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Journal of Clinical Oncology, Vol 26, No 25 (September 1), 2008: pp. 4060-4062 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.4250
Obesity and Cancer Treatment: Weighing the EvidenceDivisions of Medical Oncology and Surgical Oncology at the University of Michigan Comprehensive Cancer Center, Ann Arbor, MI Obesity rates in the United States have increased tremendously over the past few decades.1 Obesity is associated with an increased risk of several cancers, including breast cancer, colorectal cancer, and endometrial cancer, and is associated with higher cancer mortality rates.2,3 Multiple factors contribute to the unfavorable survival rates in obese patients with cancer, including a higher likelihood of comorbid conditions and a higher likelihood of unfavorable tumor characteristics. In addition, systematic underdosing of chemotherapy in overweight and obese patients with breast cancer,4-7 which occurs in up to 40% of patients, may contribute to the poorer survival rates, particularly among those with estrogen receptor (ER)–negative cancers.8 This issue of the Journal of Clinical Oncology features three studies that broadly address the complicated relationship between weight, factors associated with obesity, and cancer, spanning the bench to the bedside. Creighton and colleagues9 examined the effect of insulinlike growth factor-2 (IGF-1) exposure on gene expression profiles in MCF-7 breast cancer cells. After developing an IGF-1 gene signature, the investigators assessed the IGF activation score in tumor samples contained within publicly available expression profile databases. The IGF gene signature was associated in this study with other known poor prognostic factors, such as ER-negative status, higher tumor grade, and higher stage. The authors conclude "Transcriptional targets of IGF-1 represent pathways of increased aggressiveness and possibly hormone independence in . . . breast cancer." The findings of this study contribute to our understanding of cancer biology in obese patients, who have higher levels of IGF-1 activity10 and, in some studies (including the paper by Litton and colleagues in this issue of the Journal11), a higher likelihood of ER-negative breast cancer. Moving to the bedside, Litton and colleagues,11 in a single-institution study of 1,169 patients receiving neoadjuvant chemotherapy breast cancer, investigated the relationship between body mass index (BMI) and pathologic response rates. Increasing BMI was associated with significantly more advanced disease and a higher rate of ER-negative tumors. In multivariate analysis, the authors report lower pathologic complete response rates among overweight and obese women. Chemotherapy dosing patterns (dose selection and completion rates of chemotherapy) were not available in this study. Despite institutional guidelines at this study site that actual body weight was to be used in chemotherapy dosing, use of adjusted ideal or ideal body weight in chemotherapy dose selection may have occurred, as has been shown even in patients enrolled on clinical trials,12 where such dose reductions are considered a protocol violation. Given the equivalent outcomes achieved between lean and heavy women when full doses of chemotherapy are used8,12; the differences in pathologic response rates may be attributable to variations in treatment. Despite the limitation of not reporting chemotherapy doses, the authors’ use of pathologic response rate as an intermediate marker of response to treatment is an ideal way to study variations in breast cancer outcome among high-risk patients. Finally, Meyerhardt and colleagues13 examined the impact of BMI and weight change on disease free and overall survival in patients with colon cancer. Using data from the Cancer and Leukemia Group B (CALGB) 89803 study, a prospective randomized trial examining the addition of irinotecan to adjuvant fluorouracil and leucovorin in the adjuvant treatment of stage III colon cancer, the authors demonstrated no statistically significant association between initial BMI or weight change and survival in multivariate analyses. The findings of this study differ from the National Surgical Adjuvant Breast and Bowel Project (NSABP) studies that have demonstrated poorer outcomes among obese patients. Notably, CALGB studies, at least in breast cancer, have specified full weight-based dosing in adjuvant treatment since the mid-1980s.14 In contrast, NSABP trials specify dose limits in obese patients. Dose specifications may account for the difference between the CALGB study and the NSABP studies. In addition, Meyerhardt and colleagues also investigated the survival impact of weight change and did not demonstrate a disease-free or overall survival benefit in the 89 patients who reported weight loss at 6 months after completion of chemotherapy. Each of these studies raises interesting points but suffer from the inherent challenges of retrospective research or subgroup analysis. They also serve to highlight the added difficulty of trying to treat diet or obesity as single variables in a multivariable analysis with age, tumor size, or nodal status. To start with, the definition of obesity is controversial. It is unclear whether BMI is the most appropriate measure of obesity. While it is commonly used and easily calculated from information immediately available in the patient chart, BMI makes no distinction between body weight from muscle and body weight from fat. Muscular individuals can be categorized as overweight or obese when they clearly are not. It is also extremely difficult to separate diet from obesity. Patients who eat a low-fat diet, full of fruits and vegetables can be still be overweight while slim individuals can have some of the worst nutrition imaginable. Most, if not all, studies of diet and nutrients suffer to some degree from recall bias, even prospective studies where patients record food diaries. Even when obesity is accurately measured, it becomes difficult to separate the direct biologic effects of increased adiposity from the influences of dietary factors that may both result in obesity and impact malignant cells and from the challenges that obesity creates in delivering appropriate therapy. This last category may include limiting the extent of a cancer operation (as well as increasing the morbidity), complicating the planning or delivery of radiation therapy, or inadequate dosing of chemotherapeutic agents as described earlier. Despite these challenges and limitations, as we continue to examine the relationship between obesity and cancer, a picture is emerging that can not be ignored: there is a growing body of literature that patient weight influences outcome after cancer treatment. How do we, as clinicians, incorporate this information into clinical practice? Certainly, the increased risk of malignancy among overweight individuals, and the worse outcomes if cancer does occur, provides the primary care physicians with additional arguments for patients to improve their diet and control their weight. However, these are just two of many arguments that are being ignored by a population that is eating worse and gaining weight at an unprecedented rate. As oncologists, we have no impact on patients’ lifestyles before they develop cancer. We are instead faced with the challenges of treating the overweight patient. Weight loss before therapy is clearly not an option; surgeons must accept the unique challenges and increased complications associated with operating on the obese patient and adjust appropriately to be sure that the oncologic principles of resection are not compromised. The same is true for the planning and delivery of radiation therapy. And certainly, the medical oncologist must carefully consider the patient's weight when designing and implementing therapy. But what is our responsibility as oncologists after the overweight patient completes their initial cancer treatment? Assume that you have just learned of a new drug entering the oncology marketplace. The idea for the drug is based on multiple observational studies and laboratory examinations of biochemical changes that occur in cancer patients. Ultimately, the drug enters a phase III randomized study, delivered in conjunction with standard cancer therapy. The results of the study demonstrate a significant improvement in disease-free survival, with a relapse hazard ratio of 0.76 (95% CI, 0.6 to 0.98; P = .034). Assuming the drug received US Food and Drug Administration approval, would you offer it to your patients? What if administering the drug requires frequent nurse visits for the first 2 months (twice a week) followed by every 3 months for the duration of treatment, with each visit requiring an hour? Compared with other adjuvant chemotherapies, is this too intensive to justify its use? What if you then learned that the drug had no toxicity and no long-term adverse effects? What if you found out that other studies have shown that the drug improves overall survival? Would you consider this standard of care? How aggressively would you urge your patients to take the drug? These are the results of the Women's Intervention Nutrition Study (WINS), a prospective, randomized trial designed to test whether reducing dietary fat in women with resected, early-stage breast cancer receiving conventional cancer management would improve outcome.15 The "administration of the drug" consisted of in-person counseling sessions with a dietician. And while this interim report demonstrated no impact on overall survival, there is clear evidence that weight loss, proper nutrition, and exercise will improve overall survival by reducing noncancer deaths. There are certainly limitations to the study and questions regarding its interpretation. For example, it is not possible to discern whether the improved survival was secondary to the decreased fat intake or to weight loss or dietary changes other than fat intake. While these questions need to be answered to better understand the biology of cancer development and progression, do we need more evidence to incorporate lifestyle changes into our treatment paradigm? Discussing weight loss with an overweight patient is certainly not an easy conversation and not one with which many physicians are comfortable.16,17 However, if a 10% or 15% reduction in the risk of recurrence is enough to justify the use of an expensive and toxic drug, then how can a possible 25% reduction not justify an aggressive promotion of lifestyle changes? Many oncologists would acknowledge that they devote little to no time to a discussion of weight loss with their overweight patients with cancer. Even among those who do mention it, it is usually listed as one of several suggestions as the patient transitions from active treatment to surveillance. However, one might argue that we are being negligent in not making this a more integral component of our treatment paradigm. Even if the recurrence data is overstated or difficult to reproduce, the additional benefits of weight loss on reducing therapy-related complications, improving quality of life, and most importantly, reducing death by noncancer causes, makes any contrary argument relatively moot. If our ultimate objective is the improvement of overall survival, with a secondary goal of maintaining or improving the quality of life of our patients, and weight reduction clearly affects both of those goals, do we not have an obligation to promote this to our patients with as much gusto as we advocate other adjuvant therapies? There is no doubt that this presents a challenge. If we have trouble convincing patients with head and neck or lung cancer to give up tobacco, or patients with melanoma to stop tanning, we certainly have to expect great resistance to convincing patients with other malignancies to change their diet or lose weight. This is particularly true in light of the fact that patients often use food as a comfort measure as they try to restore normalcy to their lives and that activity may be decreased secondary to the effects of cancer treatment. However, many patients may also feel empowered by taking a proactive role in their cancer management. This is also not to imply that as surgeons, radiation oncologists, or medical oncologists, we need to, or should, manage the patient's weight loss plan. The key to successful cancer therapy is the multidisciplinary approach, and this extends beyond surgery, radiation, and chemotherapy. Survivorship issues, including counseling with a dietician and establishment of an exercise program, should—must—be a routine component of the multidisciplinary approach to cancer.18 Finally, oncologists, other medical providers, and the organizations that advocate for patients and providers can support legislative and other public policy measures that promote healthy lifestyles and prevent or reduce obesity19,20 thereby contributing to improved cancer outcomes along the continuum of care, from prevention to survival. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Manuscript writing: Jennifer J. Griggs, Michael S. Sabel Final approval of manuscript: Jennifer J. Griggs, Michael S. Sabel REFERENCES
1. Mokdad AH, Ford ES, Bowman BA, et al: Prevalence of obesity, diabetes and obesity-related health risk factors, 2001. JAMA 289:76-79, 2003 2. Reeves GK, Pirie K, Beral V, et al: Cancer incidence and mortality in relation to body mass index in the MIllion Women Study: Cohort study. BMJ 335:1107-1108, 2007 3. Calle EE, Rodriguez C, Walker-Thurmond K, et al: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625-1638, 2003 4. Griggs JJ, Sorbero ME, Lyman GH: Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med 165:1267-1273, 2005 5. Lyman GH, Dale DC, Crawford J: Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: A nationwide study of community practices. J Clin Oncol 21:4524-4531, 2003 6. Shayne M, Crawford J, Dale DC, et al: Predictors of reduced dose intensity in patients with early-stage breast cancer receiving adjuvant chemotherapy. Breast Cancer Res Treat 100:255-262, 2006[CrossRef][Medline] 7. Madamas Y, Sawka CA, Franssen E, et al: Are medical oncologists biased in their treatment of the large woman with breast cancer? Breast Cancer Res Treat 66:123-133, 2001[CrossRef][Medline] 8. Colleoni M, Li S, Gelber RD, et al: Relation between chemotherapy dose, oestrogen receptor expression, and body-mass index. Lancet 368:1108-1110, 2005 9. Creighton CJ, Casa A, Lazard Z, et al: Insuln-like growth factor-I (IGF-I) activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol 26:4078-4085, 2008 10. Calle EE, Kaaks R: Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4:579-591, 2004[CrossRef][Medline] 11. Litton JK, Gonzalez-Angulo AM, Warneke CL, et al: Relationship between obesity and pathologic response to neoadjuvant chemotherapy among women with operable breast cancer. J Clin Oncol 26:4072-4077, 2008 12. Rosner GL, Hargis JB, Hollis DR, et al: Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: Results from Cancer and Leukemia Group B Study 8541. J Clin Oncol 14:3000-3008, 1996[Abstract] 13. Meyerhardt JA, Niedzwiecki D, Hollis D, et al: Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: Findings from CALGB 89803. J Clin Oncol 26:4109-4115, 2008 14. Greenman CG, Jagielski CH, Griggs JJ: Breast cancer adjuvant chemotherapy dosing in obese patients: Dissemination of information from clinical trials to clinical practice. Cancer 112:2159-2165, 2008[CrossRef][Medline] 15. Chlebowski RT, Blackburn GL, Thomson CA, et al: Dietary fat reduction and breast cancer outcome: Interim efficacy results from the Women's Intervention Nutrition Study. JNCI 98:1767-1776, 2006 16. Galuska DA, Will JC, Serdula MK, et al: Are health care professionals advising obese patients to lose weight? JAMA 282:1576-1578, 1999 17. Scott JG, Cohen D, DiCicco-Bloom B, et al: Speaking of weight: How patients and primary care clinicians initiate weight loss counseling. Prev Med 38:819-827, 2004[CrossRef][Medline] 18. Demark-Wahnefried W, Aziz NM, Rowland JH, et al: Riding the crest of the teachable moment: Promoting long-term health after the diagnosis of cancer. J Clin Oncol 23:5814-5830, 2005 19. Kersh R, Morone J: The politics of obesity: Seven steps to government action. Health Aff (Millwood) 21:142-153, 2002 20. Gostin LO: Law as a tool to facilitate healthier lifestyles and prevent obesity. JAMA 297:87-90, 2007
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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