CommentaryPublication Exclusive

Back to the future: Chemotherapy dosing in overweight and obese patients with cancer

Early in the history of modern cancer chemotherapy, treatment efficacy as well as toxicity were found to demonstrate a clear dose–response relationship for most chemotherapeutic agents in both preclinical as well as clinical studies, most notably in highly sensitive malignancies. Animal tumor models showed that as little as a 20% reduction in chemotherapy dose could essentially eliminate the usual high complete remission and cure rates by as much as 50%. Goldie and colleagues and Norton and colleagues also demonstrated that increased chemotherapy dose intensity by virtue of higher chemotherapy doses or shortened interval between doses reduced the emergence of drug resistance.

Therefore, chemotherapy dose finding and safety studies in humans are undertaken to define a maximum tolerable dose in order to conduct definitive trials with the most promising, effective and tolerable dose and schedule of new agents. At the same time, combination chemotherapy was undertaken to enable simultaneous or sequential administration of two or more agents ideally with different mechanisms of action and toxicities in order that each agent be delivered at relatively full dose (RDI). Favorable efficacy and safety results from comparative trials based on regimens with specified chemotherapy doses and schedules then become integrated into standard practice and clinical practice guidelines.

More than 3 decades ago, Hryniuk and colleagues demonstrated a strong relationship between chemotherapy dose intensity and complete and overall response rates in several common human malignancies. In addition, retrospective and prospective clinical trials have also shown a strong association between chemotherapy dose intensity and DFS as well as OS. Although data from prospective controlled trials is more limited, randomization to different dose-intensity schedules has demonstrated a significant association with DFS and OS. Despite compelling data supporting maintaining chemotherapy dose and schedule in responsive malignancies based on pivotal clinical trials, practice pattern surveys have demonstrated a high frequency of major reductions in chemotherapy dose intensity in actual clinical practice. Likewise, despite excitement about emerging novel targeted therapies, for the present it is apparent that the optimal use of many of these agents will remain in combination with conventional myelosuppressive chemotherapeutic agents.

Gary H. Lyman

Greater uncertainty and variation in the appropriate dosing of chemotherapy in overweight and obese patients with cancer has been shown to represent one of the major factors associated with reduced chemotherapy dose intensity. Dose capping and other arbitrary reductions in chemotherapy dose in obese patients with cancer has been frequently demonstrated despite compelling evidence on the importance of sustaining chemotherapy dose intensity when treating with curative intent. In addition, multiple studies have demonstrated higher disease-specific mortality in obese patients with cancer. Finally, Rosner and colleagues demonstrated that full weight-based chemotherapy dosing in obese patients does not increase rates of treatment-related toxicities compared to similar treatment of healthy weight individuals.

Pharmacokinetic studies, such as that by Sparreboom and colleagues, have provided supporting evidence that chemotherapy dose calculations should generally be based on actual rather than ideal body weight. To reduce practice variation and improve clinical outcomes for obese patients with cancer, ASCO developed clinical practice guidelines based on an exhaustive review of the literature. In the absence of major comorbid conductions, the guideline recommends chemotherapy dose calculations based on actual body weight and discourages dose capping or other arbitrary reductions in chemotherapy dose intensity. It is encouraged that treatment-related toxicities in obese patients be handled in the same fashion as for healthy-weight patients. The guideline concludes that there is no evidence to support greater dose reductions for obese patients than healthy-weight individuals.

Although much of the available data have been derived from studies of patients with early-stage breast cancer, there is an increasing body of evidence that similar relationships of chemotherapy-dose intensity and outcomes can be seen across categories and stages of other responsive malignancies, including ovarian cancer. In a study of patients with ovarian cancer receiving first-line therapy with carboplatin and paclitaxel with curative intent in the Kaiser Permanente Northern California health care setting, Bandera and colleagues reported that lower RDI was associated with lower OS and ovarian cancer-specific survival at a median follow-up of nearly 5 years. In multivariable analysis, healthy-weight women with an average RDI less than 85% of standard experienced an HR for mortality 50% greater than those with an RDI greater than 85%. Significant reductions in OS and cancer-specific survival were observed with reduced dose intensity individually for paclitaxel and carboplatin, as well as reduced average RDI for both agents combined. Researchers observed this finding across all levels of BMI, but it appeared strongest in healthy-weight women. They also observed that obese patients with ovarian cancer receiving full-dose intensity chemotherapy experienced no greater toxicity than fully dosed healthy-weight women. Although interesting in its own right based on the size of the study population and comprehensiveness of the data, these results confirm a previous report demonstrating an association between reduced chemotherapy dose intensity in patients with ovarian cancer and OS. In multivariable analysis, Hanna and colleagues observed that the only two predictors of OS in women with stage III and IV ovarian cancer receiving systemic chemotherapy were delivered RDI less than 85% and elevated baseline CA-125.

Although some will still question the validity of the conclusions reached by Bandera and colleagues as well as other clinicians and investigators and comprehensive clinical practice guidelines, compelling evidence continues to grow supporting full weight-based dosing of chemotherapy in women with ovarian cancer being treated with curative intent, including those who are overweight or obese. Appropriate supportive care, when indicated to enable delivery of full-dose chemotherapy, should be considered along with full discussion of the potential benefits, harms and goals of systemic therapy in patients with ovarian cancer.

References:

Bonadonna G, et al. N Engl J Med. 1995;332:901-906.

Bonneterre J, et al. J Clin Oncol. 2005;23:2686-2693.

Budman DR, et al. J Natl Cancer Inst. 1998;90:1205-1211.

Del Mastro L, et al. Lancet. 2015;doi:10.1016/S0140-6736(14)62048-1.

Fauci JM, et al. Gynecol Oncol. 2011;doi:10.1016/j.ygyno.2011.05.023.

Field KM, et al. J Oncol Pract. 2008;doi:10.1200/JOP.0832001.

Frei E 3rd and Canellos GP. Am J Med. 1980;69:585-594.

Fust K, et al. Gynecol Oncol. 2014;doi:10.1016/j.ygyno.2014.03.014.

Goldie JH and Coldman AJ. Cancer Treat Rep. 1970;63:1727-1733.

Goldie JH and Coldman AJ. Cancer Res. 1984;44:3643-36453.

Griggs JJ, et al. Arch Intern Med. 2005;165:1267-1273.

Hanna RK, et al. Gynecol Oncol. 2013;doi:10.1016/j.ygyno.2012.12.017.

Hryniuk W and Bush H. J Clin Oncol. 1984;2:1281-1288.

Hryniuk W and Levine MN. J Clin Oncol. 1986;4:1162-1170.

Lyman GH. J Oncol Pract. 2001;doi:10.1200/JOP.2010.000200.

Lyman GH, et al. J Clin Oncol. 2003;21:4524-4531.

Lyman GH, et al. J Clin Oncol. 2004;22:4302-4311.

Lyman GH and Sparreboom A. Nat Rev Clin Oncol. 2013;doi:10.1038/nrclinonc.2013.108.

Norton L and Simon R. Cancer Treat Rep. 1977;61:1307-1317.

Norton L and Simon R. J Natl Cancer Inst. 1977;58:1735-1741.

Rosner GL, et al. J Clin Oncol. 1996;14:3000-3008.

Schabel FM Jr. Cancer Res. 1969;29:2384-2389.

Shayne M, et al. Cancer. 2009;doi:10.1002/cncr.24560.

Skipper HE. Cancer. 1971;28:1479-1499.

Sparreboom A, et al. J Clin Oncol. 2007;25:4707-4713.

For more information:

Gary H. Lyman, MD, MPH, FASCO, FRCP(Edin), is co-director of Hutchinson Institute for Cancer Outcomes Research at Fred Hutchinson Cancer Research Center and professor of medicine at University of Washington School of Medicine in Seattle. He can be reached at Seattle Cancer Care Alliance, 825 Eastlake Ave. West, Seattle, WA 98109; email: glyman@fredhutch.org.

Disclosure: Lyman reports being a primary investigator on an institutional research grant from Amgen.

Early in the history of modern cancer chemotherapy, treatment efficacy as well as toxicity were found to demonstrate a clear dose–response relationship for most chemotherapeutic agents in both preclinical as well as clinical studies, most notably in highly sensitive malignancies. Animal tumor models showed that as little as a 20% reduction in chemotherapy dose could essentially eliminate the usual high complete remission and cure rates by as much as 50%. Goldie and colleagues and Norton and colleagues also demonstrated that increased chemotherapy dose intensity by virtue of higher chemotherapy doses or shortened interval between doses reduced the emergence of drug resistance.

Therefore, chemotherapy dose finding and safety studies in humans are undertaken to define a maximum tolerable dose in order to conduct definitive trials with the most promising, effective and tolerable dose and schedule of new agents. At the same time, combination chemotherapy was undertaken to enable simultaneous or sequential administration of two or more agents ideally with different mechanisms of action and toxicities in order that each agent be delivered at relatively full dose (RDI). Favorable efficacy and safety results from comparative trials based on regimens with specified chemotherapy doses and schedules then become integrated into standard practice and clinical practice guidelines.

More than 3 decades ago, Hryniuk and colleagues demonstrated a strong relationship between chemotherapy dose intensity and complete and overall response rates in several common human malignancies. In addition, retrospective and prospective clinical trials have also shown a strong association between chemotherapy dose intensity and DFS as well as OS. Although data from prospective controlled trials is more limited, randomization to different dose-intensity schedules has demonstrated a significant association with DFS and OS. Despite compelling data supporting maintaining chemotherapy dose and schedule in responsive malignancies based on pivotal clinical trials, practice pattern surveys have demonstrated a high frequency of major reductions in chemotherapy dose intensity in actual clinical practice. Likewise, despite excitement about emerging novel targeted therapies, for the present it is apparent that the optimal use of many of these agents will remain in combination with conventional myelosuppressive chemotherapeutic agents.

Gary H. Lyman

Greater uncertainty and variation in the appropriate dosing of chemotherapy in overweight and obese patients with cancer has been shown to represent one of the major factors associated with reduced chemotherapy dose intensity. Dose capping and other arbitrary reductions in chemotherapy dose in obese patients with cancer has been frequently demonstrated despite compelling evidence on the importance of sustaining chemotherapy dose intensity when treating with curative intent. In addition, multiple studies have demonstrated higher disease-specific mortality in obese patients with cancer. Finally, Rosner and colleagues demonstrated that full weight-based chemotherapy dosing in obese patients does not increase rates of treatment-related toxicities compared to similar treatment of healthy weight individuals.

Pharmacokinetic studies, such as that by Sparreboom and colleagues, have provided supporting evidence that chemotherapy dose calculations should generally be based on actual rather than ideal body weight. To reduce practice variation and improve clinical outcomes for obese patients with cancer, ASCO developed clinical practice guidelines based on an exhaustive review of the literature. In the absence of major comorbid conductions, the guideline recommends chemotherapy dose calculations based on actual body weight and discourages dose capping or other arbitrary reductions in chemotherapy dose intensity. It is encouraged that treatment-related toxicities in obese patients be handled in the same fashion as for healthy-weight patients. The guideline concludes that there is no evidence to support greater dose reductions for obese patients than healthy-weight individuals.

Although much of the available data have been derived from studies of patients with early-stage breast cancer, there is an increasing body of evidence that similar relationships of chemotherapy-dose intensity and outcomes can be seen across categories and stages of other responsive malignancies, including ovarian cancer. In a study of patients with ovarian cancer receiving first-line therapy with carboplatin and paclitaxel with curative intent in the Kaiser Permanente Northern California health care setting, Bandera and colleagues reported that lower RDI was associated with lower OS and ovarian cancer-specific survival at a median follow-up of nearly 5 years. In multivariable analysis, healthy-weight women with an average RDI less than 85% of standard experienced an HR for mortality 50% greater than those with an RDI greater than 85%. Significant reductions in OS and cancer-specific survival were observed with reduced dose intensity individually for paclitaxel and carboplatin, as well as reduced average RDI for both agents combined. Researchers observed this finding across all levels of BMI, but it appeared strongest in healthy-weight women. They also observed that obese patients with ovarian cancer receiving full-dose intensity chemotherapy experienced no greater toxicity than fully dosed healthy-weight women. Although interesting in its own right based on the size of the study population and comprehensiveness of the data, these results confirm a previous report demonstrating an association between reduced chemotherapy dose intensity in patients with ovarian cancer and OS. In multivariable analysis, Hanna and colleagues observed that the only two predictors of OS in women with stage III and IV ovarian cancer receiving systemic chemotherapy were delivered RDI less than 85% and elevated baseline CA-125.

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Although some will still question the validity of the conclusions reached by Bandera and colleagues as well as other clinicians and investigators and comprehensive clinical practice guidelines, compelling evidence continues to grow supporting full weight-based dosing of chemotherapy in women with ovarian cancer being treated with curative intent, including those who are overweight or obese. Appropriate supportive care, when indicated to enable delivery of full-dose chemotherapy, should be considered along with full discussion of the potential benefits, harms and goals of systemic therapy in patients with ovarian cancer.

References:

Bonadonna G, et al. N Engl J Med. 1995;332:901-906.

Bonneterre J, et al. J Clin Oncol. 2005;23:2686-2693.

Budman DR, et al. J Natl Cancer Inst. 1998;90:1205-1211.

Del Mastro L, et al. Lancet. 2015;doi:10.1016/S0140-6736(14)62048-1.

Fauci JM, et al. Gynecol Oncol. 2011;doi:10.1016/j.ygyno.2011.05.023.

Field KM, et al. J Oncol Pract. 2008;doi:10.1200/JOP.0832001.

Frei E 3rd and Canellos GP. Am J Med. 1980;69:585-594.

Fust K, et al. Gynecol Oncol. 2014;doi:10.1016/j.ygyno.2014.03.014.

Goldie JH and Coldman AJ. Cancer Treat Rep. 1970;63:1727-1733.

Goldie JH and Coldman AJ. Cancer Res. 1984;44:3643-36453.

Griggs JJ, et al. Arch Intern Med. 2005;165:1267-1273.

Hanna RK, et al. Gynecol Oncol. 2013;doi:10.1016/j.ygyno.2012.12.017.

Hryniuk W and Bush H. J Clin Oncol. 1984;2:1281-1288.

Hryniuk W and Levine MN. J Clin Oncol. 1986;4:1162-1170.

Lyman GH. J Oncol Pract. 2001;doi:10.1200/JOP.2010.000200.

Lyman GH, et al. J Clin Oncol. 2003;21:4524-4531.

Lyman GH, et al. J Clin Oncol. 2004;22:4302-4311.

Lyman GH and Sparreboom A. Nat Rev Clin Oncol. 2013;doi:10.1038/nrclinonc.2013.108.

Norton L and Simon R. Cancer Treat Rep. 1977;61:1307-1317.

Norton L and Simon R. J Natl Cancer Inst. 1977;58:1735-1741.

Rosner GL, et al. J Clin Oncol. 1996;14:3000-3008.

Schabel FM Jr. Cancer Res. 1969;29:2384-2389.

Shayne M, et al. Cancer. 2009;doi:10.1002/cncr.24560.

Skipper HE. Cancer. 1971;28:1479-1499.

Sparreboom A, et al. J Clin Oncol. 2007;25:4707-4713.

For more information:

Gary H. Lyman, MD, MPH, FASCO, FRCP(Edin), is co-director of Hutchinson Institute for Cancer Outcomes Research at Fred Hutchinson Cancer Research Center and professor of medicine at University of Washington School of Medicine in Seattle. He can be reached at Seattle Cancer Care Alliance, 825 Eastlake Ave. West, Seattle, WA 98109; email: glyman@fredhutch.org.

Disclosure: Lyman reports being a primary investigator on an institutional research grant from Amgen.