Temporal Change in Treatment Patterns of Metastatic Colorectal Cancer and Its Association with Patient Survival: A Retrospective Cohort Study Based on an Intelligent Big-Data Platform

Abstract

There is a lack of high-quality, large-scale, real-world evidence from patients with metastatic colorectal cancer (mCRC), especially in China. It remains unclear whether efforts to improve the quality of care for mCRC would improve patient survival outcomes in real-world practice. On the basis of an intelligent bigdata platform, we established a large-scale retrospective cohort of mCRC patients. We investigated the temporal changes in the systemic and local treatment (resection, ablation, or radiation to liver, lung, or extrahepatic and/or extrapulmonary metastases) patterns of mCRC, and whether these changes were associated with improved overall survival (OS) over time. Between July 2012 and December 2018, 3403 eligible patients were included in this research. The median OS was 42.8 months (95% confidence interval (CI), 40.7– 46.6) for the entire cohort, 25.6 months (95% CI, 24.7–26.9) for those treated with systemic therapy only, and not reached (95% CI, 78.6 months–not reached) for those receiving local therapy. The utility rate of local therapy increased continuously from 37.9% in 2012–2014 to 46.9% in 2017–2018. A dramatic increase in the utility rate of either cetuximab or bevacizumab was observed since 2017 (39.9%, 43.2%, and 60.3% in 2012–2014, 2015–2016, and 2017–2018, respectively). Compared with 2012–2014, the OS of the entire population significantly improved in 2015–2016 (hazard ratio (HR) = 0.87 (95% CI, 0.78–0.99); P = 0.034), but not for patients receiving systemic therapy only (HR = 0.99 (95% CI, 0.86–1.14); P = 0.889), whereas an improved OS was found in 2015–2018 for both the entire population (HR = 0.75 (95% CI, 0.70–0.81); P < 0.001) and for patients receiving systemic therapy only (HR = 0.83 (95% CI, 0.77–0.91); P < 0.001). In summary, the quality of care for mCRC, as indicated by the utility rate of targeted and local therapies, has been continuously improving over time in this study cohort, which is associated with continuously improving survival outcomes for these patients.

Keywords

Metastatic colorectal cancer / Real-world evidence / Treatment pattern / Survival / Big-data platform

References

[[1]] Piedbois P, Rougier P, Buyse M, Pignon J, Ryan L, Hansen R, et al.; Meta-analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16(1):301–8.

[[2]] National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): colon cancer [Internet]. Plymouth Meeting: National Comprehensive Cancer Network; [cited 2020 Jan 17]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf.

[[3]] Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369(11):1023–34.

[[4]] Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360(14):1408–17.

[[5]] Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as firstline therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26(12):2013–9.

[[6]] Raoof M, Haye S, Ituarte PHG, Fong Y. Liver resection improves survival in colorectal cancer patients: causal-effects from population-level instrumental variable analysis. Ann Surg 2019;270(4):692–700.

[[7]] Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 2009;27(22):3677–83.

[[8]] Vera R, González-Flores E, Rubio C, Urbano J, Valero Camps M, Ciampi-Dopazo JJ, et al. Multidisciplinary management of liver metastases in patients with colorectal cancer: a consensus of SEOM, AEC, SEOR, SERVEI, and SEMNIM. Clin Transl Oncol 2020;22(5):647–62.

[[9]] Chow FL, Chok KH. Colorectal liver metastases: an update on multidisciplinary approach. World J Hepatol 2019;11(2):150–72.

[[10]] Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007;25(29):4575–80.

[[11]] Hur H, Ko YT, Min BS, Kim KS, Choi JS, Sohn SK, et al. Comparative study of resection and radiofrequency ablation in the treatment of solitary colorectal liver metastases. Am J Surg 2009;197(6):728–36.

[[12]] Sucandy I, Cheek S, Golas BJ, Tsung A, Geller DA, Marsh JW. Longterm survival outcomes of patients undergoing treatment with radiofrequency ablation for hepatocellular carcinoma and metastatic colorectal cancer liver tumors. HPB 2016;18(9):756–63.

[[13]] Rusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg SJ, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol 2009;27(10):1572–8.

[[14]] Åberg T, Malmberg KÅ, Nilsson B, Nõu E. The effect of metastasectomy: fact or fiction? Ann Thorac Surg 1980;30(4):378–84.

[[15]] Gonzalez M, Poncet A, Combescure C, Robert J, Ris HB, Gervaz P. Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis. Ann Surg Oncol 2013;20(2):572–9.

[[16]] Gonzalez M, Gervaz P. Risk factors for survival after lung metastasectomy in colorectal cancer patients: systematic review and meta-analysis. Future Oncol 2015;11(2S):31–3.

[[17]] Abrams TA, Meyer G, Schrag D, Meyerhardt JA, Moloney J, Fuchs CS. Chemotherapy usage patterns in a US-wide cohort of patients with metastatic colorectal cancer. J Natl Cancer Inst 2014;106(2):djt371.

[[18]] McLean J, Rho YS, Kuruba G, Mamo A, Gilabert M, Kavan T, et al. Clinical practice patterns in chemotherapeutic treatment regimens for metastatic colorectal cancer. Clin Colorectal Cancer 2016;15(2):135–40.

[[19]] Xu R, Wang W, Zhu Bo, Lin X, Ma D, Zhu L, et al. Disease characteristics and treatment patterns of Chinese patients with metastatic colorectal cancer: a retrospective study using medical records from China. BMC Cancer 2020;20 (1):131.

[[20]] Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, et al. Efficacy and tolerability of firstline cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol 2018;36(30):3031–9.

[[21]] Zeng H, Chen W, Zheng R, Zhang S, Ji JS, Zou X, et al. Changing cancer survival in China during 2003–15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health 2018;6(5):e555–67.

[[22]] Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, et al. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer 2011;30 (10):682–9.

[[23]] 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(6):1074–81.

[[24]] Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, et al. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol 2018;19(5):660–71.

[[25]] Li J, Qin S, Xu R, Yau TCC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2015;16(6):619–29.

[[26]] Xu RH, Li J, Bai Y, Xu J, Liu T, Shen L, et al. Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study. J Hematol Oncol 2017;10 (1):22.

[[27]] Li J, Qin S, Xu RH, Shen L, Xu J, Bai Y, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA 2018;319(24):2486–96.

[[28]] Peng J, Li W, Zhang R, Lin J, Tang J, Wen Y, et al. Safety and efficacy of a modified XELOX adjuvant regimen for patients with operated stage III colon cancer: a Chinese single-center experience. Cancer Commun 2019;39(1):59.

[[29]] Wang F, Wang ZX, Chen G, Luo HY, Zhang DS, Qiu MZ, et al. Expert opinions on immunotherapy for patients with colorectal cancer. Cancer Commun 2020;40 (10):467–72.

[[30]] Adam R, Avisar E, Ariche A, Giachetti S, Azoulay D, Castaing D, et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001;8(4):347–53.

[[31]] Kataoka K, Kanazawa A, Iwamoto S, Kato T, Nakajima A, Arimoto A. Does, ‘‘conversion chemotherapy” really improve survival in metastatic colorectal cancer patients with liver-limited disease? World J Surg 2014;38(4):936–46.

[[32]] Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010;11(1):38–47.

[[33]] Garufi C, Torsello A, Tumolo S, Ettorre GM, Zeuli M, Campanella C, et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer 2010;103(10):1542–7.

[[34]] Tejpar S, Stintzing S, Ciardiello F, Tabernero J, van Cutsem E, Beier F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol 2017;3(2):194–201.

[[35]] Venook AP, Niedzwiecki D, Innocenti F, Fruth B, Greene C, O’Neil BH, et al. Impact of primary (10) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol 2016;34(Suppl 15):3504.

[[36]] Arnold D, Lueza B, Douillard JY, Peeters M, Lenz HJ, Venook A, et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol 2017;28(8):1713–29.

[[37]] Wang ZX, Wu HX, He MM, Wang YN, Luo HY, Ding PR, et al. Chemotherapy with or without anti-EGFR agents in left- and right-sided metastatic colorectal cancer: an updated meta-analysis. J Natl Compr Canc Netw 2019;17(7):805–11.

[[38]] Messersmith WA. Systemic management of colorectal cancer. J Natl Compr Canc Netw 2017;15(5S):699–702.

[[39]] Wang F, Bai L, Liu TS, Yu YY, He MM, Liu KY, et al. Right-sided colon cancer and left-sided colorectal cancers respond differently to cetuximab. Chin J Cancer 2015;34(9):384–93.

[[40]] Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: a metaanalysis of first-line clinical trials. Eur J Cancer 2017;70:87–98.

[[41]] Sasaki K, Andreatos N, Margonis GA, He J, Weiss M, Johnston F, et al. The prognostic implications of primary colorectal tumor location on recurrence and overall survival in patients undergoing resection for colorectal liver metastasis. J Surg Oncol 2016;114(7):803–9.

[[42]] Creasy JM, Sadot E, Koerkamp BG, Chou JF, Gonen M, Kemeny NE, et al. The impact of primary tumor location on long-term survival in patients undergoing hepatic resection for metastatic colon cancer. Ann Surg Oncol 2018;25(2):431–8.

[[43]] Le H, Ziogas A, Taylor TH, Lipkin SM, Zell JA. Survival of distinct Asian groups among colorectal cancer cases in California. Cancer 2009;115(2):259–70.

[[44]] 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 clinical trial. JAMA 2017;317(23): 2392–401.

[[45]] Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol 2016;17(10):1426–34.

[[46]] Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014;371(17):1609–18.

[[47]] Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracilleucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004;22(7):1209–14.

[[48]] Tournigand C, André 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(2):229–37.

[[49]] Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014;15(10):1065–75.