Magnitude of advantage in tumor response contributes to a better correlation between treatment effects on overall survival and progression-free survival: a literature-based meta-analysis of clinical trials in patients with metastatic colorectal cancer
- 21 Downloads
Although it is suggested that the endpoints originated from the concept of tumor shrinkage dynamics, such as early tumor shrinkage and depth of response, are strongly associated with overall survival (OS) in patients with metastatic colorectal cancer (mCRC), they are yet to be validated as a single surrogate endpoint of OS by themselves. This study aimed to investigate the impact of advantage in tumor response on the correlation between treatment effects on progression-free survival (PFS) and OS in mCRC patients.
Based on an electronic search, we identified randomized controlled trials of first-line therapy for mCRC. The impact of advantage in objective response rate (ORR) on the correlation between treatment effects on PFS and OS was evaluated based on Spearman correlation coefficients (rs).
Forty-seven trials with a total of 24,018 patients were identified. The hazard ratio for PFS showed a relatively higher correlation with that for OS (rs = 0.63) when the trials were limited to those that demonstrated a larger difference in ORR, compared to the case for trials that demonstrated a smaller difference (rs = 0.32). This tendency was also observed in the subgroup analysis stratified by the types of treatment agents (targeted or non-targeted).
The magnitude of advantage in tumor response was suggested to contribute to a better prediction of OS benefit based on PFS in patients with mCRC. The accuracy of OS estimation in mCRC is expected to be improved by considering the degree of tumor shrinkage in conjunction with PFS.
KeywordsColorectal cancer Survival Surrogate endpoint Meta-analysis
We would like to thank Kae Nakashima, Ph.D., for her support in English editing.
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by YY and MK. The first draft of the manuscript was written by YY and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
Compliance with ethical standards
Conflict of interest
All authors have no conflicts of interest that are directly relevant to this research. Yosuke Yoshida is an employee of MSD K.K., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
- 1.Food and Drug Administration (2018) Guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. US department of health and human services. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trial-endpoints-approval-cancer-drugs-and-biologics
- 4.Schwartzberg LS, Rivera F, Karthaus M et al (2014) 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 32(21):2240–2247. https://doi.org/10.1200/JCO.2013.53.2473 CrossRefPubMedGoogle Scholar
- 5.Stintzing S, Modest DP, Rossius L et al (2016) 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 17:1426–1434. https://doi.org/10.1016/S1470-2045(16)30269-8 CrossRefPubMedGoogle Scholar
- 8.Mansmann UR, Sartorius U, Laubender RP et al (2013) Quantitative analysis of the impact of deepness of response on post-progression survival time following first-line treatment in patients with mCRC. J Clin Oncol 31(15). https://ascopubs.org/doi/abs/10.1200/jco.2013.31.15_suppl.3630
- 9.Cremolini C, Loupakis F, Antoniotti C et al (2015) Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol 26:1188–1194. https://doi.org/10.1093/annonc/mdv112 CrossRefPubMedGoogle Scholar
- 11.Tsuji A, Sunakawa Y, Ichikawa W et al (2016) Early tumor shrinkage and depth of response as predictors of favorable treatment outcomes in patients with metastatic colorectal cancer treated with FOLFOX Plus Cetuximab (JACCRO CC-05). Targ Oncol 11:799–806. https://doi.org/10.1007/s11523-016-0445-6 CrossRefGoogle Scholar
- 15.Giessen C, Laubender RP, Ankerst DP et al (2013) Progression-free survival as a surrogate endpoint for median overall survival in metastatic colorectal cancer: literature-based analysis from 50 randomized first-line trials. Clin Cancer Res 19(1):225–235. https://doi.org/10.1158/1078-0432.CCR-12-1515 CrossRefPubMedGoogle Scholar
- 18.Burzykowski T, Buyse M, Piccart-Gebhart MJ et al (2008) Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol 26:1987–1992. https://doi.org/10.1200/JCO.2007.10.8407 CrossRefPubMedGoogle Scholar
- 19.Tang PA, Bentzen SM, Chen EX et al (2007) Surrogate end points for median overall survival in metastatic colorectal cancer: literature-based analysis from 39 randomized controlled trials of first-line chemotherapy. J Clin Oncol 25(29):4562–4568. https://doi.org/10.1200/JCO.2006.08.1935 CrossRefPubMedGoogle Scholar
- 20.Aparicio T, Lavau-Denes S, Phelip JM et al (2016) Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001–02). Ann Oncol 27:121–127. https://doi.org/10.1093/annonc/mdv491 CrossRefPubMedGoogle Scholar
- 21.Passardi A, Nanni O, Tassinari D et al (2015) Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol 26:1201–1207. https://doi.org/10.1093/annonc/mdv130 CrossRefPubMedGoogle Scholar
- 22.Brodowicz T, Ciuleanu TE, Radosavljevic D et al (2013) FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study. Ann Oncol 24:1769–1777. https://doi.org/10.1093/annonc/mdt116 CrossRefPubMedGoogle Scholar
- 25.Glimelius B, Sørbye H, Balteskard L et al (2008) A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer. Ann Oncol 19(5):909–914. https://doi.org/10.1093/annonc/mdm588 CrossRefPubMedGoogle Scholar
- 27.Blanke CD, Shultz J, Cox J et al (2002) A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Ann Oncol 13(1):87–91. https://doi.org/10.1093/annonc/mdf043 CrossRefPubMedGoogle Scholar
- 28.Kalofonos HP, Papakostas P, Makatsoris T et al (2010) Irinotecan/fluorouracil/leucovorin or the same regimen followed by oxaliplatin/fluorouracil/leucovorin in metastatic colorectal cancer. Anticancer Res 30(10): 4325–4333. https://ar.iiarjournals.org/content/30/10/4325.long
- 29.Souglakos J, Ziras N, Kakolyris S et al (2012) Randomised phase trial of CAPIRI capecitabine, irinotecan plus bevacizumab vs FOLFIRI folinic acid, 5fluorouracil, irinotecan plus bevacizumab as first-line treatment of patients with unresectablemetastatic colorectal cancer mCRC. Br J Cancer 106(3):453–459. https://doi.org/10.1038/bjc.2011.594 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Yamazaki K, Kuwano H, Ojima H et al (2015) A randomized phase II study of combination therapy with S-1, oral leucovorin, and oxaliplatin (SOL) and mFOLFOX6 in patients with previously untreated metastatic colorectal cancer. Cancer Chemother Pharmacol 75(3):569–577. https://doi.org/10.1007/s00280-015-2676-0 CrossRefPubMedGoogle Scholar
- 33.Tabernero J, Garcia-Carbonero R, Cassidy J et al (2013) Sorafenib in combination with oxaliplatin, leucovorin, and fluorouracil (modified FOLFOX6) as first-line treatment of metastatic colorectal cancer: the RESPECT trial. Clin Cancer Res 19(9):2541–2550. https://doi.org/10.1158/1078-0432.CCR-13-0107 CrossRefPubMedGoogle Scholar
- 35.Gravalos C, Salut A, García-Girón C et al (2012) A randomized phase II study to compare oxaliplatin plus 5-fluorouracil and leucovorin (FOLFOX4) versus oxaliplatin plus raltitrexed (TOMOX) as first-line chemotherapy for advanced colorectal cancer. Clin Transl Oncol 14(8):606–612. https://doi.org/10.1007/s12094-012-0843-x CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Comella P, Massidda B, Filippelli G et al (2009) 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 135(2):217–226. https://doi.org/10.1007/s00432-008-0454-7 CrossRefPubMedGoogle Scholar
- 38.Hoff PM, Hochhaus A, Pestalozzi BC et al (2012) Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol 30(29):3596–3603. https://doi.org/10.1200/JCO.2012.42.6031 CrossRefPubMedGoogle Scholar
- 39.Schmoll HJ, Cunningham D, Sobrero A et al (2012) Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol 30(29):3588–3595. https://doi.org/10.1200/JCO.2012.42.5355 CrossRefPubMedGoogle Scholar
- 40.Tveit KM, Guren T, Glimelius B et al (2012) 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 30(15):1755–1762. https://doi.org/10.1200/JCO.2011.38.0915 CrossRefPubMedGoogle Scholar
- 41.Douillard JY, Siena S, Cassidy J et al (2010) 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 28(31):4697–4705. https://doi.org/10.1200/JCO.2009.27.4860 CrossRefPubMedGoogle Scholar
- 42.Tebbutt NC, Wilson K, Gebski VJ et al (2010) Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. J Clin Oncol 28(19):3191–3198. https://doi.org/10.1200/JCO.2009.27.7723 CrossRefPubMedGoogle Scholar
- 44.Porschen R, Arkenau HT, Kubicka S et al (2007) 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 25(27):4217–4223. https://doi.org/10.1200/JCO.2006.09.2684 CrossRefPubMedGoogle Scholar
- 45.Falcone A, Ricci S, Brunetti I et al (2007) Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 25(13):1670–1676. https://doi.org/10.1200/JCO.2006.09.0928 CrossRefPubMedGoogle Scholar
- 47.Köhne CH, van Cutsem E, Wils J et al (2005) Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: european organisation for research and treatment of cancer gastrointestinal group study 40986. J Clin Oncol 23(22):4856–4865. https://doi.org/10.1200/JCO.2005.05.546 CrossRefPubMedGoogle Scholar
- 48.Schilsky RL, Levin J, West WH et al (2002) Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol 20(6):1519–1526. https://doi.org/10.1200/JCO.2002.20.6.1519 CrossRefPubMedGoogle Scholar
- 49.Seymour MT, Slevin ML, Kerr DJ et al (1996) Randomized trial assessing the addition of interferon alpha-2a to fluorouracil and leucovorin in advanced colorectal cancer. Colorectal Cancer Working Party of the United Kingdom Medical Research Council. J Clin Oncol 14(8):2280–2288. https://doi.org/10.1200/JCO.1918.104.22.1680 CrossRefPubMedGoogle Scholar
- 50.Venook AP, Niedzwiecki D, Lenz HJ et al (2017) 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 317(23):2392–2401. https://doi.org/10.1001/jama.2017.7105 CrossRefPubMedPubMedCentralGoogle Scholar
- 51.Maughan TS, Adams RA, Smith CG et al (2011) Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 377(9783):2103–2114. https://doi.org/10.1016/S0140-6736(11)60613-2 CrossRefPubMedPubMedCentralGoogle Scholar
- 53.Heinemann V, von Weikersthal LF, Decker T et al (2014) 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 15(10):1065–1075. https://doi.org/10.1016/S1470-2045(14)70330-4 CrossRefPubMedPubMedCentralGoogle Scholar
- 61.Cunningham D, Lang I, Marcuello E et al (2013) Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol 14(11):1077–1085. https://doi.org/10.1016/S1470-2045(13)70154-2 CrossRefPubMedGoogle Scholar
- 62.Goldberg RM, Sargent DJ, Morton RF et al (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22(1):23–30. https://doi.org/10.1200/JCO.2004.09.046 CrossRefPubMedGoogle Scholar
- 63.Yamazaki K, Nagase M, Tamagawa H et al (2016) Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol 27(8):1539–1546. https://doi.org/10.1093/annonc/mdw206 CrossRefPubMedGoogle Scholar
- 64.García-Carbonero R, van Cutsem E, Rivera F et al (2017) Randomized phase II trial of Parsatuzumab (Anti-EGFL7) or placebo in combination with FOLFOX and Bevacizumab for first-line metastatic colorectal cancer. Oncologist 22(4):375–e30. https://doi.org/10.1634/theoncologist.2016-0133 CrossRefPubMedPubMedCentralGoogle Scholar
- 65.Pinter T, Klippel Z, Cesas A et al (2017) A phase III, randomized, double-blind, placebo-controlled trial of pegfilgrastim in patients receiving first-line FOLFOX/Bevacizumab or FOLFIRI/Bevacizumab for locally advanced or metastatic colorectal cancer: final results of the Pegfilgrastim and Anti-VEGF evaluation study (PAVES). Clin Colorectal Cancer 16(2):103–14. https://doi.org/10.1016/j.clcc.2016.08.008 CrossRefPubMedGoogle Scholar
- 66.Shi Q, De Gramont A, Grothey A et al (2015) Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database. J Clin Oncol 33(1):22. https://doi.org/10.1200/JCO.2014.56.5887 CrossRefPubMedGoogle Scholar
- 69.Daud A, Ribas A, Robert C et al (2015) Long-term efficacy of pembrolizumab pembro MK-3475 in a pooled analysis of 655 patients with advanced melanoma MEL enrolled in KEYNOTE001. ASCO Meet Abstr 33(15):9005. https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.9005