Document Type : Original Article(s)

Authors

1 Clinical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

2 Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

3 Otorhinolarngology-Head and Neck Surgery Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

10.30476/mejc.2024.101525.2034

Abstract

Background: Patients with platinum-refractory disease who experience early treatment failure of head and neck squamous cell carcinoma (HNSCC) exhibit a dismal prognosis. Metronomic chemotherapy is a promising treatment schedule in clinical practice for HNSCC. Oral metronomic chemotherapy with methotrexate, celecoxib, and capecitabine regimens was effective because of overcoming drug resistance and antiangiogenesis effects. We aimed to improve treatment outcomes of recurrent, platinum–resistant, and metastatic HNSCC.
Method: In this prospective clinical trial, 94 patients diagnosed with advanced/recurrent HNSCC were enrolled. Patients received triple therapy, including capecitabine, methotrexate, and celecoxib. The multidisciplinary team evaluated treatment toxicity, response, progression-free survival (PFS), and overall survival (OS). Kaplan Meier curve was used to show the survival/Wilcoxon signed-rank test.
Results: The most common observable toxicity findings were grade 1 plus grade 2 fatigue in 49 (52.1%), oral mucositis in 40 patients (42.5%), and anemia in 37 patients (39.4%) in the absence of notified grade 3 or 4 toxicities. 20patients out of 94 exhibited complete responses (CRs). One and two-year PFS rates were 16% and 11.7%; and one and two-year OS were 21.3% and 17 %, respectively. Two median years PFS was 4 months, and two median years OS was 8 months (SPSS 16.0 for Windows, Wilcoxon signed-rank test, P value ≤ 0.05 is significant).
Conclusion: Capecitabine, methotrexate, and celecoxib combined chemotherapy are effective and tolerable in treating platinum-refractory, recurrent, and metastatic HNSCC with non-inferior clinical outcome results, especially in poor societies.

Highlights

  Amira Elwan (Google Scholar)

Keywords

Main Subjects

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination, and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.30476/mejc.2024.101525.2034

  1. Menezes FDS, Fernandes GA, Antunes JLF, Villa LL, Toporcov TN. Global incidence trends in head and neck cancer for HPV-related and -unrelated subsites: A systematic review of population-based studies. Oral Oncol. 2021;115:105177. doi: 10.1016/j.oraloncology.2020.105177.
  2. Fouda S, Kelany M, Moustafa N, Abushouk AI, Hassane A, Sleem A, et al. Tobacco smoking in Egypt: a scoping literature review of its epidemiology and control measures. East Mediterr Health J. 2018;24(2):198-215. https://doi.org/10.26719/2018.24.2.198.
  3. Moawad MHED, Shalaby MM, Sadeq MA, Al-Jafari M, A'amar JW, Alsayed O, et al. Insights into head and neck cancer research in Egypt: A scoping review. Cancer Treat Res Commun. 2023;37:100782. doi: 10.1016/j.ctarc.2023.100782.
  4. Patil VM, Noronha V, Joshi A, Pinninti R, Dhumal S, Bhattacharjee A, et al. Metronomic chemotherapy in platinum-insensitive failures and/or early failures postmultimodality management in oral cancers. Indian J Med Paediatr Oncol. 2015;36(3):161-5. doi: 10.4103/0971-5851.166725.
  5. Filippi R, Lombardi P, Depetris I, Fenocchio E, Quarà V, Chilà G, et al. Rationale for the use of metronomic chemotherapy in gastrointestinal cancer. Expert Opin Pharmacother. 2018;19(13):1451-63. doi: 10.1080/14656566.2018.1512585.
  6. Cazzaniga ME, Cortesi L, Ferzi A, Scaltriti L, Cicchiello F, Ciccarese M, et al. Metronomic chemotherapy in triple-negative metastatic breast cancer: The future is now? Int J Breast Cancer. 2017;2017:1683060. doi: 10.1155/2017/1683060.
  7. Lambrescu I, Fica S, Martins D, Spada F, Cella C, Bertani E, et al. Metronomic and metronomic-like therapies in neuroendocrine tumors—Rationale and clinical perspectives. Cancer Treat Rev. 2017;55:46-56. doi:10.1016/j.ctrv.2017.02.007.
  8. Woo IS, Jung YH. Metronomic chemotherapy in metastatic colorectal cancer. Cancer Lett. 2017;400:319-24. doi:10.1016/j.canlet.2017.02.034.
  9. Romiti A, Falcone R, Roberto M, Marchetti P. Tackling pancreatic cancer with metronomic chemotherapy. Cancer Lett. 2017;394:88-95. doi:10.1016/j.canlet.2017.02.017.
  10. Romiti A, Falcone R, Roberto M, Marchetti P. Current achievements and future perspectives of metronomic chemotherapy. Investig New Drugs. 2017;35(3):359-74. doi:10.1007/s10637-016-0408-x.
  11. Gourd E. Metronomic chemotherapy option for advanced oral cancer. Lancet Oncol. 2019;20(11):e614. doi:10.1016/S1470-2045(19)30623-0.
  12. Kerbel RS. A decade of experience developing preclinical models of advanced- or early-stage spontaneous metastasis to study antiangiogenic drugs, metronomic chemotherapy, and the tumor microenvironment. Cancer J. 2015;21(4):274-83. doi: 10.1097/PPO.0000000000000134.
  13. Natale G, Bocci G. Does metronomic chemotherapy induce tumor angiogenic dormancy? A review of available preclinical and clinical data. Cancer Lett. 2018,432:28-37. doi:10.1016/j.canlet.2018.06.002.
  14. Patil VM, Noronha V, Joshi A, Muddu VK, Dhumal S, Bhosale B, et al. A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck. Oral Oncol. 2015;51(3):279-286. doi: 10.1016/j.oraloncology.2014.12.002.
  15. Patil VM, Noronha V, Joshi A, Dhumal S, Mahimkar M, Bhattacharjee A, et al. Phase I/II study of palliative triple metronomic chemotherapy in platinum-refractory/early-failure oral cancer. J Clin Oncol. 2019;37(32):3032-41. doi: 10.1200/JCO.19.01076.
  16. Harsh KK, Maharia SR, Nirban RK, Khatri P, Beniwal S, Kumar HS, et al. Metronomic palliative chemotherapy in locally advanced, recurrent and metastatic head-and-neck cancer: A single-arm, retrospective study of a regional cancer center of North India (Asia). J Cancer Res Ther. 2020;16(3):559-64. doi: 10.4103/jcrt.JCRT_702_18.
  17. Péron J, Polivka V, Chabaud S, Poupart M, Ceruse P, Ramade A, et al. An effective and well-tolerated strategy in recurrent and/or metastatic head and neck cancer: successive lines of active chemotherapeutic agents. BMC Cancer. 2014;14:504. doi: 10.1186/1471-2407-14-504.
  18. Nautiyal V, Kumar V, Arora A, Gupta M, Mehra S, Bansal S, et al. Assessment of quality of life in recurrent and metastatic head and neck cancer after oral metronomic chemotherapy: A prospective interventional study. J Clin Diagn Res. 2021;15(7):XCo1-XCo5.‏ doi:10.7860/JCDR/2021/48916.15089.
  19. Mateen A, Adil AR, Maken RN, Khan SA, Arif M. Metronomic chemotherapy in recurrent head and neck cancer. J Clin Oncol. 2015;33(15_suppl):e17007. doi:10.1200/jco.2015.33.15_suppl.e17007.
  20. Ruchalski K, Braschi-Amirfarzan M, Douek M, Sai V, Gutierrez A, Dewan R, et al. A primer on RECIST 1.1 for oncologic imaging in clinical drug trials. Radiol Imaging Cancer. 2021;3(3):e210008. doi: 10.1148/rycan.2021210008.
  21. Chung AE, Shoenbill K, Mitchell SA, Dueck AC, Schrag D, Bruner DW, et al. Patient free text reporting of symptomatic adverse events in cancer clinical research using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). J Am Med Inform Assoc. 2019;26(4):276-85. doi: 10.1093/jamia/ocy169.
  22. Patil V, Noronha V, Dhumal SB, Joshi A, Menon N, Bhattacharjee A, et al. Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial. Lancet Glob Health. 2020;8(9):e1213-e1222. doi: 10.1016/S2214-109X(20)30275-8.
  23. De Felice F, Musio D, Tombolini V. Head and neck cancer: metronomic chemotherapy. BMC Cancer. 2015;15:677. doi: 10.1186/s12885-015-1705-z.
  24. Patil VM, Noronha V, Thiagarajan S, Joshi A, Chandrasekharan A, Talreja V, et al. Salvage surgery in head and neck cancer: Does it improve outcomes? Eur J Surg Oncol. 2020;46(6):1052-8. doi: 10.1016/j.ejso.2020.01.019.
  25. Patil V, Noronha V, Joshi A, Menon N, Mathrudev V, Bhattacharjee A, et al. RMAC study: A randomized study for evaluation of metronomic adjuvant chemotherapy in recurrent head and neck cancers post salvage surgical resection in those who are ineligible for re-irradiation. Oral Oncol. 2022;128:105816. doi: 10.1016/j.oraloncology.2022.105816.
  26. Baa AK, Sharma A, Bhaskar S, Biswas A, JeeBharti S, Thakar A, et al. A single-arm feasibility phase II study of EMF (erlotinib + methotrexate + 5-fluorouracil) regimen in platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Ecancermedicalscience. 2022;16:1451. doi: 10.3332/ecancer.2022.1451.
  27. Ferris RL, Licitra L, Fayette J, Even C, Blumenschein G Jr, Harrington KJ, et al. Nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: Efficacy and safety in CheckMate 141 by prior cetuximab use. Clin Cancer Res. 2019;25:5221-30. doi:10.1158/1078-0432.CCR-18-3944.
  28. Harrington KJ, Ferris RL, Blumenschein G Jr, Colevas AD, Fayette J, Licitra L, et al. Nivolumab versus standard, single‑agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): Health‑related quality‑of‑life results from a randomized, phase 3 trial. Lancet Oncol. 2017;18:1104-15. doi:10.1016/S1470-2045(17)30421-7.
  29. Rajappa SJ, Pinninti R. Real‑world evidence with nivolumab in head-and-neck cancer: Access is key! Cancer Res Stat Treat. 2022;5(3):541-3. doi: 10.4103/crst.crst_264_22.
  30. Parikh PM, Hingmire SS, Deshmukh CD. Selected current data on metronomic therapy (and its promise) from India. South Asian J Cancer. 2016;5:37-47. doi: 10.4103/2278-330X.181623.
  31. Patil V, Muthuluri H, Choudhary J, Parekh D, Abraham G, Noronha V, et al. Nivolumab in platinum-refractory head-and-neck cancers – Retrospective observational audit from a tertiary cancer center. Cancer Res Stat Treat. 2022;5(3):468-73. doi: 10.4103/crst.crst_185_22.
  32. Choudhary J, Hemanth K, Ravikrishna M, Patil V, Prabhash K. Real-world data of using nivolumab in platinum-refractory head and neck cancers. J Clin Oncol. 2022;40(16_suppl):e18686. doi:10.1200/JCO.2022.40.16_suppl.e18686.
  33. Patil VM, Noronha V, Menon NS, Bhattacharjee A, Kumar S, Purandare N, et al. Phase 3 randomized study evaluating the addition of low‑dose nivolumab to palliative chemotherapy in head and neck cancer. J Clin Oncol. 2022;40(17_suppl):LBA6016. doi:10.1200/JCO.2022.40.17_suppl.LBA6016.
  34. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-28. doi: 10.1016/S0140-6736(19)32591-7. Erratum in: Lancet. 2020;395(10220):272. Erratum in: Lancet. 2020;395(10224):564. Erratum in: Lancet. 2021;397(10291):2252.