Abstract
The introduction of therapeutic agents such as irinotecan, oxaliplatin, and more recently biologic agents such as vascular endothelial growth factor and epidermal growth factor receptor (EGFR) inhibitors has significantly improved survival of patients with metastatic colorectal cancer. These novel agents have also contributed to added toxicities. Therefore, several studies have evaluated the role of maintenance therapy with less intensive regimens in patients who experienced stable disease or treatment response following induction therapy as a strategy to reduce toxicity and improve quality of life. The success of such strategies, however, requires assurance that their survival would not be compromised. We therefore reviewed studies that have explored the various strategies of treatment de-escalation with an emphasis on survival and toxicity outcomes. Recent studies evaluated the role of maintenance therapy with chemotherapy only, chemotherapy plus bevcizumab, bevacizumab only, and EGFR inhibitors. Current evidence suggests that maintenance strategies offer significant benefit to patients by providing continuous clinical benefit while minimizing the risks associated with continuous therapy. Strategies to improve selection of patients for maintenance therapy versus identifying subgroups of patients that will benefit from a chemotherapy-free interval need to continue to be studied. Finally, as our understanding of the molecular and genetic drivers of colorectal cancer continues to expand, refining these strategies to include more target-specific agents should become more routine.
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References
Siegel R, Desantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220. doi:10.3322/caac.21149.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277. doi:10.3322/caac.20073.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917. doi:10.1002/ijc.25516.
Benson AB 3rd, Bekaii-Saab T, Chan E, Chen YJ, Choti MA, Cooper HS, et al. Metastatic colon cancer, version 3.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2013;11(2):141.
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(16):2938–47.
Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML, Kiernan MC. Long-term neuropathy after oxaliplatin treatment: challenging the dictum of reversibility. Oncologist. 2011;16(5):708–16. doi:10.1634/theoncologist.2010-0248.
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(3):394–400. doi:10.1200/jco.2005.03.0106.
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(34):5727–33. doi:10.1200/jco.2009.23.4344.
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(6):1172–8. doi:10.1093/annonc/mdu107.
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(6):328–35. doi:10.1159/000355914.
Koopman MSL, May AM, Mol L, van Tinteren H, Punt C, editors. Final results and subgroup analyses of the phase 3 CAIRO3 study: Maintenance treatment with capecitabine + bevacizumab versus observation after induction treatment with chemotherapy + bevacizumab in metastatic colorectal cancer (mCRC). In: ASCO Annual Meeting: Chicago; 2014.
Arnold DGU, Lerchenmuller C, Killing B, Depenbusch R, Steffens CC, Al-Batran SE, Lnage T, Dietrich G, Stoehlmacher J, Tannapfel A, Schmoll HJ, Reinacher-Schick A, Hegewisch-Becker S, editors. Maintenance strategy with fluoropyrimidines (FP) plus Bevacizumab (Bev), Bev alone, or no treatment, following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC): a phase III non-inferiority trial (AIO KRK 0207). In: ASCO Annual Meeting: Chicago; 2014.
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(1):15–25. doi:10.1634/theoncologist.2011-0249.
Koeberle D, Betticher DC, von Moos R, Dietrich D, Brauchli P, Baertschi D, et al. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann Oncol. 2015. doi:10.1093/annonc/mdv011.
Johnsson A, Hagman H, Frodin JE, Berglund A, Keldsen N, Fernebro E, et al. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013;24(9):2335–41. doi:10.1093/annonc/mdt236.
Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, 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. doi:10.1200/jco.2011.38.0915.
Berry SR, Cosby R, Asmis T, Chan K, Hammad N, Krzyzanowska MK. Continuous versus intermittent chemotherapy strategies in metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol. 2014. doi:10.1093/annonc/mdu272.
Wasan H, Meade AM, Adams R, Wilson R, Pugh C, Fisher D, et al. Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial. Lancet Oncol. 2014;15(6):631–9. doi:10.1016/s1470-2045(14)70106-8.
Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011;12(7):642–53. doi:10.1016/s1470-2045(11)70102-4.
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(12):2013–9. doi:10.1200/jco.2007.14.9930.
Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21(1):60–5.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335. doi:10.1056/NEJMoa032691.
Giantonio BJ. Bevacizumab in the treatment of metastatic colorectal cancer (mCRC) in second- and third-line settings. Semin Oncol. 2006;33(5 Suppl 10):S15–8. doi:10.1053/j.seminoncol.2006.08.003.
Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539 (pii:25/12/1539).
Aparicio GLB, Le Malicot K, Bouche O, Boige V, Francois E, Ghiringhelli F, Legoux J-L, Ben Abdelghani M, Phelip J, Faroux R, Dahan L, Taieb J, Bedenne L. FOLFIRI + bevacizumab induction chemotherapy followed by bevacizumab or observation in metastatic colorectal cancer, a phase III trial (PRODIGE 9-FFCD 0802). Dig Liver Dis. 2015;47:271–2.
Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011. doi:10.1200/jco.2010.33.5091.
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(31):4697. doi:10.1200/jco.2009.27.4860.
Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32(21):2240–7. doi:10.1200/jco.2013.53.2473.
Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626. doi:10.1200/jco.2007.14.7116.
Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65. doi:10.1056/NEJMoa0804385.
Lim SH, Becker TM, Chua W, Caixeiro NJ, Ng WL, Kienzle N, et al. Circulating tumour cells and circulating free nucleic acid as prognostic and predictive biomarkers in colorectal cancer. Cancer Lett. 2014;346(1):24–33. doi:10.1016/j.canlet.2013.12.019.
Meyerhardt JA, Zhu AX, Enzinger PC, Ryan DP, Clark JW, Kulke MH, et al. Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol. 2006;24(12):1892–7. doi:10.1200/jco.2005.05.3728.
Chibaudel B, Tournigand C, Samson B, Scheithauer W, Mesange P, Lledo G, et al. Bevacizumab-erlotinib as maintenance therapy in metastatic colorectal cancer. Final results of the GERCOR dream study. Ann Oncol. 2014;25(suppl 4):iv167. doi:10.1093/annonc/mdu333.1.
Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR, et al. Non-small cell lung cancer, version 6.2015. J Natl Compr Canc Netw. 2015;13(5):515–24.
Martinelli ETT, Venturini F, Cervantes A, Douillard J, Falcone A, Folprecht G, Kohne C, Taieb J, Tabernero J, Cardone C, Sforza V, Martini G, Napolitano S, Capuano A, Auricchio F, Ciardiello F. Phase III study of regorefenib versus placebo as maintenance therapy in RAS wild type metastatic colorectal cancer (RAVELLO trial). In: ASCO Gastrointestinal Cancers Symposium: San Francisco; 2015.
Perez-Staub Nc B, Figer A, Cervantes G, Lledo G, Larsen AK, Maindrault-Goebel F, Louvet C, Tournigand C, De Gramont A, editors. Who can benefit from chemotherapy holidays after first-line therapy for advanced colorectal cancer? A GERCOR study. ASCO Annual Meeting: Chicago; 2008.
Labianca R, Sobrero A, Isa L, Cortesi E, Barni S, Nicolella D, et al. Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised ‘GISCAD’ trial. Ann Oncol. 2011;22(5):1236–42. doi:10.1093/annonc/mdq580.
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Tanios Bekaii-Saab: consulting fees from Genenteach, BMS, Amgen, Taiho, Bayer. Fees for participation in review activities: Polaris, exel exis. Sameh Mikhail has no conflicts to declare.
Appendix: Trial acronyms
Appendix: Trial acronyms
OPTIMOX 1 | OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer—a GERCOR study |
OPTIMOX2 | Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study |
CONcePT | Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT |
STOP and GO trial | 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 |
CAIRO3 | Final results and subgroup analyses of the phase 3 CAIRO3 study: maintenance treatment with capecitabine + bevacizumab versus observation after induction treatment with chemotherapy + bevacizumab in metastatic colorectal cancer (mCRC) |
AIO KRK 0207 | Maintenance strategy with fluoropyrimidines (FP) plus Bevacizumab (Bev), Bev alone, or no treatment, following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC): a phase III non-inferiority trial (AIO KRK 0207) |
MACRO-TTD study | 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 |
SAKK 4106 | Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06) |
NORDIC ACT | A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial |
NORDIC VII | 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 |
COIN-B | Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial |
COIN | Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial |
PRODIGE 9 | FOLFIRI + bevacizumab induction chemotherapy followed by bevacizumab or observation in metastatic colorectal cancer, a phase III trial (PRODIGE 9-FFCD 0802) |
PRIME study | 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 |
PEAK study | A randomized phase II study of mFOLFOX6 with either panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) in patients (pts) with unresectable wild-type (WT) KRAS metastatic colorectal cancer (mCRC) |
DREAM | Bevacizumab-erlotinib as maintenance therapy in metastatic colorectal cancer. Final results of the gercor dream study |
RAVELLO | Phase III study of regorefenib versus placebo as maintenance therapy in RAS wild type metastatic colorectal cancer (RAVELLO trial) |
GISCAD | Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised ‘GISCAD’ trial |
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Mikhail, S., Bekaii-Saab, T. Maintenance Therapy for Colorectal Cancer: Which Regimen and Which Patients?. Drugs 75, 1833–1842 (2015). https://doi.org/10.1007/s40265-015-0467-x
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DOI: https://doi.org/10.1007/s40265-015-0467-x