Survival outcome and prognostic model of patients with colorectal cancer on phase 1 trials

  • Audrey E. Kam
  • Gopichand Pendurti
  • Umang H. Shah
  • Mohammad H. Ghalib
  • Imran Chaudhary
  • Jennifer Chuy
  • Lakshmi Rajdev
  • Andreas Kaubisch
  • Santiago Aparo
  • Ioannis Mantzaris
  • Sanjay GoelEmail author


Background Patients with metastatic colorectal cancer (mCRC) who progress on standard therapies may be eligible for phase I trials. To better delineate the risk-benefit ratio, we assessed toxicities, clinical outcomes and prognostic factors. Methods Records of mCRC patients on phase I trials at our institution over 18 years were reviewed. Univariable (UVA) and multivariable analyses (MVA) were undertaken and a prognostic model developed. Results There were 187 enrollments on 37 phase I trials. Median age was: 59 (29–83) years and number of prior therapies: 3 (0–8). The clinical benefit rate (CBR): response (5.6%) + stable disease, was 43.1%. Median progression free survival (PFS) and overall survival (OS) was 7.7 weeks and 43.7 weeks, respectively. The MVA identified age > 60 years (HR 1.63, p < 0.004), albumin<3.5 g/dL (HR 3.69, p < 0.001), direct bilirubin>ULN (HR1.69, p < 0.01), and WBC ≥ 5.2 k/uL (HR 1.97, p < 0.001) as negative prognostic factors. A risk score based on the MVA revealed that patients with a score of 0–1 had an improved OS (58.7 weeks) compared to a score of 2 (49.9 weeks, p < 0.01) and 3 (14.1 weeks, p < 0.001). Conclusions Phase 1 trials may offer similar or better clinical outcome for mCRC patients than standard third line therapies; the prognostic model could assist in selecting appropriate patients.


Survival Colorectal cancer Phase I trials 


Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

Each individual clinical trial from which data was extracted was approved by the ethics committee of Montefiore Medical Center. Each individual trial was performed in accordance with the 1964 Helsinki declaration and its later amendments.

Informed consent

All patients entering the clinical trials have signed the informed consent document.

Supplementary material

10637_2018_675_MOESM1_ESM.doc (42 kb)
Supplementary Table A1 (DOC 41 kb)


  1. 1.
    SEER Cancer Stat Facts: Colorectal Cancer [Internet]. Bethesda, MD: National Cancer Institute. 1975 – [cited 2017 Oct 9]. Available from:
  2. 2.
    Hoff PM, Ansari R, Batist R, Cox J, Kocha W, Kuperminc M et al (2001) Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19:2282–2292CrossRefGoogle Scholar
  3. 3.
    Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-batran SE 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
  4. 4.
    Venook A, Niedzwiecki D, Lenz H, Mahoney M, Innocenti F, O’Neil B et al (2014) CALGB/SWOG 80405: Analysis of patients undergoing surgery as part of treatment strategy. Ann Oncol 25:1–41 (abstr LBA10)CrossRefGoogle Scholar
  5. 5.
    U.S. Food and Drug Administration: FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. Available at: Accessed May 30, 2018
  6. 6.
    Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, André T (2017) Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142). Lancet Oncol 18:1182–1191CrossRefGoogle Scholar
  7. 7.
    Arkenau H, Olmos D, Ang JE, de Bono J, Judson I, Kaye S (2008) Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience. Br J Cancer 98(6):1029–1033CrossRefGoogle Scholar
  8. 8.
    Arkenau H, Barriuso J, Olmos D, Ang JE, de Bono J, Judson I et al (2009) Prospective validation of a prognostic score to improve patient selection for oncology phase I trials. J Clin Oncol 27:2692–2696CrossRefGoogle Scholar
  9. 9.
    Bachelot T, Ray-Coquard I, Catimel G, Ardiet C, Guastalla JP, Dumortier A, Chauvin F, Droz JP, Philip T, Clavel M (2000) Multivariable analysis of prognostic factors for toxicity and survival for patients enrolled in phase I clinical trials. Ann Oncol 11(2):151–156CrossRefGoogle Scholar
  10. 10.
    Han C, Braybrooke JP, Deplanque G, Taylor M, Mackintosh D, Kaur K, Samouri K, Ganesan TS, Harris AL, Talbot DC (2003) Comparison of prognostic factors in patients in phase I trials of cytotoxic drugs vs new noncytotoxic agents. Br J Cancer 89(7):1166–1171CrossRefGoogle Scholar
  11. 11.
    Italiano A, Massard C, Bahleda R, Vataire AL, Deutsch E, Magné N, Pignon JP, Vassal G, Armand JP, Soria JC (2008) Treatment outcome and survival in participants of phase I oncology trials carried out from 2003 to 2006 at Institut Gustave Roussy. Ann Oncol 19(4):787–792CrossRefGoogle Scholar
  12. 12.
    Wheler J, Tsimberidou AM, Hong D, Naing A, Falchook G, Piha-Paul S, Fu S, Moulder S, Stephen B, Wen S, Kurzrock R (2012) Survival of 1,181 patients in a phase I clinic: the MD Anderson Clinical Center for targeted therapy experience. Clin Cancer Res 18(10):2922–2929CrossRefGoogle Scholar
  13. 13.
    Yamamoto N, Tamura T, Fukuoka M, Saijo N (1999) Survival and prognostic factors in lung cancer patients treated in phase I trials: Japanese experience. Int J Oncol 15(4):737–741PubMedGoogle Scholar
  14. 14.
    Arkenau H, Olmos D, Ang JE, Barriuso J, Karavasillis V, Ashley S et al (2008) 90-days mortality rate in patients treated within the context of a phase-I trial: how should we identify patients who should not go on trial? Eur J Cancer 44:1536–1540CrossRefGoogle Scholar
  15. 15.
    Chau NG, Florescu A, Chan K, Wang L, Chen EX, Bedard P et al (2011) Early mortality and overall survival in oncology phase 1 trial participants: can we improve patient selection? BMC Cancer 11(426):1–10Google Scholar
  16. 16.
    Grothey A, Van Custem E, Sobrero A, Siena S, Falcone A, Ychou M et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312CrossRefGoogle Scholar
  17. 17.
    Mayer RJ, Van Custem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N et al (2015) Randomized trial of TAS-102 for refractory metastatic colorectal Cancer. N Engl J Med 372:1909–1919CrossRefGoogle Scholar
  18. 18.
    Saltz L, Rubin M, Hochster H, Tchekmeydian NS, Waksa H, Needl MA (2001) Cetuximab (IMC-225) plus irinotecan is active in CPT-11-refractory colorectal cancer that expresses epidermal growth factor receptor (abstract). Proc Am Soc Clin Oncol 3a:20Google Scholar
  19. 19.
    Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA III (2008) EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26:2311–2319CrossRefGoogle Scholar
  20. 20.
    Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417CrossRefGoogle Scholar
  21. 21.
    Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S 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
  22. 22.
    Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, van Cutsem E (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345CrossRefGoogle Scholar
  23. 23.
    Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M (2002) Interferon alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289–296CrossRefGoogle Scholar
  24. 24.
    Heng DY, Xie W, Regan M, Warren MA, Golshayan AR, Sahi C et al (2009) Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor–targeted agents: results from a large, multicenter study. J Clin Oncol 27(34):5794–5799CrossRefGoogle Scholar
  25. 25.
    Janisch L, Mick R, Schilsky RL, Vogelzang NJ, O’Brien S, Kuf M et al (1994) Prognostic factors for survival in patients treated in phase I clinical trials. Cancer 74:1965–1973CrossRefGoogle Scholar
  26. 26.
    Penel N, Vanseymortier M, Bonneterre ME, Clisant S, Dansin E, Vendel Y, Beuscart R, Bonneterre J (2008) Prognostic factors among cancer patients with good performance status screened for phase I trials. Investig New Drugs 26:53–58CrossRefGoogle Scholar
  27. 27.
    Penel N, Delord JP, Bonneterre ME, Bachelot T, Ray-Coquard I, Blay JY, Pascal LB, Borel C, Filleron T, Adenis A, Bonneterre J (2010) Development and validation of a model that predicts early death among cancer patients participating in phase 1 clinical trials investigating cytotoxics. Investig New Drugs 28:76–82CrossRefGoogle Scholar
  28. 28.
    Fussenich LM, Desar IME, Peters ME, Teerenstra S, van der Graaf WT, Timmer-Bonte JN et al (2011) A new, simple and objective prognostic score for phase I cancer patients. Eur J Cancer 47:1152–1160CrossRefGoogle Scholar
  29. 29.
    Stavraka C, Pinato DJ, Turnbull SJ, Flynn MJ, Forster MD, O’Cathail SM et al (2013) Developing an objective marker to optimize patient selection and predict survival benefit in early-phase cancer trials. Cancer 120(1):262–270PubMedGoogle Scholar
  30. 30.
    Denson A, Burke N, Wapinsky G, Bertels B, Juan TH, Lee J, Springett GM, Strosberg JR, Kim RD, Sullivan DM, Mahipal A (2018) Clinical outcomes of patients with gastrointestinal malignancies participating in phase I clinical trials. Am J Clin Oncol 41(2):133–139PubMedGoogle Scholar
  31. 31.
    Hong DS, Patel JC, Wheler J, Naing A, Garrido-Laguna I, Falchook G, Fu S, Tsimberidou AM, Kopetz S, Win S, Kurzrock R (2012) Outcomes in 144 patients with colorectal cancer treated in a phase I clinic: the MD Anderson Cancer Center experience. Clin Colorectal Canc 11:297–303CrossRefGoogle Scholar
  32. 32.
    So KA, Hong JH, Jin HM, Kim JW, Song JY, Lee JK, Lee NW (2014) The prognostic significance of preoperative leukocytosis in epithelial ovarian carcinoma: a retrospective cohort study. Gynecol Oncol 132(3):551–555CrossRefGoogle Scholar
  33. 33.
    Mabuchi S, Matsumoto Y, Hamasaki T, Kawano M, Hisamatsu T, Mutch DG, Kimura T (2012) Elevated white blood cell count at the time of recurrence diagnosis is an indicator of short survival in patients with recurrent cervical cancer. Int J Gynecol Cancer 22(9):1545–1551PubMedGoogle Scholar
  34. 34.
    Tomita M, Shimizu T, Hara M, Ayabe T, Onitsuka T (2009) Preoperative leukocytosis, anemia and thrombocytosis are associated with poor survival in non-small cell lung cancer. Anticancer Res 29(7):2687–2690PubMedGoogle Scholar
  35. 35.
    Clarke CN, Kopetz ES (2015) BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies. J Gastrointestinal Oncol 6(6):660–667Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Audrey E. Kam
    • 1
  • Gopichand Pendurti
    • 2
    • 3
  • Umang H. Shah
    • 1
  • Mohammad H. Ghalib
    • 1
  • Imran Chaudhary
    • 1
  • Jennifer Chuy
    • 1
    • 3
  • Lakshmi Rajdev
    • 1
    • 3
  • Andreas Kaubisch
    • 1
    • 3
  • Santiago Aparo
    • 1
    • 3
  • Ioannis Mantzaris
    • 1
    • 3
  • Sanjay Goel
    • 1
    • 3
    Email author
  1. 1.Montefiore Medical CenterBronxUSA
  2. 2.Jacobi Medical CenterBronxUSA
  3. 3.Department of MedicineAlbert Einstein College of MedicineBronxUSA

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