Dose adjustment for organ dysfunction - PowerPoint Presentation

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Dose adjustment for organ dysfunction

By :

Manal

Mostafa

Saleh

Demonstrator of clinical oncology , Nuclear medicine

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References :

Physicians Cancer Chemotherapy Drug Manual (2015).

2013-ESMO-Handbook-of-Cancer-Treatments-in-Special-Clinical-Situations.

Oncology - An Evidence-Based Approach (Springer, 2005).

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Successful administration of chemotherapy relies on several critical patient factors: age; performance status; co-morbid illnesses; prior therapy; and baseline hematologic, hepatic, and renal status. The dose of a given chemotherapeutic agent should be adjusted accordingly to these parameters.

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It is important to treat the patient not to treat the disease

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GFR (

glomerular filtration rate) is the optimal way to measure kidney function. Generally, the creatinine clearance is a good estimation of the glomerular filtration rate.

Renal

insufficiency

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There are two main ways doctors use

creatinine

tests to measure kidney function:

24 hours urine collection test. Although the urine

creatinine

measurement method is inconvenient, it may be necessary to diagnose some kidney conditions.

GFR can be estimated using a single blood level of

creatinine

, which enters into a formula. Different formulas are available, which take into account

age,sex

, and sometimes weight .

For practical reasons, the blood test estimation method for GFR is used far more often than the 24-hour urine collection test for

creatinine

clearance.

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Different equations for GFR calculation

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Normally it is 90 ml/min /1.73m2 or higher

Renal insufficiency is defined as a

glomerular

filtration rate (GFR) of consistently less than 60 ml/min/1.73 m2. It is considered chronic when the condition persists for more than three months

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impaired renal function is a common condition in adults and in the elderly, and is a predictor of diminished survival. Its incidence is high in cancer patients who are treated regularly with

nephrotoxic

molecules. Thus, the clinician’s dilemma is how to prevent the deterioration of renal function and determine the adjusted dosage of a drug with regard to the patient’s GFR without reducing the effectiveness of potentially

nephrotoxic

therapies.

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Changes should apply to the disease management strategy as a whole, from specific treatment (chemotherapy) to supportive care (pain relief) and

complementaryexaminations

(iodinated contrast).

In everyday practice, the majority of cancer therapies require no dose modification for a

creatinine

clearance of between 60 and 90 ml/min.

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Case 1

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Postmenopausal female patient 55

ys

old

acase

of breast cancer , now attend for 1

st

cycle

paclitaxel

as adjuvant

ttt

after 4 FAC , CBC and LFT are ok but

S.creat

1.6 (calculated

cr.clearance

42 ml/min acc. To CKD equation) , What will you do?

Give the cycle now

Good hydration and postpone I cycle 1 week

Give the cycle with reduction of the dose

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For

docetaxel

and

paclitaxel

No dose reduction is necessary in patients with renal dysfunction.

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Chemotherapy metabolized or excreted through

Kidney

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B BleomycinC (Capecitabine- Carboplatin -Cisplatin-Cytarabine-cyclophosphamide)D DacarbazineE EtoposideM o t i(methotrexate,mitomycin , oxaliplatin ,temodal, topotecan , ifosphamide)

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Iodinated contrast-induced acute kidney injury (ICI-AKI) is the third leading cause of acute kidney failure during

hospitalisation

, after antibiotics and NSAIDs. The main risk factor for ICI-AKI is pre-existing renal insufficiency.

The other risk factors are age >65 years, diabetes, dehydration, concomitant

nephrotoxic

drug intake,

anaemia

and

hypoalbuminaemia

. Thus, a patient designated to receive an ICM injection should first be screened for these risk factors.

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Oncologists should be aware of liver toxicity from anti-cancer drugs, and oversee dosing strategies for patients with HD. The therapeutic index of anti-cancer drugs undergoing hepatic metabolism and

biliary elimination is even narrower in the case of HD, increasing the risk of severe toxicity and/or impaired activity. Often patients present with several causes of HD, including liver metastases, paraneoplastic hepatotoxicity,pre-existing liver infections and concurrent medication .

Hepatic dysfunction

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Case 2

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Male patient 65

ys

old

acase

of metastatic cancer prostate (bone), failed on hormonal

ttt

, the panel

descision

was starting

taxotere

single agent, this is the 1

st

cycle , CBC is ok ,

S.creat

1.2 , SGPT 45, SGOT 70 What will you do?

Give the cycle now

postpone I cycle 1 week , with liver support

Give the cycle with reduction of the dose

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Docetaxel

is

metabolised

by liver, followed by

biliary

excretion.

Clearance is 50% of normal in patients with AST/ALT ≥2.5× ULN and 25% in patients with TB ≥1.5× ULN..

Docetaxel

should be omitted in patients with TB >ULN

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Omit if

bilirubin .1.5 mg/dL, SGOT .60 mg/dL.

Docetaxel

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No formal recommendation for dose reduction if

bilirubin 1.5–3.0 mg/dL or SGOT 60–180 mg/dL.Omit if bilirubin .5.0 mg/dL or SGOT .180 mg/dL.

Paclitaxel

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Paclitaxel

Normal LF 175 mg/m2/3 w

AST/ALT >ULN 135 mg/m2/3 w

Bilirubin

1.25–2× ULN 115 mg/m2/3 w

Bilirubin

2–3.5× ULN 100 mg/m2/3 w

Bilirubin

>3.5× ULN Omit

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Chemotherapy metabolized or excreted through

liver

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C

campto

–

capcitabine

D

docetaxel

,

paclitaxel

, doxorubicin

E

etoposide

F

flourouracil

,

vinca

alkaloids

methotrexate

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B

BleomycinC (Capecitabine- Carboplatin -Cisplatin -Cytarabine-cyclophosphamide)D DacarbazineE EtoposideM o t i(methotrexate , oxaliplatin ,temodal, ifosphamide)

C campto –capcitabineD docetaxel , paclitaxel , doxorubicinE etoposideFlourouracil , vinca alkaloidsmethotrexate

kidney

liver

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Case 3

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40

ys

old hepatic male patient

acase

of nasopharyngeal NHL stage I , the panel decision was chemotherapy CHOP followed by RTH,

ptn

received 1

st

cycle full lab was satisfactory, attend for 2

nd

cycle , CBC and

s.creat

ok , SGOT 60 , SGPT 45, you asked him to do

T.bilirubin

and the result was 1.6

What will you do??

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Reduce by 25% if

bilirubin 3.0–5.0 mg/dL orSGOT more than 180 mg/dL.Omit if bilirubin .5.0 mg/dL.

Cyclophosphamide

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Reduce dose by 50% if

bilirubin 1.5–3.0 mg/dL.Reduce dose by 75% if bilirubin 3.1–5.0 mg/dL.Omit if bilirubin .5.0 mg/dL.

Doxorubicin

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No dose reduction if

bilirubin less than 1.5 mg/dL and SGOT ,60 mg/dL.Reduce by 50% if bilirubin 1.5–3.0 mg/dL andSGOT 60–180 mg/dL.

Vincristine

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Anastrozole

(arimidex) Dose reduction may be necessary in patients with Hepatic dysfunction but No formal recommendation for dose reduction.Bicalutamide (casodex) Dose reduction may be necessary if bilirubin more than 3.0 mg/dL

N.B

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No formal recommendations for dose reduction.

Omit if bilirubin .5.0 mg/dL.

5-Fluorouracil

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Chemotherapy in patients with hepatitis

Liver injury is a frequent complication of chemotherapy. The main sources of this injury are drug

hepatotoxicity

and viral infections such as hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus and herpes simplex virus.

Liver infections particularly HBV and HCV, have been reported as causes of severe liver disease, including

fulminant

hepatitis, either by reactivation or by enhanced replication of the virus in the context of induced

immunosuppression

by chemotherapy

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Risk of HBV reactivation depends on the balance between replication of the virus and the host’s immune response. Thus, the risk of reactivation differs according to the patient´s HBV infection status prior to chemotherapy as well as to the degree of

immunosuppression

due to systemic chemotherapy.

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Risk Factors for HBV Reactivation in HBV-positive Individuals with Cancer Who Receive Chemotherapy

HBsAg

positivity

High baseline HBV DNA levels (>105 copies/ml)

Male gender

Young age

High basal serum ALT levels

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Absence or decrease of anti-HBs

titres

during chemotherapy

Type of malignancy (

haematological

malignancies: lymphoma)

Chemotherapeutic agents:

anthracyclines

,

cyclophosphamide

,

fludarabine

,

vinca

alkaloids

Steroid-containing regimens

Monoclonal antibodies:

rituximab

,

alemtuzumab

Haematopoietic

stem cell transplantation (HSCT

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Treatment of HCV Reactivation

At present, treatment of HCV reactivation is mainly supportive

Anti-HCV therapy has traditionally been avoided during chemotherapy because the

haematological

adverse effects of antiviral drugs can exacerbate the toxicity of chemotherapy.

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Prevention of HCV Reactivation

No drugs are currently approved for the prevention of HCV reactivation in patients who undergo chemotherapy. The risk of HCV reactivation may be reduced by using lower doses of immunosuppressive drugs or giving less aggressive chemotherapy to prevent

hepatotoxicity

. However, this approach is not feasible since fatal hepatitis has been described even in patients treated with only one immunosuppressive agent. Hence, base line screening for HCV infection is crucial in patients undergoing chemotherapy, especially in those with lymphoma.

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conclusion

Reactivation of HBV or HCV can occur after

immunosuppression

in patients with cancer who receive chemotherapy. This complication can be clinically severe and result in progressive liver disease or death due to liver dysfunction. Patients needing

cytotoxic

agents should be screened

forHBV

and HCV infection before initiating chemotherapy. Periodic monitoring of ALT and HBV or HCV viral load levels should be performed during chemotherapy and after treatment is withdrawn.

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In high-risk patients, HBV reactivation can be preventable . As current treatment of HCV may not be used concomitantly with chemotherapy, management of HCV reactivation is mainly supportive

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