Cancer Res Treat.  2021 Jul;53(3):703-713. 10.4143/crt.2020.805.

Optimal Maintenance Strategy for First-Line Oxaliplatin-Containing Therapy with or without Bevacizumab in Patients with Metastatic Colorectal Cancer: A Meta-Analysis

Affiliations
  • 1Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  • 2Department of Biostatistics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

Abstract

Purpose
Maintenance therapy after oxaliplatin withdrawal is useful in patients with metastatic colorectal cancer (mCRC). This study aimed to investigate the timing of discontinuation or reintroduction of oxaliplatin and the optimal maintenance therapy regimen for survival.
Materials and Methods
PubMed and conference abstracts were searched to select phase II and III trials of first-line oxaliplatin-containing therapy with or without bevacizumab using maintenance therapy for mCRC. Correlations of median overall survival (OS) with induction therapy regimens, induction therapy duration, maintenance therapy regimens (fluoropyrimidine plus bevacizumab [FP+Bev], FP/Bev alone, and no treatment), and oxaliplatin reintroduction were investigated using correlation and weighted multivariate regression analyses.
Results
Twenty-two treatment arms were analyzed, including 2,581 patients. The maintenance therapy regimen FP+Bev showed the strongest correlation with a prolonged OS (Spearman’s partial correlation coefficient=0.42), and the other three variables correlated weakly with the OS. The maintenance therapy regimen significantly interacted with the induction chemotherapy duration (p=0.019). The predicted OS for FP+Bev crossed the lines of FP/Bev alone at 18 weeks of induction therapy, and of no treatment at 23 weeks. The corresponding OS at 12 and 27 weeks of induction therapies were 28.6 and 24.2 months for FP+Bev, 25.9 and 28.8 months for FP/Bev alone, and 20.5 and 27.5 months for no treatment.
Conclusion
The optimal maintenance therapy regimen for the OS is a continuous induction therapy as long as possible followed by FP/Bev alone and switching to FP+Bev within approximately 4 months if induction therapy is discontinued.

Keyword

Bevacizumab; Colorectal neoplasms; Fluoropyrimidine; Maintenance therapy; Meta-analysis; Oxaliplatin; Survival

Figure

  • Fig. 1 Study selection according to the PRISMA diagram. ASCO, American Society of Clinical Oncology; ESMO, European Society of Medical Oncology; PRISMA, Preferred Reporting Items for Systemic Reviews.

  • Fig. 2 Correlations between the overall survival or progression-free survival and variables: induction therapy regimen (A, B), duration of induction therapy (C, D), maintenance therapy regimen (E, F), and oxaliplatin reintroduction rate (G). The size of each circle is proportional to the sample size. The solid line indicates the estimated regression line, and the dotted line indicates the 95% confidence interval. Bev, bevacizumab; FP, fluoropyrimidine; pR, Spearman’s partial correlation coefficient; R, Spearman’s correlation coefficient.

  • Fig. 3 Relationships between observed and predicted survival times in the extra-validation treatment arms: overall survival (A) and progression-free survival (B). Predicted progression-free survival was calculated in treatment arms recommended to continue maintenance therapy until disease progression. Bev, bevacizumab; CAPOX, capecitabine and oxaliplatin; CI, confidence interval; FOLFOX, infusional 5-fluorouracil, folinic acid, and oxaliplatin; mFOLFOX, modified infusional 5-fluorouracil, folinic acid, and oxaliplatin.

  • Fig. 4 Relationships between the predicted survival time and duration of induction therapy, and maintenance therapy regimen, with maintenance therapy rate of 100%: overall survival (A) and progression-free survival (B). CI, confidence interval; FP, fluoropyrimidine.


Reference

References

1. 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; 18:2938–47.
Article
2. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: a North American Intergroup Trial. J Clin Oncol. 2006; 24:3347–53.
Article
3. Porschen R, Arkenau HT, Kubicka S, Greil R, Seufferlein T, Freier W, et al. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol. 2007; 25:4217–23.
Article
4. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, 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.
Article
5. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010; 28:4697–705.
Article
6. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008; 26:2013–9.
Article
7. Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, 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 cinical trial. JAMA. 2017; 317:2392–401.
8. Grothey A, Nikcevich DA, Sloan JA, Kugler JW, Silberstein PT, Dentchev T, et al. Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol. 2011; 29:421–7.
Article
9. Hochster HS, Grothey A, Hart L, Rowland K, Ansari R, Alberts S, et al. Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT. Ann Oncol. 2014; 25:1172–8.
Article
10. Loprinzi CL, Qin R, Dakhil SR, Fehrenbacher L, Flynn KA, Atherton P, et al. Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance). J Clin Oncol. 2014; 32:997–1005.
Article
11. Oki E, Emi Y, Kojima H, Higashijima J, Kato T, Miyake Y, et al. Preventive effect of Goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial): a placebo-controlled, double-blind, randomized phase III study. Int J Clin Oncol. 2015; 20:767–75.
Article
12. Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013; 309:1359–67.
13. 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.
Article
14. Berry SR, Cosby R, Asmis T, Chan K, Hammad N, Krzyzanowska MK, et al. Continuous versus intermittent chemotherapy strategies in metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol. 2015; 26:477–85.
Article
15. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009; 6:e1000100.
Article
16. Andre T, Tournigand C, Mineur L, Fellague-Chebra R, Flesch M, Mabro M, et al. Phase II study of an optimized 5-fluorouracil-oxaliplatin strategy (OPTIMOX2) with celecoxib in metastatic colorectal cancer: a GERCOR study. Ann Oncol. 2007; 18:77–81.
17. Scalamogna R, Brugnatelli S, Tinelli C, Sagrada P, Gattoni E, Tronconi MC, et al. UFT as maintenance therapy in patients with advanced colorectal cancer responsive to the FOLFOX4 regimen. Oncology. 2007; 72:267–73.
Article
18. 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; 27:5727–33.
Article
19. Comella P, Massidda B, Filippelli G, Farris A, Natale D, Barberis G, et al. Randomised trial comparing biweekly oxaliplatin plus oral capecitabine versus oxaliplatin plus i.v. bolus fluorouracil/leucovorin in metastatic colorectal cancer patients: results of the Southern Italy Cooperative Oncology study 0401. J Cancer Res Clin Oncol. 2009; 135:217–26.
Article
20. Waddell T, Gollins S, Soe W, Valle J, Allen J, Bentley D, et al. Phase II study of short-course capecitabine plus oxaliplatin (XELOX) followed by maintenance capecitabine in advanced colorectal cancer: XelQuali study. Cancer Chemother Pharmacol. 2011; 67:1111–7.
Article
21. Tezuka T, Hamada C, Ishida H, Ooshiro M, Matsuoka H, Kawasaki S, et al. Phase II clinical study of modified FOLFOX7 (intermittent oxaliplatin administration) plus bevacizumab in patients with unresectable metastatic colorectal cancer-CRAFT study. Invest New Drugs. 2013; 31:1321–9.
Article
22. Yalcin S, Uslu R, Dane F, Yilmaz U, Zengin N, Buyukunal E, et al. Bevacizumab+capecitabine as maintenance therapy after initial bevacizumab+XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III ‘Stop and Go’ study results: a Turkish Oncology Group Trial. Oncology. 2013; 85:328–35.
23. Hong YS, Lee SS, Kim KP, Lee JL, Kang YK, Shin SJ, et al. A phase II study of bevacizumab, oxaliplatin, and capecitabine in patients with previously untreated metastatic colorectal cancer: a prospective, multicenter trial of the Korean Cancer Study Group. Am J Clin Oncol. 2014; 37:19–23.
24. Kim ST, Hong YS, Lim HY, Lee J, Kim TW, Kim KP, et al. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial. BMC Cancer. 2014; 14:883.
Article
25. Hegewisch-Becker S, Graeven U, Lerchenmuller CA, Killing B, Depenbusch R, Steffens CC, et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2015; 16:1355–69.
Article
26. Nakayama N, Sato A, Tanaka S, Shimada K, Konishi K, Sasaki E, et al. A phase II study of bevacizumab with modified OPTIMOX1 as first-line therapy for metastatic colorectal cancer: the TCOG-GI 0802 study. Invest New Drugs. 2015; 33:954–62.
Article
27. Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015; 385:1843–52.
Article
28. Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, et al. Single-agent capecitabine as 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; 27:1074–81.
Article
29. Nakayama G, Ishigure K, Yokoyama H, Uehara K, Kojima H, Ishiyama A, et al. The efficacy and safety of CapeOX plus bevacizumab therapy followed by capecitabine plus bevacizumab maintenance therapy in patients with metastatic colorectal cancer: a multi-center, single-arm, phase II study (CCOG-0902). BMC Cancer. 2017; 17:243.
Article
30. Kosugi C, Koda K, Denda T, Ishibashi K, Ishida H, Seike K, et al. VOICE trial: Final results from multicenter phase II study of assessment of clinical efficiency and safety in capecitabine plus intermittent oxaliplatin together with bevacizumab as first-line therapy for patients with advanced colorectal cancer. J Clin Oncol. 2018; 36(4 Suppl):740.
31. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009; 360:563–72.
Article
32. Qvortrup C, Jensen BV, Fokstuen T, Nielsen SE, Keldsen N, Glimelius B, et al. A randomized study comparing short-time infusion of oxaliplatin in combination with capecitabine XELOX(30) and chronomodulated XELOX(30) as first-line therapy in patients with advanced colorectal cancer. Ann Oncol. 2010; 21:87–91.
Article
33. Vaidyanathan G, Groman A, Wilding G, Fakih MG. Stop and go FOLFOX plus bevacizumab chemotherapy in the first-line treatment of metastatic colorectal cancer. Oncology. 2010; 79:67–71.
Article
34. Ducreux M, Bennouna J, Hebbar M, Ychou M, Lledo G, Conroy T, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2011; 128:682–90.
Article
35. Diaz-Rubio E, Gomez-Espana A, Massuti B, Sastre J, Abad A, Valladares M, 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. 2012; 17:15–25.
36. Okita NT, Esaki T, Baba E, Sakai D, Tokunaga S, Takiuchi H, et al. A multicenter phase II study of the stop-and-go modified FOLFOX6 with bevacizumab for first-line treatment of patients with metastatic colorectal cancer. Invest New Drugs. 2012; 30:2026–31.
Article
37. Antonuzzo L, Giommoni E, Pastorelli D, Latiano T, Pavese I, Azzarello D, et al. Bevacizumab plus XELOX as first-line treatment of metastatic colorectal cancer: The OBELIX study. World J Gastroenterol. 2015; 21:7281–8.
Article
38. Grothey A. Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer. 2005; 5(Suppl 1):S38–46.
Article
39. Beijers AJ, Mols F, Vreugdenhil G. A systematic review on chronic oxaliplatin-induced peripheral neuropathy and the relation with oxaliplatin administration. Support Care Cancer. 2014; 22:1999–2007.
Article
40. de Gramont A, Buyse M, Abrahantes JC, Burzykowski T, Quinaux E, Cervantes A, et al. Reintroduction of oxaliplatin is associated with improved survival in advanced colorectal cancer. J Clin Oncol. 2007; 25:3224–9.
Article
41. Chibaudel B, Bonnetain F, Shi Q, Buyse M, Tournigand C, Sargent DJ, et al. Alternative end points to evaluate a therapeutic strategy in advanced colorectal cancer: evaluation of progression-free survival, duration of disease control, and time to failure of strategy: an Aide et Recherche en Cancerologie Digestive Group Study. J Clin Oncol. 2011; 29:4199–204.
42. Owonikoko TK, Ramalingam SS, Belani CP. Maintenance therapy for advanced non-small cell lung cancer: current status, controversies, and emerging consensus. Clin Cancer Res. 2010; 16:2496–504.
Article
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