Updated guidelines1 recommend that patients with cancer and obesity receive the full approved doses of immunotherapy and targeted therapies, but do oncologists agree with this approach?
In the past, many oncologists routinely underdosed chemotherapy in patients with obesity and cancer due to concerns about excess toxicity. However, studies have shown that patients with obesity tend to experience less toxicity than other patients, and underdosing chemotherapy can negatively impact survival outcomes.2
As a result, in 2012, the American Society of Clinical Oncology (ASCO) released guidelines recommending against underdosing chemotherapy in patients with obesity and cancer, stating that “full, weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer.”3
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Now, in updated guidelines, ASCO is recommending an analogous dosing strategy for immunotherapy and targeted therapies in patients with cancer and obesity.1
To develop the updated recommendations, the guideline authors reviewed 60 studies published from November 1, 2010, to March 27, 2020. Their analysis spanned retrospective and prospective cohort studies, meta-analyses of observational studies, and post hoc analyses of randomized controlled trials.
The authors’ findings support ASCO’s previous recommendation to administer full, weight-based doses of cytotoxic chemotherapy to patients with obesity and cancer.
The findings also support the new recommendation that prescribing information provided by the U.S. Food and Drug Administration (FDA) should be used uniformly for patients with and without obesity when it comes to dosing of checkpoint inhibitors and targeted therapies.
“These guidelines are basically to say that FDA-approved prescribing information for all these new agents, just like the original cytotoxic, should be used in patients with cancer, regardless of whether the patient is overweight, obese, or a healthy weight,” said Gary Lyman, MD, MPH, a medical oncologist and the senior lead of health care quality and policy at the Hutchinson Institute for Cancer Outcomes Research in Seattle, Washington, who coauthored the ASCO guideline update.
Moreover, if a dose should be reduced in response to high-grade toxicity, the same reduction guidelines should be applied to all patients, whether they are obese or not.
“In other words, there should be no unique dose modification because the patient is obese or overweight,” Dr Lyman said.
In another addition to the guidelines, the authors concluded that any of the standard formulas used to measure body surface area are fine to use, and there is no one formula that is superior to another.
The Consequences of Underdosing
Coral Omene, MD, PhD, expressed support for ASCO’s new dosing recommendations for immunotherapy and targeted therapies, stating that they align with how she and her colleagues have already been practicing. Dr Omene is a medical oncologist at Rutgers Cancer Institute of New Jersey in New Brunswick, and she was not involved in the guideline update.
“I think we have more and more data that suggest that we should maintain the same doses for both normal-weight and obese patients,” Dr Omene said.
She noted that, before ASCO introduced the original recommendation for chemotherapy dosing in 2012, oncologists would routinely cap doses in patients with obesity. That strategy ended up backfiring because it reduced the effectiveness of chemotherapy in these patients and affected their outcomes.
Underdosing had particularly dramatic consequences for Black patients, a group in which obesity is highly prevalent, Dr Omene said. For example, researchers found that Black women with breast cancer tended to receive lower doses of adjuvant chemotherapy than White women.4 Meanwhile, other research suggested that such reductions led to worse survival outcomes.5
“So I think we know enough [to support] that underdosing or capping doses would actually affect the patient negatively,” Dr Omene said.
She added that she hopes this new update will encourage any oncologists who are underdosing novel cancer therapies to stop that practice.
“Hopefully, this ASCO guideline will help inform those oncologists and help to bolster the culture of not capping doses,” Dr Omene said.
She also pointed to a need for studies that would examine effects of the new guidelines on patient outcomes. “And, hopefully, we will see that maybe patients were doing better because they were getting proper dosing,” she said.
Making Exceptions: A Tailored Approach
Neil M. Iyengar, MD, said he generally agrees with the new ASCO recommendations but favors a tailored approach to treatment in some cases. Dr Iyengar is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, who was not involved in the guideline update.
“Overall, yes, I think this is a good idea because we know, historically, at least from the standpoint of chemotherapy, that obese patients used to generally be underdosed because of this expectation that there would be greater toxicity,” Dr Iyengar said.
However, he suggested taking a more tailored approach to certain targeted therapies while keeping an eye on a patient’s metabolic health. For example, he noted that the use of phosphoinositide 3-kinase (PI3K) inhibitors is associated with a higher risk of hyperglycemia and hyperinsulinemia in people with metabolic dysfunction, which commonly overlaps with obesity.
In fact, Dr Iyengar said most of the trials that led to the FDA approval of PI3K inhibitors excluded patients whose levels of hemoglobin A1c (HbA1c) were in the insulin-resistance range, which often occurs in patients with obesity.
Hence, Dr Iyengar recommends that oncologists examine HbA1c in patients with obesity — most of whom have HbA1c levels above 5.7% — before potentially proceeding with PI3K inhibitors.
As an example, Dr Iyengar mentioned the SOLAR-1 trial (ClinicalTrials.gov Identifier NCT02437318) of the PI3K inhibitor alpelisib in patients with breast cancer. Only patients with an HbA1c under 8% were initially allowed to participate. The investigators later introduced an even stricter restriction by only allowing patients with an HbA1c of less than 6.5% because of the high incidence of hyperglycemia.
Dr Iyengar said he would therefore wait to administer alpelisib in patients with HbA1c above 6.5% at baseline until their HbA1c could be lowered to a safe range via lifestyle interventions, diabetes medications, or a combination of both. For patients with an HbA1c of 5.7% to 6.4%, he would use alpelisib “with caution,” he said.
Patients with breast cancer who are at highest risk for toxicity from PI3K inhibitors are those who have obesity and tumors with PIK3CA mutations because they likely also have baseline insulin resistance, Dr Iyengar explained. In these cases, he would advise bringing patients’ HbA1c to a safe range before administering a PI3K inhibitor.
Dr Iyengar also said that up to one-third of normal-weight patients have metabolic obesity, so the same recommendations for PI3K inhibitors apply to them as well.
Wasif M. Saif, MD, also expressed general agreement with the updated ASCO guidelines but pointed to cases in which a tailored treatment approach might be necessary. Dr Saif is deputy physician-in-chief and medical director at Northwell Health Cancer Institute in New Hyde Park, New York, and was not involved in the guideline update.
“Though we have limited data and most [are] retrospective, I feel comfortable agreeing with the recommendations of the expert panel based on our experience,” Dr Saif wrote in an email.
However, he urged caution regarding the use of targeted therapies, such as sunitinib malate or sorafenib, that are linked to cardiovascular toxicities such as hypertension. He noted that some patients with obesity and cancer may need supportive care along with potential dose adjustments when receiving those therapies.
References
- Griggs JJ, Bohlke K, Balaban EP, at al. Appropriate systemic therapy dosing for obese adult patients with cancer: ASCO guideline update. J Clin Oncol. Published online May 3, 2021. doi:10.1200/JCO.21.00471
- Lyman GH. Commentary: Chemotherapy Dosing in Obese Patients With Cancer—The Need for Evidence-Based Clinical Practice Guidelines. J Oncol Pract. 2011 Jan; 7(1): 17–18. doi: 10.1200/JOP.2010.000200
- Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2012;30(13):1553-1561. doi:10.1200/JCO.2011.39.9436
- Griggs JJ, Sorbero MES, Stark AT, Heininger SE, Dick AW. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat. 2003;81:21-31. doi:10.1023/A:1025481505537
- Veitch Z, Khan OF, Tilley D, et al. Impact of cumulative chemotherapy dose on survival with adjuvant FEC-D chemotherapy for breast cancer. J Natl Compr Canc Netw. 2019;17(8):957-967. doi:10.6004/jnccn.2019.7286
This article originally appeared on Cancer Therapy Advisor
