strategies. Australian Journal of General Practice, 47(11), 758–762. https://doi.org/10.31128/AJGP-07-18-4629
Zagzag, J., Hu, M. I., Fisher, S. B., & Perrier, N. D. (2018). Hypercalcemia and cancer: Differential diagnosis and treatment. CA: A Cancer Journal for Clinicians, 68(5), 377–386. https://doi.org/10.3322/caac.21489
Zhang, F., Shen, A., Jin, Y., & Qiang, W. (2018). The management strategies of cancer-associated anorexia: A critical appraisal of systematic reviews. BMC Complementary and Alternative Medicine, 18(1), 236. https://doi.org/10.1186/s12906-018-2304-8
Zhou, C., Shi, Z., Ouyang, N., & Ruan, X. (2021). Hyperphosphatemia and cardiovascular disease. Frontiers in Cell and Developmental Biology, 9, 644363. https://doi.org/10.3389/fcell.2021.644363