UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Therapy for metastatic colorectal cancer in elderly patients and those with a poor performance status

Author
Hanna K Sanoff, MD, MPH
Section Editor
Richard M Goldberg, MD
Deputy Editor
Diane MF Savarese, MD

INTRODUCTION

Colorectal cancer (CRC) is a leading cause of cancer-related death in the United States and other developed countries. Rarely diagnosed before the age of 40 except in familial CRC syndromes, the incidence of CRC steadily increases with age [1]. Approximately 70 percent of cases develop over the age of 65; 40 percent are 75 years or older. The United States Census bureau projects that by the year 2030 the number of Americans over age 65 will double [2]. As a result, the number of patients over the age of 70 presenting for CRC care is expected to rise.

Although a few patients with metastatic CRC (mCRC) are potentially resectable for cure (particularly those with isolated liver metastases), treatment for most patients is palliative and generally consists of systemic chemotherapy. For decades, fluorouracil (FU) was the sole active agent. This has changed markedly since the year 2000, with the approval of irinotecan; oxaliplatin; three humanized monoclonal antibodies that target either vascular endothelial growth factor (VEGF, bevacizumab) or the epidermal growth factor receptor (EGFR, cetuximab and panitumumab); and most recently, intravenous aflibercept, a recombinant fusion protein consisting of VEGF binding portions from the human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1, the small molecule multikinase inhibitor regorafenib, and trifluridine-tipiracil (TAS-102), an oral cytotoxic agent that consists of the nucleoside analog trifluridine (a cytotoxic antimetabolite that inhibits thymidylate synthetase and induces DNA strand breaks) and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well. The best way to combine and sequence these agents is still not established. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations".)

This topic review will cover issues related to systemic chemotherapy for nonresectable mCRC in elderly patients and those with a poor performance status. General principles of chemotherapy treatment for mCRC, clinical trials data, and specific treatment recommendations for non-elderly patients are presented elsewhere, as is adjuvant chemotherapy for elderly patients with colon cancer and the management of potentially resectable CRC liver and lung metastases. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles" and "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials" and "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations" and "Adjuvant therapy for resected colon cancer in elderly patients" and "Management of potentially resectable colorectal cancer liver metastases" and "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation and techniques".)

CHALLENGES SPECIFIC TO THE ELDERLY

The essential principles of treating metastatic colorectal cancer (mCRC) in the elderly are the same as in younger patients. However, in older patients, who may have age-related organ function decline and medical comorbidity, special attention must be paid to the risks of chemotherapy (both treatment-related toxicity and quality of life [QOL] issues), particularly in the context of estimated life expectancy. Age-related organ function changes that are relevant to the treatment of patients with CRC are outlined in the table (table 1). A thorough discussion of the age-related changes that should be considered when assessing the risk of systemic chemotherapy for mCRC is presented elsewhere. (See "Systemic chemotherapy for cancer in elderly persons".)

Quality of life issues — Quality of life (QOL) is a crucial component of decision-making when treating older patients. The available data suggest that older patients are just as willing to try chemotherapy as their younger counterparts, but less willing to endure severe treatment-related side effects.

                           

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Tue Aug 30 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Ries L, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/csr/1975_2006/ (Accessed on March 14, 2011).
  2. http://www.census.gov/population/www/projections/usinterimproj/ (Accessed on March 14, 2011).
  3. Sanoff HK, Goldberg RM, Pignone MP. A systematic review of the use of quality of life measures in colorectal cancer research with attention to outcomes in elderly patients. Clin Colorectal Cancer 2007; 6:700.
  4. Seymour MT, Thompson LC, Wasan HS, et al. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet 2011; 377:1749.
  5. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006; 24:4085.
  6. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol 2011; 29:3457.
  7. Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22:229.
  8. Papamichael D, Audisio RA, Glimelius B, et al. Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013. Ann Oncol 2015; 26:463.
  9. Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. Colorectal Cancer Collaborative Group. BMJ 2000; 321:531.
  10. Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004; 22:1209.
  11. Sanoff HK, Sargent DJ, Campbell ME, et al. Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol 2008; 26:5721.
  12. Howard DH, Kauh J, Lipscomb J. The value of new chemotherapeutic agents for metastatic colorectal cancer. Arch Intern Med 2010; 170:537.
  13. McKibbin T, Frei CR, Greene RE, et al. Disparities in the use of chemotherapy and monoclonal antibody therapy for elderly advanced colorectal cancer patients in the community oncology setting. Oncologist 2008; 13:876.
  14. Stein BN, Petrelli NJ, Douglass HO, et al. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer 1995; 75:11.
  15. D'Andre S, Sargent DJ, Cha SS, et al. 5-Fluorouracil-based chemotherapy for advanced colorectal cancer in elderly patients: a north central cancer treatment group study. Clin Colorectal Cancer 2005; 4:325.
  16. Rothenberg ML, Cox JV, DeVore RF, et al. A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 1999; 85:786.
  17. Hochster HS, Luo W, Popa EC, et al. Phase II study of uracil-tegafur with leucovorin in elderly (> or = 75 years old) patients with colorectal cancer: ECOG 1299. J Clin Oncol 2007; 25:5397.
  18. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355:1041.
  19. Folprecht G, Seymour MT, Saltz L, et al. Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer: combined analysis of 2,691 patients in randomized controlled trials. J Clin Oncol 2008; 26:1443.
  20. Aparicio T, Desramé J, Lecomte T, et al. Oxaliplatin- or irinotecan-based chemotherapy for metastatic colorectal cancer in the elderly. Br J Cancer 2003; 89:1439.
  21. Sastre J, Marcuello E, Masutti B, et al. Irinotecan in combination with fluorouracil in a 48-hour continuous infusion as first-line chemotherapy for elderly patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors study. J Clin Oncol 2005; 23:3545.
  22. Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999; 341:2061.
  23. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA 2004; 291:2720.
  24. Folprecht G, Cunningham D, Ross P, et al. Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: a pooled analysis of clinical trials. Ann Oncol 2004; 15:1330.
  25. Sargent DJ, Goldberg RM, Jacobson SD, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 2001; 345:1091.
  26. Sastre J, Aranda E, Massutí B, et al. Elderly patients with advanced colorectal cancer derive similar benefit without excessive toxicity after first-line chemotherapy with oxaliplatin-based combinations: comparative outcomes from the 03-TTD-01 phase III study. Crit Rev Oncol Hematol 2009; 70:134.
  27. Arkenau HT, Graeven U, Kubicka S, et al. Oxaliplatin in combination with 5-fluorouracil/leucovorin or capecitabine in elderly patients with metastatic colorectal cancer. Clin Colorectal Cancer 2008; 7:60.
  28. Jackson NA, Barrueco J, Soufi-Mahjoubi R, et al. Comparing safety and efficacy of first-line irinotecan/fluoropyrimidine combinations in elderly versus nonelderly patients with metastatic colorectal cancer: findings from the bolus, infusional, or capecitabine with camptostar-celecoxib study. Cancer 2009; 115:2617.
  29. Aparicio T, Jouve JL, Teillet L, et al. Geriatric factors predict chemotherapy feasibility: ancillary results of FFCD 2001-02 phase III study in first-line chemotherapy for metastatic colorectal cancer in elderly patients. J Clin Oncol 2013; 31:1464.
  30. Popescu RA, Norman A, Ross PJ, et al. Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older. J Clin Oncol 1999; 17:2412.
  31. Daniele B, Rosati G, Tambaro R, et al. First-line chemotherapy with fluorouracil and folinic acid for advanced colorectal cancer in elderly patients: a phase II study. J Clin Gastroenterol 2003; 36:228.
  32. Magné N, François E, Broisin L, et al. Palliative 5-fluorouracil-based chemotherapy for advanced colorectal cancer in the elderly: results of a 10-year experience. Am J Clin Oncol 2002; 25:126.
  33. de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 1997; 15:808.
  34. Ho C, Ng K, O'Reilly S, Gill S. Outcomes in elderly patients with advanced colorectal cancer treated with capecitabine: a population-based analysis. Clin Colorectal Cancer 2005; 5:279.
  35. Ershler WB. Capecitabine use in geriatric oncology: an analysis of current safety, efficacy, and quality of life data. Crit Rev Oncol Hematol 2006; 58:68.
  36. Petrioli R, Pascucci A, Francini E, et al. Continuous oral capecitabine at fixed dose in patients older than 75 years with metastatic colorectal and gastric cancer: a study of the Multidisciplinary Oncology Group on Gastrointestinal Tumors. Anticancer Drugs 2008; 19:91.
  37. Pasetto LM, Monfardini S. The role of capecitabine in the treatment of colorectal cancer in the elderly. Anticancer Res 2006; 26:2381.
  38. Feliu J, Escudero P, Llosa F, 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.
  39. Cassidy J, Twelves C, Van Cutsem E, et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 2002; 13:566.
  40. Louie SG, Ely B, Lenz HJ, et al. Higher capecitabine AUC in elderly patients with advanced colorectal cancer (SWOGS0030). Br J Cancer 2013; 109:1744.
  41. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: Oral chemotherapy. J Natl Compr Canc Netw 2008; 6 Suppl 3:S1.
  42. Figer A, Perez-Staub N, Carola E, et al. FOLFOX in patients aged between 76 and 80 years with metastatic colorectal cancer: an exploratory cohort of the OPTIMOX1 study. Cancer 2007; 110:2666.
  43. Mattioli R, Massacesi C, Recchia F, et al. High activity and reduced neurotoxicity of bi-fractionated oxaliplatin plus 5-fluorouracil/leucovorin for elderly patients with advanced colorectal cancer. Ann Oncol 2005; 16:1147.
  44. Cen P, Liu C, Du XL. Comparison of toxicity profiles of fluorouracil versus oxaliplatin regimens in a large population-based cohort of elderly patients with colorectal cancer. Ann Oncol 2012; 23:1503.
  45. Folprecht G, Rougier P, Saltz L, et al. Irinotecan in first line therapy of elderly and non-elderly patients wtih metastatic colorectal cancer: Meta-analysis of four trials investigating 5-FU and irinotecan (abstract #3578). J Clin Oncol 2006; 24:165s.
  46. Souglakos J, Pallis A, Kakolyris S, et al. Combination of irinotecan (CPT-11) plus 5-fluorouracil and leucovorin (FOLFIRI regimen) as first line treatment for elderly patients with metastatic colorectal cancer: a phase II trial. Oncology 2005; 69:384.
  47. François E, Berdah JF, Chamorey E, et al. Use of the folinic acid/5-fluorouracil/irinotecan (FOLFIRI 1) regimen in elderly patients as a first-line treatment for metastatic colorectal cancer: a Phase II study. Cancer Chemother Pharmacol 2008; 62:931.
  48. Mitry E, et al. Phase III trial of chemotherapy with or without irinotecan in the front-line treatment of metastatic colorectal cancer in elderly patients (FFCD 2001-02 trial): Results of a planned interim analysis (abstract). Data presented at the 2008 ASCO Gastrointestinal Cancers symposium, Orlando, Fl, January 25-27, 2008.
  49. Kuboki Y, Mizunuma N, Chin K, et al. Grade 3/4 neutropenia and febrile neutropenia in elderly patients with mCRC receiving second-line FOLFIRI4 after first-line FOLFOX4: a single institution experience qwith 35 patients (abstract #429). Data presented at the 2009 ASCO Gastrointestinal Cancers Symposium, January 15-17, San Francisco, CA, USA.
  50. Aparicio T, Lavau-Denes S, Phelip JM, et al. 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 2016; 27:121.
  51. Rothenberg ML, Meropol NJ, Poplin EA, et al. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001; 19:3801.
  52. Cunningham D, Pyrhönen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998; 352:1413.
  53. Rougier P, Van Cutsem E, Bajetta E, et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998; 352:1407.
  54. Fuchs CS, Moore MR, Harker G, et al. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 2003; 21:807.
  55. Chau I, Norman AR, Cunningham D, et al. Elderly patients with fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer derive similar benefit without excessive toxicity when treated with irinotecan monotherapy. Br J Cancer 2004; 91:1453.
  56. Sanoff HK, Bleiberg H, Goldberg RM. Managing older patients with colorectal cancer. J Clin Oncol 2007; 25:1891.
  57. Comella P, Natale D, Farris A, et al. Capecitabine plus oxaliplatin for the first-line treatment of elderly patients with metastatic colorectal carcinoma: final results of the Southern Italy Cooperative Oncology Group Trial 0108. Cancer 2005; 104:282.
  58. Feliu J, Salud A, Escudero P, et al. XELOX (capecitabine plus oxaliplatin) as first-line treatment for elderly patients over 70 years of age with advanced colorectal cancer. Br J Cancer 2006; 94:969.
  59. Comondone P, Pochettino P, Bergnolo A, et al. Capecitabine and oxaliplatin: A phase II study with a new schedule of adminstration in elderly patients with advanced colorectal cancer (abstract # 3681). J Clin Oncol 2005; 23:291s.
  60. Fiorentini G, Dentico P, Cantore M, et al. Capecitabine (XE) plus irinotecan (IRI) as second-line treatment (XELIRI) for metastatic colorectal cancer in elderly patients: feasibility and safety results from a phase II study (abstract # 3676). J Clin Oncol 2005; 23:289s.
  61. Twelves CJ, Butts CA, Cassidy J, et al. Capecitabine/oxaliplatin, a safe and active first-line regimen for older patients with metastatic colorectal cancer: post hoc analysis of a large phase II study. Clin Colorectal Cancer 2005; 5:101.
  62. Rosati G, Cordio S, Bordonaro R, et al. Capecitabine in combination with oxaliplatin or irinotecan in elderly patients with advanced colorectal cancer: results of a randomized phase II study. Ann Oncol 2010; 21:781.
  63. Hurwitz HI, Tebbutt NC, Kabbinavar F, et al. Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. Oncologist 2013; 18:1004.
  64. Cassidy J, Saltz LB, Giantonio BJ, et al. Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies. J Cancer Res Clin Oncol 2010; 136:737.
  65. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007; 99:1232.
  66. Avastin full prescribing information http://www.gene.com/gene/products/information/oncology/avastin/insert.jsp (Accessed on March 14, 2011).
  67. Sugrue MM, Yi J, Purdie D, et al. Serious arterial thromboembolic events (SATE) in patients with metastatic colorectal cancer (mCRC) treated with bevcizumab: results from the BRiTE registry (abstract). J Clin Oncol 2007; 25:197s.
  68. Kabbinavar FF, Schulz J, McCleod M, 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.
  69. Giantonio BJ, Levy DE, O'dwyer PJ, et al. A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200. Ann Oncol 2006; 17:1399.
  70. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335.
  71. Kozloff MF, Sugrue MM, Purdie DM, et al. Safety and effectiveness of bevacizumab and chemotherapy in elderly patients with metastatic colorectal cancer: Results from the BRiTE observational cohort study (abstract). J Clin Oncol 2008; 26:184s.
  72. Feliu J, Safont MJ, Salud A, et al. Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer. Br J Cancer 2010; 102:1468.
  73. Puthillath A, Mashtare T Jr, Wilding G, 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.
  74. Meyerhardt JA, Li L, Sanoff HK, et al. Effectiveness of bevacizumab with first-line combination chemotherapy for Medicare patients with stage IV colorectal cancer. J Clin Oncol 2012; 30:608.
  75. Tsai HT, Marshall JL, Weiss SR, et al. Bevacizumab use and risk of cardiovascular adverse events among elderly patients with colorectal cancer receiving chemotherapy: a population-based study. Ann Oncol 2013; 24:1574.
  76. Kozloff MF, Berlin J, Flynn PJ, 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.
  77. Cunningham D, Lang I, Marcuello E, et al. 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 2013; 14:1077.
  78. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012; 30:3499.
  79. Tabernero J, Van Cutsem E, Lakomý R, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 2014; 50:320.
  80. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance) (abstract). J Clin Oncol 34, 2016 (suppl; abstr 3504). http://meetinglibrary.asco.org/content/161936-176 (Accessed on August 26, 2016).
  81. Bouchahda M, Macarulla T, Spano JP, 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.
  82. Jehn CF, Böning L, Kröning H, et al. Cetuximab-based therapy in elderly comorbid patients with metastatic colorectal cancer. Br J Cancer 2012; 106:274.
  83. 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 KRAS status from a Spanish TTD Group Study. Oncologist 2012; 17:339.
  84. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25:1658.
  85. Pietrantonio F, Cremolini C, Aprile G, et al. Single-Agent Panitumumab in Frail Elderly Patients With Advanced RAS and BRAF Wild-Type Colorectal Cancer: Challenging Drug Label to Light Up New Hope. Oncologist 2015; 20:1261.
  86. Sastre J, Massuti B, Pulido G, et al. First-line single-agent panitumumab in frail elderly patients with wild-type KRAS metastatic colorectal cancer and poor prognostic factors: A phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours. Eur J Cancer 2015; 51:1371.
  87. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381:303.
  88. Van Cutsem E, Sobrero AF, Siena S, et al. Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC) (abstract). J Clin Oncol 30, 2012 (Suppl Abstr 3502). http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=114&abstractID=94460 (Accessed on February 04, 2013).
  89. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015; 372:1909.
  90. Adam R, Frilling A, Elias D, et al. Liver resection of colorectal metastases in elderly patients. Br J Surg 2010; 97:366.
  91. de Liguori Carino N, van Leeuwen BL, Ghaneh P, et al. Liver resection for colorectal liver metastases in older patients. Crit Rev Oncol Hematol 2008; 67:273.
  92. Tamandl D, Gruenberger B, Herberger B, et al. Surgery after neoadjuvant chemotherapy for colorectal liver metastases is safe and feasible in elderly patients. J Surg Oncol 2009; 100:364.
  93. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; 24:2065.
  94. Onaitis MW, Petersen RP, Haney JC, et al. Prognostic factors for recurrence after pulmonary resection of colorectal cancer metastases. Ann Thorac Surg 2009; 87:1684.
  95. Lee WS, Yun SH, Chun HK, et al. Pulmonary resection for metastases from colorectal cancer: prognostic factors and survival. Int J Colorectal Dis 2007; 22:699.
  96. Yedibela S, Klein P, Feuchter K, et al. Surgical management of pulmonary metastases from colorectal cancer in 153 patients. Ann Surg Oncol 2006; 13:1538.
  97. Iizasa T, Suzuki M, Yoshida S, et al. Prediction of prognosis and surgical indications for pulmonary metastasectomy from colorectal cancer. Ann Thorac Surg 2006; 82:254.
  98. Kanemitsu Y, Kato T, Hirai T, Yasui K. Preoperative probability model for predicting overall survival after resection of pulmonary metastases from colorectal cancer. Br J Surg 2004; 91:112.
  99. Crosara Teixeira M, Marques DF, Ferrari AC, et al. The effects of palliative chemotherapy in metastatic colorectal cancer patients with an ECOG performance status of 3 and 4. Clin Colorectal Cancer 2015; 14:52.
  100. Sargent DJ, Köhne CH, Sanoff HK, et al. Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer. J Clin Oncol 2009; 27:1948.
  101. Seymour MT, Maughan TS, Wasan HS, et al. Capecitabine and oxaliplatin in elderly and/or frail patrients with metastatic colorectal cancer: the FOCUS2 trial (abstract #9030). J Clin Oncol 2007; 25:500s.
  102. Kim GP, Sargent DJ, Mahoney MR, et al. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol 2009; 27:2848.