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New guidelines recommend full-dose chemotherapy for obese cancer patients
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Due to concerns of potential toxicity from administering large doses of chemotherapy, doses frequently are capped for obese patients.
A survey distributed to oncologists in Australia found that only 6% of physicians routinely used actual body weight when calculating chemotherapy doses for obese patients. However, administering reduced doses may compromise efficacy in this population.
In April, ASCO released a clinical practice guideline related to appropriate chemotherapy dosing among obese adults with cancer. Those in the oncology community eagerly awaited this release, as no similar guidelines exist and this clinical dilemma is increasingly common.
The ASCO panelists reviewed literature published through October 2010 that was relevant to chemotherapy dosing in obese and overweight adult cancer patients. They excluded data that pertained to targeted agents or monoclonal antibodies, as well as patients who were undergoing bone marrow transplantation. There were no prospective randomized trials included.
Obesity was defined by BMI according to the CDC (see Table 1).
The clinical questions addressed by the panel — as well as its subsequent recommendations — are summarized in Table 2.
Key findings
The panel recommends full-dose chemotherapy based on actual body weight in both obese and morbidly obese patients. This recommendation is based on two key findings.
First, most data indicate that toxicity from full-dose chemotherapy is the same between obese and nonobese populations. For example, a retrospective analysis of 1,435 women receiving adjuvant chemotherapy for early-stage breast cancer demonstrated similar grade-3 hematologic and nonhematologic toxicity in obese patients and nonobese patients at all dose levels.
Source: CDC
Source: Modified from Griggs JJ. J Clin Oncol. 2012;30:1553-1561.
Second, reduced doses of chemotherapy in the curative setting may compromise DFS and OS. In a retrospective analysis of four adjuvant trials in breast cancer, a subgroup analysis of obese patients with ER-negative tumors demonstrated that those patients who received less than 85% of full weight-based dosing had reduced DFS and OS compared with patients who received at least 85%.
The panel made some exceptions to its recommendation for full weight-based chemotherapy dosing, instead recommending fixed dosing for agents such as carboplatin, bleomycin and vincristine due to excessive toxicity with higher doses.
The guidelines emphasize a lack of sufficient pharmacokinetic data to influence the question of dosing in obese cancer patients.
First, the effects on pharmacokinetic parameters in this population vary between drugs. Creatinine clearance, a measure of renal function — and frequently of drug elimination — has been measured at higher, lower and similar rates in obese patients as in nonobese patients. Additionally, even when a pharmacokinetic parameter demonstrates variation, this may not translate into changes in clinical outcomes.
For example, a small study of 21 adult patients with cancer demonstrated reduced clearance and prolonged half-life of doxorubicin in obese patients compared with nonobese patients. However, studies in adjuvant breast cancer patients have indicated that obese patients who received less than the full weight-based dosing of anthracycline had worse DFS rates.
Therefore, until further validated pharmacokinetic data are obtained, adjusting the dose of chemotherapy based on a measured pharmacokinetic change is not warranted.
Questions remain
Although these guidelines address many significant issues regarding the dosing of chemotherapy in obese patients with cancer, a number of questions still remain.
The guidelines acknowledge there are few adequately powered trials that assess the influence of obesity on the pharmacokinetic parameters of most anticancer drugs. This limitation is partly due to study eligibility restrictions that limit inclusion of obese patients, and partly due to the small number of pharmacokinetic analyses published in this population.
In the future, as this growing contingent of the population is treated appropriately with full weight-based chemotherapy doses, prospective pharmacokinetic subgroup analyses will be important in determining the relationship of these parameters to dose and outcome. Additionally, supporting inclusion of obese patients in clinical trials is essential to obtain this valuable information. These guidelines demonstrate that previous concerns of excessive toxicity from full weight-based dosing of chemotherapy per protocol are unfounded, so exclusion of this population from clinical trials based solely on weight is unnecessary.
Also in question is the appropriate dose of chemotherapy for the obese cancer patient with metastatic disease. Treatment goals are different in patients with advanced cancer. At this stage, when cure is not an option and palliation of disease symptoms is the primary goal, the value placed on risks and benefits may change.
Most published literature that supports full weight-based dosing is from the treatment of early-stage disease. Data in the metastatic setting are limited. However, given the lack of excess toxicity in patients receiving full weight-based dosing in the adjuvant setting, either full-dose or reduced-dose chemotherapy may be a reasonable option in these patients. Dosing in this setting should be an individualized decision based on a patient’s personal goals of therapy.
Conclusion
The major limitation of these guidelines is that they are based primarily on retrospective data, including subgroup analyses of randomized trials and observational studies. No prospective randomized studies have been published comparing full weight-based chemotherapy dosing and reduced chemotherapy dosing.
Due to the evidence supporting improved efficacy with full weight-based dosing, it could be considered unethical to design such a trial at this time, so it is unlikely that these data will be available in the future. However, predetermined subgroup analyses from randomized clinical trials of efficacy and toxicity outcomes in obese patients compared with nonobese patients would continue to add to this body of literature and is recommended.
These guidelines provide a starting point to standardize practices of chemotherapy dosing in the obese population. Continued research in these patients will help to answer remaining questions and further eliminate variation in outcomes.
References:
- CDC. Defining overweight and obesity. Available at: www.cdc.gov/obesity/adult/defining.html. Accessed June 22, 2012.
- Colleoni M. Lancet. 2005;366:1108-1110. Field KM. J Oncol Pract. 2008;4:108-113.
- Griggs JJ. J Clin Oncol. 2012;30:1553-1561.
- Rodvold KA. J Clin Oncol. 1988;6:1321-1327. Rosner GL. J Clin Oncol. 1996;14:3000-3008.
For more information:
- Karen Eckmann, PharmD, BCOP, is a clinical pharmacy specialist at The University of Texas MD Anderson Cancer Center in Houston.
- Disclosure: Dr. Eckmann reports no relevant financial disclosures.