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© 2003 American Society for Clinical Oncology Impact of Diabetes Mellitus on Outcomes in Patients With Colon Cancer
From the Dana-Farber Cancer Institute, Eastern Cooperative Oncology Group Statistical Center, and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; University of Pennsylvania Cancer Center, Philadelphia, PA; St. Vincent Clinical Cancer Center, New York, NY; Northwestern University, Division of Hematology-Oncology, Chicago, IL Address reprint requests to Jeffrey Meyerhardt, MD, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115; email: jmeyerhardt{at}partners.org.
Purpose: To determine the influence of diabetes mellitus on long-term outcomes and treatment-related toxicity among patients with curatively resected colon cancer. Patients and Methods: This study was a cohort study within a large, randomized adjuvant chemotherapy trial of 3,759 patients with high-risk stage II and stage III colon cancer treated between 1988 and 1992 throughout the United States. In the cohort, 287 patients were identified as having diabetes mellitus. With a median follow-up of 9.4 years, we analyzed differences in overall survival (OS) and colon cancer recurrence as well as treatment-related toxicity between patients with diabetes and those without diabetes. Results: At 5 years, patients with diabetes mellitus, compared with patients without diabetes, experienced a significantly worse disease-free survival (DFS; 48% diabetics v 59% nondiabetics; P < .0001), OS (57% v 66%; P < .0001), and recurrence-free survival (RFS; 56% v 64%, P = .012). Median survival was 6.0 years and 11.3 years for diabetics and nondiabetics, respectively. Compared with patients without a history of diabetes, those with diabetes had a 42% increased risk of death from any cause (P < .0001) and 21% increased risk for recurrence (P = .05) after adjustment for other predictors of colon cancer outcome. Treatment-related toxicities were similar between the two groups, although patients with diabetes experienced an increase in treatment-related diarrhea. Conclusion: Patients with diabetes mellitus and high-risk stage II and stage III colon cancer experienced a significantly higher rate of overall mortality and cancer recurrence, even after adjustment for other predictors of colon cancer outcome. These results underscore the need for further research to understand the mechanism that underlies this relation.
BOTH CASE-CONTROL1,2 and cohort studies3–10 have demonstrated that a history of non-insulin-dependent diabetes mellitus (NIDDM) significantly elevates a person’s lifetime risk of colorectal cancer. This association persisted even after adjustment of other colorectal cancer risk factors including body mass index (BMI), physical activity, screening patterns, and dietary factors. Although NIDDM could influence colorectal carcinogenesis through several mechanisms, elevated levels of both circulating postprandial insulin and C-peptide have been shown to increase colorectal cancer risk in two large cohort studies.11,12 In contrast, the influence of diabetes mellitus on the long-term outcome of patients with established colon cancer remains uncertain. In selected studies, a history of diabetes mellitus has been associated with an inferior long-term survival among patients with pancreatic,13 hepatocellular,14 and breast15 cancers. Among patients with colorectal cancer, two studies16,17 have reported a significant increase in overall mortality among participants with diabetes mellitus. However, in both studies, the number of diabetic patients was small, and data on patient, tumor, and treatment characteristics were limited. Moreover, because information regarding cancer relapse was not available, it remained unclear whether the influence of diabetes was directly related to a higher rate of cancer recurrence. We used data from a large, randomized trial of adjuvant chemotherapy to examine the effect of diabetes mellitus on long-term outcomes after primary surgical treatment of high-risk stage II and stage III colon cancer. The adjuvant chemotherapy trial had four treatment arms. However, because there were no significant differences in survival among any of the four study arms, we could use this entire large cohort of colon cancer patients for this analysis. Further, by using patients enrolled in a prospective clinical trial, we could minimize confounding by controlling for the use of postoperative adjuvant therapy and other clinical predictors of outcome and directly examine the influence of diabetes on both long-term survival and cancer recurrence.
Study Population Patients for this analysis were participants in a clinical trial comparing different adjuvant chemotherapy regimens for stage II and III colon cancer, conducted between August 1988 and July 1992 (Intergroup 0089 [INT-0089]).18,19 The study enrolled 3,759 patients, with participation by institutions affiliated with one of the following cooperative groups: Eastern Cooperative Oncology Group (ECOG, the sponsoring group), Southwest Oncology Group, or Cancer and Leukemia Group B. Among the 3,759 patients enrolled in the trial, 198 patients (5.3%) were deemed ineligible, principally because of failure to meet predefined eligibility criteria,18,19 and therefore were excluded from the current analysis. Eligible patients of any age had histologically proven adenocarcinoma of the colon that had been resected en bloc without evidence of residual gross or microscopic disease. Patients were eligible if there was evidence of spread of tumor to regional lymph nodes (Dukes’ C or tumor, lymph node, metastasis stage III tumor). In addition, patients with penetration of the tumor into or through the bowel serosa without regional lymph node spread (Dukes’ B2 or tumor, lymph node, metastasis stage II) were eligible provided there was evidence of bowel obstruction, bowel perforation, peritoneal implants, or adherence to or invasion of adjacent organs by the primary tumor. The inferior margin of the primary tumor must have been above the peritoneal reflection.
Patients were required to give written informed consent, and all patients were randomly allocated to a study arm between 21 and 35 days after surgery. Patients must have had an ECOG performance status (PS) of 2 or less (ambulatory for at least 50% of the day or better). Patients were also required to have adequate bone marrow, renal, and hepatic function (WBC During the enrollment of patients into INT 0089, data managers were required to complete an on-study form for all patients in the trial. On the form, past medical history and medications were recorded. Data managers used clinic notes and medical records to complete these sections. Study staff, who were blinded to patient outcomes, reviewed the charts of all eligible patients (3,561 patients) to identify presence or absence of diabetes mellitus. Patients that either had diabetes mellitus listed in their past medical history or had a diabetes-controlling medication (insulin or an oral hypoglycemic agent) listed among their current medications were classified as diabetic. Among the patients considered eligible for the treatment trial, we excluded 12 from this analysis because their study charts were not available at time of data extraction. Thus, a cohort of 3,549 patients was eligible for the analysis. Within this population, 287 patients (7.9% of all eligible patients) had either a reported history of diabetes mellitus or were currently taking one or more diabetes-controlling medications. The remaining 3,262 patients were classified as nondiabetics for these analyses.
Treatment
Study End Points The primary end point of this analysis was overall survival (OS) in the study subjects, defined as the time from study entry to death from any cause. Disease-free survival (DFS) was defined as time from study entry to tumor recurrence, occurrence of a new primary colon tumor, or death from any cause. Finally, recurrence-free survival (RFS) was defined as time from study entry to tumor recurrence or occurrence of a new primary colon tumor. For RFS, patients who died without known tumor recurrence were censored at their final documented evaluation by their treating provider. Treatment-related toxicity was recorded by grade according to the National Cancer Institute Common Toxicity Criteria (version 1). Toxicity was assessed and documented at each treatment administration by qualified medical personnel.
Follow-Up
Statistical Considerations
Toxicity rates were calculated for severe toxicity. These rates were compared between diabetic and nondiabetic patients using Fisher’s exact tests. We further assessed maximum toxicity, defined as the highest grade of any toxicity experienced by each subject during the course of adjuvant chemotherapy. Logistic regression was performed to adjust toxicity rates for age, race, sex, baseline ECOG PS, BMI, stage of disease, and treatment arm assignment. Differences in the maximum toxicity experienced by patients with diabetes compared with patients without diabetes were assessed with the Mantel-Haenszel
Baseline Characteristics by Diabetes Mellitus Status Of the 3,549 patients included in our analysis, 287 were defined as diabetics (7.9%) and 3,262 were classified as nondiabetic (92.1%). We examined baseline characteristics according to diabetes mellitus status (Table 1  ). Compared with patients without a history of diabetes mellitus, diabetic patients were older and more likely to be male and African-American. Of note, in a recent analysis of the influence of race on survival using this cohort of patients, no difference in survival was demonstrated between Caucasians and African-American patients.22 In addition, diabetic patients had a significantly higher BMI at baseline. However, baseline ECOG PS, adjuvant treatment arm assignment, and tumor stage were not significantly different between diabetics and nondiabetics. Furthermore, rates of completion of planned chemotherapy did not differ between the two groups.
Survival and Cancer Recurrence Among Diabetics As previously reported,18,19 no significant OS advantage was observed among any of the four treatment arms in this study of adjuvant chemotherapy. Consequently, patients in all four treatment arms were analyzed jointly according to presence or absence of diabetes mellitus.
Kaplan-Meier curves representing DFS and OS are shown in Figs 2
We also examined the influence of diabetes mellitus on the risk of colon cancer recurrence (Fig 4 ). Patients were defined as recurring if there was documentation of recurrence from colon cancer or a new primary tumor. For the definition of RFS, patients who died without known tumor recurrence were censored at their final documented evaluation by their treating provider. Patients with diabetes had significantly worse RFS compared with nondiabetics; 5-year RFS was 56% among diabetics, compared with 64% for patients without a history of diabetes (log rank P = .012). Further, during the follow-up period, 41% of diabetic patients died with recurrent disease, compared with only 33% of nondiabetic patients (P = .006).
In Cox proportional hazards models, we examined the influence of diabetes after adjusting for relevant confounders (Table 2 ). Compared with patients without a history of diabetes, those with diabetes had a 42% increased risk of death from any cause (P < .0001) and a 21% increased risk for recurrence (P = .05) after adjustment for known or suspected predictors of colon cancer survival.
Because OS and cancer recurrence could be influenced by the amount of treatment delivered, we repeated our analysis after excluding patients who did not complete their assigned adjuvant chemotherapy. For diabetic patients, the adjusted hazard ratio (HR) was 1.42 (95% confidence interval [CI], 1.19 to 1.70) for overall mortality and 1.28 (95% CI, 1.03 to 1.58) for cancer recurrence. We further examined dose intensity by diabetes mellitus status to determine whether clinicians were using a modified dose of therapy for diabetics. We calculated the expected first dose of FU (in milligrams) based on the patient’s body-surface area23 and on the patient’s treatment assignment on the study. We then compared the actual first dose of FU delivered to the expected first dose of FU. There was no significant difference in the percentages of patients receiving less than 95% of the expected dose (2.1% of diabetics v 3.2% of nondiabetics; P = .29). Further, administration of less than 95% of the expected first FU dose was not predictive of overall mortality or cancer recurrence in our multivariate model. The influence of diabetes on outcome could reflect the greater comorbidity and diminished PS among diabetics. We therefore repeated our analyses after excluding patients with an ECOG PS of 2 (n = 117). Among patients with a PS of 0 or 1, diabetics continued to experience a significantly increased risk of overall mortality (HR = 1.49; 95% CI, 1.26 to 1.75) and cancer recurrence (HR = 1.23; 95% CI, 1.01 to 1.50). The influence of diabetes did not differ according to baseline BMI. Among patients whose baseline BMI was below the median (25.2 kg/m2), diabetics experienced an HR of 1.57 (95% CI, 1.20 to 2.06) for overall mortality and 1.21 (95% CI, 0.86 to 1.70) for cancer recurrence. Among patients whose baseline BMI was above or equal to the median, diabetics experienced an HR of 1.39 (95% CI, 1.14 to 1.69) for overall mortality and 1.20 (95% CI, 0.95 to 1.50) for cancer recurrence. We considered the possibility that misclassification of cases of diabetes could have influenced our findings. We repeated our analyses whereby only patients on a diabetes medication (oral agent or insulin) were defined as diabetic (n = 219). Even if we assume that all the patients with diabetes listed only in their past medical history are not diabetic (an extreme measure to bias toward a null result), diabetes mellitus still was associated with increased overall mortality (HR 1.41; 95% CI, 1.18 to 1.68) and cancer recurrence (HR 1.20; 95% CI, 0.97 to 1.49), albeit with some loss of statistical power.
Treatment-Related Toxicity Among Patients With Diabetes
Patients with diabetes mellitus did experience a moderately higher rate of severe treatment-related diarrhea. Twenty-nine percent of diabetics experienced grade 3/4 diarrhea compared with 20% of nondiabetics (P < .001). This difference remained significant after adjusting for age, treatment arm, race, sex, initial ECOG PS, BMI, and stage of disease (P = .0002). We considered the possibility that differences in the rate of severe treatment-related diarrhea may have accounted for the inferior survival among patients with diabetes. However, among the entire cohort, the development of treatment-related grade 3/4 diarrhea was not associated with an increased risk of overall mortality (adjusted HR = 1.02; 95% CI, 0.90 to 1.16) or cancer recurrence (adjusted HR = 0.97; 95% CI, 0.86 to 1.14) when compared with patients who did not develop severe diarrhea. Moreover, when we added the development of severe diarrhea to our multivariate model, diabetic patients continued to experience an increased risk in overall mortality (HR 1.42; 95% CI, 1.21 to 1.66) and cancer recurrence (HR=1.21; CI, 95% 1.00 to 1.46). We further assessed maximum chemotherapy-related toxicity, defined as the highest grade of any toxicity experienced by each subject during the course of adjuvant chemotherapy. Fifty-six percent of diabetic patients experienced any grade 3 or greater toxicity, compared with 57% of nondiabetics. In addition, there was no difference in treatment-related death according to diabetes status (1.3% for diabetics v 1.1% for nondiabetics; adjusted P = .56).
Using data from a large, adjuvant chemotherapy trial of patients with high-risk stage II and stage III colon cancer, we found that patients with diabetes mellitus experienced a significant increase in overall mortality as well as cancer recurrence when compared with patients without diabetes, even after adjusting for other known or suspected predictors of colon cancer survival. Furthermore, with the exception of a modest increase in treatment-related diarrhea, diabetic patients experienced a similar rate of treatment-related adverse events to those without diabetes. In a previous study, Yancik et al17 reviewed the medical records of a subset of patients in the Surveillance, Epidemiology, and End Results registry to obtain data on comorbid conditions. They found a significant increase in overall mortality among diabetics (HR = 1.37; 95% CI, 1.05 to 1.79) after adjustment for age, sex, and tumor stage. However, residual confounding by other predictors of outcome, including type of cancer therapy and baseline patient PS, could not be excluded. Moreover, data on cancer recurrence were not available. Using clinical trial data to examine the influence of diabetes mellitus offers several advantages over the use of other data sources. First, the stage of disease is comparable within the constraints of the protocol entry criteria. Second, treatment and follow-up care are conducted according to a uniform standard, and the date and nature of cancer recurrence are prospectively recorded. Finally, detailed information on prognostic variables, such as the number of positive lymph nodes and PS, are routinely collected. Patients who participate in randomized trials may differ from the population at large, thereby influencing the generalizability of our findings. Because the study population included patients throughout the United States and Canada, from both community and academic medical centers, we believe that our findings reflect the general population of colon cancer patients. Moreover, despite the potential exclusion of less robust patients, we continued to observe a significant influence of diabetes on recurrence and survival. Several other potential limitations for our study should be considered. Diabetes status was exclusively based on the past medical history and medications sections of the on-study forms, and thus, misclassification of diabetes status remained possible. However, because data on past medical history and current medications were recorded at study entry, any errors in the diagnosis of diabetes would have attenuated rather than exaggerated a true association between diabetes and colon cancer outcome. Moreover, the prevalence of diabetes (7.9%) is comparable with a population of colon cancer patients in a large prospective cohort of comparably aged women (7.0%).8 Differential follow-up is unlikely to have influenced our findings because follow-up rates in this clinical trial remain high (97.5% of the cohort). In contrast to prior registry studies, data on cancer recurrence were prospectively recorded as part of routine follow-up. Residual confounding by other predictors of colon cancer survival may have limited prior studies that examined the effect of diabetes on long-term outcomes. However, because patients in our cohort were enrolled into a prospective clinical trial, our analyses could adjust for such confounders. Moreover, as opposed to prior registry studies, all patients in our cohort received a prospectively assigned regimen of adjuvant therapy, and information on completion of therapy was available. Because all patients were enrolled in a clinical trial of postoperative adjuvant therapy, our analyses excluded patients with immediate postoperative mortality and likely excluded most patients with serious postoperative morbidity. However, we specifically wanted to address the effect of diabetes on long-term outcomes, making immediate operative complications potentially related to diabetes less relevant to the current study. Previous epidemiologic studies have demonstrated a positive association between NIDDM and colon cancer risk, possibly mediated through hyperinsulinemia.24 Insulin has been shown to be a colon tumor promoter in an animal model,25 and elevated circulating insulin and C-peptide levels have been related prospectively to colon cancer risk.11,12 In addition, circulating levels of insulin-like growth factor I (IGF-I), which promotes cell proliferation and inhibits apoptosis, have been positively associated with colon cancer risk in several studies.11,26–29 Moreover, insulin increases the bioactivity of IGF-1 by inhibiting the synthesis of certain IGF-binding proteins30 and enhances growth hormone–stimulated IGF-1 synthesis.31 Recently, Goodwin32 et al reported on insulin levels in 512 nondiabetic women with early-stage breast cancer. They found that the highest levels of fasting insulin were significantly associated with distant recurrence and death, even after adjustment for BMI, age, hormonal receptor status, and other known prognostic factors of breast cancer. The relation between NIDDM and the outcome among colon cancer patients is likely to be complex because hyperinsulinemia exists early in the development of NIDDM; however, in the later stages of NIDDM, beta-cell depletion leads to a hypoinsulinemic response.8,33 Given the older age of our population of colon cancer patients, the vast majority of patients in our cohort likely suffered from NIDDM rather than insulin-dependent (type I) diabetes. Nonetheless, our study did not obtain subclassification data on the type of diabetes, nor did it provide information on duration of diabetes. Diabetes mellitus could influence colon cancer outcome through alternative mechanisms. The presence of concurrent adverse health conditions, or comorbidities, has been shown to increase overall mortality among cancer patients.15,17,34,35 As such, the presence of diabetes may negatively influence prognosis because of other associated comorbidities, as well as the risk of non-cancer-related causes of death. However, in this study, the presence of diabetes increased not only total mortality but also cancer recurrence, possibly suggesting a more specific role for diabetes on colon cancer progression. Although the correlation between comorbidity and PS in cancer patients is debatable,36 poorer PS is associated with coexistent diseases in the postoperative setting (the time of study entry for this cohort).37,38 The significant influence of diabetes mellitus on both OS and cancer recurrence remained unchanged after excluding patients with an ECOG PS of 2. In conclusion, our data support the hypothesis that diabetes mellitus is associated with an increased risk of mortality and cancer recurrence in patients with high-risk stage II and stage III colon cancer. These results underscore the need for further research to understand the mechanism that underlies this relation. Nonetheless, individuals with diabetes tolerate adjuvant chemotherapy well and should not be treated differently from those without diabetes.
We thank Shandi Smith and Trong Ao for their assistance in data collection for this study.
Dr. Meyerhardt is a trainee in the Program in Cancer Epidemiology, National Research Service Award T32 CA 090001-27.
1. Williams JC, Walsh DA, Jackson JF: Colon carcinoma and diabetes mellitus. Cancer 54:3070–3071, 1984[CrossRef][Medline] 2. O’Mara BA, Byers T, Schoenfeld E: Diabetes mellitus and cancer risk: A multisite case-control study. J Chronic Dis 38:435–441, 1985[CrossRef][Medline] 3. Adami HO, McLaughlin J, Ekbom A, et al: Cancer risk in patients with diabetes mellitus. Cancer Causes Control 2:307–314, 1991[CrossRef][Medline] 4. La Vecchia C, D’Avanzo B, Negri E, et al: History of selected diseases and the risk of colorectal cancer. Eur J Cancer 27:582–586, 1991[Medline] 5. Ragozzino M, Melton LJ 3rd, Chu CP, et al: Subsequent cancer risk in the incidence cohort of Rochester, Minnesota, residents with diabetes mellitus. J Chronic Dis 35:13–19, 1982[CrossRef][Medline] 6. Kono S, Honjo S, Todoroki I, et al: Glucose intolerance and adenomas of the sigmoid colon in Japanese men (Japan). Cancer Causes Control 9:441–446, 1998[CrossRef][Medline]
7. Will JC, Galuska DA, Vinicor F, et al: Colorectal cancer: Another complication of diabetes mellitus? Am J Epidemiol 147:816–825, 1998
8. Hu FB, Manson JE, Liu S, et al: Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J Natl Cancer Inst 91:542–547, 1999 9. Nilsen TI, Vatten LJ: Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: Exploring the hyperinsulinaemia hypothesis. Br J Cancer 84:417–422, 2001[CrossRef][Medline]
10. Le Marchand L, Wilkens LR, Kolonel LN, et al: Associations of sedentary lifestyle, obesity, smoking, alcohol use, and diabetes with the risk of colorectal cancer. Cancer Res 57:4787–4794, 1997
11. Kaaks R, Toniolo P, Akhmedkhanov A, et al: Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst 92:1592–1600, 2000
12. Schoen RE, Tangen CM, Kuller LH, et al: Increased blood glucose and insulin, body size, and incident colorectal cancer. J Natl Cancer Inst 91:1147–1154, 1999 13. Sperti C, Pasquali C, Piccoli A, et al: Survival after resection for ductal adenocarcinoma of the pancreas. Br J Surg 83:625–631, 1996[Medline] 14. Toyoda H, Kumada T, Nakano S, et al: Impact of diabetes mellitus on the prognosis of patients with hepatocellular carcinoma. Cancer 91:957–963, 2001[CrossRef][Medline]
15. Yancik R, Wesley MN, Ries LA, et al: Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 285:885–892, 2001 16. Payne JE, Meyer HJ: The influence of other diseases upon the outcome of colorectal cancer patients. Aust N Z J Surg 65:398–402, 1995[Medline] 17. Yancik R, Wesley MN, Ries LA, et al: Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients: A population-based study. Cancer 82:2123–2134, 1998[CrossRef][Medline] 18. Haller DG, Catalano PJ, Macdonald JS, et al: Fluorouracil (FU), leucovorin (LV) and levamisole (LEV) adjuvant therapy for colon cancer: Four-year results of INT-0089. Proc Am Soc Clin Oncol1997 (abstr 940) 19. Haller DG, Catalano PJ, Macdonald JS, et al: Fluorouracil (FU), leucovorin (LV) and levamisole (LEV) adjuvant therapy for colon cancer: Five-year final report of INT-0089. Proc Am Soc Clin Oncol1998 (abstr 982) 20. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 21. Cox D: Regression models and life tables. J R Stat Soc B 34:187–220, 1972
22. McCollum AD, Catalano PJ, Haller DG, et al: Outcomes and toxicity in African-American and Caucasian patients in a randomized adjuvant chemotherapy trial for colon cancer. J Natl Cancer Inst 94:1160–1167, 2002 23. Mosteller RD: Simplified calculation of body-surface area. N Engl J Med 317:1098, 1987[Medline] 24. Giovannucci E: Insulin and colon cancer. Cancer Causes Control 6:164–179, 1995[CrossRef][Medline] 25. Tran TT, Medline A, Bruce WR: Insulin promotion of colon tumors in rats. Cancer Epidemiol Biomarkers Prev 5:1013–1015, 1996[Abstract]
26. Ma J, Pollak MN, Giovannucci E, et al: Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 91:620–625, 1999 27. Ma J, Pollak M, Giovannucci E, et al: A prospective study of plasma levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3, and colorectal cancer risk among men. Growth Horm IGF Res10:S28–S29,2000 (suppl A)
28. Giovannucci E, Pollak MN, Platz EA, et al: A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women. Cancer Epidemiol Biomarkers Prev 9:345–349, 2000 29. Manousos O, Souglakos J, Bosetti C, et al: IGF-I and IGF-II in relation to colorectal cancer. Int J Cancer 83:15–17, 1999[CrossRef][Medline]
30. Rechler MM: Growth inhibition by insulin-like growth factor (IGF) binding protein-3—what’s IGF got to do with it? Endocrinology 138:2645–2647, 1997 31. Kaaks R, Lukanova A: Energy balance and cancer: The role of insulin and insulin-like growth factor-I. Proc Nutr Soc 60:91–106, 2001[Medline]
32. Goodwin PJ, Ennis M, Pritchard KJ, et al: Fasting insulin and outcome in early-stage breast cancers: Results of a prospective cohort study. J Clin Oncol 20:42–51, 2002 33. La Vecchia C, Negri E, Decarli A, et al: Diabetes mellitus and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 6:1007–1010, 1997[Abstract] 34. Extermann M: Measuring comorbidity in older cancer patients. Eur J Cancer 36:453–471, 2000[CrossRef][Medline] 35. Extermann M: Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol 35:181–200, 2000[Medline]
36. Extermann M, Overcash J, Lyman GH, et al: Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 16:1582–1587, 1998 37. Jaeger AA, Hlatky MA, Paul SM, et al: Functional capacity after cardiac surgery in elderly patients. J Am Coll Cardiol 24:104–108, 1994[Abstract] 38. Greenfield S, Apolone G, McNeil BJ, et al: The importance of co-existent disease in the occurrence of postoperative complications and one-year recovery in patients undergoing total hip replacement. Comorbidity and outcomes after hip replacement. Med Care 31:141–154, 1993[CrossRef][Medline] Submitted July 22, 2002; accepted October 9, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3,500/mm3, platelets 
three times upper limit of normal [ULN], and bilirubin, aspartate amino-transferase [AST], and alkaline phosphatase 
2 tests in the case of categorical variables and Wilcoxon rank sum tests in the case of continuous variables. OS, DFS, and RFS at 5 years were examined using the method of Kaplan and Meier,
