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Impact of Body Mass Index on Outcomes and Treatment-Related Toxicity in Patients With Stage II and III Rectal Cancer: Findings From Intergroup Trial 0114

From the Department of Medical Oncology, Dana-Farber Cancer Institute; Department of Radiation Oncology, Massachusetts General Hospital; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill; Cancer and Leukemia Group B Statistical Center, Durham, NC; Baylor-Sammons Cancer Center, Dallas, TX; Allegheny Cancer Center, Allegheny General Hospital, Pittsburgh, PA; St Vincent's Clinical Cancer Center, New York, NY; Division of Hematology-Oncology, Northwestern University, Chicago, IL; and Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada

Address reprint requests to Jeffrey A. Meyerhardt, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: jmeyerhardt{at}partners.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
PURPOSE: To study the relationship between body mass index (BMI) and rates of sphincter-preserving operations, overall survival, cancer recurrence, and treatment-related toxicities in patients with rectal cancer.

PATIENTS AND METHODS: We evaluated a nested cohort of 1,688 patients with stage II and III rectal cancer participating in a randomized trial of postoperative fluorouracil-based chemotherapy and radiation therapy.

RESULTS: Obese patients were more likely to undergo an abdominoperineal resection (APR) than normal-weight patients (odds ratio, 1.77; 95% CI, 1.27 to 2.46). When analyzed by sex, increasing adiposity in men was a strong predictor of having an APR (P < .0001). Obese men with rectal cancer were also more likely than normal-weight men to have a local recurrence (hazard ratio [HR], 1.61; 95% CI, 1.00 to 2.59). In contrast, obesity was not predictive of cancer recurrence in women, nor was BMI predictive of overall mortality in either men or women. Underweight patients had an increased risk of death (HR, 1.43; 95% CI, 1.08 to 1.89) compared with normal-weight patients but no increase in cancer recurrences. Among all study participants, obese patients had a significantly lower rate of grade 3 to 4 leukopenia, neutropenia, and stomatitis and a lower rate of any grade 3 or worse toxicity when compared with normal-weight individuals.

CONCLUSION: Increasing BMI in male patients with rectal cancer is associated with a decreased likelihood of sphincter preservation and a higher chance of local recurrence. For both men and women, overweight and obese patients experience less toxicity associated with adjuvant chemoradiotherapy, suggesting that actual body weight dosing of fluorouracil for obese patients is justified.

	INTRODUCTION

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Obesity is considered one of the more urgent health concerns today [1-3]. Increased body mass index (BMI) is a risk factor for the development of a variety of cancers [4]. Data from both retrospective [5-8] and prospective [9-15] studies suggest a compelling association between obesity and the risk of developing colon cancer. In a large prospective study of male health professionals, BMI 29 kg/m² (obese patients) was associated with an 82% increase in risk when compared with a BMI of less than 22 kg/m² (normal and underweight subjects) [10]. Whether obesity increases the risk of developing rectal cancer is less certain [5,16-18]. Using the Hawaiian Tumor Registry, Le Marchard et al [11] found that male patients with the highest tertile of BMI had an odds ratio of 2.9 for being diagnosed with rectal cancer compared with male patients in the lowest tertile; no association was demonstrated for female patients.

The influence of BMI on the outcome of patients with established rectal cancer is largely unknown. Obesity has been associated with increased perioperative complications, including anastomotic leakage and blood transfusion requirements [19,20]. Whether obesity influences sphincter preservation, cancer recurrence, or survival has not been reported specifically for rectal cancer.

We therefore used data from a large, randomized trial of adjuvant chemoradiotherapy to examine the influence of BMI on rates of abdominoperineal resections (APR), treatment-related toxicities, and long-term outcomes after primary surgical treatment of stage II and stage III rectal cancer. By using patients enrolled in a prospective clinical trial, we could minimize confounding by inconsistent use of postoperative adjuvant therapy, control for other clinical predictors of outcome, and directly examine the influence of body habitus on patient outcome.

	PATIENTS AND METHODS

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Study Population
Patients for this analysis were drawn from a randomized trial of adjuvant postoperative chemotherapy and radiation therapy for stage II and III rectal cancer conducted between August 1990 and November 1992, National Cancer Institute–sponsored Intergroup Trial 0114 (INT-0114; Fig 1) [21,22]. The study had an enrollment of 1,792 patients, with participation by institutions affiliated with one of the following cooperative groups: Cancer and Leukemia Group B (CALGB; the coordinating group), North Central Cancer Treatment Group, Eastern Cooperative Oncology Group (ECOG), National Cancer Institute –Canada Clinical Trials Group, Radiation Therapy Oncology Group, and Southwest Oncology Group. As previously described, 97 patients were deemed ineligible for this trial and were excluded from analysis. Other details of study eligibility and treatment trial results have been reported elsewhere [21,22].

View larger version (52K): [in this window] [in a new window]   Fig 1. Chemotherapy randomization for Intergroup Trial 0114. 5-FU, fluorouracil; RT, radiotherapy.

BMI and Body-Surface Area
Degree of adiposity was measured by BMI. BMI was calculated as the patient's weight on day 1 of chemotherapy (in kilograms) divided by the patient's height squared (in meters). Patients were divided into five categories of BMI (< 20 kg/m² [underweight], 20 to 24.9 [normal weight], 25 to 26.9 [overweight], 27.0 to 29.9 [overweight], and 30 [obese]), consistent with prior studies [9,14] and the World Health Organization classifications [23]. Body-surface area (BSA in meters squared), a unit of measure used in the calculation of chemotherapy dosage, was calculated as follows: square root of (height in centimeters multiplied by day 1 weight in kilograms, divided by 3,600) [24]. We calculated the patient's weight-based dose from the expected initial dose of 5-FU and the calculated BSA. The percentage of the weight-based doses each patient actually received was calculated as the ratio of the dose recorded in the patient's study chart to the weight-based dose the patient was expected to receive.

Study End Points
The following definitions were used for overall mortality and cancer recurrence end points. Overall survival (OS) was defined as the time from study entry to death from any cause. Disease-free survival (DFS) was defined as the time from study entry to tumor recurrence, occurrence of a new primary colorectal tumor, or death from any cause. Recurrence-free survival (RFS) was defined as the time from study entry to tumor recurrence (local, distant, or both) or occurrence of a new primary colorectal tumor; patients who died without known tumor recurrence were censored at the time of death. Finally, local RFS (LFS) was defined as the time from study entry to local tumor recurrence; patients who died without known local recurrence were censored at time of death.

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 (physician or oncology nurse).

Statistical Considerations
The distribution of baseline characteristics across BMI categories was evaluated using ² tests in the case of categoric variables and analysis of variance or Wilcoxon rank sum test in the case of continuous variables. For all variables, fewer than 20 patients had missing values (though indicator variables were used in multivariate models for variables with greater than five missing values). Survival and time-to-event probabilities were estimated using the methods of Kaplan and Meier [25], and differences were assessed by the log-rank test. The entire cohort was analyzed using Cox proportional hazards regression [26], with inclusion in the model of age, sex, race, bowel obstruction at presentation, performance status, number of positive lymph nodes, extent of disease through bowel wall, and BMI classes. We hypothesized that patients who were underweight could have a worse outcome, and thus assigned patients with normal BMI of 20 to 24.9 kg/m² as the reference category. In these models, we evaluated monotonic trends by using the median value of each category and modeling it as a continuous variable.

Operation type was recorded on study eligibility forms by data managers at individual institutions and entered into the database by data coordinators at CALGB. An additional physician reviewer also reviewed operative reports to confirm the correct surgery type was identified. Operation type was classified as either low anterior resection (LAR) or APR, as local excision was not an option for trial entry. Differences in rates of APR by BMI class were analyzed using logistic regression, with adjustments for age, race, sex, bowel obstruction at presentation, number of positive lymph nodes, distance from anal verge (based on operative, sigmoidoscopy or colonoscopy report), and extent of disease through bowel wall.

Toxicity rates were calculated for severe toxicities. These rates were compared across BMI categories using ² tests. Logistic regression was performed to adjust toxicity rates for age, race, sex, baseline ECOG performance status, and treatment arm assignment.

We used SAS Software 8.2 (SAS Institute, Cary, NC) for all statistical analyses. All P values are two-sided.

	RESULTS

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Baseline Characteristics by BMI Category
Baseline characteristics by BMI categories of the 1,688 patients enrolled in this multicenter, adjuvant chemoradiotherapy trial are shown in Table 1. Based on the World Health Organization definitions [23], 39.2% of patients (662 of 1,688 patients) were overweight (BMI, 25 to 29.9 kg/m²) and 18.1% of patients (306 of 1,688 patients) were obese (BMI 30 kg/m²). Compared with normal-weight individuals (BMI, 20 to 24.9 kg/m²), underweight patients (BMI < 20 kg/m²) were more likely to be female (P < .0001), to present with clinical bowel obstruction (P = .04), and to have greater extension of their tumor through the bowel wall (P = .04). Underweight patients did not differ significantly from normal-weight patients with respect to race (P = .75), age (P = .47), number of positive lymph nodes (P = .51), baseline ECOG performance status (P = .45), grade of differentiation (P = .23), or completion of all prescribed adjuvant therapy (P = .20).

Sphincter Preservation Rates by BMI
We examined the rates of permanent colostomy as defined by the use of an APR as compared with a low anterior resection with sphincter preservation (Table 2). Overall, 40% of the study population underwent an APR. Patients with increasing BMI were more likely to undergo an APR (37.2% of normal-weight patients v 46.7% of obese patients; P = .003). Compared with normal-weight patients, the adjusted odds ratio of an obese patient undergoing an APR was 1.77 (95% CI, 1.27 to 2.46).

Among female patients, BMI was not predictive of undergoing an APR (Table 2). However, greater BMI among male patients significantly increased the likelihood of having an APR (38.5% of normal-weight males compared with 52% of obese males). Obese males had an odds ratio of 2.41 (95% CI, 1.57 to 3.71) of undergoing an APR compared with normal-weight males (P trend among BMI classes 20 kg/m² < .0001) When the cross-product for interaction between sex and BMI was entered into our logistic regression model, the test for interaction was significant (P = .005).

Survival and Cancer Recurrence by BMI Class
All patients enrolled onto this trial were randomly assigned to receive postoperative 5-FU–based chemotherapy and external-beam radiotherapy. As has been previously reported, no significant survival or recurrence advantage was observed among any of the four treatment arms [21,22]. Consequently, patients in all four treatment arms were analyzed jointly according to categories of BMI. The median follow-up time as of this analysis was 9.9 years, with a maximum follow-up of 11.8 years.

We hypothesized that the BMI of underweight patients may be a reflection of a worse disease state and thus increased risk of mortality. Thus based on this a priori assumption, we established normal-weight patients as the referent group for all analyses of survival outcomes. After excluding underweight patients, we observed no significant differences in DFS, OS, RFS (local or distant), or LFS by BMI class (Table 3; Fig. 2 and 3). Underweight patients did experience a worse 5-year OS (53.1%) compared with normal-weight patients (65.5%; log-rank P = .08, excluding patients with BMI 25 kg/m²⁾. However, there were no significant differences in 5-year DFS (P = .6), RFS (P = .5), and LFS (P = .6) between underweight and normal-weight patients.

View larger version (21K): [in this window] [in a new window]   Fig 2. Overall survival by body mass index class among patients with rectal cancer.

View larger version (21K): [in this window] [in a new window]   Fig 3. Recurrence-free survival by body mass index class among patients with rectal cancer.

The distribution of adipose differs considerably between men and women [29]. Moreover, the influence of obesity on the risk of developing colorectal cancer seems to vary according to sex [11,30-33]. We examined the impact of BMI on rectal cancer survival according to sex (Table 4). Although BMI had no significant influence on rectal cancer outcome among women, obese men had an increased risk of local recurrence (HR, 1.61; 95% CI, 1.00 to 2.59) and overall cancer recurrence (HR, 1.23; 95% CI, 0.93 to 1.61) when compared with normal-weight men. When the cross-product for interaction between BMI and sex was entered into our model, the P values for the interaction terms were .12 and .11 for cancer recurrence and local recurrence, respectively.

Because the adequacy of the surgical resection can be predictive of local and distant recurrences, we sought to see if potential surrogates of quality of resection impact these associations. Patients enrolled in INT-0114 were required to have negative surgical margins. However, the number of lymph nodes examined [34] and hospital volume [35]were added into multivariate analyses and did not appreciably change the above survival and recurrence associations.

Chemotherapy Dosing
Physicians may treat patients with higher BMI with doses of chemotherapy based on ideal body weight rather than actual, although the protocol called for dosing according to actual body weight. We examined concordance with protocol dosage by BMI to determine whether clinicians were using a modified dose of therapy for overweight and obese patients. Among patients who were normal-weight or heavier, there were no appreciable differences in the rates of chemotherapy underdosing (0.0% of patients with BMI < 20 kg/m², 2.0% of patients with BMI of 21 to 24.9 kg/m², 1.9% of patients with BMI of 25 to 26.9 kg/m², 2.0% of patients with BMI of 27 to 29.9 kg/m², and 2.3% of patients with BMI 30 kg/m²; ² P = .66). Adjustment for underdosing in the proportional hazards models did not alter the relation between obesity and survival outcomes in the entire cohort analysis or within each sex. Given the small percentage of patients receiving less than 95% of the expected first 5-FU dose, there was not sufficient statistical power to stratify patients by underdosing or not.

Treatment-Related Toxicity by BMI Class
We examined the influence of BMI on the rates of major chemotherapy-related toxicity at any time during the course of therapy (Table 5). Although unadjusted rates of grade 3 to 4 diarrhea, leukopenia, and stomatitis were higher in underweight patients compared with normal-weight patients, these differences were no longer significant after adjusting for other predictors of toxicity in multivariate analysis. In contrast, among patients who were normal weight or heavier, increasing BMI was associated with a significantly lower rate of grade 3 and 4 leukopenia (P = .04), neutropenia (P = .003), and stomatitis (P = .03), even after adjustment for other confounders, including rates of chemotherapy underdosing. Further, compared with normal-weight patients, obese patients were significantly less likely to experience any grade 3 or 4 toxicity (P = .05). These relationships were not materially different with the inclusion of completion of adjuvant therapy entered into the model.

	DISCUSSION

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Using data from a large, adjuvant chemoradiotherapy trial of patients with stage II and stage III rectal cancer, we found that a higher baseline BMI was associated with an increased rate of APRs and, consequently, permanent colostomy. This inverse relation between BMI and sphincter preservation was most apparent among men. Obesity was also predictive of an increased risk of local recurrence among male, though not female, patients. In contrast, obesity did not impact overall mortality for either men or women. In addition, increasing adiposity was associated with less treatment-related toxicity during adjuvant therapy.

Previous studies have reported an increased risk of perioperative complications (ie, anastomotic leakage) in obese patients after resection of rectal cancer. Two studies have reported an inferior RFS [36] and OS [37] among obese patients with colon cancer. However, these studies were performed before the standard initiation of adjuvant chemotherapy, and the authors were unable to control for other known predictors of cancer recurrence. We are unaware of prior studies specifically focusing on the influence of obesity on outcomes in patients with rectal cancer.

Although in the current analysis obesity did not influence overall mortality or cancer recurrence among women, obese men were 61% more likely to have a local recurrence of rectal cancer when compared with normal-weight men. Several studies have observed an inferior short-term [20,38] and long-term outcome [27,39,40]for men with rectal cancer, including an earlier report from our own cohort [22]. Such differences in rectal cancer outcome could reflect several potential explanations, including anatomic differences in the male and female pelvis. The wide female pelvis allows for more accurate dissection under direct visualization [27]. Consequently, the narrower pelvis in males combined with increased adiposity may have a greater detrimental influence on local recurrence in men as compared with women. In fact, this local recurrence disadvantage among obese men was particularly striking in patients undergoing an LAR (86% increased risk) rather than an APR (a nonsignificant 28% increased risk), suggesting that the combined influences of obesity and the male pelvis may substantially compromise the adequacy of a less extensive resection (LAR).

Although the increased recurrences in obese men may be purely anatomically, an additional biologic explanation is worth considering. Excess visceral adiposity, which is preferentially found in men, is associated with insulin resistance and higher levels of circulating insulin [41-43]. Insulin has been shown to be a promoter of colorectal neoplasia in animal models [44]. In addition, circulating levels of insulin-like growth factor I (IGF-I), which promotes cell proliferation and inhibits apoptosis, have been positively associated with colorectal cancer risk in several studies [45-49]. Insulin increases the bioactivity of IGF-I by inhibiting the synthesis of certain IGF-binding proteins [50] and enhancing growth hormone–stimulated IGF-I synthesis [51].

The increased risk of death in underweight patients may be a reflection of disease severity or other comorbidities. Restriction of the cohort to patients surviving at least 6 months or at least 1 year did not alter the results, suggesting that undetected metastatic disease in this patient population is less likely an explanation. Further, cancer recurrences were not greater among underweight compared with normal-weight patients. Of note, prior obesity studies in patients without cancer have shown that smoking confounds the relationship between underweight patients and mortality [52]. Further studies should examine this population of patients to understand factors influencing this worse outcome.

Previous studies have reported a disparate use of APR by sex, with an increased rate among male patients with rectal cancer [28,53]. Such a disparity may reflect the greater technical ease in reconstituting bowel continuity in women because of the anatomic considerations of the pelvis. It has been anecdotally suggested that biased perceptions toward the acceptability of a colostomy by sex may also play a minor role in this decision [28]. Our finding of a higher rate of APR in obese patients (particularly men) may also be reflective of anatomic constraints engendered by such body habitus. To better interpret rates of APR and LAR, future studies should elicit more data on the factors that influence a surgeon's operative approach for rectal cancer.

In the current study of rectal cancer, obese patients did not experience a higher rate of chemotherapy-related toxicity when compared with normal-weight individuals. These results are consistent with reports of chemotherapy in obese patients with colon, breast, and lung cancer [54-56]. Although we did not have sufficient statistical power to examine the effect of therapy underdosing on outcome, our study suggests that overweight and obese patients can tolerate full-dose therapy with 5-FU and should be treated by actual body weight.

The generalizability of a cohort derived from a clinical trial could be a limitation of secondary analysis studies. Although the patients in this cohort may not fully reflect the general population of rectal cancer patients, the distribution of adiposity in this cohort is very consistent with that seen in the general population. In the 1988 to 1994 National Health and Nutrition Examination Survey III (NHANES III) report on BMI distribution in the United States, [57] 33% of the population were overweight (BMI of 25 to 29.9 kg/m²) and 22% were obese (BMI 30 kg/m²), similar to our cohort of 39% being overweight and 18% being obese.

Several potential limitations for our study should be considered. Because adjuvant chemotherapy was initiated within 10 weeks of rectal cancer surgery, the body weight recorded at the time of first dose of chemotherapy may not reflect the patient's presurgery level of adiposity. We were able to adjust for some important variables associated with perioperative weight loss, particularly bowel obstruction and performance status [57]. The initiation of adjuvant chemoradiotherapy in all patients in this cohort may have attenuated any potential deleterious impact of obesity on the outcome after surgical resection. Studies to examine the influence of adiposity among patients with stage I or early stage II rectal cancer may clarify this issue further. Finally, because patients were enrolled onto this clinical trial several weeks after primary resection of rectal cancer, we could not examine perioperative complication rates according to BMI.

In conclusion, these findings illustrate significant differences between male and female patients treated for rectal cancer. Increasing adiposity seems to be an important consideration among surgeons when approaching men with rectal cancer, though this is potentially less critical in females. Further, the increase in local recurrences among obese males, particularly those treated with an LAR, suggests either an anatomic distinction by sex or a possible biologic influence of visceral adiposity. Importantly, rectal cancer patients with increased BMI tolerate adjuvant chemoradiotherapy at least as well as normal-weight patients, even when treated at actual weight-based doses.

	Appendix

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The following institutions participated in the study: CALGB Statistical Office, Durham, NC (Stephen George, PhD; supported by CA33601); Christiana Care Health Services, Inc CCOP, Wilmington, DE (Irving M. Berkowitz, DO; supported by CA45418); Community Hospital–Syracuse CCOP, Syracuse, NY (Jeffrey Kirshner, MD; supported by CA45389); Dana-Farber Cancer Institute, Boston, MA (George P. Canellos, MD; supported by CA32291); Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, NH (L. Herbert Maurer, MD; supported by CA04326); Duke University Medical Center, Durham, NC (Jeffrey Crawford, MD; supported by CA47577); Eastern Cooperative Oncology Group, Philadelphia, PA (Robert L. Comis, MD, Chairman); Eastern Maine Medical Center CCOP, Bangor, ME (Philip L. Brooks, MD; supported by CA35406); Kaiser Permanente CCOP, San Diego, CA (Jonathan A. Polikoff, MD; supported by CA45374); Long Island Jewish Medical Center, Lake Success, NY (Marc Citron, MD; supported by CA11028); Massachusetts General Hospital, Boston, MA (Michael L. Grossbard, MD; supported by CA12449); Milwaukee CCOP, Milwaukee, WI (Ronald Hart, MD; supported by CA45400); Mount Sinai Medical Center CCOP–Miami, Miami Beach, FL (Enrique Davila, MD; supported by CA45564); Mount Sinai School of Medicine, New York, NY (James F. Holland, MD; supported by CA04457); National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada (Joseph L. Pater, MD, Director); North Central Cancer Treatment Group, Rochester, MN (Michael J. O'Connell, MD, Chairman; supported by CA25224); Radiation Therapy Oncology Group, Philadelphia, PA (Walter J. Curran, MD, Chairman); Rhode Island Hospital, Providence, RI (Louis A. Leone, MD; supported by CA08025); Roswell Park Cancer Institute, Buffalo, NY (Ellis Levine, MD; supported by CA02599); Southeast Cancer Control Consortium Inc CCOP, Goldsboro, NC (James N. Atkins, MD; supported by CA45808); Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV (John Ellerton, MD; supported by CA35421); Southwest Oncology Group, San Antonio, TX (Charles Coltman, MD, Chairman); State University of New York Health Sciences, Center at Syracuse, Syracuse, NY (Stephen L. Graziano, MD; supported by CA21060); University of Alabama Birmingham, Birmingham, AL (Robert Diasio, MD; supported by CA47545); University of California San Diego, San Diego, CA (Stephen L. Seagren, MD; supported by CA11789); University of Chicago Medical Center, Chicago, IL (Gini Fleming, MD; supported by CA41287); University of Iowa Hospitals, Iowa City, IA (Gerald H. Clamon, MD; supported by CA47642); University of Maryland Cancer Center, Baltimore, MD (David Van Echo, MD; supported by CA31983); University of Massachusetts Medical Center, Worcester, MA (F. Marc Stewart, 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 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); Wake Forest University School of Medicine, Winston-Salem, NC (David D. Hurd, MD; supported by CA03927); Walter Reed Army Medical Center, Washington, DC (John C. Byrd, MD; supported by CA26806); Washington University School of Medicine, St Louis, MO (Nancy L. Bartlett, MD; supported by CA77440); Weill Medical College of Cornell University, New York, NY (Michael Schuster, MD; supported by CA07968).

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
J.A.M. is supported in part by a K07 award from the National Cancer Institute (1K07CA097992-01A1) and an American Society of Clinical Oncology career development award. Other support provided by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B.

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.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted July 17, 2003; accepted December 10, 2003.

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