Dosing for Obesity New Chemotherapy Guidelines Linked to Body Weight

Martha Polovich, PhD, RN, AOCN®

In the course of an average day, a medical oncologist may have to break terrible news to several patients, telling them they have cancer, or that their disease has recurred.

In comparison, sitting down in a quiet room to write out a prescription for chemotherapy might seem much less nerve-wracking.

But oncologists know that’s not always the case. For those who treat overweight or obese cancer patients, choosing doses of chemotherapy can be a sweat-producing endeavor. While some physicians prescribe the way they do for normal-weight patients— based on body surface area (BSA), a calculation of height and weight—others cap the amount of chemotherapy for larger patients, for fear that full doses will spark too many side effects.

“You’re sometimes talking about really whopping doses of drugs, and it makes everyone a little nervous,” said Martha Polovich, PhD, RN, AOCN®, director of Clinical Practice for Nursing Education and Research at Duke Oncology Network. “If you have a 300-lb breast cancer patient with a BSA of 2.56, many oncologists would cap the BSA at 2.0 and give 120 mg of doxorubicin. If you dosed based on the actual BSA, you’d give 150 mg. It’s more than we’ve ever given in the past.”

Now, however, oncologists are being encouraged to give full doses without the worry. A clinical practice guideline1 issued in April by the American Society of Clinical Oncology (ASCO) recommends that chemotherapy doses—particularly those with curative intent— be based on full body weight in obese patients, unless it is contraindicated due to comorbidities.

Dosing based on body weight will improve a trend toward poorer outcomes among heavy patients without increasing toxicities, according to the guideline, which is based on an ASCO expert panel’s review of data on the topic published over 46 years.

The guideline does not address the dosing of radiation or targeted cancer therapies.

Jennifer Griggs, MD, MPH

Many Patients Affected

Currently, up to 40% of obese cancer patients are given reduced chemotherapy doses, ASCO has said.² Yet a 1996 study by Rosner, et al³ demonstrated that underdosing such patients by even 6% can compromise their chances of survival, noted Jennifer Griggs, MD, MPH, associate professor in the Departments of Internal Medicine and Health Management & Policy at the University of Michigan, and a member of the ASCO expert panel that drafted the guideline.

The issue affects a significant number of patients with cancer. According to the guideline, more than 60% of America’s adults are overweight, obese, or morbidly obese. The World Health Organization defines overweight people as those who have a body mass index (BMI) of 25 to 29.9 kg/m²; obese individuals as those with a BMI of 30 kg/m² or more; and morbidly obese people as those with a BMI over 40 kg/m².²

Gary Lyman, MD, MPH, professor of Medicine in the Division of Medical Oncology, Department of Internal Medicine at Duke University School of Medicine and the Duke Cancer Institute, North Carolina, proposed several years ago that ASCO draft a guideline on chemotherapy dosing in the overweight and obese population. By then, he said, cooperative organizations for clinical cancer research, including Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group, had recommended against the capping of chemotherapy doses in obese patients. Yet, practice varied widely throughout the country, with dose capping occurring in both academic and community oncology settings.

ASCO convened an expert panel to investigate the issue, chaired by Lyman and Griggs.

Gary Lyman, MD, MPH

“We felt as a society and as a panel that this was a guideline that was probably long overdue, and was going to become even more important because of the rising wave of obesity in patients we see in our clinic,” Lyman said. “Obese patients should have the same chance at curative treatment as healthy-weight individuals.”

Griggs added that she hopes the recommendation will lead to full chemotherapy dosing of others who are less likely than average patients to receive best treatment.

While physicians realize they’re dose reducing in heavier patients, they may use the same practice in minority, poor, or disabled patients without being aware of it,⁴ Griggs said. The problem, she said, stems from physician perceptions that such patients lack education or strong social support systems, and either don’t want intensive treatments or won’t be able to follow instructions about medications to take at home.

“Because the guideline will help make dosing decisions explicit and measurable—something people track—and because better outcomes in heavier patients will create positive reinforcement, we’re likely to see an extension of full dosing cross from the obesity group to the medically underserved,” Griggs said. “We have to achieve high fidelity to treatments we already know work. That’s important to me in public health and common sense.”

In its look at the issue of overweight and obese patients with cancer, the ASCO expert panel found a number of justifications for administering chemotherapy doses based on actual BSA.

“We and others had done several practice-pattern surveys of oncology treatment across the country in different practices and institutions, and we reported a considerable amount of reduction in relative dose intensity—in other words, the dose intensity of the chemotherapy delivered as compared to that recommended in guidelines,” Lyman said. “When we dove into it in more detail, one of the biggest reasons for that appeared to be a frequent use of dose capping, or the use of idealized body weights, in individuals who were overweight or obese.” According to the results of one very large study of patients with early-stage breast cancer, the likelihood of physicians to plan capped chemotherapy doses in advance of treatment increased in accordance with patient obesity levels, meaning that the heaviest patients were treated at the lowest relative dose intensities (Figure).

Figure. BMI and Reductions in Dose Intensity

Early-Stage Breast Cancer

BMI indicates body mass index; RDI, relative-dose intensity.

A study of the records of more than 20,000 patients with early-stage breast cancer collected from 1243 community oncology practices demonstrated the relationship between patient weight and chemotherapy dose capping that was planned by physicians prior to the start of treatment. Shown are planned reductions in dose intensity; unplanned reductions due to problems, such as neutropenia; and relative dose intensities received. Patients are grouped according to World Health Organization body-mass index category.

Sources:

Lyman GH. Weight-based chemotherapy dosing in obese patients with cancer: back to the future [published online ahead of print April 3, 2012]. J of Oncol Pract. 2012;8(4):62e-64e. 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. 2003;21:4524-4531.

Reprinted with permission. ©2012 American Society of Clinical Oncology.

All rights reserved.

“At the same time,” Lyman said, “there had been a number of studies suggesting that reduced dose intensity of chemotherapy for any reason in the curative setting may well be associated with a higher risk of cancer recurrence or poor long-term survival. Finally, several studies found that overweight and obese patients with cancer treated with full calculated doses had no higher rates of treatment-related complications than healthy-weight individuals getting full doses of chemotherapy. In some studies, obese patients had fewer toxicities, which has yet to be explained.”

Lyman said he hopes the guideline will “alleviate some of the confusion” about the advisability of dosing patients based on actual BSA, regardless of their weight.

“Oncologists can still choose to dose as they see fit,” he said, “but we wanted to make clear that if they did dose based on actual body weight, they’d not be doing their patient any harm or disservice. Also, we wanted physicians to know that there’s a real possibility this could lead to better outcomes in patients being treated with curative intent.”

There are, however, some instances in which physicians should consider limiting doses of chemotherapy in obese patients—the same situations that would trigger dose reductions in normal-weight patients, the guideline dictates.

“For all patients, physicians should consider comorbidities (eg, heart, kidney, or lung problems) when selecting the chemotherapy dose, and should monitor toxicities closely,” ASCO said in a written statement.² “Dose reduction for side effects should be made consistently for all patients.”

The guideline also recommends adherence to established dosing limits on some specific chemotherapy drugs: vincristine, because of the risk of nerve damage; bleomycin, because of the risk of lung scarring; and carboplatin, which should be dosed based on kidney function.

Polovich added that in palliative settings, full chemotherapy doses with the potential for optimal effectiveness are not always as crucial as when cure is the goal. In palliative care, she pointed out, “patient response to treatment and managing side effects are the most important things.”

That said, the new guideline seems right on target to Polovich.

More Clarity for Providers

In recent years, Polovich, who serves as a chemotherapy expert within the Oncology Nursing Society (ONS), has heard increasing calls for a change in dosing practices.

“I’ve been working on the ONS chemotherapy and biotherapy guidelines since 2001, and since then we’ve always labeled chemotherapy dosing as something left up to the provider,” Polovich said. “In the last edition, we said it was controversial, because people were beginning to question whether that was appropriate. Next year will be the first time we recommend using actual body weight in calculating chemotherapy doses for overweight and obese patients.”

For Polovich, the change will resolve some troubling questions about how best to treat overweight patients with cancer.

“We’ve had data about obese breast cancer patients having poorer outcomes for a long time,” she said. “It wasn’t clear whether the reason was chemotherapy dosing, and a lot of people have tried to attribute it to other things. I don’t think we can ignore that information anymore; we need to dose patients based on actual BSA, and should not dose-reduce without a reason. We’ve known for 15 years that older patients who aren’t dosed fully don’t do as well, but I guess we never thought to apply that to obese patients.”

An important next step, Lyman said, will be for healthcare practitioners to absorb the information in the guideline and begin incorporating it into practice.

“Practices, universities, and cancer centers should discuss this and decide whether they will modify their policies for dosing obese patients,” he said. “My guess is that’s already taking place, and if this just stimulates discussion and thoughtful decision-making, we will have fulfilled much of our goal.”

If you ask Polovich, though, that won’t happen with a snap of the fingers.

“I think it will take some time to filter down to smaller settings,” she said. “People at Duke are paying attention to this, but for small, rural places in Montana or Nebraska, it will take a while for that practice to change.”

Lyman said practitioners can find the guideline, and related tools and resources, on ASCO’s website for healthcare professionals at http://tinyurl.com/9ju3ece. Patients, he said, can learn what the guideline means to them by visiting http://tinyurl.com/95grxue.

In the North Carolina area served by Duke, Polovich is doing what she can to teach her colleagues about the guideline.

“For the nurses in rural hospitals in our network, we did an educational program letting them know what the ASCO guideline says,” Polovich explained. “We gave examples of patients who are obese and what the dose would be for some common regimens like doxorubicin for breast cancer or R-CHOP for lymphoma, showing that, yes, these doses are higher than what you’re used to giving, but based on the size of these patients, it’s an appropriate dose. We had them go through calculations, look at the numbers, and get over that reluctance to treat at full dose.”

Polovich added that, beyond developing a comfort level with full chemotherapy dosing, nurses can help uphold the new standard in other ways.

“If the doctors they work with aren’t up on the recommendations, or are hesitant, there is nothing wrong with nurses questioning a capped dose to get clarification,” she said.

Bradley Burton, PharmD, BCOP, CACP

In fact, that’s something all oncology professionals should do, said Bradley Burton, PharmD, BCOP, CACP, a clinical pharmacy specialist in the medical oncology division of the Johns Hopkins Hospital in Baltimore, Maryland.

“It should be a collaborative effort among nurses, physicians, and pharmacists,” Burton said. “Across the entire oncology landscape, healthcare professionals should educate each other about this new guideline.”

Ultimately, that could help patients like Brian Kissinger, said the 33-year-old Californian who for 3 years has been battling a stage IV carcinoid tumor on his bronchus near his left lung.

Brian Kissinger and family

At 6 foot 1 inch and 270 pounds, and with a history of working in construction and lifting weights, Kissinger said he “wasn’t fat, but was bigger than the average person” when he was diagnosed with cancer. After being told by a first physician that he had 6 months to live, Kissinger chose a different oncologist who gave him the most aggressive dose of paclitaxel plus carboplatin that was safe for his body size.

On the day of his first treatment, “the pack on the IV stand looked like it was about to burst—it was filled to capacity,” Kissinger said. “My nurse laughed, because it was the biggest dose she’d ever seen.”

The married father of a 3-year-old, who had no side effects besides hair loss, said he agrees with ASCO’s dosing guideline and hopes it will encourage physicians to give larger patients, like himself, full chemotherapy doses. Likewise, the founder of an organization that has offered Kissinger support throughout his illness, the Bonnie J. Addario Lung Cancer Foundation, advocates reliance on the guideline.

What About Cost?

From the patient perspective, the benefits of the new standard are obvious. But will the change in chemotherapy dosing practices also carry costs?

Future work of the ASCO expert panel will focus on that question, specifically as it relates to community oncology practice, Griggs said.

While full dosing of obese patients with cancer is not likely to be a sticking point for health insurers, which may actually use the practice as a quality measure under pay-for-performance programs, Griggs said, increased dosing could be expensive for community oncologists, causing “pushback” against the guideline or the rounding down of doses.

“I am sensitive to the cost issues,” she said, “especially for doctors who have to pay for the drugs out of pocket and then get reimbursed.”

To get an idea of the potential monetary costs of the change, Griggs said, “I’d love to calculate, for patients at different body sizes, the number of vials they’d need of an expensive drug like oxaliplatin, and what the cost would be to crack a second vial for a portion of that dose. The obvious implication is to have two vial sizes, like we do for growth factor. That way, the marginal cost of that second, larger vial won’t be twice the amount, and patients will get appropriate care.”

It’s a plan the medical community should consider proposing to drug manufacturers, the doctor suggested.

But even if such spending-control measures are put into place, Griggs said, it will be difficult to predict the overall benefits versus the costs of the new guideline to America’s healthcare system.

While the doctor noted that overweight and obese patients generate heftier medical costs across the spectrum of healthcare due to a higher rate of comorbidities, she added that, in oncology, “if you save a life, you’ll save the downstream costs of care. For instance, in colorectal cancer, they use really expensive drugs in people who have a relapse.”

Despite those conflicting pressures, Lyman is convinced that the new guideline won’t have long-term costs for America.

“In the long run, at worst, this will be a breakeven as far as cost to the system or society, and it could well be a cost savings,” he said. “More important, the saving of lives that could come out of this would be tremendous.”

In addition to cost-benefit research, the new guideline is almost certain to stimulate scientific queries, Lyman said.

“The panel did call for more research to better refine our recommendations, particularly looking at the pharmacokinetics of chemotherapy dosing, where you look at the amounts of drugs in patients of different levels of obesity,” Lyman said. “The ultimate question is how much drug actually gets to the tumor cells. While there’s almost no data in humans, animal studies suggest that the concentration of chemotherapy drugs getting to the tumor site may be somewhat less in obese patients, because some drugs are cleared (from the body) more rapidly. We especially need these studies in the morbidly obese.”

Griggs hopes the guideline will also serve as a prelude to additional public-policy efforts to protect obese patients with cancer.

“The guideline was just a first step, because full dosing won’t address all the cancer disparities we see,” she said. “There’s no cancer where the outcome is better if you’re heavy, because obesity is a chronic inflammatory state, and inflammation is a trigger for the growth of cancer cells.”

As a result, Griggs said, policymakers need to help stem America’s epidemic of obesity.

“Public policy,” she said, “needs to address sweetened drinks, safe places to play, and things like physical education, which is no longer mandatory in some schools.”

References

1. American Society of Clinical Oncology. Appropriate Chemotherapy Dosing for Obese Adult Patients With Cancer: American Society of Clinical Oncology Clinical Pr actice Guideline. ASCO website. http://tinyurl.com/9ju3ece. Published April 2, 2012. Accessed Sept. 27, 2012.
2. American Society of Clinical Oncology. ASCO Guideline Recommends the Use of Actual Body Weight to Calculate Appropriate Dose of Chemotherapy Drugs for Obese Patients. ASCO website. http://tinyurl.com/8hmp9e6. Published April 2, 2012. Accessed Oct. 3, 2012.
3. 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. 1996;14(11):3000-3008.
4. van Ryn M, Burke J. The effect of patient race and socio-economic status on physicians’ perceptions of patients. Soc Sci Med. 2000;50(6):813-828.