Left Versus Right: Does Location Matter for Refractory Metastatic Colorectal Cancer Patients in Phase 1 Clinical Trials?

  • Sukeshi Patel Arora
  • Norma S. Ketchum
  • Joel Michalek
  • Jonathon Gelfond
  • Devalingam Mahalingam
Original Research
  • 77 Downloads

Abstract

Purpose

Location of the primary tumor is prognostic and predictive of efficacy with VEGF-inhibitors (I) versus EGFR-I given first-line to metastatic colorectal cancer (mCRC) patients. However, little is known regarding the effect of location on prognosis and prediction in refractory mCRC. We assessed the efficacy of VEGF-I and EGFR-I in regards to location of the primary tumor in patients with refractory mCRC enrolled in early phase studies.

Methods

A historical cohort analysis of mCRC patients, including 44 phase I trials our institution, from March 2004 to September 2012. Median Progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log-rank test.

Results

One hundred thirty-nine patients with a median age 59 (33–81). 73.9% received 3+ lines of therapy. All KRAS wild-type patients had received prior EGFR-I. Location: right 20.9%, left 61.9%, and transverse 4.3%. For survival analysis, transverse CRC were included with right. Of the 112 patients, mOS was left (N = 80) 6.6 months versus right (N = 32) 5.9 months, P = 0.18. mPFS was left (n = 86) 2.0 months versus right (N = 35) 2.0 months, P = 0.76. In subgroup analysis, survival was significant for KRAS wild-type patients with left-sided mCRC had mOS of 6.2 months with other agents versus 9.4 months with EGFR-I (P = 0.03).

Conclusions

In phase 1 clinical trials, although location alone was not prognostic in heavily pretreated patients, left-sided mCRC had improved survival with EGFR-I. Despite progression on EGFR-I, left-sided KRAS wild mCRC patients should be considered for phase 1 studies of agents targeting growth factor pathways.

Keywords

Colorectal cancer Early phase clinical trials Location EGFR inhibitors 

Notes

Acknowledgements

NCI P30CA054174 (All Authors), NIA P30AG044271 (Sukeshi Patel Arora).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Funding

P30 Cancer Center Support Grant No. CA054174 (all authors), NIA P30AG044271 (Sukeshi Patel Arora).

Ethical Approval

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 or comparable ethical standards.

References

  1. 1.
    Benson 3rd AB, Bekaii-Saab T, Chan E, Chen YJ, Choti MA, Cooper HS, Engstrom PF, Enzinger PC, Fakih MG, Fenton MJ, Fuchs CS, Grem JL, Hunt S, Kamel A, Leong LA, Lin E, May KS, Mulcahy MF, Murphy K, Rohren E, Ryan DP, Saltz L, Sharma S, Shibata D, Skibber JM, Small Jr W, Sofocleous CT, Venook AP, Willett CG, Gregory KM, Freedman-Cass DA. Metastatic colon cancer, version 3.2013: featured updates to the NCCN guidelines. Journal of the National Comprehensive Cancer Network : JNCCN. 2013;11(2):141–52. quiz 152CrossRefPubMedGoogle Scholar
  2. 2.
    Gervaz P, Bucher P, Morel P. Two colons-two cancers: paradigm shift and clinical implications. J Surg Oncol. 2004;88(4):261–6. doi: 10.1002/jso.20156.CrossRefPubMedGoogle Scholar
  3. 3.
    Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med. 1990;113(10):779–88.CrossRefPubMedGoogle Scholar
  4. 4.
    Warschkow R, Sulz MC, Marti L, Tarantino I, Schmied BM, Cerny T, Guller U. Better survival in right-sided versus left-sided stage I – III colon cancer patients. BMC Cancer. 2016;16:554. doi: 10.1186/s12885-016-2412-0.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F, Esser R, Lenz HJ, Heinemann V. 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. 2016; doi: 10.1001/jamaoncol.2016.3797.Google Scholar
  6. 6.
    Brule SY, Jonker DJ, Karapetis CS, O'Callaghan CJ, Moore MJ, Wong R, Tebbutt NC, Underhill C, Yip D, Zalcberg JR, Tu D, Goodwin RA. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015;51(11):1405–14. doi: 10.1016/j.ejca.2015.03.015.CrossRefPubMedGoogle Scholar
  7. 7.
    Kim SE, Paik HY, Yoon H, Lee JE, Kim N, Sung MK. Sex- and gender-specific disparities in colorectal cancer risk. World journal of gastroenterology : WJG. 2015;21(17):5167–75. doi: 10.3748/wjg.v21.i17.5167.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Nitsche U, Stogbauer F, Spath C, Haller B, Wilhelm D, Friess H, Bader FG. Right sided colon cancer as a distinct histopathological subtype with reduced prognosis. Dig Surg. 2016;33(2):157–63. doi: 10.1159/000443644.CrossRefPubMedGoogle Scholar
  9. 9.
    Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, Marisa L, Roepman P, Nyamundanda G, Angelino P, Bot BM, Morris JS, Simon IM, Gerster S, Fessler E, De Sousa EMF, Missiaglia E, Ramay H, Barras D, Homicsko K, Maru D, Manyam GC, Broom B, Boige V, Perez-Villamil B, Laderas T, Salazar R, Gray JW, Hanahan D, Tabernero J, Bernards R, Friend SH, Laurent-Puig P, Medema JP, Sadanandam A, Wessels L, Delorenzi M, Kopetz S, Vermeulen L, Tejpar S. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6. doi: 10.1038/nm.3967.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mao C, Wu XY, Yang ZY, Threapleton DE, Yuan JQ, Yu YY, Tang JL. Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases. Sci Rep. 2015;5:8065. doi: 10.1038/srep08065.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Janku F. Tumor heterogeneity in the clinic: is it a real problem? Ther Adv Med Oncol. 2014;6(2):43–51. doi: 10.1177/1758834013517414.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Sukeshi Patel Arora
    • 1
  • Norma S. Ketchum
    • 1
  • Joel Michalek
    • 1
  • Jonathon Gelfond
    • 1
  • Devalingam Mahalingam
    • 1
  1. 1.Cancer Therapy and Research CenterUniversity of Texas Health Science Center San AntonioSan AntonioUSA

Personalised recommendations