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Multivitamin use is widespread in the United States, especially among patients with cancer. However, the influence of multivitamin supplementation on cancer recurrence and death after a curative resection of colon cancer is unknown.
We conducted a prospective, observational study of 1,038 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial. Patients reported on multivitamin use during and 6 months after adjuvant chemotherapy. Patients were observed until March 2009 for disease recurrence and death. To minimize bias by occult recurrence, we excluded patients who recurred or died within 90 days of their multivitamin assessment.
Among 1,038 patients, 518 (49.9%) reported multivitamin use during adjuvant chemotherapy. Compared with nonusers, the multivariate hazard ratio (HR) for disease-free survival was 0.94 (95% CI, 0.77 to 1.15) for patients who used multivitamins. Similarly, multivitamin use during adjuvant chemotherapy was not significantly associated with recurrence-free survival (multivariate HR, 0.93; 95% CI, 0.75 to 1.15) or overall survival (multivariate HR 0.92; 95% CI, 0.74 to 1.16). Multivitamin use reported 6 months after completion of adjuvant chemotherapy was also not associated with improved patient outcome, and consistent use both during and following adjuvant therapy conferred no benefit. Neither an increasing number of tablets nor increasing duration of use before cancer diagnosis was associated with cancer recurrence or mortality. Multivitamin use also did not improve the rates of grade 3 and higher GI toxicity.
Multivitamin use during and after adjuvant chemotherapy was not significantly associated with improved outcomes in patients with stage III colon cancer.
More than half of the American population currently uses dietary supplements.1 Among these, multivitamins comprise the majority of supplements, used by approximately 30% of Americans in the belief that they will prevent and treat chronic diseases such as cancer. Although vitamin deficiency is uncommon in the United States, multivitamin use is growing, resulting in annual sales of more than $20 billion. Despite health product claims touting the benefits of multivitamins, studies examining their efficacy in decreasing the risk of and mortality from cancer have been conflicting.
Epidemiologic and laboratory studies indicate that diet and other lifestyle factors have a significant influence on colon carcinogenesis. In particular, preclinical studies have demonstrated the antineoplastic properties of folate,2,3 vitamin C,4 vitamin D,5–7 vitamin E,4 calcium,8 and retinol.9 Administration of various nutrient mixtures have also resulted in growth inhibition of colon cancer xenografts10 and prevention of lung tumors in mice.11 However, an observational study in the Women's Health Initiative found that multivitamin use did not reduce the risk of cancer, including colorectal cancer.12 In contrast, other epidemiologic studies show a decreased risk of colorectal cancer with multivitamin supplementation,13 often only after past use14 or many years of supplementation.15
Beyond primary prevention, the effect of multivitamins on the outcome of patients with established colon cancer is unknown. In the United States, 26% to 77% of cancer survivors report multivitamin use.16 Consequently, it is critical to assess the impact of multivitamins on treatment and survival. We prospectively examined the influence of multivitamin use on survival in stage III colon cancer patients enrolled in a completed National Cancer Institute (NCI) –sponsored clinical trial of adjuvant chemotherapy.
Patients in this prospective cohort study were participants in the NCI-sponsored Cancer and Leukemia Group B (CALGB) trial for stage III colon cancer (89803) that compared adjuvant fluorouracil and leucovorin to irinotecan, fluorouracil, and leucovorin.17 From April 1999 to May 2001, 1,264 patients were enrolled. A self-administered questionnaire that captured diet and lifestyle habits was given to patients midway through their therapy (4 months after surgery; questionnaire 1 [Q1]) and again 6 months after completion of treatment (14 months after surgery; questionnaire 2 [Q2]). The protocol amendment to survey diet and lifestyle was activated after the first 87 patients were enrolled; therefore, only 1,177 patients were eligible for this companion study (Fig 1).
Patients were eligible for the treatment trial if they had undergone a complete surgical resection of the primary tumor within 56 days of study entry and had regional lymph node metastases but no distant metastases. Patients were required to have a baseline Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate bone marrow, renal, and hepatic function. Median household income was estimated using concurrent census data determined by the patient's zip code. All patients signed informed consent, approved by each institution's review board.
Multivitamin use was assessed both during (Q1) and after completion of adjuvant chemotherapy (Q2). On Q1, participants were asked, “Have you ever regularly taken multivitamins?” with an option for “Never have,” “Have in the past only,” or “Currently taking them.” Those who reported past use were asked to provide the number of years of use (1 year or shorter, 2 to 4 years, 5 to 9 years, or 10 years or longer). Those who reported current use were asked about number of multivitamins taken per week (2 or fewer, 3 to 5, 6 to 9, or 10 or more) and years of use. In addition, current users were instructed to write in the brand of multivitamin consumed. On Q2, participants were asked, “Do you currently take a multivitamin?” with an option for yes or no. Current users were then asked to provide the number of multivitamins taken per week and brand used. We excluded patients who recurred or died within 90 days of their multivitamin assessment to avoid potential bias related to underlying illness.
The primary end point was disease-free survival (DFS), defined as time from completion of the questionnaire to tumor recurrence, occurrence of a new primary colon cancer, or death from any cause. Recurrence-free survival (RFS) was defined as the time from completion of the questionnaire to tumor recurrence, death with evidence of recurrence, or occurrence of a new primary colon tumor; patients who died without known recurrence were censored at the last documented evaluation. Finally, overall survival was defined as the time from completion of the questionnaire to death from any cause.
Methods for detection of microsatellite instability (MSI) have been previously described,18,19 and results for the treatment trial have been reported.17 No significant differences were found between treatment arms, thus data for patients were combined and analyzed according to categories of multivitamin use during (Q1) and after adjuvant chemotherapy (Q2). All three end points were examined using Kaplan-Meier curves20 and the log-rank test.21 Cox proportional hazards regression was used to determine the simultaneous impact of potential confounders.22 The proportionality of hazards assumption for the effect of multivitamin use was satisfied by examining it as a time-dependent covariate in the model. We tested for linear trend by entering the median value of each category of multivitamin use as a continuous variable in the model.23 Tests of interaction between multivitamin use and potentially modifying covariates were assessed by entering the cross product of multivitamin use and the covariate of interest. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria version 2.0, and logistic regression performed to examine the impact of multivitamins on grade 3 and higher toxicity.
Statistical significance was considered at the .05 level, and all P values were two sided. The sample size for the cohort was determined by the chemotherapy treatment trial, which had 82% power to detect hazard ratios (HR) of 0.77 (protective) or 1.3 (detrimental) for overall survival based on an estimated 356 deaths among 1,260 patients. In a posthoc calculation of power based on the known sample size and number of DFS events for this analysis, we had 80% power to detect HRs of 0.67 or 1.50.
Patient registration and clinical data collection were conducted by the CALGB Statistical Center, and analyses performed in conjunction with CALGB statisticians based on the database frozen on March 31, 2009. Using Clark's C,24 the completeness of follow-up for this study was 84.2%; applying Wu's modification to adjust for unreported deaths,25 a more realistic assessment was 85.9%.
Baseline characteristics for the patients for whom data on multivitamin use were captured are presented in Table 1. Among 1,038 patients who completed Q1 shortly after initiation of adjuvant chemotherapy, 518 (49.9%) reported multivitamin use. Among 810 patients who remained cancer free and completed Q2 administered 6 months after completion of therapy, 416 (51.4%) used multivitamins. Patients who reported multivitamin use were more likely to be female, had higher household income, had tumors with less extension through the bowel wall, had lower body mass index (BMI), were more physically active, were less likely to consume a Western pattern diet, and were more likely to report regular aspirin use and higher intake of individual vitamins. Other potentially prognostic patient and tumor characteristics did not differ significantly.
After a median follow-up of 7.3 years (10th and 90th percentiles: 4.4 and 8.1 years, respectively) among the 1,038 patients who completed Q1 shortly after initiation of adjuvant therapy, 351 patients recurred and 314 died. Among the 810 patients who completed Q2 6 months after completion of chemotherapy, after a median follow-up of 6.5 years (10th and 90th percentiles: 4.0 and 7.3 years), 190 recurred and 169 died. Compared to nonusers, multivitamin users during adjuvant chemotherapy did not experience a statistically significant difference in DFS, RFS, or overall survival (Fig 2). Multivitamin use after adjuvant therapy was also not associated with improved outcomes. The results remained largely unchanged after adjusting for other predictors of cancer recurrence (Table 2). Compared to patients who did not use multivitamins during adjuvant chemotherapy, those who did had a multivariate HR for cancer recurrence or death of 0.94 (95% CI, 0.77 to 1.15). Similarly, multivitamin use after completion of adjuvant therapy did not significantly improve DFS (adjusted HR, 1.08; 95% CI, 0.83 to 1.41). We assessed the influence of socioeconomic status using concurrent census data on household income as determined by the patient's zip code, and found that it did not confound the relationship between multivitamin use and patient outcome. Household income also did not change the final adjusted HRs for DFS, RFS, and overall survival when added to our model.
We investigated whether there was a dose effect. Based on data reported during adjuvant therapy (Q1), we did not find a significant association between an increasing number of multivitamins consumed per week and patient outcome (P trend = .90 for DFS, .96 for RFS, and .93 for overall survival). There was also no improvement in DFS, RFS, or overall survival with increasing multivitamin tablets consumed after completion of chemotherapy (Q2). Similarly, we did not observe a significant relationship between increasing years of multivitamin use and patient outcome.
We further examined the influence of consistent multivitamin use on patient outcome, as defined by use both during and after adjuvant chemotherapy. Among 799 patients who completed both questionnaires, 26% never used multivitamins and 40% reported consistent use. Compared to never-users, patients who reported consistent multivitamin use did not experience a significant DFS, RFS, or overall survival benefit (Table 3).
We examined selected vitamins that are present in multivitamin supplements. Addition of total dietary and supplemental intake of each vitamin individually to the multivariable model did not change the null relationship between multivitamin use during adjuvant chemotherapy and DFS (data not shown). Moreover, total intake of these individual vitamins during adjuvant treatment was not significantly associated with DFS after adjusting for multivitamin use and other prognostic factors (P trend = .84 for vitamin A; .34 for vitamin B6; .49 for vitamin B12; .49 for folate; .71 for vitamin C; .12 for vitamin D; .63 for vitamin E; .24 for calcium, and .45 for retinol). No significant interactions were seen between any of the vitamins and multivitamin use. The same results were seen when we added total individual vitamin intakes to the multivariate model assessing multivitamin use after completion of adjuvant chemotherapy (Q2).
We examined the influence of multivitamin use during adjuvant chemotherapy on DFS across strata of other predictors of cancer outcome (Fig 3). Although most subgroups did not show a significant relationship between multivitamins and outcome, a significant interaction was observed with age (P = .007). In patients ≤ 60 years old, multivitamin use was associated with a significantly decreased risk of recurrence and death (adjusted HR, 0.68; 95% CI, 0.51 to 0.91), whereas no association was seen in patients older than 60. We considered the possibility that the benefit of multivitamin use among younger subjects may reflect the greater likelihood of a family history of colorectal cancer. However, further stratification of patients ≤ 60 years old by family history did not reveal significant differences in the beneficial effect of multivitamin use on DFS (adjusted HR, 0.63; 95% CI, 0.24 to 1.66 in patients with a family history; adjusted HR, 0.72; 95% CI, 0.53 to 0.99 in those without). In a related analysis, we explored the association between multivitamins, age, and tumoral microsatellite instability (MSI). Further adjustment of the multivariable model for MSI as determined by both genotyping of microsatellite markers and immunostaining for mismatch repair proteins did not alter the positive association between multivitamin use and DFS in patients ≤ 60 years of age (P interaction = .004 and .006, respectively). Of note, we did not see a significant interaction between age and multivitamin use after completion of adjuvant chemotherapy (P interaction = 0.11).
BMI may also modify the relationship between multivitamin use and DFS (P interaction = .05). Obese patients (BMI ≥ 30 kg/m2) who used multivitamins during adjuvant chemotherapy had significantly improved DFS (adjusted HR, 0.57; 95% CI, 0.39 to 0.82) compared to those who did not report multivitamin use (Fig 3). In contrast, overweight patients (BMI 25 to 29.9 kg/m2) who used multivitamins experienced an inferior outcome (adjusted HR, 1.52; 95% CI, 1.06 to 2.17), whereas multivitamin use in those with BMI lower than 25 kg/m2 was not significantly associated with DFS (adjusted HR, 0.87; 95% CI, 0.61 to 1.24). Of note, the test for statistical interaction between BMI and multivitamin use after completion of adjuvant chemotherapy was not significant (P interaction = .38).
We explored the influence of multivitamins on the incidence of the most common grade 3 and higher toxicities.17 There were no significant differences in the rates of grade 3 and higher leukopenia, neutropenia, nausea, vomiting, and diarrhea between multivitamin users and nonusers after adjusting for potential confounding factors (Table 4). However, multivitamin use was inversely associated with grade 3 and higher fatigue (adjusted odds ratio [OR], 0.61; 95% CI, 0.39 to 0.94).
In this large cohort of patients with stage III colon cancer treated with surgery and adjuvant chemotherapy, neither multivitamin use during or after adjuvant therapy was significantly associated with improved DFS, RFS, or overall survival. Moreover, multivitamin use did not improve chemotherapy-related gastrointestinal toxicity, although there was a potential benefit on fatigue. Importantly, multivitamin use was not found to be detrimental to patient outcome. To our knowledge, this is the first study to examine the impact of multivitamin use on survival among patients with established colon cancer.
Several observational studies have investigated the association between multivitamin use and colorectal cancer incidence, with conflicting results. A case-control analysis using the Surveillance, Epidemiology, and End Results registry found a 51% reduction in the risk of colorectal cancer in those who used multivitamins for 10 years (P trend < .001).13 Similarly, in a prospective cohort study using the Nurses' Health Study, there was no benefit of multivitamin use on colorectal cancer until 15 years of use, at which time a 75% reduction in risk was observed (P trend < .001).15 In contrast, a prospective cohort study using the Women's Health Study showed no association between multivitamin use and colorectal cancer during 10 years of follow-up,26 and participants in the Women's Health Initiative who used multivitamins did not have a lower risk of several cancers, including colorectal cancer (HR, 0.99; 95% CI, 0.88 to 1.11).12
Multivitamins consist of several vitamins and micronutrients that have been purported to influence colorectal carcinogenesis. Among these, folate is thought to be the micronutrient most likely responsible for any potential benefit of multivitamins. Folate acts as a cofactor in single-carbon transfer in nucleic and amino acid metabolism, therefore a deficiency could lead to disturbances in DNA replication, methylation, and repair.2,3 The amount of folic acid in multivitamins was increased in 1973 from 100 to 400 μg,27 a level considerably higher than median dietary intake. Numerous epidemiologic studies have demonstrated that higher folate intake is associated with a lower risk of colorectal adenoma and cancer.28,29 However, a placebo-controlled trial demonstrated a 67% increase in the risk of advanced colorectal lesions and a more than two-fold increase in the risk of developing at least three adenomas with supplemental folic acid among subjects with prior adenomas.30 Animal studies have suggested that the timing of folic acid supplementation may be critical; administration before the existence of neoplastic lesions may prevent tumor development, whereas administration afterwards may promote tumor progression.31 Of note, in another analysis of stage I to III colorectal cancer patients, higher plasma folate levels were not associated with inferior survival.32
Higher circulating plasma 25-hydroxyvitamin D3 [25(OH)D] has been associated with a reduced risk of colorectal cancer,33 and in a cohort of 304 patients with stage I to IV disease, we observed a significant reduction in overall mortality with increasing plasma 25(OH)D.34 However, given the limited quantity of vitamin D in standard multivitamin tablets (200 to 400 U), regular multivitamin use is unlikely to materially increase 25(OH)D levels.35
In our secondary subset analyses, multivitamin use was associated with improved DFS in patients ≤ 60 years of age, but not in those older than 60. Of note, this exploratory finding may simply reflect chance. Nonetheless, the Nutrition Intervention Trials conducted in Linxian County, China, found that the benefit of beta-carotene, vitamin E, and selenium in reducing cancer mortality was greater in participants younger than 55 years of age.36 In addition, we observed a significant benefit from multivitamin use among obese patients, who often have greater levels of oxidative stress.37 It is possible that one or several of the micronutrients with antioxidant properties in multivitamins is contributing to improved outcomes in this subgroup of patients. These interactions with younger age and higher BMI require confirmation in other studies.
There are several advantages to using a cohort within a NCI-sponsored clinical trial. First, all patients had stage III cancer, reducing the impact of heterogeneity by disease stage. Second, treatment and follow-up were standardized, and the date and nature of recurrence were recorded prospectively. Finally, detailed information on prognostic factors was collected routinely.
Several potential limitations deserve comment. Patients who enroll in randomized trials may differ from the population at large. However, the prevalence of multivitamin use in our cohort falls within the range reported for patients with cancer overall.16 Moreover, since the study included patients from both community and academic centers throughout North America, our findings should reflect the general population.
Because we relied on self-reported multivitamin use, misclassification of the exposure is possible. However, prior studies have demonstrated such data to be reliable.38 Moreover, multivitamin use was recorded before any knowledge of cancer-related outcomes, thus reducing the likelihood of reporting biases. Finally, patients who consume supplements often engage in other healthful behaviors. In this study, we controlled for physical activity, BMI, and performance status, among other factors. However, residual confounding from unknown variables is possible.
In conclusion, our large prospective study of patients with stage III colon cancer found no significant benefit for multivitamin supplementation on patient outcome. These results are consistent with a conference statement from the National Institutes of Health that concluded there was insufficient evidence to recommend either for or against the use of multivitamins for chronic disease prevention.1 Nonetheless, further research is needed to assess the utility of individual vitamins in patients with established colorectal cancer.
Baptist Cancer Institute Community Clinical Oncology Program (CCOP), TN–Lee S. Schwartzberg, MD, supported by CA71323; Christiana Care Health Services Inc CCOP, Wilmington, DE–Stephen Grubbs, MD, supported by CA45418; Dana-Farber Cancer Institute, Boston, MA–Harold J. Burstein, MD, supported by CA32291; Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH–Konstantin Dragnev, MD, supported by CA04326; Duke University Medical Center, Durham, NC–Jeffrey Crawford, MD, supported by CA47577; Georgetown University Medical Center, Washington, DC–Minetta C. Liu, MD, supported by CA77597; Cancer Centers of the Carolinas, Greenville, SC–Jeffrey K. Giguere, MD, supported by CA29165; Hematology-Oncology Associates of Central New York CCOP, Syracuse, NY–Jeffrey Kirshner, MD, supported by CA45389; Long Island Jewish Medical Center, Lake Success, NY–Kanti R. Rai, MD, supported by CA35279; Massachusetts General Hospital, Boston, MA–Jeffrey W. Clark, MD, supported by CA32291; Memorial Sloan-Kettering Cancer Center, New York, NY–Clifford A. Hudis, MD, supported by CA77651; Mount Sinai School of Medicine, New York, NY–Lewis R. Silverman, MD, supported by CA04457; Nevada Cancer Research Foundation CCOP, Las Vegas, NV– John A. Ellerton, MD, supported by CA35421; Rhode Island Hospital, Providence, RI–William Sikov, MD, supported by CA08025; Roswell Park Cancer Institute, Buffalo, NY–Ellis Levine, MD, supported by CA59518; Southeast Cancer Control Consortium Inc CCOP, Goldsboro, NC–James N. Atkins, MD, supported by CA45808; State University of New York Upstate Medical University, Syracuse, NY–Stephen L. Graziano, MD, supported by CA21060; The Ohio State University Medical Center, Columbus, OH–Clara D Bloomfield, MD, supported by CA77658; University of California at San Diego, San Diego, CA–Barbara A. Parker, MD, supported by CA11789; University of Chicago, Chicago, IL–Hedy L. Kindler, MD, supported by CA41287; University of Illinois MBCCOP, Chicago, IL–David J. Peace, MD, supported by CA74811; University of Iowa, Iowa City, IA–Daniel A. Vaena, MD, supported by CA47642; University of Maryland Greenebaum Cancer Center, Baltimore, MD–Martin Edelman, MD, supported by CA31983; University of Massachusetts Medical School, Worcester, MA–William V. Walsh, MD, supported by CA37135; University of Minnesota, Minneapolis, MN–Bruce A. Peterson, MD, supported by CA16450; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO–Michael C. Perry, MD, supported by CA12046; University of Nebraska Medical Center, Omaha, NE–Anne Kessinger, MD, supported by CA77298; University of North Carolina at Chapel Hill, Chapel Hill, NC–Thomas C. Shea, MD, supported by CA47559; University of Tennessee Memphis, Memphis, TN–Harvey B. Niell, MD, supported by CA47555; University of Vermont, Burlington, VT–Steven M. Grunberg, MD, supported by CA77406; Wake Forest University School of Medicine, Winston-Salem, NC–David D. Hurd, MD, supported by CA03927; Walter Reed Army Medical Center, Washington, DC–Brendan M. Weiss, MD, supported by CA26806; Washington University School of Medicine, St Louis, MO–Nancy Bartlett, MD, supported by CA77440; Weill Medical College of Cornell University, New York, NY–John Leonard, MD, supported by CA07968.
Written on behalf of Cancer and Leukemia Group B.
Supported by Grants No. P50CA127003 and T32CA009001-34 from the National Cancer Institute, National Institutes of Health (K.N.); by an American Society of Clinical Oncology Young Investigator Award (K.N.); by the Charles A. King Trust Postdoctoral Fellowship Award, Bank of America, Co-Trustee (K.N.); and by Pharmacia & Upjohn Company, now Pfizer Oncology. The research for CALGB (Cancer and Leukemia Group B) 89803 was also supported, in part, by grants from the National Cancer Institute (CA31946) to CALGB and to the CALGB Statistical Center (CA33601).
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health, American Society of Clinical Oncology (ASCO), or The ASCO Foundation.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Charles S. Fuchs, Amgen, AstraZeneca, Imclone, Genentech, Bristol-Myers Squibb, Roche, Mersana, Pozen, Myriad Genetics, Alnylam, Merck, Genomic Health Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Kimmie Ng, Leonard B. Saltz, Charles S. Fuchs
Financial support: Kimmie Ng, Richard M. Goldberg, Charles S. Fuchs
Administrative support: Kimmie Ng
Provision of study materials or patients: Leonard B. Saltz, Robert J. Mayer, Al B. Benson III, Paul L. Schaefer, Renaud Whittom, Alexander Hantel, Richard M. Goldberg
Collection and assembly of data: Kimmie Ng, Jeffrey A. Meyerhardt, Jennifer A. Chan, Donna Niedzwiecki, Donna R. Hollis, Leonard B. Saltz, Robert J. Mayer, Al B. Benson III, Paul L. Schaefer, Renaud Whittom, Alexander Hantel, Richard M. Goldberg, Charles S. Fuchs
Data analysis and interpretation: Kimmie Ng, Jeffrey A. Meyerhardt, Jennifer A. Chan, Donna Niedzwiecki, Donna R. Hollis, Charles S. Fuchs
Manuscript writing: Kimmie Ng, Donna R. Hollis, Charles S. Fuchs
Final approval of manuscript: Kimmie Ng, Jeffrey A. Meyerhardt, Jennifer A. Chan, Donna Niedzwiecki, Donna R. Hollis, Leonard B. Saltz, Robert J. Mayer, Al B. Benson III, Paul L. Schaefer, Renaud Whittom, Alexander Hantel, Richard M. Goldberg, Charles S. Fuchs