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Dosing Chemotherapy in Obese Patients: What is the BIG Deal?

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?

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  1. Dosing Chemotherapy in Obese Patients: What is the BIG Deal? Haley Gill VCH-PHC Pharmacy Resident 2009-2010

  2. Outline • Learning Objectives • Case • Background • Clinical Question • Review of Literature • Recommendation • Monitoring • Follow-up

  3. 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

  4. 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

  5. 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

  6. 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

  7. Review of Systems

  8. Review of Systems

  9. Lab Values

  10. Size Descriptors

  11. 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

  12. Alternative Dosing Regimens

  13. Medications in Hospital

  14. 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

  15. CML Chronic leukemia of myeloid stem cell origin

  16. 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

  17. HSCT • IV infusion of hematopoietic progenitor cells • Replacement or Rescue • Conditioning regimen • Transplant • Supportive Care

  18. 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

  19. Busulfan PK Properties

  20. Cyclophosphamide PK Properties

  21. PK Alterations in Obesity Hunter et al. Cancer Treatment Reviews 2009

  22. PK Alterations in Obesity

  23. 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?

  24. 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

  25. Literature in Breast Cancer Patients

  26. 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

  27. 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

  28. Sparreboom AC, et al

  29. 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

  30. 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

  31. Obesity and autologous stem cell transplantation in acute myeloid leukemia Meloni G, et al Bone Marrow Transplantation 2001;28:365-367

  32. 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

  33. Meloni G, et al - Results

  34. Meloni G, et al - Results

  35. 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

  36. 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

  37. 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

  38. Fleming DR, et al Results  OS in obese adults (P = 0.003) OS Non-obese = 30% OS Obese = 16%

  39. 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

  40. 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

  41. 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

  42. Monitoring

  43. Follow-up • Complications: nausea/vomiting, diarrhea, mucositis • Engraftment ~ Day 12

  44. 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

  45. 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

  46. 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

  47. 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)

  48. Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients Powis G, et al Cancer Chemother Pharmacol 1987;20:219-222

  49. 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

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