Dose adjustment for organ dysfunction By Manal Mostafa

Dose adjustment for organ dysfunction By : Manal Mostafa Saleh Demonstrator of clinical oncology , Nuclear medicine

References : �Physicians Cancer Chemotherapy Drug Manual (2015). � 2013 -ESMO-Handbook-of-Cancer-Treatments-in- Special-Clinical-Situations. �Oncology - An Evidence-Based Approach (Springer, 2005).

�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 chemotherapeutic of agent a should given be adjusted accordingly to these parameters.

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

Renal insufficiency �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.

�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.

Different equations for GFR calculation

Normally it is 90 ml/min /1. 73 m 2 or higher �Renal insufficiency is defined as a glomerular filtration rate (GFR) of consistently less than 60 ml/min/1. 73 m 2. It is considered chronic when the condition persists for more than three months

�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.

�Changes should apply to the disease management strategy as a whole, from specific supportive treatment care (chemotherapy) (pain complementaryexaminations relief) to and (iodinated contrast). �In everyday practice, the majority of cancer therapies require no dose modification for a creatinine clearance of between 60 and 90

Case 1

�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

For docetaxel and paclitaxel No dose reduction necessary is in patients with renal dysfunction.

Chemotherapy metabolized or excreted through Kidney

�B Bleomycin �C (Capecitabine- Carboplatin -Cisplatin- Cytarabine-cyclophosphamide) �D Dacarbazine �E Etoposide �M o t i (methotrexate, mitomycin , oxaliplatin , temodal, topotecan , ifosphamide)

�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.

Hepatic dysfunction �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.

Case 2

�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

�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

Docetaxel �Omit if bilirubin. 1. 5 mg/d. L, SGOT . 60 mg/d. L.

Paclitaxel �No formal recommendation for dose reduction if bilirubin 1. 5– 3. 0 mg/d. L or SGOT 60– 180 mg/d. L. �Omit if bilirubin. 5. 0 mg/d. L or SGOT. 180 mg/d. L.

Paclitaxel �Normal LF 175 mg/m 2/3 w �AST/ALT >ULN 135 mg/m 2/3 w �Bilirubin 1. 25– 2× ULN �Bilirubin 2– 3. 5× ULN �Bilirubin >3. 5× ULN 115 mg/m 2/3 w 100 mg/m 2/3 w Omit

Chemotherapy metabolized � or excreted through liver �

�C campto –capcitabine �D docetaxel , paclitaxel , doxorubicin �E etoposide �F flourouracil , vinca alkaloids �methotrexate

kidney �B Bleomycin �C (Capecitabine. Carboplatin -Cisplatin -Cytarabinecyclophosphamide) �D Dacarbazine �E Etoposide �M o t i (methotrexate , oxaliplatin , temodal, ifosphamide) liver �C campto – capcitabine �D docetaxel , paclitaxel , doxorubicin �E etoposide �Flourouracil , vinca alkaloids �methotrexate

Case 3

� 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? ?

Cyclophosphamide �Reduce by 25% if bilirubin 3. 0– 5. 0 mg/d. L or SGOT more than 180 mg/d. L. �Omit if bilirubin. 5. 0 mg/d. L.

Doxorubicin �Reduce dose by 50% if bilirubin 1. 5– 3. 0 mg/d. L. �Reduce dose by 75% if bilirubin 3. 1– 5. 0 mg/d. L. �Omit if bilirubin. 5. 0 mg/d. L.

Vincristine �No dose reduction if bilirubin less than 1. 5 mg/d. L and SGOT , 60 mg/d. L. �Reduce by 50% if bilirubin 1. 5– 3. 0 mg/d. L and SGOT 60– 180 mg/d. L.

N. B �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/d. L

5 -Fluorouracil �No formal recommendations for dose reduction. �Omit if bilirubin. 5. 0 mg/d. L.

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

�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 immunosuppression due chemotherapy. degree to of systemic

Risk Factors for HBV Reactivation in HBV-positive Individuals with Cancer Who Receive Chemotherapy � HBs. Ag positivity � High baseline HBV DNA levels (>105 copies/ml) � Male gender � Young age � High basal serum ALT levels

�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

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 chemotherapy. the toxicity of

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 chemotherapy to drugs prevent or giving hepatotoxicity. less aggressive 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.

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 for. HBV 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.

�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