Drug Dose Per Kilogram Lean Body Mass Predicts Hematologic Toxicity From Carboplatin-Doublet Chemotherapy in Advanced Non-Small-Cell Lung Cancer.
Variations in lean body mass (LBM) have been suggested to explain variations in toxicity from systemic cancer treatment. We investigated if drug doses per kilogram of LBM were associated with severe hematologic toxicity (HT) in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) enrolled onto randomized trials comparing first-line carboplatin-doublets.



Patients received carboplatin (AUC [area under the plasma concentration vs. time curve] = 5) plus either pemetrexed 500 mg/m2, gemcitabine 1000 mg/m2, or vinorelbine 60 mg/m2. LBM was estimated from the cross-sectional muscle area at the third lumbar vertebra on computed tomographic scans. Administered doses on day 1, first cycle, were recalculated as milligram of drug per kilogram of LBM. Primary outcome was Common Terminology Criteria for Adverse Events version 3.0 grade 3/4 HT after cycle 1.



Data from 424 patients were analyzed. Mean age was 65 years, 57% were men, and 78% had stage IV disease. Despite dose individualization by body surface area for the nonplatinum drugs, mean (range) doses expressed as mg/kg LBM showed ∼3-fold range: gemcitabine 38.0 (22.5-61.7) mg/kg LBM, pemetrexed 19.1 (8.1-27.9) mg/kg LBM, and vinorelbine 2.4 (1.4-3.6) mg/kg LBM. For these drugs, dose per kilogram of LBM was associated with HT in adjusted multivariate models (P = .004). Taking mean dose per kilogram LBM for each drug as reference, a 1% increase (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.01-1.06) or 1% decrease (OR = 0.97; 95% CI, 0.95-0.99) was associated with altered risk of grade 3/4 HT. For doses > 20% above and below mean (14% and 15% of patients, respectively) the risk of grade 3/4 HT was almost doubled (OR = 1.93, 95% CI, 1.21-3.10) and halved (OR = 0.52; 95% CI, 0.32-0.83), respectively.



Dose per kilogram of LBM varied considerably and was an independent predictor of HT. Computed tomography-defined LBM may provide a future basis for better dose individualization.
Department of Internal Medicine, Innlandet Hospital Trust, Hamar, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway. Electronic address: uxsjbj@ous-hf.no.
Bjørg
B
Sjøblom
Institute of Clinical Medicine, Campus Ahus, University of Oslo, Norway; HØKH, Research Centre, Akershus University Hospital, Norway.
Jūratė Šaltytė
JŠ
Benth
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Clinic of Oncology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
Bjørn H
BH
Grønberg
Division of Palliative Care Medicine, Department of Oncology, University of Alberta, Edmonton, Canada.
Vickie E
VE
Baracos
Division of Medical Oncology, Department of Oncology, University of Alberta, Edmonton, Canada.
Michael B
MB
Sawyer
Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.
Øystein
Ø
Fløtten
Regional Centre for Excellence in Palliative Care, South Eastern Norway, Oslo University Hospital, Oslo, Norway; European Palliative Care Research Centre, Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, Trondheim, Norway.
Marianne J
MJ
Hjermstad
Regional Centre for Excellence in Palliative Care, South Eastern Norway, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Nina
N
Aass
Department of Internal Medicine, Innlandet Hospital Trust, Hamar, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Marit
M
Jordhøy
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D016190:Carboplatin / Q000008:administration & dosage; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006402:Hematologic Diseases / Q000139:chemically induced* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology*; D009367:Neoplasm Staging; D000068437:Pemetrexed / Q000008:administration & dosage; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine; D000093542:Gemcitabine
D000068437:Pemetrexed; D003841:Deoxycytidine; D014747:Vinblastine; D016190:Carboplatin; D000077235:Vinorelbine; D000093542:Gemcitabine
Body composition; Chemotherapy dosing; Chemotherapy toxicity; Muscle wasting; Skeletal muscle