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Dosing Chemotherapy in Obese Patients: What is the BIG Deal?. Haley Gill VCH-PHC Pharmacy Resident 2009-2010. Outline. Learning Objectives Case Background Clinical Question Review of Literature Recommendation Monitoring Follow-up. Learning Objectives.
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Dosing Chemotherapy in Obese Patients: What is the BIG Deal? Haley Gill VCH-PHC Pharmacy Resident 2009-2010
Outline • Learning Objectives • Case • Background • Clinical Question • Review of Literature • Recommendation • Monitoring • Follow-up
Learning Objectives • To review the pathophysiology of Chronic Myeloid Leukemia (CML) • To review hematopoietic stem cell transplantation (HSCT) as treatment for CML • To review the pharmacokinetic (PK) alterations that occur in obesity • To evaluate the literature surrounding the dosing of chemotherapy in obese patients
Case ID: LS, 58 y/o female Admitted for sib-allo peripheral blood-stem cell transplant (PB-SCT) Busulfan/Cyclophosphamide (BU/CY) conditioning Shx: Non-smoker, occasional EtOH, 1 sister Fhx: father passed away of pulmonary fibrosis/liver cancer
Case HPI: June 2009 - Diagnosed with CML - Imatinib therapy → Complete Remission October 2009 - Blast crisis, Blasts = 50% - Hydroxyurea & Dasatinib November 2009 – Admit for sib-allo PB-SCT
Case PMHx: Mild HTN Depression Diverticulitis 2001 – sigmoid colon resection Episodic vertigo MPTA: Dasatinib 70mg PO daily – D/C’d 2 weeks PTA Telmisartan 80mg PO daily Venlafaxine XR 150mg PO daily
Conditioning Regimen Orders Based on Corrected Body Wt: Busulfan 260 mg (3.2 mg/kg) IV daily x 4 doses Cyclophosphamide 4900 mg (60 mg/kg) IV daily x 2 doses
Drug Related Problems • LS is at risk of decreased treatment efficacy secondary to possible subtherapeutic dosing of BU/CY conditioning • LS is experiencing pulmonary edema which may be exacerbated by hyper-hydration and would benefit from re-evaluation of current therapy • LS is at risk of graft-vs-host-disease and would benefit from prophylaxis with cyclosporine & methotrexate
CML Chronic leukemia of myeloid stem cell origin
CML Treatment • Chemotherapy to suppress and normalize WBC • Most patients achieve complete remission • Tyrosine kinase inhibitors offer long term disease suppression in most cases • Some patients still need HSCT
HSCT • IV infusion of hematopoietic progenitor cells • Replacement or Rescue • Conditioning regimen • Transplant • Supportive Care
Chemotherapy Dose Calculations • Leukemia/SCT unit at VGH: • dosing based on CBW • ABW used when ABW < IBW • High dose chemotherapy regimens • BC Cancer Agency: • Dosing based on ABW • Dose adjust based on toxicities of previous cycles
PK Alterations in Obesity Hunter et al. Cancer Treatment Reviews 2009
Clinical Question • In obese patients with malignancy, does dosing chemotherapy based on actual body weight, ideal body weight, or corrected body weight have any impact on therapeutic efficacy or toxicity?
Search Strategy • Databases: Medline, Embase, Pubmed • Search terms: obesity, Busulfan, Cyclophosphamide, chemotherapy, adjusted body weight, chronic myeloid leukemia, stem cell transplantation, drug dosing, body surface area • Limited to humans & English language • Results: • 1 retrospective review • 1 case-controlled • 5 PK studies • 3 Review articles
Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese Sparreboom AC, et al J Clin Oncol 2007;25(30):4707-4713
Sparreboom AC, et al Design • 8 chemotherapy agents • PK parameters compared between lean & obese (dosed on ABW) • Target standard: actual AUC of lean patients • Compared ratio of AUCobese/AUClean • AUCobese : [theoretical AUC = theoretical dose / actual Cl] • N = 1206
Sparreboom AC, et al Author’s Conclusions • Drug exposure following dose adjustment is: • Drug specific • Sex dependent • Unrelated to intrinsic physiochemical properties or route of elimination • Empiric ↓’s in drug dose for obese patients should be discouraged
Sparreboom AC, et al Limitations • PK study → unable to determine clinical outcomes • Obesity defined by BMI does not take into account body composition • Doses not specified
Obesity and autologous stem cell transplantation in acute myeloid leukemia Meloni G, et al Bone Marrow Transplantation 2001;28:365-367
Meloni G, et al Design • Retrospective review • N = 54 patients with acute myeloid leukemia, who underwent autologous SCT • Classified as obese, non-obese, or underweight • BU/CY conditioning regimen dosed on ABW
Meloni G, et al Author’s Conclusions • Obesity = less favorable outcomes • ↑ in treatment-related toxicity and mortality in obese • Obesity may represent an independent risk factor for autografting in AML • Dose adjustment for obesity is important to avoid excessive toxicity Limitations • Small sample size • Unable to assess differences in relapse rates
Impact of obesity on allogeneic stem cell transplant patients: A matched case-controlled study Fleming DR, et al Am J Med 1997;102:265-268
Fleming DR, et al Design • Matched case-controlled study • N = 322 allogeneic SCT patients • Compared length of survival in obese (ABW >20% over IBW) vs non-obese • Chemotherapy dosed based on IBW in obese patients
Fleming DR, et al Results OS in obese adults (P = 0.003) OS Non-obese = 30% OS Obese = 16%
Fleming DR, et al Author’s Conclusions • Obesity = poorer outcomes in allogeneic transplant patients Limitations • No information regarding year of transplant provided • No mention of treatment or transplant related toxicities • Do not specify any chemotherapy regimens used • Did not report on cause of death
Summary of Evidence • Dosing based on ABW appears to be safe in obese breast cancer patients • Lower chemo doses used • Toxic effects of high-dose regimens of greater concern • Obesity itself may be a risk factor for poor transplant outcomes • Prospective trials using endpoints such as survival & toxicity vs systemic drug exposure needed
Recommendations • No dosing change recommended • Consider other factors: performance status, concomitant drugs, previous treatments, renal & hepatic function, PK properties of BU/CY • Adjust dose according to toxicity if possible • Diligent, proactive monitoring
Follow-up • Complications: nausea/vomiting, diarrhea, mucositis • Engraftment ~ Day 12
References • Hunter RJ, et al. Dosing chemotherapy in obese patients: Actual versus assigned body surface area (BSA) Cancer Treatment Reviews 2009;35:69-78 • Poikonen P, et al. Effect of obesity on the leukocyte nadir in women treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil dosed according to body surface area Acta Oncologica 2001;40(1)67-71 • Powis G, et al. Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients Cancer Chemother Pharmacol 1987;20:219-222 • Sparreboom AC, et al. Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese J Clin Oncol 2007;25(30):4707-4713 • Meloni G, et al. Obesity and autologous stem cell traqnsplantation in acute myeloid leukemia Bone Marrow Transplantation 2001;28:365-367 • Fleming DR, et al. Impact of obesity on allogeneic stem cell transplant patients: A matched case-controlled study Am J Med 1997;102:265-268
Effect of obesity on the leukocyte nadir in women treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil dosed according to body surface area Poikonen P, et al Acta Oncologica 2001;40(1)67-71
Poikonen P, et al Author’s Conclusions • When CMF doses are calculated based on BSA, obese patients have somewhat higher WBC nadirs • may have been due to decreased conversion of CY to active cytotoxic metabolites • Drug doses should not should not be reduced in obese patients receiving CMF as adjuvant therapy for breast cancer Limitations • Lower chemo doses • Surrogate marker used for efficacy • Study not powered to show difference in DFS or OS
Poikonen P, et al Results • High BMI associated with higher WBC nadirs (p = <0.001) • Substantial variation in WBC nadirs • Obese patients received lower mg/kg and mg/BMI doses during the nadir cycle • No association between body size parameters and DFS or OS (p = >0.1)
Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients Powis G, et al Cancer Chemother Pharmacol 1987;20:219-222
Powis G, et al Design • N = 16 patients with advanced breast cancer • 7 obese (>20% over IBW), 5 severely obese (>30% over IBW) • CY 150 mg/m2 or 400 mg/m2 as short IV infusion • PK study done on day 1 of 1st or 2nd cycle of treatment • Blood samples @ 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6 &7 h