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 GillVCH-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


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


Review of Systems

GI Abdomen Obese

GU Normal

MSK Normal

DERM Normal


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


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


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


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?


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


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


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


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)


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


PK Alterations in Obesity

Hunter et al. Cancer Treatment Reviews 2009


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


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


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


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



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 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



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



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 - 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


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


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


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 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


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


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


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 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


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)


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


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


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


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

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

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