Ann Surg Treat Res.  2018 Apr;94(4):196-202. 10.4174/astr.2018.94.4.196.

Analysis of reduced-dose administration of oxaliplatin as adjuvant FOLFOX chemotherapy for colorectal cancer

• Park D
• Baek SJ
• Kwak JM
• Kim J
• Kim SH

• KMID: 2407749
• DOI: http://doi.org/10.4174/astr.2018.94.4.196

Abstract

PURPOSE
An oxaliplatin-based regimen is the most common adjuvant chemotherapy for patients with stage II/III colorectal cancer, but many patients experience dose reduction or early termination of chemotherapy due to side effects. We conducted this study to verify the range of reduction with oncologic safety.
METHODS
Patients with stage II/III colorectal cancer who received adjuvant FOLFOX chemotherapy were enrolled in this study. The total amount of oxaliplatin administered per patient was calculated as a percentile based on 12 cycles of full-dose FOLFOX as a standard dose. The cutoff values showing significant differences in survival were calculated, and the clinicopathologic outcomes of patient groups classified by the value were compared.
RESULTS
Among a total of 611 patients, there were 107 stage II patients, and 504 stage III patients. At 60% of the standard dose of oxaliplatin, the patients in the dose reduction group were older (62 years vs. 58 years, P = 0.003), had lower body mass index (BMI) (23.1 kg/m2 vs. 24.0 kg/m2, P = 0.005), and were more exposed to neoadjuvant treatment (18.0% vs. 9.1%, P = 0.003) in comparison to the standard group. At 60% of the standard dose, there were no significant differences in 5-year disease-free survival (DFS) and overall survival (OS) between the 2 groups (5-year DFS: 73.5% vs. 74.2%, P = 0.519; 5-year OS: 71.9% vs. 81.5%, P = 0.256, respectively).
CONCLUSION
Patients with old age, low BMI, and more frequent exposure to neoadjuvant treatment tended to show lower compliance with chemotherapy. More than 60% dose should be administered to patients with stage II/III colorectal cancer as adjuvant chemotherapy to achieve acceptable oncologic outcomes.

Keyword

Colorectal neoplasms; Adjuvant chemotherapy; Oxaliplatin; Folfox protocol; Survival

MeSH Terms

Body Mass Index
Chemotherapy, Adjuvant
Colorectal Neoplasms*
Compliance
Disease-Free Survival
Drug Therapy*
Humans
Neoadjuvant Therapy

Figure

• 

  Fig. 1 Five-year disease-free survival (A) and overall survival (B) for the dose reduction group and the standard group at the reduced dose of oxaliplatin (60%).

Reference

1. Sharif S, O'Connell MJ, Yothers G, Lopa S, Wolmark N. FOLFOX and FLOX regimens for the adjuvant treatment of resected stage II and III colon ancer. Cancer Invest. 2008; 26:956–963.

2. Chau I, Cunningham D. Chemotherapy in colorectal cancer: new options and new challenges. Br Med Bull. 2002; 64:159–180.

3. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004; 350:2343–2351.

4. Andre T, Afchain P, Barrier A, Blanchard P, Larsen AK, Tournigand C, et al. Current status of adjuvant therapy for colon cancer. Gastrointest Cancer Res. 2007; 1:90–97.

5. Rothenberg ML. Efficacy of oxaliplatin in the treatment of colorectal cancer. Oncology (Williston Park). 2000; 14:12 Suppl 11. 9–14.

6. 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; 27:3109–3116.

7. Argyriou AA. Updates on oxaliplatin-induced peripheral neurotoxicity (OXAIPN). Toxics. 2015; 3:187–197.

8. Kuebler JP, Colangelo L, O'Connell MJ, Smith RE, Yothers G, Begovic M, et al. Severe enteropathy among patients with stage II/III colon cancer treated on a randomized trial of bolus 5- fluorouracil/leucovorin plus or minus oxaliplatin: a prospective analysis. Cancer. 2007; 110:1945–1950.

9. Grothey A. Clinical management of oxaliplatin- associated neurotoxicity. Clin Colorectal Cancer. 2005; 5:Suppl 1. S38–S46.

10. Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, Andre T, Bennamoun M, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol. 2009; 27:5727–5733.

11. 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; 25:2198–2204.

12. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000; 18:2938–2947.

13. Graham J, Mushin M, Kirkpatrick P. Oxaliplatin. Nat Rev Drug Discov. 2004; 3:11–12.

14. Alcindor T, Beauger N. Oxaliplatin: a review in the era of molecularly targeted therapy. Curr Oncol. 2011; 18:18–25.

15. Argyriou AA, Polychronopoulos P, Iconomou G, Chroni E, Kalofonos HP. A review on oxaliplatin-induced peripheral nerve damage. Cancer Treat Rev. 2008; 34:368–377.

16. Pasetto LM, D'Andrea MR, Rossi E, Monfardini S. Oxaliplatin-related neurotoxicity: how and why? Crit Rev Oncol Hematol. 2006; 59:159–168.

17. Argyriou AA, Polychronopoulos P, Iconomou G, Koutras A, Makatsoris T, Gerolymos MK, et al. Incidence and characteristics of peripheral neuropathy during oxaliplatin-based chemotherapy for metastatic colon cancer. Acta Oncol. 2007; 46:1131–1137.

18. Park YS, Ji J, Zalcberg JR, El-Serafi M, Buzaid A, Ghosn M. Oxaliplatin/5-fluorouracil-based adjuvant chemotherapy as a standard of care for colon cancer in clinical practice: outcomes of the ACCElox registry. Asia Pac J Clin Oncol. 2015; 11:334–342.

19. Aspinall SL, Good CB, Zhao X, Cunningham FE, Heron BB, Geraci M, et al. Adjuvant chemotherapy for stage III colon cancer: relative dose intensity and survival among veterans. BMC Cancer. 2015; 15:62.

20. Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006; 24:394–400.

21. Tsai YJ, Lin JK, Chen WS, Jiang JK, Teng HW, Yen CC, et al. Adjuvant FOLFOX treatment for stage III colon cancer: how many cycles are enough. Springerplus. 2016; 5:1318.

22. Maindrault-Goebel F, de Gramont A, Louvet C, André T, Carola E, Gilles V, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Oncology Multidisciplinary Research Group (GERCOR). Ann Oncol. 2000; 11:1477–1483.