Factors associated with the efficiency of maintenance therapy in patients with metastatic colorectal cancer

Objective: to evaluate tolerability and efficacy of maintenance treatment in the absence of progression after 16 weeks of first-line therapy in patients with unresectable metastatic colon cancer.

Materials and methods. We have analyzed medical case histories of patients with metastatic colorectal cancer who underwent treatment in the department of clinical pharmacology and chemotherapy of N. N. Blokhin Russian Cancer Research Center from 2007 to 2015 years. Inclusion criteria were the following: 16–24 weeks of first-line chemotherapy with no signs of progression and the inability to perform metastasectomy. Progression-free survival was the main criterion for effectiveness in our study.

Results. 160 (44.5 %) of 359 treated patients met the inclusion criteria. 102 (63.7 %) patients were followed up, while the other 58 (36.3 % – comparison group) patients underwent maintenance chemotherapy. Grade I–II toxic reactions and grade III complications associated with first-line chemotherapy were insignificantly more common in the group of patients left on maintenance chemotherapy: 72.4 % and 37.9 % versus 57.8 % and 24.5 % in the comparison group, p = 0.07 and p = 0.07 respectively. The frequency of grade I–II toxic reactions and grade III complications in the second-line treatment did not differ between treatment groups (p = 0.9 and p = 0.8). The median of progression-free survival in observation group and comparison group was 4, and 6 months (odds ratio (OR) 0.6; p = 0.009), and life expectancy – 23 and 31 months (OR 0.75; p = 0.1), respectively. Statistically significant differences between groups with respect to achieving the objective response and/or normalization of carcinoembryonic antigen level were revealed: median of progression-free survival was 13 (n = 26 of 57; 45.6 %) and 4 months (n = 31 of 57, 54.4 %), respectively (HR 0.38; p = 0.002), median of life expectancy – 34 months versus 26 months (OR 0.37; p = 0.3).

Conclusions. Carrying out maintenance therapy is associated with increased incidence of grade III complications during the first-line treatment, but does not affect the tolerability of the second-line treatment. Supportive chemotherapy with fluoropyrimidines remains to be the most effective in patients with favorable prognostic factors such as normalization of carcinoembryonic antigen and/or achievement of the objective response on the background of first-line chemotherapy.

1. Miller A. B., Hoogstraten B., Staquet M., Winkler A. Reporting results of cancer treatment. Cancer 1981;47(1):207–14.

2. Chibaudel B., Tournigand C., Perez- Staub N. et al. Duration of disease control (DDC) or time to failure of strategy (TFS) to evaluate a chemotherapy strategy in advanced colorectal cancer (ACC). J Clin Oncol 2009;27 (suppl; abstr 4073):15s.

3. Tournigand C., Cervantes A., Figer A. 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.

4. Chibaudel B., Bonnetain F., Tournigand C., et al. Simplified prognostic model in patients with oxaliplatin-based or irinotecan-based first-line chemotherapy for metastatic colorectal. The cancer: a GERCOR study. Oncologist 2011;16(9):1228–38.

5. Perez-Staub N., Chibaude B., Figer A. et al. Who can benefit from chemotherapy holidays after first-line therapy for advanced colorectal cancer? A GERCOR study. J Clin Oncol 2008;26 (Suppl):4037.

6. Li Y. H., Luo H. Y., Wang F. H. et al. Phase II study of capecitabine plus oxaliplatin (XELOX) as first-line treatment and followed by maintenance of capecitabine in patients with metastatic colorectal cancer. J Cancer Res Clin Oncol 2010;136(4):503–10.

7. Petrioli R., Paolelli L., Marsili S. et al. FOLFOX4 stop and go and capecitabine maintenance chemotherapy in the treatment of metastatic colorectal cancer. Oncology 2006;70(5):345– 50.

8. Scalamogna R., Brugnatelli S., Tinelli C. et al. UFT as maintenance therapy in patients with advanced colorectal cancer responsive to the FOLFOX4 regimen. Oncology 2007;72(5–6):267–73.

9. Nakayama G., Kodera Y., Yokoyama H. et al. Modified FOLFOX6 with oxaliplatin stop-and- go strategy and oral S-1 maintenance therapy in advanced colorectal cancer: CCOG-0704 study. Int J Clin Oncol 2011;16:506–11.

10. Luo H. Y., Li Y. H., Wang W. et al. Singleagent capecitabineas maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol 2016;27(6):1074–81.

11. Diaz-Rubio E., Gomez-Espana A., Massuti B. et al. First-Line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: The phase III MACRO TTD study. Oncologist

12. ;17(1):15–25.

13. Koopman M., Simkens L. H. J., Tije A. J. T. et al. Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): The phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol 2013;31(suppl):abstr 3502.

14. Koeberle D., Betticher D. C., von Moos R. et al. Bevacizumab continuation versus no continuation after first-line chemobevacizumab therapy in patients with metastatic colorectal cancer: A randomized phase III noninferiority trial (SAKK 41/06). J Clin Oncol 2013;31(suppl):abstr 3503.

15. Moscetti L., Cortesi E., Gamucci T. et al. Maintenance treatment with bevacizumab after chemotherapy (CT) plus B in metastatic colorectal cancer: An Italian multicenter retrospective analysis. J Clin Oncol 2011;29 (suppl):abstr e14043.

16. Tournigand C., Chibaudel B., Samson B. et al. Maintenance therapy with bevacizumab with or without erlotinib in metastatic colorectal cancer (mCRC) according to KRAS: Results of the GERCOR DREAM phase III trial. J Clin Oncol 2013;31(suppl):abstr 3515.

17. Pfeiffer P., Sorbye H., Qvortrup C. et al. Maintenance therapy with biweekly cetuximab (C) in the first-line treatment of metastatic colorectal cancer (mCRC): The NORDIC 7.5 study (NCT00660582), by the Nordic Colorectal Cancer Biomodulation Group. J Clin Oncol 2012;30:(suppl):abstr 3538.

18. Tveit K. M., Guren T., Glimelius B. et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC–VII study. J Clin Oncol 2012;30(15):1755–62.

19. Wasan H., Adams R. A., Wilson R. H. et al. Intermittent chemotherapy (CT) plus continuous or intermittent cetuximab (C) in the first-line treatment of advanced colorectal cancer (aCRC): Results of the twoarm phase II randomized MRC COIN-b trial. J Clin Oncol 2012;30(suppl 4):abstr 536.

20. Koopman M., Simkens L., May A. et al. Final results and subgroup analyses of the phase 3 CAIRO3 study: Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC). J Clin Oncol 2014;32(suppl 3):abstr LBA388.