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Beyond increased risk: Obesity hinders cancer diagnosis, treatment

A global population that is steadily gaining weight faces challenges, from self-exam to survivorship.

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The paper trail linking excess weight to increased cancer risk is long.

As obesity rates climb worldwide, research into the complications associated with diagnosing and treating cancer in this portion of the population is becoming more prevalent.

Some of the findings are self-evident: Due to body-image issues and other psychosocial concerns, for example, obese women are less likely to get Pap smears and other invasive tests that may detect gynecologic cancers.

Other data present a more confounding picture. Many obese patients seek treatment for cardiovascular disease, diabetes or other conditions that arise from being overweight. In some cases, their relationship with the health care system gives clinicians an opportunity to diagnose  and treat  cancer in a timely manner. Other times, the health concerns that necessitated the initial visit require so much attention, cancer may go undetected.

Obesity rates  the percentage of people with a BMI of 30 or greater  have doubled worldwide since 1980, with an estimated 9.8% of men and 13.8% of women meeting that criteria, according to research published last year in The Lancet.

Nearly one-third of Americans are obese now, and if trends continue, half of the US population could be classified as such by 2030, findings published in The Lancet show.



Photo courtesy of Dana-Farber Cancer Institute

HemOnc Today spoke with several physicians and researchers about the extent to which these populations are screened for cancers, challenges related to surgical options and chemotherapy dosing, the increased risk for drug interactions among those who are taking medications to control other diseases, and obstacles to effective post-treatment care.

Perhaps the most basic challenge is determining what is overweight or obese, said Heather Bittner Fagan, MD, FAAFP, MPH, associate professor at Thomas Jefferson University and director of health services research in the department of family and community medicine at Christiana Care Health System. Given how heavy people in the United States are, it is difficult to know where to draw the line. This may also impact the direction of the research and the outcomes we see. Many of the data are still inconclusive.

Screening

Fagan and colleagues recently published a review paper in the Journal of Obesity that examined the association between weight and cancer screening, while also examining screening rates across race/ethnicity and gender.

Among the findings:

Obesity is associated with higher rates of prostate cancer screening among all races.

Obesity is associated with lower rates of cervical cancer screening, particularly among white women.

No correlation appeared between weight and mammography use in women.

Obese women were less likely to be screened for colorectal cancer, while the relationship between weight and colorectal screening in men was inconsistent.

It is striking how variable the relationship between obesity and screening can be, Fagan said. There are big differences based on the type of screening and the type of cancer.

More clinical barriers to screening overweight women for certain cancers may exist.

Many severely obese women need special accommodations such as larger examination tables, but even with these in place, it may be difficult to examine all the reproductive organs satisfactorily, Bryan C. Bordeaux, DO, MPH, of the division of general internal medicine at Johns Hopkins University School of Medicine, and colleagues wrote in a review paper in the Cleveland Clinic Journal of Medicine . Clinical breast examinations may be less reliable because increased tissue volume may make some tumors difficult to palpate.

The results of Fagans paper indicated that fewer body image-based effects were seen in men than in women, but that screening men also can be complex.

Most data indicate that obese men are less likely than nonobese men to undergo a digital rectal exam to screen for prostate cancer. However, because prostate cancer can be detected by a much less invasive blood test, obese men are being screened.

In prostate cancer, obesity can actually facilitate screening, Fagan said. Obese men are already in the [health care] system for other things and are therefore likely to get tested.

The data is far less consistent for colorectal cancer screening, the only test recommended for both men and women.

Two studies Fagan and colleagues examined indicated obese men had lower colorectal cancer screening rates. One study indicated a higher rate among obese men, and three studies found no association. Four of six studies that examined the same factors in women demonstrated a negative association between obesity and colorectal cancer screening.

The take-home message is that specialists need to understand obese populations have a patchier history of being screened, Fagan said.

Imaging

Obesity has unique impacts on imaging, said Munir Ghesani, MD, attending radiologist at St. Lukes-Roosevelt Hospital Center and Beth Israel Medical Center and a HemOnc Today Editorial Board member.

There are essentially two things to look at, Ghesani said. How does obesity impact image quality, and (for studies involving ionizing radiation) how does it impact radiation exposure?

The quality of the image depends on the type of scan.

Fat in areas like the abdomen can provide better image contrast and actually be helpful in reviewing a CT scan, he said. However, if you are doing a nuclear scan, you can get more severe attenuation artifacts in obese patients, and the image quality suffers. Consequently, the quality of PET and nuclear scan images is usually poorer in obese patients.

In order to achieve similar image quality, radiation doses may be higher in overweight or obese patients. Increased radiation exposure may, in turn, be linked to increased risk for other cancers.

That said, the advantage of most current-generation machines is that they are able to adapt to different-sized patients, Ghesani said.

Socioeconomic factors also can be barriers to imaging.

Obesity is more common in poorer people who are more likely to be uninsured and may be less likely to follow through with expensive procedures, according to Bordeaux and colleagues.

Then there are clinical obstacles to imaging in overweight patients.

Unfortunately, many of our imaging machines are not designed to handle people who are morbidly obese, Bordeaux told HemOnc Today. Sometimes the tables on which patients rest during the procedure cannot safely support the patients weight, they might be too narrow to prevent them from falling, or the machine openings are too narrow (in the case of a CT or MRI machine) to allow a patient to pass through to the sensors.

In some cases, patients must be transported to veterinary hospitals so larger imaging machines can be used, Bordeaux said.

Delays in diagnosis

The challenges related to screening and performing imaging on obese patients often lead to later diagnosis, said Dale R. Shepard, MD, PhD, an associate staff member in solid tumor oncology at the Taussig Cancer Institute.

Obese individuals are less likely to detect tumors by self-exam because the patients are so large, Shepard said. When the tumor is found so late, it is not surprising that the patients do not do as well.

Bordeaux echoed that point.

Obese individuals, particularly those with a BMI greater than 35, are more likely to have deeper and wider pelvic structures, making it harder to palpate their cervix, ovaries or prostate, he said. Also, examining joints, the heart and lungs, breasts, thyroid and testes are more challenging because of the increased adipose tissue overlying these areas.

Conversely, there are instances when a cancer diagnosis is unexpected.

People often get a diagnosis because they are obese, Bordeaux said. They are in the health care system because of obesity, which means they may be more likely to get scanned for something else. They felt fine, or at least cancer wasnt on the horizon, but they got a CT scan for another reason and a cancer was discovered. How many times do we have people in the system and they find things sort of accidentally?

Little is known about the relationship between obesity and cancer diagnosis because little research has been done about it.

The focus of research is largely on risk prevention, Bordeaux said. It would be difficult to conduct this kind of study, to follow obese individuals and nonobese individuals and see what kind of diagnosis and outcomes might occur. This is a huge undertaking, and data like this usually come out of studies like [the National Health and Nutrition Examination Survey]  big studies looking at dozens of associations.

Chemotherapy dosing

The most comprehensive research on obesity and cancer treatment has focused on drug dosing.

A landmark paper by Smith and Desch, published in Southern Medical Journal in 1991, provided a defining statement on how obese patients should be dosed.

We propose that patients being treated with curative intent receive full-dose intensity, using body surface area calculated on actual body weight or on ideal body weight with dose escalations if tolerated, they wrote.

The discussion in the clinical community eventually evolved to whether the doses should be capped and, if so, what the limit should be.

Under-dosing of chemotherapy for breast cancer among obese women has been reported and may be associated with poorer outcomes, Bordeaux and colleagues wrote. Nevertheless, data on the appropriate dosing of chemotherapeutic agents in obese patients are limited, and the effects that this potential under dosing might have on mortality rates are unclear.

In a 2006 study published in Hospital Pharmacy , DuBeshter and colleagues found most oncologists use a dose limit less than that for a body surface area of 2.2 m2.

This user set limiting dose was rarely exceeded, with 97% of dosages below the limits set in this computer order entry system, they wrote.

In a 2005 study published in Archives in Internal Medicine , Griggs and colleagues studied chemotherapy doses in women with breast cancer.

Overweight and obese women with breast cancer often receive intentionally reduced doses of adjuvant chemotherapy, they wrote. Administration of initial and overall full weight-based doses of adjuvant chemotherapy in overweight and obese women is likely to improve outcomes in this group of patients.

Adam M. Brufsky, MD, PhD, professor of medicine and associate chief of hematology-oncology at the Womens Cancer Center at Magee-Womens Hospital of UPMC and the University of Pittsburgh Cancer Institute, acknowledged the under-dosing of patients but noted the opposite also is a concern.

Like many clinicians, I have been cautious because the fear is that we are going to overdose patients, said Brufsky, who also is a HemOnc Today Editorial Board member. There are just too many complications that can arise, such as the links between carboplatins and thrombocytopenia and neutropenia.

Brufsky emphasized the importance of understanding body fat content.

The difference between 20% body fat content and 40% body fat content is huge, he said.

Shepard noted some drugs go into the bloodstream, while others are absorbed into fatty tissue.

We need to account for this, but the complications do not stop there, Shepard said. A man who is 6 feet and 300 lb may be nearly twice the size of a man who is 6 feet and 180 lb, but that does not mean he will have twice the blood volume. It is a complex equation.

Drug interactions

Obese patients  particularly those who are older  tend to be on more medications to treat conditions such as cardiovascular disease, kidney disease or diabetes, Shepard said. On a basic level, these drugs interfere with cancer treatment. They also can reduce liver function.

It is sort of an indirect complication from the obesity, and it can make things particularly tricky if you are trying to treat a cancer with drugs that are metabolized by the liver, Shepard said.

There also is another complication with cancer drugs, said Carrie Tompkins Stricker, PhD, RN, director of clinical programs and oncology nurse practitioner at the Livestrong Survivorship Center of Excellence at the Abramson Cancer Center of the University of Pennsylvania.

A particular concern is weight gain associated with treatments for hormonally mediated cancers, including breast and testicular cancers, said Stricker, who also is a clinical assistant professor of nursing at Penn, where she leads a pilot study of an Internet-based weight loss program for survivors of these two cancers. Chemotherapy has been linked to weight gain. The classic thought, supported by a wealth of research in these cancers, is that you are going to gain weight as you move into and beyond treatment.

Women who gained weight under these circumstances had an increased risk for breast cancer death. Such weight gain could also affect adherence to life-saving hormonal therapy in these women, although no studies have specifically examined this, Stricker said.

Despite the fact that most studies  including randomized clinical trials  have failed to link tamoxifen to weight gain, many breast cancer survivors attribute their weight gain to it since this is the only medication they are taking as they continue to gain weight post-chemotherapy, Stricker said. This perception could reduce adherence to prolonged tamoxifen treatment, and poor adherence has been linked to increased breast cancer death. Patients also report weight gain on aromatase inhibitors.

Weight gain and an increased risk for metabolic syndrome are increasingly being recognized as effects of testicular cancer treatment, contributing to the increased risk of cardiovascular death in this population, Stricker said.

Surgery

The complications associated with surgery in obese patients cause a similar level of concern as drug interactions, according to Jeffrey A. Meyerhardt, MD, MPH, associate professor in the department of medicine at Harvard Medical School and a gastrointestinal oncologist at Dana-Farber Cancer Institute.

Meyerhardt and colleagues conducted a study of nearly 1,700 rectal cancer patients participating in an adjuvant therapy clinical trial. Patients who were obese had a significantly higher likelihood of having a permanent colostomy in analyses adjusted for tumor stage and location of rectal cancer. Obese men also had a higher likelihood of a local recurrence compared with normal-weight men.

Meyerhardt concluded it is more difficult to perform rectal surgery on an obese patient. That may limit the effectiveness of the surgery or lead to adverse outcomes, including a higher risk for colostomy and local recurrence.

In Shepards opinion, the problem is more fundamental.

Obese patients are just not fit enough to have surgery, he said. They have poor lung function, which makes it difficult to go under anesthesia.

Bordeaux and colleagues cited other similar complications, noting obese patients are more prone to blood loss requiring transfusions and are more likely to have pulmonary complications.

They also run a higher risk of pneumonia, Brufsky said.

Surgeons are getting better at performing on obese patients, but there is still the healing issue, Brufsky said. These patients can go through the surgery OK, but there is difficulty tolerating postoperative complications.

Post-treatment and beyond

Much of Strickers research has focused on breast cancer treatment and survivorship.

We are looking at the next step: As they come out of treatment, what future risks do they face? she said. Obesity and weight gain may increase the risk of recurrence and has also been linked to greater risk for certain late effects such as lymphedema, not to mention increasing risk of cardiovascular disease and other comorbidities. Obese patients thus face unique survivorship issues.

Although breast cancer treatment has been linked to weight gain, most clinicians are faced with the opposite problem.

We fall victim to seeing patients who are sick, not eating well and losing weight, so we sometimes encourage them to eat high-fat foods simply because we want them eating something, Shepard said. The problem is that, at a certain point when their condition has stabilized, you have to stem the tide.

Many obese patients had poor diet and exercise habits long before they were diagnosed with cancer, Shepard said.

Clinicians often must battle a lifetime of unhealthy behaviors when they advocate for post-treatment wellness, a challenge made much more formidable given that the majority of research suggests poorer outcomes  particularly recurrence and death  among patients with higher BMI.

Yoon and colleagues found that excess BMI among never smokers was linked to poorer disease-specific survival, DFS and OS in 778 patients who underwent potentially curative esophagectomy.

In the Cancer Prevention Study II, Calle and colleagues found that men in the heaviest cohort had a 52% higher rate of cancer death than normal-weight men after adjusting for several variables. After adjusting for the same variables, the heaviest women were 62% more likely to die of cancer than normal-weight women. About 14% of cancer deaths in men and 20% of cancer deaths in women are linked to overweight or obesity, indicating that about 90,000 preventable cancer deaths occur per year, according to the results.

Fagan emphasized that clinicians should take these types of data as a warning.

If current trends in obesity continue, it becomes increasingly important to understand if, how and when this condition confers a disparity in health outcomes, she said.

Meyerhardt agreed.

Some of the data are conflicting, but the trend is clear, he said. With the growing rate of obesity in the US and other countries, the percentage of our cancer patients who will be obese will continue to grow. There needs to be much more research to understand how to manage these patients.

Further, strategies to break the increasing trend toward increased adiposity in our population are critical, Meyerhardt added. This will have a twofold effect  it may decrease the incidence of certain cancers that obesity is associated with and help with the management of patients who do develop cancer.  by Rob Volansky

Disclosure: Drs. Bordeaux, Brufsky, Fagan, Ghesani, Meyerhardt, Shepard and Stricker report no relevant financial disclosures.

For more information: Bordeaux BC. Cleve Clin J Med. 2006;73:945-950.

2006;73:945-950. Calle EE. N Engl J Med. 2003; 348:1625-1638.

2003; 348:1625-1638. DuBeshter B. Hospital Pharmacy. 2006;41:136-142.

2006;41:136-142. Fagan HB. J Obes. 2011;218250.

2011;218250. Griggs JJ. Arch Intern Med. 2005;165:1267-1273.

2005;165:1267-1273. Meyerhardt JA. J Clin Oncol. 2004;22:648-657.

2004;22:648-657. Smith TJ. South Med J. 1991;84:883-885.

1991;84:883-885. Wang YC. Lancet. 2011;378:815-825.

2011;378:815-825. Yoon HH. J Clin Oncol. 2011; 34:4561-4567.

Does current research demonstrate support for capping chemotherapy doses in overweight or obese patients?

We should avoid capping or limiting doses.

We have done a lot of research in this area and found that heavy women with breast cancer frequently receive lower doses of chemotherapy than standard.

There are systematic differences in the treatment of these populations. In 1996, Rosner and colleagues demonstrated that obese patients whose doses were reduced by a mere 5% had a higher rate of recurrence or death. Moreover, they found that toxicity was not increased in fully dosed obese patients, but that more than 50% of obese patients were given reduced doses.

For obese patients, there is much less wiggle room for dosing. Research we published in 2005 demonstrated that practices varied greatly in the use of dose reductions in overweight and obese patients.

Obese women were more likely (37%) to receive reduced chemotherapy doses compared with healthy-weight women (9%). Furthermore, among those patients who were obese and did receive full weight-based dosing, rates of hospitalization for febrile neutropenia were actually lower than in lean and overweight women who were fully dosed. Conversely, 63% of severely obese patients received full weight-based dosing, indicating that many physicians are aware of what I consider ideal dosing strategies.

Although we do not have data that dose escalation in obese patients will achieve the same level of neutropenia as in lean women, the key point is that we should avoid dose reduction (capping or limiting doses). Administration of full chemotherapy doses may improve cancer outcomes at the population level, given the increasing rates of obesity and the fact that obesity is associated with a higher risk of many cancers.

The American Society of Clinical Oncology is currently developing practice guidelines to address the uncertainties in chemotherapy dose selection. The hope would be that standardizing chemotherapy dose selection will improve care among this growing population.

Jennifer J. Griggs, MD, MPH, is associate professor in the department of internal medicine, hematology and oncology division, associate professor in the department of health management and policy, and director of the breast cancer survivorship program at the University of Michigan School of Public Health. References: Griggs JJ. J Clin Oncol. 2007;3:277-284. Rosner GL. J Clin Oncol. 1996;14:3000-3008. Disclosure: Dr. Griggs reports no relevant financial disclosures.

There are not sufficient data to conclusively answer the question of capped chemotherapy doses in these patient populations for all cancer types.

The majority of the data do not support capping, but individual decisions need to be based on several factors, including curative vs. palliative intent; the healthiness of the patient; the disposition of the chemotherapy agent in the body; and the specific dose-limiting side effects of the particular chemotherapy agent and whether the patient would be particularly sensitive to that agent.

Regarding intent of therapy, the risk/benefit analysis for a patient receiving potentially curative chemotherapy would lean toward giving the full calculated dose to ensure the patients best chance at cure, and in this case, the potentially higher risk of toxicities would be better tolerated. However, if the patient is receiving palliative chemotherapy for metastatic cancer, without any realistic chance for cure, you would not want to cause much toxicity.

Although the weight of the patient is a factor, a bigger predictor of whether a patient can tolerate chemotherapy is based on the underlying health or performance status of the patient.

As for the disposition of the agent in the body, pharmacokinetic prediction of the risk would depend on whether the chemotherapy agent would have a larger or smaller volume of distribution depending on obesity, and whether the clearance of the chemotherapy would be faster or slower depending on organ function changes in obesity.

With regard to dose-limiting adverse events, myelosuppression may serve as an example. If the dose-limiting side effect is myelosuppression and the patient already has poor marrow reserve, perhaps the dose ought to be capped.

In summary, most obese patients would not be best served by across-the-board policies regarding capping of chemotherapy doses. In general, doses should not be peremptorily capped, but individual dosing decisions should be made based on additional considerations as outlined above.

Lisa K. Lohr, PharmD, BCOP, BCPS, is an oncology pharmacy specialist and oncology medication therapy management provider at the University of Minnesota Masonic Cancer Center. Disclosure: Dr. Lohr reports no relevant financial disclosures.