Oncology clinicians have long known that lean cancer patients outlive obese ones, but they're just starting to realize that poor outcomes might be tied to misguided treatment. Whether they're treated with drugs, radiation, or surgery, obese patients have unique risks that might warrant a different approach.
“Very little research is being done in this area,” said Otis Brawley, MD, Chief Medical Officer for the American Cancer Society and Medical Director of the Georgia Cancer Center for Excellence at Grady Memorial Hospital. “This is one of the huge issues that needs to be overcome if we want to do better in cancer.”
Currently 34 percent of American adults are obese—they have a body mass index of 30 or higher—according to the Centers for Disease Control and Prevention. Some 14 percent of cancer deaths in men and 20 percent in women are linked to obesity and individuals being overweight, according to a report in The Oncologist (2010;15:556-565).
A lack of participation among obese individuals in clinical trials leaves many oncologists guessing the optimal chemotherapy dose. Weight-based formulas used in dosing normal-weight patients raise concerns about toxicity when applied to obese patients. Wary oncologists often abandon the formula and cap the dose in their heaviest patients.
“If you're uncertain about how much chemo to give, you'll fall back on what you know is safest,” said Jennifer Griggs, MD, Associate Professor of Hematology and Oncology and Director of the Breast Cancer Survivorship Program at the University of Michigan Comprehensive Cancer Center.
Ironically, what oncologists think is safest may be riskier, suggests a study Griggs led. Her 2005 retrospective cohort study in Archives of Internal Medicine (2005;165:1267-1273) of overweight and obese breast-cancer patients showed that doses of chemotherapy were reduced in 9% of normal-weight women, 20% of obese women, and 37% of those who were severely obese. But, the obese subjects had the lowest levels of toxicity from treatment, and even those who received the full weight-based dose had fewer hospital admissions for febrile neutropenia than leaner subjects did.
“People are not afraid of full doses,” Griggs said. “They're afraid of dying of cancer.”
Further support for full dosing of obese patients comes from a 2007 study in the Journal of Clinical Oncology (2007;25:4707-4713), which suggests that dose be based on body surface area, which is calculated from height and weight. The drugs studied by the researchers, led by Alex Sparreboom, PhD, of the Department of Pharmaceutical Sciences at St Jude Children's Research Hospital, included cisplatin, paclitaxel, troxacitabine, doxorubicin, irinotecan, and topotecan. An exception to the dosing rule is carboplatin, which the authors say should be dosed according to predicted normal weight, or the mean of ideal and actual weight.
Confusion should ease within the next few months, when the American Society of Clinical Oncology publishes its first guidelines for chemotherapy dosing in obese patients. The protocols, which Griggs helped develop, will apply to adults with solid tumors.
Problems in Surgery
Surgery presents its own set of risks in obese patients, some serious enough to discourage procedures. Brawley related the situation of a surgery candidate, 5 feet 3 inches tall and 350 pounds: “The anesthesiologist was concerned that if he laid her flat on her back, she wouldn't be able to breathe. The surgeon could not operate because the anesthesiologist refused.”
An article now online ahead of print in British Journal of Anaesthesia (doi:10.1093/bja/aer058Br) indicates the anesthesiologist had reason for his concern. Twice as many obese patients in the study developed serious airway complications under general anesthesia as non-obese patients. Obese patients also face a higher risk of postoperative complications including heart attack, nerve injury, and wound infection.
“It's more physically exerting to operate on obese patients,” said Garrett Nash, MD, MPH, a surgeon at Memorial Sloan-Kettering Cancer Center. “If I see an obese patient, I plan on the operation taking more time.”
He pointed to robotics as being especially helpful in rectal and other hard-to-reach cancers: “We're doing more robotic rectal surgery,” he said. “I feel more satisfied using robotics in a heavy patient because I'm seeing things better. Wound complications are less.”
Improved technology has solved many of the problems clinicians once had administering radiation therapy by making positioning of patients easier. Yet, higher toxicity in overweight patients still presents lingering challenges.
“I can handle obese patients much better than I could 13 years ago,” said Sarah Hoffe, MD, Chief of Radiation Oncology at H. Lee Moffitt Cancer Institute & Research Center. “It requires more planning time, more effort, more technology, and more careful daily setup.”
She uses aids such as a body-fix device for patients with abdomens that can't squeeze into a standard donut-shaped belly board and an abdominal compression belt to contain fat for patients lying on their backs. Many radiation tables hold patients up to 500 pounds, but Hoffe said getting morbidly obese patients onto the table can still be difficult.
Both Hoffe and Brawley said they see more radiation burns in patients with excess fat over the area being irradiated.
“Obese patients with breast cancer have more skin toxicity,” Hoffe said.
A study published last September in the International Journal of Radiation Oncology (2011;81:91-96) showed that obese patients had twice the incidence of chronic chest-wall pain as non-obese patients following stereotactic body radiation therapy.
The problem is significant, said the authors, led by James Welsh, MD, of MD Anderson Cancer Center, because stereotactic body radiation therapy is replacing surgery in a growing number of early-stage lung cancers. The authors suggested that the pain wasn't directly tied to obesity, but was rather a result of comorbid diabetes. Diabetic subjects were three times as likely to develop chest-wall pain as non-diabetics were.
“Diabetics sometimes have nerve issues,” Hoffe said. “Nerves along the ribs can be irradiated by the treatment.”
Unanswered Questions, Continuing Research
Despite the confusion in treating obese patients, some clinicians favor flexible over black-and-white protocols.
“I try not to cap any chemotherapy, but if the body surface area is above 2.2 m² and I am about to use a myelosuppressive regimen, I consider capping the dose of the first cycle to a BMI of 2.2 m²,” said Alvaro Moreno-Aspitia, MD, a breast cancer specialist at the Mayo Clinic in Jacksonville, FL. “Depending on the toxicity observed, I would adjust the dose upward to the target BMI.”
He said he also makes adjustments according to his treatment goal, using a higher dose if it's curative and lower if it's palliative.
Another breast cancer specialist, Sao Jiralerspong, MD, PhD, Assistant Professor at Baylor College of Medicine, said he also believes that as researchers delve deeper into how treatments affect the obese, dosing will become more complex. A study he reported at the most recent CTRC-AACR San Antonio Breast Cancer Symposium (Abstract P1-08-04) had the unexpected result that obesity had a protective effect in treating early-stage breast-cancer patients with endocrine therapy, primarily tamoxifen. Yet, in a similar group treated with chemotherapy, obese patients had worse outcomes.
“We're trying to figure out what might be the implication,” he said. “It suggests that maybe there's not a blanket approach.”
Martine Extermann, MD, PhD, Associate Professor of Oncology and Medicine at the University of South Florida and Attending Physician in the Senior Adult Oncology Program at H. Lee Moffitt Cancer Institute & Research Center, predicts that more attention will focus on the tumor's environment, which may be related to obesity: “Insulin resistance can stimulate growth of cancer,” she said.
“Fat is metabolically active. Inflam-mation [linked to fat] may play a role in progression. A lot of treatment is focused on the tumor, but we need to consider the patients as well. More attention needs to be paid to comorbidities than in the past. I expect to see an onco-geriatric approach. We need to individualize cancer care.”