Advertisement

Targeted Therapies in Older Patients with Metastatic Colorectal Cancer

  • Javier SastreEmail author
  • Jon Zugazagoitia
  • Aranzazu Manzano
  • Eduardo Díaz-Rubio
Chapter

Abstract

During the last years, targeted therapies have been incorporated to the treatment of patients with metastatic colorectal cancer. Whereas the main pivotal or registry studies of these drugs did not systematically exclude elderly people, they formed a minority of these cohorts. Data from studies nonselected by age and age-selected suggest that age alone should not be an exclusion criterion for receiving bevacizumab plus CT in mCRC. Fit elderly patients derive similar benefit in terms of RR, PFS, and OS with the use of bevacizumab plus CT. All studies are consistent in establishing that elderly patients have an increased incidence of ATEs with respect to younger ones, and therefore, those with a recent episode of myocardial infarction, stroke, or any other arterial thrombotic event should be excluded from receiving bevacizumab. Cetuximab and panitumumab seem to have a similar safety profile in the elderly compared to younger patients, either as single agent or in combination with CT. Thus, age alone should not be a condition to exclude the use of these drugs in the mCRC treatment setting.

Keywords

Metastatic Colorectal Older patients Monoclonal antibodies Elderly patients Colorectal cancer Bevacizumab EGFR inhibitors Targeted therapies 

References

  1. 1.
    Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist. 2000;5:224–37.PubMedCrossRefGoogle Scholar
  2. 2.
    Köhne CH, Folprecht G, Goldberg RM, Mitry E, Rougier P. Chemotherapy in elderly patients with colorectal cancer. Oncologist. 2008;13:390–402.PubMedCrossRefGoogle Scholar
  3. 3.
    Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol. 2001;19:1207–25.PubMedGoogle Scholar
  4. 4.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Kabbinavar F, Hurwitz H, Yi J, Sarkar S, Rosen O. Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. J Clin Oncol. 2008;27:199–205.PubMedCrossRefGoogle Scholar
  6. 6.
    Cassidy J, Saltz L, Giantonio B, Kabbinavar F, Hurwitz H, Rohr UP. Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies. J Cancer Res Clin Oncol. 2010;136:737–43.PubMedCrossRefGoogle Scholar
  7. 7.
    Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23:3697–705.PubMedCrossRefGoogle Scholar
  8. 8.
    Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;20:2013–9.CrossRefGoogle Scholar
  9. 9.
    Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from de Eastern Cooperative Oncology Group study E3200. J Clin Oncol. 2007;25:1539–44.PubMedCrossRefGoogle Scholar
  10. 10.
    Jackson N, Barrueco J, Soufi-Mahjoubi R, Marshall J, Mitchell E, Zhang X, et al. Comparing safety and efficacy of first-line irinotecan/fluoropyrimidine combinations in elderly versus nonelederly patients with metastatic colorectal cancer. Cancer. 2009;115:2617–29.PubMedCrossRefGoogle Scholar
  11. 11.
    Kozloff M, Yood MU, Berlin J, Flynn PJ, Kabbinavar FF, Purdie DM, et al. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist. 2009;14:862–70.PubMedCrossRefGoogle Scholar
  12. 12.
    Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, Di Bartolomeo M, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. 2009;20:1842–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Kozloff MF, Berlin J, Flyn PJ, Kabbinavar F, Ashby M, Dong W, et al. Clinical outcomes in elderly patients with metastatic colorectal cancer receiving bevacizumab and chemotherapy: results from the BRITE observational cohort study. Oncology. 2010;78:329–39.PubMedCrossRefGoogle Scholar
  14. 14.
    Van Cutsem E, Rivera F, Kretzchmar A, et al. Safety and efficacy of bevacizumab (BEV) and chemotherapy in elderly patients with metastatic colorectal cancer (mCRC): results from the BEAT observational cohort study. Eur J Cancer. 2009;7(2):349, Abstr 6.088.Google Scholar
  15. 15.
    Kubala E, Bartos J, Petruzelka LB, et al. Safety and effectiveness of bevacizumab (BEV) in combination with chemotherapy (CT) in elderly patients (pts) with metastatic colorectal cancer (mCRC) results from a large Czech observational registry. Gastrointestinal cancer symposium. 2010;Abstr 467.Google Scholar
  16. 16.
    Puthillath A, Mashtare T, Wilding G, Khushalani N, Steinbrenner L, Ross ME, et al. A phase II study of first-line biweekly capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer. Crit Rev Oncol Hematol. 2009;71:242–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Feliu J, Safont MJ, Salud A, Llosa F, García-Girón C, Bosch V, et al. Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer. Br J Cancer. 2010;102:1468–73.PubMedCrossRefGoogle Scholar
  18. 18.
    Feliu J, Escudero P, Llosa F, Bolanos M, Vicent JM, Yubero A, et al. Capecitabine as first-line treatment for patients older than 70 years with metastatic colorectal cancer: an oncopaz cooperative group study. J Clin Oncol. 2005;23:3104–11.PubMedCrossRefGoogle Scholar
  19. 19.
    Vrdoljak E, Omrcen T, Boban M, Hrabar A. Phase II study of bevacizumab in combination with capecitabine as first-line treatment in elderly patients with metastatic colorectal cancer. Anticancer Drugs. 2011;22:191–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Carreca IU, Bellomo F, Burgio SL, Carreca AP, Pernice G, Piazza D, et al. Capecitabine (XEL) and oxaliplatin (OX) in combination with bevacizumab (BEV) in the management of elderly patients with advanced colorectal cancer (ACRC): preliminary outcomes on safety and efficacy. Gastrointestinal cancer symposium. 2010;Abstr 411.Google Scholar
  21. 21.
    García-Foncillas J, Díaz-Rubio E. Progress in metastatic colorectal cancer: growing role of cetuximab to optimize clinical outcome. Clin Transl Oncol. 2010;12:533–42.PubMedCrossRefGoogle Scholar
  22. 22.
    Van Cutsem E, Köhne C-H, Lang I, et al. 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. 2011;29:2011–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011;22:1535–46.PubMedCrossRefGoogle Scholar
  24. 24.
    Saltz LB, Meropol NJ, Loehrer PJ, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22:1201–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-C335) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol. 2001;20:3a.Google Scholar
  26. 26.
    Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.PubMedCrossRefGoogle Scholar
  27. 27.
    Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Healther-Jane AU, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, et al. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)-results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol. 2011;22:118–26.PubMedCrossRefGoogle Scholar
  29. 29.
    Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr Y, Lutz MP, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:2311–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Van Cutsem E, Kohne 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;360:1408–17.PubMedCrossRefGoogle Scholar
  31. 31.
    Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.PubMedCrossRefGoogle Scholar
  32. 32.
    Folprecht G, Köhne C, Bokemeyer C, Rougier P, Schlichting M, Heeger S, et al. Cetuximab and 1st-line chemotherapy in elderly and younger patients with metastatic colorectal cancer (mCRC): a pooled analysis of the CRYSTAL and OPUS studies. Ann Oncol. 2010;21:Abstr 597P.Google Scholar
  33. 33.
    Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, et al. 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. 2011;377:2103–14.PubMedCrossRefGoogle Scholar
  34. 34.
    Bouchahda M, Macarulla T, Spano JP, Bachet JB, Lledo G, Andre T, et al. Cetuximab efficacy and safety in a retrospective cohort of elderly patients with heavily pretreated metastatic colorectal cancer. Crit Rev Oncol Hematol. 2008;67:255–62.PubMedCrossRefGoogle Scholar
  35. 35.
    Fornaro L, Baldi GG, Masi G, Allegrini G, Loupakis F, Vasile E, et al. Cetuximab plus irinotecan after irinotecan failure in elderly metastatic colorectal cancer patients: clinical outcome according to KRAS and BRAF mutational status. Crit Rev Oncol Hematol. 2011;78:243–51.PubMedCrossRefGoogle Scholar
  36. 36.
    Sastre J, Aranda E, Grávalos C, Massutí B, Varella-García M, Rivera F, et al. First-line single-agent cetuximab in elderly patients with metastátic colorectal cancer. A phase II clinical and molecular study of the Spanish group for digestive tumor therapy (TTD). Crit Rev Oncol Hematol. 2011;77:78–84.PubMedCrossRefGoogle Scholar
  37. 37.
    Sastre J, Grávalos C, Rivera F, et al. First-line cetuximab plus capecitabine in elderly patients with advanced colorectal cancer: clinical outcome and subgroup analysis according to k-ras status from a Spanish TTD Group Study. Oncologist. 2012;17:339–45.PubMedCrossRefGoogle Scholar
  38. 38.
    Van Cutsem E, Peeters M, Siena S, Humblet Y, Canon JL, Maurel J, et al. Open-label phase III trial of panitumumab plus best supportive care compared to best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658–64.PubMedCrossRefGoogle Scholar
  39. 39.
    Van Cutsem E, Siena S, Humblet Y, Canon JL, Maurel J, Bajetta E, et al. An open label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Ann Oncol. 2008;19:92–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. 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. 2010;28:4697–705.PubMedCrossRefGoogle Scholar
  41. 41.
    Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706–13.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  • Javier Sastre
    • 1
    Email author
  • Jon Zugazagoitia
    • 2
  • Aranzazu Manzano
    • 2
  • Eduardo Díaz-Rubio
    • 2
  1. 1.Gastrointestinal Unit, Oncology DepartmentHC San CarlosMadridSpain
  2. 2.Oncology DepartmentHC San CarlosMadridSpain

Personalised recommendations