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Dosing Chemotherapy in Obese Patients:
What is the BIG Deal?
Haley Gill
VCH-PHC Pharmacy Resident 2009-2010
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Outline
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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 PBSCT
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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
LIVER
GGT 46
AST 22
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CrCl ~ 134ml/min
ALP 84 TBili 7 DBili 1
LDH 299 Albumin 42
ALT 46
Size Descriptors
Height
Actual Body Weight (ABW)
161 cm
110.4 kg
Ideal Body Weight (IBW)
2.22 m2
54.26 kg
Corrected Body Weight (CBW)
82.3 kg
Corrected Body Surface Area (CBSA)
1.92m2
Body Surface Area (BSA)
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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 Regimens
Body
BSA BU Dose
CY dose
Dose
Weight
(3.2 mg/kg) (60 mg/kg) Difference
Descriptor
vs ABW
ABW =
2.22 353 mg
6624 mg
110.4 kg
IBW =
54.26 kg
Possible
Concern
Risk of 
toxicity
1.56 174 mg
3256 mg
50% dose Risk of 
reduction efficacy
1.92 263 mg
4938 mg
25% dose Risk of 
reduction efficacy?
(48.67+0.65(ht in
cm-152.4))
CBW =
82.3 kg
(IBW+1/2(ABW-IBW))
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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 hyper-hydration while on
CY
@ 250 ml/hr
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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
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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 Properties
A
IV administration
D
Vd 0.6-1.0 L/kg
Protein Binding 7-55% (albumin)
Highly lipophilic
Extensive hepatic metabolism
M
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 Properties
A
IV Administration
D
Vd 0.56 L/kg
Protein binding 12-14% (unchanged drug),
67% (metabolites)
Pro-drug converted by CYP enzymes in liver
(primarily CYP 2B6)
M
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:
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1 retrospective review
1 case-controlled
5 PK studies
3 Review articles
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Literature in Breast Cancer Patients
Study
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
No association
between body size
parameters & DFS
or OS (p=>0.1)
Obese pts.
had ↓ toxicity
Substantial
variation in WBC
nadirs
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
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No effect on txt
response
↓ CY Cl with ↑
body weight
may be due
to↓ metabolite
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 al
Results
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;28:365367
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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 - Results
Outcome
All
Patients
(N = 54)
Obese
(N = 9)
Non-Obese
(N = 37)
Underweight
(N = 8)
P-value
Median time to NR
WBC recovery
(days)
33
24
17.5
NSS
Documented
infections
78%
44%
NR
0.04
NR
Platelet
Recovery
No difference
Hemorrhagic
cystitis
No difference
Transplantrelated
mortality
6 (9%)
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3 (33%) 3 (8%)
0 (0%)
0.04
Meloni G, et al - Results
All
Patients
(N = 54)
Obese
(N = 9)
Non-Obese Underweight
(N = 8)
(N = 37)
P-value
OS
0.55
Probability
0.22
0.63
0.56
0.012
DFS
0.53
Probability
0.22
0.58
0.62
0.021
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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
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Impact of obesity on allogeneic stem cell
transplant patients: A matched casecontrolled 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 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
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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
CNS
EENT
GI
GU
T, BP
Seizure activity while on BU
mucositis
Nausea, Vomiting, Diarrhea
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
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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):47074713
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 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
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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)
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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
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