New Developments in the Adjuvant Therapy of Stage II Colon Cancer
Risk Assessments in the Older Patient
By Nadine Jackson McCleary, MD, MPH1, Jeffrey A. Meyerhardt, MD, MPH2 |
January 25, 2010
1Department of Medical Oncology, Gastrointestinal Cancer Center, Instructor in Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts
2Assistant Professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts
When considering all patients with stage II colon cancer, 5-year overall survival is 82.5%. When this is delineated by substage of disease based on the American Joint Committee on Cancer’s AJCC Cancer Staging Manual (6th edition), overall survival is 85% for those with stage IIa (T3) and 72% for those with stage IIb (T4) disease. However, as with all solid tumors, AJCC staging alone does not fully predict recurrence rates and outcomes. Other factors impact on the cancer recurrence and mortality outcomes of patients. Oncologists often consider these other factors in guiding patients on the use of adjuvant therapy for stage II colon cancer.
Risk assessment depends largely on pathologic characteristics of the tumor, as well as clinical presentation, which indicate underlying tumor biology and potential for recurrence. Poor-risk pathologic factors include depth of invasion (T4 stage), less than 12 lymph nodes sampled at the time of resection, clinical bowel obstruction, clinical bowel perforation, poor histologic tumor grade, and lymphatic or vessel invasion.[24-29] In a single-center study of 448 patients with stage II colon cancer prospectively evaluated from 1990 to 2001, presence of T4 disease, preoperative carcinoemryonic antigen (CEA) level of 5 ng/mL, and lymphovascular or perineural invasion were identified as poor prognostic factors for disease-specific survival. Five-year disease-specific survival was greatly diminished for patients with two or more of these factors at 57%, compared to those with one factor (85%) or none (95%). These results indicate a need for further evaluation of this high-risk subset in clinical trials.
In a combined analysis of two early fluoropyrimidine adjuvant therapy trials (NCCTG and ECOG INT 0035), investigators have reported on subset analyses of stage II patients based on clinical prognostic features. In a cohort of 403 stage II patients, there was a 38% reduction in the rate of recurrence for treatment when compared with observation (P = .02, adjusting for perforation and location of primary tumor), but no improvement in survival (P = .91, adjusting for location of primary tumor and age). However, 5-year DFS was appreciably improved with adjuvant chemotherapy compared to observation in patients whose tumors adhered to another organ (87% vs 55%), invaded another organ (79% vs 45%), obstructed (76% vs 56%), or perforated (67% vs 43%). In exploratory analyses of MOSAIC, 5-year DFS in high-risk stage II patients (defined as at least one of the following: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion, or fewer than 10 lymph nodes examined) were 82.3% and 74.6% in the oxaliplatin(Drug information on oxaliplatin) arm compared to fluorouracil(Drug information on fluorouracil) and leucovorin alone (HR = 0.72; 95% CI = 0.50–1.02).
Molecular markers have been studied as tools for risk assessment in all stages of colon cancer, particularly stage II disease. While most studies have shown that microsatellite instability bodes a more favorable prognosis, the presence of tumoral 18q loss of heterozygosity has been associated with an inferior survival in some,[30-32] but not all, studies. Recently, Kerr and colleagues presented data on the value of a panel of markers in formulating a recurrence risk score as a predictive marker for stage II colon cancer. John Marshall further discusses molecular markers later in this supplement to ONCOLOGY.
Although some data are emerging regarding treatment effect of chemotherapy for stage III colon cancer in older patients,[35-38] there is a paucity of such data in the same population with stage II disease. In a review of Surveillance Epidemiology and End Results (SEER) and Medicare registries during 1991 to 1996, 62% of 3,151 Medicare patients diagnosed with stage II disease were 70 to 75 years old. Of those patients, 24% received chemotherapy. Ten percent of the cohort had two or more comorbid conditions. Older patients had a 23% increase risk of death compared to those 65 to 69 years old. Those with an increased number of comorbid conditions had a threefold higher increased risk of death. Data on patients ≥ 75 were not collected given prior evidence of low chemotherapy rates among those with stage III disease. While treatment was not predictive of survival, 5-year OS for the cohort was 78% in the treated group compared to 75% in the untreated group.
A key limitation of evidence to date is the relatively small number of elderly patients with stage II colon cancer enrolled in clinical trials. Whereas 70% to 75% of colorectal cancers are diagnosed in patients older than 65, only 40% to 48% of patients enrolled in National Cancer Institute (NCI)-sponsored or cooperative group trials are drawn from this age group . This underrepresentation of elderly patients with colorectal cancer has not improved in the past several years. From 2000 through 2002, only 0.5% of colorectal cancer patients ≥ 75 years enrolled in NCI-sponsored trials, substantially less than the 4% enrollment recorded for patients 30 to 64 years old. A possible explanation for this discrepancy may be financial, although a similarly low rate of enrollment for older patients has been documented in Canada, where the national health care program provides reimbursement for all health care costs. More plausible explanations for the lack of participation of elderly patients in clinical trials may include lack of social support, physician reluctance to offer research protocols, difficulties with access to clinics and hospitals, potential noncoverage of investigational treatments by Medicare, patient refusal, increasing concomitant medication usage and comorbidities with advancing age, and fewer trials specifically aimed at elderly patients.[41-45]
Prediction tools may be useful in guiding treatment decisions for stage II colon cancer. Weiser and colleagues developed a recurrence nomogram based on a cohort of 1,320 patients diagnosed with AJCC stage I to III colon cancer during January 1990 to December 2000 at the Memorial Sloan-Kettering Cancer Center. Nearly 40% of these patients had stage II disease. Of note, the age distribution of the cohort was not provided. Using prognostic factors of age, preoperative CEA, number of negative nodes, tumor location, T stage, tumor differentiation, lymphovascular invasion, and perineural invasion, the nomogram correctly predicted likelihood of colon cancer recurrence 77% of the time, a 3% improvement over that of the AJCC Cancer Staging Manual (6th edition). Caveats to this approach include the need for validation in other populations. Additionally, this nomogram as well as the recently proposed recurrence score may not account for the impact of comorbid medical conditions or functional status that impact life expectancy and consequently decrease the opportunity for cancer recurrence in older patients.[47-49] Furthermore, the presence of two or more comorbid medical conditions predicted for worse outcome among a SEER/Medicare cohort of older patients with stage II disease.
Cancer-Specific Geriatric Assessment Tool
Patient selection may be further improved by identifying those older patients vulnerable to toxicity and functional decline from chemotherapy. Geriatric assessment has been shown to predict for tolerance and survival in other cancers.[50-52] The Cancer Specific Geriatric Assessment developed by Hurria et al, a brief tool developed specifically for older cancer patients, is currently undergoing validation in large clinical trials (see Table 3).[53-55] It includes independently validated measures of functional status, comorbid medical conditions, cognition, mental health, social functioning and support, medication usage, and nutritional status.
In 2004, the American Society of Clinical Oncology (ASCO) published guidelines on the use of adjuvant chemotherapy in stage II colon cancer. Following a systematic review of the evidence on the use of adjuvant therapy in stage II colon cancer by the Cancer Care Ontario Practice Guideline Initiative in 2004, ASCO released its recommendations based on data from 37 randomized clinical trials and 11 meta-analyses. ASCO’s expert panel concluded that there is no direct evidence to support the use of adjuvant therapy in stage II colon cancer, even for those with high-risk features, estimating an absolute improvement in 5-year survival of 2% to 4% based on findings from IMPACT B2. A large number of subjects would need to be enrolled to detect a small difference in overall survival for a group with a high rate of survival at baseline.[56,57] No specific recommendations were made regarding the subset of older patients with stage II disease. The authors did recommend incorporating informed patient preferences and considering the impact of comorbid medical conditions and life expectancy in addition to potential treatment effect and toxicity when making treatment decisions.
Similarly, the International Society of Gastrointestinal Oncology recommended against the routine use of chemotherapy for stage II disease but made allowances for patients interested in receiving it. Citing data from the QUASAR study, the National Cancer Comprehensive Network guidelines support the use of adjuvant chemotherapy in high-risk stage II colon cancer.
Current evidence does not support the widespread use of adjuvant therapy in stage II colon cancer. Subsets of patients with stage II disease that have a higher risk of cancer recurrence may derive a survival benefit similar to that seen in stage III disease. Risk-stratified treatment approaches may identify this high-risk subset. Given the large portion of patients who are older, such strategies should include assessments of comorbid medical conditions and functional status to increase delivery of appropriate therapy to this growing population.
This supplement and associated publication costs were funded by Genomic Health.
Risk Assessment in Stage II Colon Cancer
1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA Cancer J Clin 59:225-249, 2009.
2. Surveillance Epidemiology and End Results (SEER). http://seer.cancer.gov/statistics/
3. Gill S, Loprinzi CL, Sargent DJ, et al: Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: Who benefits and by how much? J Clin Oncol 22:1797-1806, 2004.
4. Adjuvant therapy for patients with colon and rectum cancer. National Institutes of Health Consens Statement 8:1-25, 1990.
5. National Institutes of Health Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 264:1444-1450, 1990.
6. Schrag D, Rifas-Shiman S, Saltz L, et al: Adjuvant chemotherapy use for Medicare beneficiaries with stage II colon cancer. J Clin Oncol 20:3999-4005, 2002.
7. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators: IMPACT1: Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 345:939-944, 1995.
8. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators: IMPACT2: Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol 17:1356-1363, 1999.
9. Moertel CG, Fleming TR, Macdonald JS, et al: Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes’ B2 colon cancer. J Clin Oncol 13:2936-2943, 1995.
10. Laurie JA, Moertel CG, Fleming TR, et al: Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 7:1447-1456, 1989.
11. Moertel CG, Fleming TR, Macdonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352-358, 1990.
12. Marsoni S: Efficacy of adjuvant fluorouracil and leucovorin in stage B2 and C colon cancer. International Multicenter Pooled Analysis of Colon Cancer Trials Investigators. Semin Oncol 28:14-19, 2001.
13. Mamounas E, Wieand S, Wolmark N, et al: Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: Results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 17:1349-1355, 1999.
14. Wolmark N, Rockette H, Fisher B, et al: The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: Results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 11:1879-1887, 1993.
15. Figueredo A, Charette ML, Maroun J, et al: Adjuvant therapy for stage II colon cancer: A systematic review from the Cancer Care Ontario Program in evidence-based care’s gastrointestinal cancer disease site group. J Clin Oncol 22:3395-3407, 2004.
16. Figueredo A, Coombes ME, Mukherjee S: Adjuvant therapy for completely resected stage II colon cancer. Cochrane Database Syst Rev 2008:CD005390.
17. Sargent D, Sobrero A, Grothey A, et al: Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 27:872-877, 2009.
18. QUASAR Collaborative Group, Gray R, Barnwell J, McConkey C, et al: Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 370:2020-2029, 2007.
19. Comparison of flourouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: A randomised trial. QUASAR Collaborative Group. Lancet 355:1588-1596, 2000.
20. 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 345:1091-1097, 2001.
21. Andre T, Boni C, Navarro M, et al: Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109-3116, 2009.
22. Kuebler JP, Wieand HS, O’Connell MJ, et al: Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 25:2198-2204, 2007.
23. O’Connell JB, Maggard MA, Ko CY: Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 96:1420-1425, 2004.
24. Marshall JL, Haller DG, de Gramont A, et al: Adjuvant therapy for stage II and III colon cancer: Consensus Report of the International Society of Gastrointestinal Oncology. Gastrointest Cancer Res 1:146-154, 2007.
25. Quah HM, Chou JF, Gonen M, et al: Identification of patients with high-risk stage II colon cancer for adjuvant therapy. Dis Colon Rectum 51:503-507, 2008.
26. Burdy G, Panis Y, Alves A, et al: Identifying patients with T3-T4 node-negative colon cancer at high risk of recurrence. Dis Colon Rectum 44:1682-1688, 2001.
27. Morris EJ, Maughan NJ, Forman D, et al: Who to treat with adjuvant therapy in Dukes B/stage II colorectal cancer? The need for high quality pathology. Gut 56:1419-1425, 2007.
28. Morris M, Platell C, de Boer B, et al: Population-based study of prognostic factors in stage II colonic cancer. Br J Surg 93:866-871, 2006.
29. Vicuna B, Benson AB, 3rd: Adjuvant therapy for stage II colon cancer: Prognostic and predictive markers. J Natl Compr Canc Netw 5:927-936, 2007.
30. Park do Y, Sakamoto H, Kirley SD, et al: The Cables gene on chromosome 18q is silenced by promoter hypermethylation and allelic loss in human colorectal cancer. Am J Pathol 171:1509-1519, 2007.
31. Thiagalingam S, Lengauer C, Leach FS, et al: Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat Genet 13:343-346, 1996.
32. Watanabe T, Wu TT, Catalano PJ, et al: Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 344:1196-1206, 2001.
33. Ogino S, Nosho K, Irahara N, et al: Prognostic significance and molecular associations of 18q loss of heterozygosity: A cohort study of microsatellite stable colorectal cancers. J Clin Oncol 27:4591-4598, 2009.
34. Kerr D, Gray R, Quirke P, et al: A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study (abstract 4000). J Clin Oncol 27(suppl 15s):2009.
35. Jackson McCleary NA, Meyerhardt J, Green E, et al: Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients (pts) with stage II/III colon cancer: Findings from the ACCENT Database (abstract 4010). J Clin Oncol 27(suppl 15s):2009.
36. Vogelaar I, van Ballegooijen M, Schrag D, et al: How much can current interventions reduce colorectal cancer mortality in the U.S.? Mortality projections for scenarios of risk-factor modification, screening, and treatment. Cancer 107:1624-1633, 2006.
37. 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 24:4085-4091, 2006.
38. 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 camptosar-celecoxib study. Cancer 115:2617-2629, 2009.
39. Schrag D, Cramer LD, Bach PB, et al: Age and adjuvant chemotherapy use after surgery for stage III colon cancer. J Natl Cancer Inst 93:850-857, 2001.
40. Stewart JH, Bertoni AG, Staten JL, et al: Participation in surgical oncology clinical trials: Gender-, race/ethnicity-, and age-based disparities. Ann Surg Oncol 14:3328-3334, 2007.
41. Yee KW, Pater JL, Pho L, et al: Enrollment of older patients in cancer treatment trials in Canada: Why is age a barrier? J Clin Oncol 21:1618-1623, 2003.
42. Talarico L, Chen G, Pazdur R: Enrollment of elderly patients in clinical trials for cancer drug registration: A 7-year experience by the US Food and Drug Administration. J Clin Oncol 22:4626-4631, 2004.
43. Trimble EL, Carter CL, Cain D, et al: Representation of older patients in cancer treatment trials. Cancer 74:2208-2214, 1994.
44. 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 341:2061-2067, 1999.
45. Lara PN, Jr., Higdon R, Lim N, et al: Prospective evaluation of cancer clinical trial accrual patterns: Identifying potential barriers to enrollment. J Clin Oncol 19:1728-1733, 2001.
46. Weiser MR, Landmann RG, Kattan MW, et al: Individualized prediction of colon cancer recurrence using a nomogram. J Clin Oncol 26:380-385, 2008.
47. Gross CP, Guo Z, McAvay GJ, et al: Multimorbidity and survival in older persons with colorectal cancer. J Am Geriatr Soc 54:1898-1904, 2006.
48. Gross CP, McAvay GJ, Krumholz HM, et al: The effect of age and chronic illness on life expectancy after a diagnosis of colorectal cancer: Implications for screening. Ann Intern Med 145:646-653, 2006.
49. Guralnik JM: Assessing the impact of comorbidity in the older population. Ann Epidemiol 6:376-380, 1996.
50. Fillenbaum GG: Multidimentional Functional Assessment of Older Adults: The Duke Older Americans Resources and Services Procedures. Hilldale, NJ, Lawrence Erlbaum Associates, 1988.
51. Freyer G, Geay JF, Touzet S, et al: Comprehensive geriatric assessment predicts tolerance to chemotherapy and survival in elderly patients with advanced ovarian carcinoma: A GINECO study. Ann Oncol 16:1795-1800, 2005.
52. George LK, Fillenbaum GG: OARS methodology. A decade of experience in geriatric assessment. J Am Geriatr Soc 33:607-615, 1985.
53. Hurria A: We need a geriatric assessment for oncologists. Nat Clin Pract Oncol 2006;3:642-643, 2006.
54. Hurria A, Gupta S, Zauderer M, et al: Developing a cancer-specific geriatric assessment: A feasibility study. Cancer 104:1998-2005, 2005.
55. Hurria A, Lachs MS, Cohen HJ, et al: Geriatric assessment for oncologists: Rationale and future directions. Crit Rev Oncol Hematol 59:211-217, 2006.
56. Benson AB, 3rd, Schrag D, Somerfield MR, et al: American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22:3408-3419, 2004.
57. Buyse M, Piedbois P: Should Dukes’ B patients receive adjuvant therapy? A statistical perspective. Semin Oncol 28:20-24, 2001.
58. Engstrom PF, Arnoletti JP, Benson AB 3rd, et al: NCCN Clinical Practice Guidelines in Oncology: Colon cancer. J Natl Compr Canc Netw 7:778-831, 2009.
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