International Journal of Clinical Oncology

, Volume 24, Issue 11, pp 1406–1411 | Cite as

Analysis of response-related endpoints in trials of first-line medical treatment of metastatic colorectal cancer

  • Giuseppe A. CollocaEmail author
  • Antonella Venturino
  • Domenico Guarneri
Original Article



Tumor radiologic response after systemic chemotherapy has been used as endpoint of trials of patients with metastatic colorectal cancer (mCRC), which can report the best overall response rate (ORR) and the disease control rate (DCR) by RECIST criteria as well as the early tumor shrinkage (ETS). The present study perform a trial-level analysis to verify whether such response-related endpoints are predictive of overall survival (OS).


After a systematic search, randomized clinical trials (RCTs) were selected each time they evaluated the three response endpoints and progression-free survival (PFS). Two arms per trial were selected, and the correlation between the difference in each endpoint and the difference in OS was calculated. The analysis then evaluated the effects of treatment on ∆ORR, or ∆DCR, ∆ETS, ∆PFS, and on ∆OS, using separate linear regressions for each of them, and the proportion of variability explained (R2trial) on OS for each of the four endpoints was calculated.


The systematic review of the literature led to the selection of 12 RCTs, 7 phase-3 and 5 phase-2. ETS reported a different performance in the entire sample compared to phase-3 trials (R2trial = 0.172 vs. 0.842), differently from DCR (R2trial = 0.541 vs. 0.816) and ORR (R2trial = 0.349 vs. 0.740). Surprisingly, PFS predicted OS with a weak correlation, which was not significant in the subgroup of phase-3 studies (R2trial = 0.455 vs. 0.466).


The results of the present trial-level analysis report a good performance of two response-related endpoints, DCR and ETS, and suggest that they could be differently used depending on the setting of disease and the type of medical treatment.


Overall response rate Disease control rate Early tumor shrinkage Prognosis Overall survival 




Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments.

Informed consent

For this type of study, formal consent is not required.


  1. 1.
    Malvezzi M, Carioli G, Bertuccio P et al (2018) European cancer mortality predictions for the year 2018 with focus on colorectal cancer. Ann Oncol 29:1016–1022CrossRefGoogle Scholar
  2. 2.
    Siegel R, Ma J, Zou Z et al (2014) Cancer statistics, 2014. CA Cancer J Clin 64:9–29CrossRefGoogle Scholar
  3. 3.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216CrossRefGoogle Scholar
  4. 4.
    Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefGoogle Scholar
  5. 5.
    Colloca G, Venturino A, Guarneri D (2016) Analysis of clinical end points of randomised trials including bevacizumab and chemotherapy versus chemotherapy as first-line treatment of metastatic colorectal cancer. Clin Oncol 28(10):e155–e164CrossRefGoogle Scholar
  6. 6.
    Choi H, Charnsangavej C, Faria SC et al (2007) Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 25(13):1753–1759CrossRefGoogle Scholar
  7. 7.
    Chun YS, Vauthey JN, Boonsirikamchai P et al (2009) Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. J Am Med Assoc 302(21):2338–2344CrossRefGoogle Scholar
  8. 8.
    Sakamaki K, Kito Y, Yamazaki K et al (2017) Exploration of time points and cut-off values for early tumor shrinkage to predict survival outcomes of patients with metastatic colorectal cancer treated with first-line chemotherapy using a biexponential model for change in tumour size. ESMO Open 2:e000275CrossRefGoogle Scholar
  9. 9.
    Colloca GA, Venturino A, Guarneri D (2019) Early tumor shrinkage after first-line medical treatment of colorectal cancer: a meta-analysis. Int J Clin Oncol 24:231–240CrossRefGoogle Scholar
  10. 10.
    Piessevaux H, Buyse M, Schlichting M et al (2013) Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 31:3764–3775CrossRefGoogle Scholar
  11. 11.
    Van Cutsem E, Kohne C-H, Lang I et al (2011) 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 29:2011–2019CrossRefGoogle Scholar
  12. 12.
    Douillard JY, Siena S, Cassidy J et al (2014) Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 25:1346–1355CrossRefGoogle Scholar
  13. 13.
    Douillard JY, Siena S, Peeters M et al (2015) Impact of early tumour shrinkage and resection on outcomes in patients with wild-type RAS metastatic colorectal cancer. Eur J Cancer 51:1231–1242CrossRefGoogle Scholar
  14. 14.
    Fischer von Weikersthal L, Schalhorn A, Stauch M et al (2011) Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. Eur J Cancer 47:206–214CrossRefGoogle Scholar
  15. 15.
    Giessen C, Laubender RP, Fischer von Weikersthal L et al (2013) Early tumor shrinkage in metastatic colorectal cancer: retrospective analysis from an irinotecan-based randomized first-line trial. Cancer Sci 104:718–724CrossRefGoogle Scholar
  16. 16.
    Ye LC, Liu TS, Ren L et al (2013) Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol 31:1931–1938CrossRefGoogle Scholar
  17. 17.
    Ye LC, Wei Y, Zhu DX et al (2015) Impact of early tumor shrinkage on clinical outcome in wild-type KRAS colorectal liver metastases treated with cetuximab. J Gastroenterol Hepatol 30:674–679CrossRefGoogle Scholar
  18. 18.
    Heinemann V, Fischer von Weikersthal L, 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 15:1065–1075CrossRefGoogle Scholar
  19. 19.
    Stintzing S, Modest DP, von Fischer Weikersthal L et al (2014) Independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306) in the final RAS evaluable population. Ann Oncol 25(suppl 5):LBA11Google Scholar
  20. 20.
    Loupakis F, Cremolini C, Masi G et al (2014) Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 371:1609–1618CrossRefGoogle Scholar
  21. 21.
    Cremolini C, Loupakis F, Lonardi S et al (2014) Early tumor shrinkage (ETS) and deepness of response (DoR) to predict progression-free, postprogression, and overall survival: results from the phase III TRIBE trial. J Clin Oncol 32(suppl 3):521CrossRefGoogle Scholar
  22. 22.
    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 27:1539–1546CrossRefGoogle Scholar
  23. 23.
    Nagase M, Yamazaki K, Tamagawa H et al (2015) The impact of early tumor shrinkage on survival in WJOG4407G trial, a randomized phase III trial of mFOLFOX6 plus bevacizumab versus FOLFIRI plus bevacizumab in first-line treatment for metastatic colorectal cancer. J Clin Oncol 33(suppl 3):679CrossRefGoogle Scholar
  24. 24.
    Bokemeyer C, Bondarenko I, Makhson A et al (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671CrossRefGoogle Scholar
  25. 25.
    Moosmann N, Fischer von Weikersthal L, Vehling-Kaiser U et al (2011) Cetuximab plus capecitabine and irinotecan compared with cetuximab plus capecitabine and oxaliplatin as first-line treatment for patients with metastatic colorectal cancer: AIO KRK-0104—a randomized trial of the German AIO CRC study group. J Clin Oncol 29:1050–1058CrossRefGoogle Scholar
  26. 26.
    Modest DP, Laubender RP, Stintzing S et al (2013) Early tumor shrinkage in patients with metastatic colorectal cancer receiving first-line treatment with cetuximab combined with either CAPIRI or CAPOX: an analysis of the German AIO KRK 0104 trial. Acta Oncol 52:956–962CrossRefGoogle Scholar
  27. 27.
    Ducreux M, Adenis A, Pignon J-P et al (2013) Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: final results from a randomized phase II study of bevacizumab plus 5-fluorouracil, leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study). Eur J Cancer 49:1236–1245CrossRefGoogle Scholar
  28. 28.
    Ichante J, Adenis A, Malka D et al (2011) Impact of early tumor shrinkage on long-term outcome in metastatic colorectal cancer (mCRC) treated with 5FU plus irinotecan plus leucovorin (FOLFIRI) or capecitabine plus irinotecan XELIRI plus bevacizumab. J Clin Oncol 29(suppl):e14041CrossRefGoogle Scholar
  29. 29.
    Schwartzberg LS, Rivera F, Karthaus M et al (2014) PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorinm and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 32:2240–2247CrossRefGoogle Scholar
  30. 30.
    Rivera F, Karthaus M, Hecht JR et al (2017) Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Colorectal Dis 32:1179–1190CrossRefGoogle Scholar
  31. 31.
    Carrato A, Abad A, Massuti B et al (2017) First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: a randomised, phase II trial (PLANET-TTD). Eur J Cancer 81:191–202CrossRefGoogle Scholar
  32. 32.
    Wolchock JD, Hoos A, O’Day S et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420CrossRefGoogle Scholar
  33. 33.
    Ciani O, Buyse M, Garside R et al (2015) Meta-analyses of randomized controlled trials show suboptimal validity of surrogate outcomes for overall survival in advanced colorectal cancer. J Clin Epidemiol 68(7):833–842CrossRefGoogle Scholar
  34. 34.
    Lamarca A, Barriuso J, Kulke M et al (2018) Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response. Br J Cancer 118:181–188CrossRefGoogle Scholar
  35. 35.
    Okuno M, Hatano E, Nishino H et al (2017) Does response rate of chemotherapy with molecular target agents correlate with the conversion rate and survival in patients with unresectable colorectal liver metastases? A systematic review. Eur J Surg Oncol 43(6):1003–1012CrossRefGoogle Scholar
  36. 36.
    Primrose J, Falk S, Finch-Jones M et al (2014) Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the new EPOC randomised controlled trial. Lancet Oncol 15(6):601–611CrossRefGoogle Scholar
  37. 37.
    Masaki C, Sugino K, Saito N et al (2017) Lenvatinib induces early tumor shrinkage in patients with advanced thyroid carcinoma. Endocrine J 64(8):819–826CrossRefGoogle Scholar
  38. 38.
    Kim ST, Jang K-T, Lee SJ et al (2015) Tumor shrinkage at 6 weeks predicts favorable clinical outcomes in a phase III study of gemcitabine and oxaliplatin with or without erlotinib for advanced biliary tract cancer. BMC Cancer 15:530CrossRefGoogle Scholar
  39. 39.
    Krajewski KM, Guo M, Van den Abbeele AD et al (2011) Comparison of four early posttherapy imaging changes (EPTIC; RECIST 1.0; tumor shrinkage, computed tomography tumor density, Choi criteria) in assessing outcome to vasculare endothelial growth factor-targeted therapy in patients with advanced renal cell carcinoma. Eur Urol 59:562–586CrossRefGoogle Scholar
  40. 40.
    Krajewski KM, Franketti Y, Nishino M et al (2014) 10% tumor diameter shrinkage on the first follow-up computed tomography predicts clinical outcome in patients with advanced renal cell carcinoma treated with angiogenesis inhibitors: a follow-up validation study. Oncologist 19:507–514CrossRefGoogle Scholar
  41. 41.
    Modest DP, Stintzing S, Fischer von Weikersthal L et al (2017) Relation of early tumor shrinkage (ETS) observed in first-line treatment to efficacy parameters of subsequent treatment in FIRE-3 (AIOKRK0306). Int J Cancer 140(8):1918–1925CrossRefGoogle Scholar
  42. 42.
    Taieb J, Rivera F, Siena S et al (2018) Exploratory analyses assessing the impact of early tumour shrinkage and depth of response on survival outcomes in patients with RAS wild-type metastatica colorectal cancer receiving treatment in three randomised panitumumab trials. J Cancer Res Clin Oncol 144(2):321–335CrossRefGoogle Scholar
  43. 43.
    Heinemann V, Stintzing S, Modest DP et al (2015) Early tumour shrinkage (ETS) and depth of response (DpR) in the treatment of patients with metastatic colorectal cancer (mCRC). Eur J Cancer 51:1927–1936CrossRefGoogle Scholar
  44. 44.
    Nakayama G, Gujii T, Murotani K et al (2016) Modified two-dimensional response as surrogate marker of overall survival in patients with metastatic colorectal cancer. Cancer Sci 107:1492–1498CrossRefGoogle Scholar
  45. 45.
    Fukada I, Araki K, Kobayashi K et al (2018) Pattern of tumor shrinkage during neoadjuvant chemotherapy is associated with prognosis in low-grade luminal early brast cancer. Radiology 286(1):49–57CrossRefGoogle Scholar
  46. 46.
    Shindoh J, Loyer EM, Kopetz S et al (2012) Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases. J Clin Oncol 30:4566–4572CrossRefGoogle Scholar
  47. 47.
    Heinemann V, Rivera F, O’Neil BH et al (2016) A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer. Eur J Cancer 67:11–20CrossRefGoogle Scholar
  48. 48.
    Ito M, Kusaba H, Mukaide S et al (2017) Early tumor shrinkage indicates a favorable response to bevacizumab-based first-line chemotherapy for metastatic colorectal cancer. Anticancer Drugs 28(10):1166–1173CrossRefGoogle Scholar
  49. 49.
    Qi W-X, Shen Z, Tang L-N et al (2014) Does the addition of targeted biological agents to first-line chemotherapy for advanced colorectal cancer increase complete response? A systematic review and meta-analysis. Colorectal Dis 16:O300–O307CrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2019

Authors and Affiliations

  1. 1.Department of OncologyOspedale Civile di SanremoSanremoItaly

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