The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study

Abstract

Purpose

We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial.

Methods

Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated.

Results

A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%).

Conclusions

Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

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References

  1. 1.

    André T, de GramontVernerey AD, Chibaudel B, Bonnetain F, Tijeras-Raballand A, et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015;33:4176–87.

    Article  Google Scholar 

  2. 2.

    Kuebler JP, Wieand HS, O’Connell MJ, Smith RE, Colangelo LH, Yothers G, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007;25:2198–204.

    CAS  Article  Google Scholar 

  3. 3.

    Schmoll HJ, Tabernero J, Maroun J, de BraudPrice FT, Van Cutsem E, et al. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015;33:3733–40.

    CAS  Article  Google Scholar 

  4. 4.

    Ishibashi K, Kumamoto K, Koda K, Kato H, Nishimura G, Yoshimatsu K, et al. A phase II clinical study of mFOLFOX6/XELOX as adjuvant chemotherapy after curative resection of stage III colon cancer: the FACOS study. Ann Cancer Res Ther. 2016;24:17–22.

    Article  Google Scholar 

  5. 5.

    Yoshimatsu K, Ishibashi K, Koda K, Yokomizo H, Oda N, Oshiro M, et al. A Japanese multicenter phase II study of adjuvant chemotherapy with mFOLFOX6/CAPOX for stage III colon cancer treatment after D2/D3 lymphadenectomy. Surg Today. 2019;49:498–506.

    CAS  Article  Google Scholar 

  6. 6.

    Kosugi C, Koda K, Ishibashi K, Yoshimatsu K, Tanaka S, Kato R, et al. Safety of FOLFOX6/XELOX as adjuvant chemotherapy after curative resection of stage III colon cancer: phase II clinical study (the FACOS study). Int J Colorectal Dis. 2018;33:809–17.

    Article  Google Scholar 

  7. 7.

    Brungs D, Aghmesheh M, de Souza P, et al. Safety and efficacy of oxaliplatin doublet adjuvant chemotherapy in elderly patients with stage III colon cancer. Clin Colorectal Cancer. 2018;17(3):e549–55.

    Article  Google Scholar 

  8. 8.

    Pietrangeli A, Leandri M, Terzoli E, Jandolo B, Garufi C. Persistence of high-dose oxaliplatin-induced neuropathy at long-term follow-up. Eur Neurol. 2006;56:13–6.

    CAS  Article  Google Scholar 

  9. 9.

    Land SR, Kopec JA, Cecchini RS, Ganz PA, Wieand HS, Colangelo LH, et al. Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: NSABP C-07. J Clin Oncol. 2007;25:2205–11.

    CAS  Article  Google Scholar 

  10. 10.

    Yoshino T, Yamanaka T, Oki E, Kotaka M, Manaka D, Eto T, et al. Efficacy and long-term peripheral sensory neuropathy of 3 vs 6 months of oxaliplatin-based adjuvant chemotherapy for colon cancer the ACHIEVE phase 3 randomized clinical trial. JAMA Oncol. 2019;5:1574–81.

    Article  Google Scholar 

  11. 11.

    Yoshino T, Kotaka M, Shinozaki K, Touyama T, Manaka D, Matsui T, et al. JOIN trial: treatment outcome and recovery status of peripheral sensory neuropathy during a 3-year follow-up in patients receiving modified FOLFOX6 as adjuvant treatment for stage II/III colon cancer. Cancer Chemother Pharmacol. 2019;84:1269–77.

    CAS  Article  Google Scholar 

  12. 12.

    Andre T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109–16.

    CAS  Article  Google Scholar 

  13. 13.

    Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29(11):1465–71.

    CAS  Article  Google Scholar 

  14. 14.

    Watanabe T, Muro K, Ajioka Y, Hashiguchi Y, Ito Y, Saito Y, Japanese Society for Cancer of the Colon and Rectum, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer. Int J Clin Oncol. 2018;23:1–34.

    Article  Google Scholar 

  15. 15.

    Japanese Society for Cancer of the Colon and Rectum. Japanese classification of colorectal carcinoma. 2nd ed. Tokyo: Kanehara; 2009.

    Google Scholar 

  16. 16.

    National Cancer Institute. National Cancer Institute common toxicity criteria, version 4.0. http://cancer.gov/. Accessed 5 Apr 2020.

  17. 17.

    Brierley JD, Gospodarowicz MK, Wittekind C. The TNM classification of malignant tumours. 8th ed. Hoboken: Wiley; 2016.

    Google Scholar 

  18. 18.

    Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, et al. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018;378:1177–88.

    CAS  Article  Google Scholar 

  19. 19.

    Kotaka M, Yoshino T, Oba K, Shinozaki K, Touyama T, Manaka D, et al. Initial safety report on the tolerability of modified FOLFOX6 as adjuvant therapy in patients with curatively resected stage II or III colon cancer (JFMC41-1001-C2: JOIN trial). Cancer Chemother Pharmacol. 2015;76:75–84.

    CAS  Article  Google Scholar 

  20. 20.

    Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, et al. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer. 2015;15:384.

    Article  Google Scholar 

  21. 21.

    Beijers AJ, Mols F, Tjan-Heijnen VC, Faber CG, van de Poll-Franse LV, Vreugdenhil G. Peripheral neuropathy in colorectal cancer survivors: the influence of oxaliplatin administration. Results from the population-based PROFILES registry. Acta Oncol. 2015;54(4):463–9.

    CAS  Article  Google Scholar 

  22. 22.

    Gill S, Sargent D. End points for adjuvant therapy trials: has the time come to accept disease-free survival as a surrogate end point for overall survival? Oncologist. 2006;11(6):624–9.

    CAS  Article  Google Scholar 

  23. 23.

    Loree JM, Sha A, Soleimani M, Kennecke HF, Ho MY, Cheung WY, et al. Survival impact of CAPOX versus FOLFOX in the adjuvant treatment of stage III colon cancer. Clin Colorectal Cancer. 2018;17(2):156–63.

    Article  Google Scholar 

  24. 24.

    Chau I, Norman AR, Cunningham D, Tait D, Ross PJ, Iveson T, et al. A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer. Ann Oncol. 2005;16:549–57.

    CAS  Article  Google Scholar 

  25. 25.

    Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352:2696–704.

    CAS  Article  Google Scholar 

  26. 26.

    Ishibashi K, Okada N, Miyazaki T, Sano M, Ishida H. Effect of calcium and magnesium on neurotoxicity and blood platinum concentrations in patients receiving mFOLFOX6 therapy: a prospective randomized study. Int J Clin Oncol. 2010;15(1):82–7.

    CAS  Article  Google Scholar 

  27. 27.

    Gamelin L, Boisdron-Celle M, Delva R, et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res. 2004;10:4055–61.

    CAS  Article  Google Scholar 

  28. 28.

    Lersch C, Schmelz R, Eckel F, Erdmann J, Mayr M, Schulte-Frohlinde E, et al. Prevention of oxaliplatin-induced peripheral sensory neuropathy by carbamazepine in patients with advanced colorectal cancer. Clin Colorectal Cancer. 2002;2(1):54–8.

    CAS  Article  Google Scholar 

  29. 29.

    Penz M, Kornek GV, Raderer M, Ulrich-Pur H, Fiebiger W, Scheithauer W. Subcutaneous administration of amifostine: a promising therapeutic option in patients with oxaliplatin-related peripheral sensitive neuropathy. Ann Oncol. 2001;12(3):421–2.

    CAS  Article  Google Scholar 

  30. 30.

    Guo Y, Jones D, Palmer JL, Forman A, Dakhil SR, Velasco MR, et al. Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: a randomized, double-blind, placebo-controlled trial. Support Care Cancer. 2014;22(5):1223–31.

    Article  Google Scholar 

  31. 31.

    Gedlicka C, Scheithauer W, Schüll B, Kornek GV. Effective treatment of oxaliplatin-induced cumulative polyneuropathy with alpha-lipoic acid. J Clin Oncol. 2002;20(15):3359–61.

    CAS  Article  Google Scholar 

  32. 32.

    Takimoto N, Sugawara S, Iida A, Sakakibara T, Mori K, Sugiura M, et al. Prevention of oxaliplatin-related neurotoxicity by glutathione infusions. Gan To Kagaku Ryoho. 2008;35(13):2373–6 (in Japanese).

    PubMed  Google Scholar 

  33. 33.

    Cascinu S, Catalano V, Cordella L, Labiance R, Giordani P, Baldelli AM, et al. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002;20(16):3478–83.

    CAS  Article  Google Scholar 

  34. 34.

    Kawashiri T, Shimizu S, Shigematsu N, Kobayashi D, Shimazoe T. Donepezil ameliorates oxaliplatin-induced peripheral neuropathy via a neuroprotective effect. J Pharmacol Sci. 2019;140(3):291–4.

    CAS  Article  Google Scholar 

  35. 35.

    Nakagawa T, Kaneko S. Roles of transient receptor potential ankyrin 1 in oxaliplatin-induced peripheral neuropathy. Biol Pharm Bull. 2017;40(7):947–53.

    CAS  Article  Google Scholar 

  36. 36.

    Nishida K, Takeuchi K, Hosoda A, Sugano S, Morisaki E, Ohishi A, et al. Ergothioneine ameliorates oxaliplatin-induced peripheral neuropathy in rats. Life Sci. 2018;207:516–24.

    CAS  Article  Google Scholar 

  37. 37.

    Guillaumot MA, Cerles O, Bertrand HC, Benoit E, Nicco C, Chouzenoux S, et al. Oxaliplatin-induced neuropathy: the preventive effect of a new super-oxide dismutase modulator. Oncotarget. 2019;10(60):6418–31.

    Article  Google Scholar 

  38. 38.

    Park SB, Kiernan MC. Oxaliplatin and neuropathy: a role for sodium channels. Clin Neurophysiol. 2018;129(3):670–1.

    Article  Google Scholar 

  39. 39.

    Starobova H, Vetter I. Pathophysiology of chemotherapy-induced peripheral neuropathy. Front Mol Neurosci. 2017;10:174.

    Article  Google Scholar 

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Correspondence to Hideyuki Ishida.

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Conflict of interest

Keiichiro Ishibashi, Michiya Kobayashi, and Hideyuki Ishida received a research grant from Yakult Co., Ltd., and Chugai Pharmaceutical Co., Ltd. Emiko Takeshita and Masatoshi Oya received a research grant from Yakult Co., Ltd., and Hiroshi Maekawa received a research grant from Chugai Pharmaceutical Co., Ltd. The other authors have no conflicts of interest to declare.

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Takeshita, E., Ishibashi, K., Koda, K. et al. The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study. Surg Today (2021). https://doi.org/10.1007/s00595-021-02230-8

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Keywords

  • Stage III colon cancer
  • Adjuvant chemotherapy
  • mFOLFOX6
  • CAPOX
  • Peripheral sensory neuropathy