5-Fluorourasil İlişkili Semptomatik Bradikardi Gelişen Bir Metastatik Kolorektal Kanser Hastasında XELİRİ-Aflibercept Kombinasyonunun Etkinlik ve Tolerabilitesi: Bir Olgu Sunumu ve Kısa Literatür Derlemesi

5-Fluorouracil (5-FU) ve oral floropirimidinler kolorektal kanser (CRC) kemoterapisinde temel yapıtaşı ilaçlardan olmasına rağmen, bu ilaçların pek çok geleneksel ve kardiyotoksik yan etkileri bulunmaktadır. Oluşabilecek yüksek mortalite riskinden dolayı genellikle iskemik belirtiler ve diğer kardiyak yan etkilerden sonra bu ilaçların yeniden kullanımları önerilmemekle birlikte, bazı hastalarda başka bir floroprimidin ya da bolus 5-FU ile devam edilmesi düşünülebilir. Aflibercept ve FOLFIRI rejimi kombinasyonu metastatik kolorektal kanserli (mCRC) hastaların ikinci basamak tedavisinde kullanılan onaylı bir tedavidir. XELIRI, bir başka etkili ve kullanılması kolay bir irinotekan ve floropirimidin kombinasyonu rejimi olmasına rağmen FOLFIRI rejiminden daha toksik oldğundan artık rutin olarak önerilmemektedir. Buna rağmen, XELIRI rejiminin modifiye doz formunun (mXELIRI), FOLFIRI ile kıyaslandığında daha az etkin olmadığı ve tolerabl olduğu saptanmıştır. Ancak henüz mXELIRI ve aflibercept kombinasyonunun etkinliği araştırılmamıştır. Bu yazıda infüzyonel 5-FU sonrası semptomatik sinüs bradikardisi gelişen ve bu kardiyak yan etki nedenli FOLFIRI-aflibercept rejimine devam edilemeyen bir hasta sunulmuştur. Hastada infüzyonel 5-FU yerine azaltılmış doz kapesitabin ve irinotekan ile mXELIRI rejimi şeklinde verilmiş ve aflibercept ile kombine edilmiştir. Hasta bu tedaviyi kardiyak ya da ciddi gastrointestinal yan etkiler olmadan iyi bir şekilde tolere etmiş, ve 12 aylık progresyonsuz sağkalım süresi sağlanmıştır. İnfüzyonel 5-FU ilişkili sinüs bradikardisinde, infüzyonel 5-FU yerine kapesitabin kullanmak bazı hastalar için bir seçenek olabilir. Ancak, yine de onkoloji uzmanları bu durumlarda mutlaka tedavi planını yarar/zarar oranına göre düzenlemelidir. Aflibercept ve mXELIRI kombinasyonu port katater takılmasını istemeyen ya da yan etki nedenli infüzyonel 5-FU alamayan hastalarda alternatif bir rejim olabilir.

Anahtar Kelimeler:

XELIRI, Aflibercept, Bradycardia, 5-Fluorouracil, Capecitabine

The Efficacy and Tolerability of Xeliri-Aflibercept Combination in A Metastatic Colorectal Cancer Patient After 5-Fu- Induced Symptomatic Bradycardia: A Case Report and A Brief Review of Literature

5-Fluorouracil (5-FU) and oral fluoropyrimidines are the backbone of colorectal cancer (CRC) chemotherapy, but these have many traditional and cardiotoxic side effects. Rechallenge is usually not recommended due to high mortality rates after ischemic symptoms and other cardiac side effects, but replacing these drugs with another fluropyrimidine, or bolus 5-FU, can be considered for some patients. Aflibercept combined with a FOLFIRI regimen is an accepted second-line therapy for metastatic colorectal cancer (mCRC) patients. XELIRI is another effective and feasible irinotecan and fluoropyrimidine combination, which is more toxic than the FOLFIRI regimen and is not routinely recommended. However, modified doses of XELIRI (mXELIRI) were found to be non-inferior to FOLFIRI. The efficacy of the mXELIRI and aflibercept combination has not investigated yet. We present a patient with infusional 5-FU-induced sinus bradycardia that we could not continue FOLFIRI-aflibercept due to this cardiac side effect. We replaced infusional 5-FU with reduced dosages of capecitabine and irinotecan as in the mXELIRI regimen and combined those with aflibercept. The patient tolerated this regimen well without cardiac or severe gastrointestinal side effects, and had 12 months of progression-free survival. Replacing capecitabine with infusional 5-FU might be an option for some patients experiencing 5-FU-related sinus bradycardia. However, oncologists should arrange the treatment plan according to the risk/benefit ratio. Aflibercept combined with mXELIRI may be an alternative regimen for patients who refuse port catheter placement or who are not able to receive infusional-5-FU due to adverse side effects.

Keywords:

XELIRI, Aflibercept, Bradycardia, 5-Fluorouracil, Capecitabine,

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1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70:7–30. 10.3322/caac.21590.
2. Piedbois P, Rougier P, Buyse M, et al. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16: 301–08.
3. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22: 229–37.
4. Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004; 22: 1209–14. 5. Geng F, Wang Z, Yin H, Yu J, Cao B. Molecular Targeted Drugs and Treatment of Colorectal Cancer: Recent Progress and Future Perspectives. Cancer Biother Radiopharm 2017;32(5):149-160.
6. Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA 2017; 317: 2392–401.
7. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30(28):3499-506.
8. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381(9863):303-12.
9. Price TJ, Tang M, Gibbs P, et al. Targeted therapy for metastatic colorectal cancer. Expert Rev Anticancer Ther 2018;18(10):991-1006.
10. Li Y, Feng Y, Dai W, Li Q, Cai S, Peng J. Prognostic Effect of Tumor Sidedness in Colorectal Cancer: A SEER-Based Analysis. Clin Colorectal Cancer 2019;18(1):e104-e116
11. Syed YY, McKeage K. Aflibercept: A Review in Metastatic Colorectal Cancer. Drugs 2015;75(12):1435-45. 12. Xu RH, Muro K, Morita S, et al. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol 2018;19(5):660-671.
13. Reitemeier RJ, Moertel CG. Comparison of rapid and slow intravenous administration of 5‐fluorouracil in treating patients with advanced carcinoma of the large intestine. Cancer Chemother Rep 1962; 25: 87–9.
14. de Forni M, Malet-Martino MC, Jaillais P, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol 1992; 10: 1795-801.
15. Akhtar SS, Salim KP, Bano ZA. Symptomatic cardiotoxicity with high-dose 5-fluorouracil infusion: a prospective study. Oncology 1993; 50:441-4.
16. Schöber C, Papageorgiou E, Harstrick A, et al. Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer. Cancer 1993; 72:2242-7.
17. Van Cutsem E, Hoff PM, Blum JL, Abt M, Osterwlder B. Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil. Ann Oncol 2002; 13:484-5.
18. Wacker A, Lersch C, Scherpinski U, Reindl L, Seyfarth M. High incidence of angina pectoris in patients treated with 5-fluorouracil: aplanned surveillance study with 102 patients. Oncology 2003;65(2):108.
19. Meydan N, Kundak I, Yavuzsen T, et al. Cardiotoxicity of de Gramont’s regimen: incidence, clinical characteristics and long-term follow-up. Jpn J Clin Oncol 2005; 35:265-70.
20. Sara JD, Kaur J, Khodadadi R, Rehman M, Lobo R, Chakrabarti S, et al. 5‐fluorouracil and cardiotoxicity: A review. Ther Adv Med Oncol 2018;10:1758835918780140. 21. Deboever G, Hiltrop N, Cool M, Lambrecht G. Alternative treatment options in colorectal cancer patients with 5-fluorouracil- or capecitabine-induced cardiotoxicity. Clin Colorectal Cancer 2013;12(1):8-14.)
22. Kosmas C, Kallistratos MS, Kopterides P, Syrios J, Skopelitis H, Mylonakis N, et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol 2008; 134: 75–82.
23. Grem JL. 5‐Fluorouracil: forty plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs 2000; 18: 299–313.
24. Hafeez I, Lone A, Beig JR, Alai MS, Dar I, Tramboo N. Effect of 5-fluorouracil on sinoatrial node and conduction system of heart. Int J Adv Med 2017;4:184-7.
25. Aziz SA, Ahmad M, Bhat GM. 5-fluorouracil induced bradycardia? is an autonomic imbalance. JK Practitioner 1995;2:189-90.
26. Tsuboya A, Fujita K-I, Kubota Y, et al. Coadministration of cytotoxic chemotherapeutic agents with irinotecan is a risk factor for irinotecan-induced cholinergic syndrome in Japanese patients with cancer. International J Clin Oncol 2019;24:222–230.
27. Aziz SA, Tramboo NA, Mohiuddin K, Iqbal K, Jalal S, Ahmad S. Supraventricular arrhythmia - a complication of 5FU therapy. Clinical Oncology 1998;10:377-8.
28. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007; 25: 4779–86
29. Strickler JH, Rushing CN, Niedzwiecki D, et al. A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer. BMC Cancer 2019;19(1):1032.