What weight (actual, adjusted, ideal) is generally recommended for chemotherapy dosing?

Comment by InpharmD Researcher

The majority of data appears focused on obese patients. Dosing by actual body weight seems to be preferred, as using ideal body weight may lead to underdosing without a significant increase in toxicity. This approach is supported by guidelines from organizations like ASCO, which warn that dose-capping can result in insufficient therapy and worse survival outcomes. Exceptions exist for certain specific agents, such as carmustine or thiotepa, where ideal or adjusted body weight may be utilized.

Background

The American Society of Clinical Oncology (ASCO) 2021 guideline update for systemic chemotherapy in obese adults do not recommend utilizing ideal body weight to adjust doses as it may lead to underdosing. The guidelines were focused on obese patients. While there may be potential increased risk of adverse events from excessive doses, using ideal body weight may lead to insufficient therapy and worse survival outcomes. Only one out of ten retrospective studies observed higher toxicity in obese patients given full, weight-based dosing compared to obese patients receiving ideal body weight-adjusted chemotherapy agents. Thus, using ideal body weight to calculate dose regimens based on weight may lead to insufficient dosage in obese patients. [1]

The American Society for Blood and Marrow Transplantation Practice Guideline Committee performed an evidence review for dose adjusting chemotherapy regimens in obese patients. Though the list of chemotherapeutic agents is limited to the setting of hematopoietic cell transplantation, three agents were identified that could utilize ideal body weight in dosing of obese individuals. These agents are carmustine, cyclophosphamide, and thiotepa. Carmustine and thiotepa may utilize ideal body weight to calculate the adjusted body weight. Cyclophosphamide may also use total or ideal body weight depending on which weight is less. For the majority of other agents, dose calculation is either done by total body weight alone or used in adjusted body weight calculation. The guidelines do not postulate on which body weight is preferred in the setting of renal dose adjustment. [2]

Guidelines created by experts in Japan discussed the available data along with dosing strategies of chemotherapeutic agents in the setting of nephropathy. If chemotherapeutic doses are calculated via body surface area or body weight (i.e. weight-based dosing), then the authors believe calculating creatinine clearance with corrected body surface area is reasonable. The use of ideal vs adjusted vs actual body weight to estimate creatinine clearance is not discussed. [3]

A 2017 study included 492 elder patients (age 65 and older) starting a new chemotherapy regimen to evaluate the incidence of grad 3-5 chemotherapy-related toxicity (CRT) when calculating dosing using actual, ideal, or adjusted body weight. Four formulas that assessed renal function were evaluated, Cockcroft-gault (CG), Jelliffe, Wright, and Modification of diet in Renal Disease (MDRD). Their findings report that decreased creatinine clearance (CrCl) calculated by CG with actual body weight was associated with increased odds of CRT (odds ratio [OR] 1.12; p<0.01; 95% confidence interval [CI] 1.04 to 1.20). This meant that every 10 mL/min decrease in CrCl increased the odds of CRT by 12% when calculated using CG and actual body weight. The other three formulas along with ideal and adjusted body weight were non-significant but trended towards similar conclusions. Yet whether the use of actual body weight is associated with worse safety outcomes is uncertain as the CG, itself, may lead to overestimation of CrCl in obese patients, resulting in higher chemotherapy doses. [4]

A 2013 systematic review and meta-analysis evaluated the toxic effects of chemotherapy dosing using actual body weight in both obese and normal-weight patients. A total of 12 studies (9314 patients), met the inclusion criteria. These studies encompassed various cancers, prominently colorectal and breast cancer, and explored 21 different chemotherapeutic agents, commonly regimens including 5-FU or capecitabine alongside other agents. The meta-analysis specifically targeted outcomes related to grade 3/4 hematologic and non-hematologic toxic effects, consolidating findings through random-effects models to offer quantitative insights. The results indicated that obese patients receiving chemotherapy dosed by actual body weight experienced similar or lower rates of grade 3/4 toxic effects compared to their normal-weight counterparts. Pooled odds ratios for grade 3/4 hematologic toxic effects and any grade 3/4 toxic effect revealed significantly lower incidences in obese patients, with odds ratios of 0.73 (95% CI 0.55–0.98) and 0.75 (95% CI 0.65–0.87), respectively. Furthermore, qualitative analysis across the studies showed that outcomes either favored obese patients or showed no significant differences, reinforcing the notion that full-dose chemotherapy, based on actual body weight, does not result in excessive toxicities in obese patients. This comprehensive review supports the practice of dosing chemotherapy by actual body weight for obese individuals, emphasizing that concerns of increased toxic effects are largely unsubstantiated. [5]

References:

[1] Griggs JJ, Bohlke K, Balaban EP, et al. Appropriate Systemic Therapy Dosing for Obese Adult Patients With Cancer: ASCO Guideline Update. J Clin Oncol. 2021;39(18):2037-2048. doi:10.1200/JCO.21.00471
[2] Bubalo J, Carpenter PA, Majhail N, et al. Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplantation practice guideline committee. Biol Blood Marrow Transplant. 2014;20(5):600-616. doi:10.1016/j.bbmt.2014.01.019
[3] Kouno T, Katsumata N, Mukai H, Ando M, Watanabe T. Standardization of the body surface area (BSA) formula to calculate the dose of anticancer agents in Japan. Jpn J Clin Oncol. 2003;33(6):309-313. doi:10.1093/jjco/hyg062
[4] Peterson LL, Hurria A, Feng T, et al. Association between renal function and chemotherapy-related toxicity in older adults with cancer. J Geriatr Oncol. 2017;8(2):96-101. doi:10.1016/j.jgo.2016.10.004
[5] Hourdequin KC, Schpero WL, McKenna DR, Piazik BL, Larson RJ. Toxic effect of chemotherapy dosing using actual body weight in obese versus normal-weight patients: a systematic review and meta-analysis. Ann Oncol. 2013;24(12):2952-2962. doi:10.1093/annonc/mdt294
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What weight (actual, adjusted, ideal) is generally recommended for chemotherapy dosing?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

Actual Body Weight for Determining Doses of Chemotherapy in Obese Cancer Patients: Evaluation of Treatment Tolerability
Design

Prospective evaluation

N= 606
Objective To prospectively evaluate the safety of calculating chemotherapy doses based on actual body weight in obese cancer patients
Study Groups

Obese patients (n= 178)

Non-obese patients (n= 428)
Inclusion Criteria All obese patients in whom the first cycle of any chemotherapy regimen was initiated with a full dose
Exclusion Criteria Patients with reduced doses due to poor performance status and/or impaired renal or hepatic function
Methods

Chemotherapy doses in obese patients were calculated according to actual body weight. Severe chemotherapy-related toxicity (SCRT) was monitored during the first three cycles. SCRT included neutropenic fever, thrombocytopenia with significant bleeding, and grade 3-4 nonhematologic toxicity. Statistical analyses were performed using SPSS.
Duration October 1999 to June 2000
Outcome Measures

Primary: Incidence of severe chemotherapy-related toxicity (SCRT) during the first three cycles

Secondary: Dose reductions and delays due to toxicity
Baseline Characteristics   Obese patients (n= 147)
Age, median years 57
Gender - Male 39 (27%)
Gender - Female 108 (73%)
BMI - Male, median 31.9
BMI - Female, median 30.55
Diagnosis - Breast cancer 70 (48%)
Diagnosis - Colorectal cancer 17 (12%)
Diagnosis - Lung cancer 12 (8%)
Results   No. of patients SCRT
Cycle 1 147 16 (11%)
Cycle 2 146 10 (7%)
Cycle 3 142 6 (4%)
Adverse Events

Severe chemotherapy-related toxicity (SCRT) included neutropenic fever, thrombocytopenia with significant bleeding, and grade 3-4 nonhematologic toxicity. No treatment-related deaths were reported.
Study Author Conclusions Calculation of standard chemotherapy dose according to actual body weight in obese patients is relatively safe and does not result in clinically significant excessive toxicity.
Critique

The study provides valuable insights into the safety of dosing chemotherapy based on actual body weight in obese patients. However, the study's generalizability may be limited due to its single-center design and the exclusion of patients with reduced doses due to poor performance status or impaired organ function.

 

References:

Abdah-Bortnyak R, Tsalic M, Haim N. Actual body weight for determining doses of chemotherapy in obese cancer patients: evaluation of treatment tolerability. Med Oncol. 2003;20(4):363-368. doi:10.1385/MO:20:4:363
Outcomes in obese and overweight acute myeloid leukemia patients receiving chemotherapy dosed according to actual body weight
Design

Retrospective, non-interventional single center study

N= 247
Objective To evaluate the efficacy and toxicity of standard induction chemotherapy dosed based on actual body weight in non-acute promyelocytic leukemia AML patients at extremes of weight
Study Groups

Underweight/Normal weight (n= 81)

Overweight (n= 81)

Obese (n= 85)
Inclusion Criteria Patients diagnosed with AML from January 2002 to October 2009, age >18 years, induction chemotherapy with an anthracycline and conventional dose cytarabine, BSA calculated using ABW
Exclusion Criteria Patients with APL, did not receive induction chemotherapy, or received therapy that did not include an anthracycline and cytarabine
Methods

Patients were categorized into BMI groups: underweight/normal weight, overweight, and obese. Induction chemotherapy included anthracycline (mitoxantrone, idarubicin, or daunorubicin) and cytarabine (100–200 mg/m2/day) dosed based on ABW. Post-remission therapy varied by age.
Duration January 2002 to October 2009
Outcome Measures

Primary: Complete remission (CR) rates

Secondary: Overall survival, early mortality, 30-day mortality, days to neutrophil and platelet recovery, length of hospitalization
Baseline Characteristics   Underweight/Normal (N= 81) Overweight (N= 81) Obese (N= 85) Total (N= 247) P-value
Age, mean (SD), year 55.2 (15.4) 56.9 (13.1) 54.9 (14.5) 55.6 (14.3) 0.119
Weight, mean, (SD), kg 63.6 (9.9) 80.2 (10.2) 103.6 (20.9)   <0.001
BMI, mean, (SD), kg/m2 22.0 (2.3) 27.3 (1.4) 36.0 (5.8) 28.6 (6.9) <0.001
BSA, mean, (SD), m2 1.73 (0.18) 1.95 (0.18) 2.20 (0.26) 1.96 (0.29) <0.001
WBC at diagnosis, mean (SD), 3109/L 39.5 (56.9) 43.8 (58.1) 30.6 (42.5) 37.8 (52.9) 0.015
Results   Underweight/Normal (N= 81) Overweight (N= 81) Obese (N= 85) Total (N= 247) P-value
Complete remission (CR) 69.1% 79.0% 76.5% 74.9% 0.321
OS, median (range), months 10.7 (0.3–100.7) 16.7 (0.3–105.6) 14.2 (0.5–95.0) 14.2 (0.3–105.6) 0.352
Death within 15 days 2.5% 1.2% 2.4% 2.0% 0.826
Death within 30 days 3.7% 2.5% 7.1% 4.5% 0.331
Length of hospitalization, mean (SD), days 36.9 (13.1) 33.7 (10.2) 33.0 (11.6) 34.5 (11.7) 0.095
Adverse Events

No significant differences in toxicity among groups. Mean days to neutrophil recovery: NW 36.9, OV 33.7, OB 33.0 days. Mean days to platelet recovery: NW 34.2, OV 31.7, OB 31.2 days. Incidence of documented bacteremia ~30%. Trend towards significance in post-therapy EF < 40% or symptomatic heart failure: NW 12.3%, OV 3.7%, OB 4.7%
Study Author Conclusions

AML patients undergoing standard induction chemotherapy can be dosed based on actual body weight, even at extremes of weight, without increased toxicity or reduced efficacy. Additional studies are necessary to confirm these results in other patient populations.
Critique

The study's retrospective design limits the ability to establish causality. The focus on standard induction regimens enhances applicability, but the exclusion of patients with dose adjustments or those in clinical trials may limit generalizability. Missing data were handled appropriately, but unmeasured confounders could still exist. Further prospective studies are needed to validate these findings.

 

References:

Wenzell CM, Gallagher EM, Earl M, et al. Outcomes in obese and overweight acute myeloid leukemia patients receiving chemotherapy dosed according to actual body weight. Am J Hematol. 2013;88(10):906-909. doi:10.1002/ajh.23530