dosing chemotherapy in obese patients: what is the big deal?
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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. - PowerPoint PPT PresentationTRANSCRIPT
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Dosing Chemotherapy in Obese Patients: What is the BIG Deal?
Haley GillVCH-PHC Pharmacy Resident 2009-2010
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Outline
• Learning Objectives
• Case
• Background
• Clinical Question
• Review of Literature
• Recommendation
• Monitoring
• Follow-up
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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
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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
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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
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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
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Review of Systems
Vitals Tmax 37.2°C, BP 115/68, HR 65 reg, RR 18, SaO2 98% RA
CNS A&O x 3
EENT Normal
CVS LVEF 73%
RESP Pulmonary Edema
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Review of Systems
GI Abdomen Obese
GU Normal
MSK Normal
DERM Normal
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Lab Values
HEME WBC 4.9 Hgb 102 Plt 188 Neut 2.6
LYTES Na 136 K 3.6 Cl 103 CO2 27 Mg 0.85 Uric Acid 332
RENAL Cr 53 Urea 6.8 CrCl ~ 134ml/min
LIVER GGT 46 ALP 84 TBili 7 DBili 1 ALT 46 AST 22 LDH 299 Albumin 42
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Size Descriptors
Height 161 cmActual Body Weight (ABW) 110.4 kg
Body Surface Area (BSA) 2.22 m2
Ideal Body Weight (IBW) 54.26 kg
Corrected Body Weight (CBW) 82.3 kg
Corrected Body Surface Area (CBSA) 1.92m2
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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
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Alternative Dosing RegimensBody Weight Descriptor
BSA BU Dose (3.2 mg/kg)
CY dose (60 mg/kg)
Dose Difference
vs ABW
Possible
Concern
ABW = 110.4 kg
2.22 353 mg 6624 mg Risk of toxicity
IBW = 54.26 kg(48.67+0.65(ht in cm-152.4))
1.56 174 mg 3256 mg 50% dose reduction
Risk of efficacy
CBW = 82.3 kg(IBW+1/2(ABW-IBW))
1.92 263 mg 4938 mg 25% dose reduction
Risk of efficacy?
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Medications in Hospital
Drug Dose Indication
Heparin 10,000 units daily veno-occlusive disease prophylaxis
Phenytoin 400 mg daily seizure prophylaxis while on BU
Ondansetron 8 mg IV daily anti-emetic
Lorazepam 1 mg SL daily anti-emetic
IV Fluids D5W/1/2NS+20mEq KCl+1g MgSO4
@ 250 ml/hr
hyper-hydration while on CY
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Drug Related Problems
1. LS is at risk of decreased treatment efficacy secondary to possible subtherapeutic dosing of BU/CY conditioning
2. LS is experiencing pulmonary edema which may be exacerbated by hyper-hydration and would benefit from re-evaluation of current therapy
3. LS is at risk of graft-vs-host-disease and would benefit from prophylaxis with cyclosporine & methotrexate
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CML
Chronic leukemia of myeloid stem cell origin
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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
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HSCT
• IV infusion of hematopoietic progenitor cells
• Replacement or Rescue
• Conditioning regimen
• Transplant
• Supportive Care
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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
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Busulfan PK PropertiesA IV administration
D Vd 0.6-1.0 L/kg
Protein Binding 7-55% (albumin)
Highly lipophilic
M Extensive hepatic metabolism
E Renal 10-50% primarily as metabolites
T1/2 2.3-2.6 h
Clearance 2.5-4.5 mL/min/kg (↑ in obese)
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Cyclophosphamide PK PropertiesA IV Administration
D Vd 0.56 L/kg
Protein binding 12-14% (unchanged drug), 67% (metabolites)
M Pro-drug converted by CYP enzymes in liver (primarily CYP 2B6)
E Renal 5-25% unchanged
T1/2 parent drug 6.5 h (1.8-12.4 h), metabolites 7.7-9.9 h & 2.5-5.5 h
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PK Alterations in Obesity
Hunter et al. Cancer Treatment Reviews 2009
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PK Alterations in Obesity Adipose tissue Vd of lipophilic medications
Alter Vd - impaired blood flow to tissue
organ mass, lean body mass, blood volume
Affect Vd
/ drug concentrations
Fatty infiltration of liver Changes in LFT’s not common
If hepatic function compromised t1/2, Vd, Cl
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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?
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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
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Literature in Breast Cancer PatientsStudy Methods Safety Efficacy Conclusion
Poikonen, et al (2001)
Retrospective
N = 340
CMF Dosing based on ABW
Median f/u 68 months
↑BMI associated with ↑ WBC nadirs
Substantial variation in WBC nadirs
No association between body size parameters & DFS or OS (p=>0.1)
Obese pts. had ↓ toxicity
May be due to ↓ metabolite
Obese pts. received lower mg/kg doses
Powis, et al (1987)
N = 16
Cyclophosphamide PK study
↑ body weight associated with:
↑ t1/2
↓Cl (normalized to BSA & IBW)
No correlation between body weight and total Cl
No effect on txt response
↓ CY Cl with ↑ body weight may be due to↓ metabolite
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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
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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
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Sparreboom AC, et alResults
Drug Effect of dose adjustment
Carboplatin None
Cisplatin ↓drug exposure
Docetaxel ↑drug exposure
Doxorubicin ↑drug exposure in women
Irinotecan None
Paclitaxel ↓drug exposure in women
Topotecan None
Troxacitabine ↓drug exposure
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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
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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
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Obesity and autologous stem cell transplantation in acute myeloid leukemia
Meloni G, et al
Bone Marrow Transplantation 2001;28:365-367
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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
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Meloni G, et al - ResultsOutcome All
Patients
(N = 54)
Obese
(N = 9)
Non-Obese
(N = 37)
Underweight (N = 8)
P-value
Median time to WBC recovery (days)
NR 33 24 17.5 NSS
Documented infections
NR 78% 44% NR 0.04
Platelet Recovery
No difference
Hemorrhagic cystitis
No difference
Transplant-related mortality
6 (9%) 3 (33%) 3 (8%) 0 (0%) 0.04
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Meloni G, et al - ResultsAll Patients
(N = 54)
Obese
(N = 9)
Non-Obese
(N = 37)
Underweight (N = 8)
P-value
OS Probability
0.55 0.22 0.63 0.56 0.012
DFS Probability
0.53 0.22 0.58 0.62 0.021
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Meloni G, et alAuthor’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
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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
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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
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Fleming DR, et al
Results
OS in obese adults (P = 0.003)
OS Non-obese = 30%
OS Obese = 16%
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Fleming DR, et alAuthor’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
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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
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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
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Monitoring
Parameter
Vitals T, BP
CNS Seizure activity while on BU
EENT mucositis
GI Nausea, Vomiting, Diarrhea
GU Hemastix to test for hematuria while on CY
Liver LFT’s, albumin
Electrolytes SCr, Urea, Lytes
HEME CBC + differential, BG, Phenytoin level
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Follow-up
• Complications: nausea/vomiting, diarrhea, mucositis
• Engraftment ~ Day 12
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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
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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
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Poikonen P, et alAuthor’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
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Poikonen P, et alResults
– 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)
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Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients
Powis G, et al
Cancer Chemother Pharmacol
1987;20:219-222
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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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Powis G, et al Results
– Increased body weight associated with increased t1/2 (p = 0.01)
– Increased body weight associated with decreased clearance when clearance was normalized to BSA (p = 0.019) and IBW (p = 0.034)
– No significant correlation between weight and total clearance (p = 0.067)
– No significant correlation between the therapeutic or myelosuppressive effects of treatment and CY PK parameters
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Powis G, et al
Author’s conclusions– Decreased CY clearance with increased body
weight may reflect a decreased hepatic metabolism of cyclophosphamide
– Decreased hepatic metabolism = less CY converted to active form which may be why no effect was seen on treatment response
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Powis G, et al
Limitations– Small number of subjects– Heaviest subject = 90.5kg– Low doses of CY– Only the inactive pro-drug, and not the
cytotoxic metabolite was assayed– Did not report on toxicity