Chemotherapy related Toxicities and Management Prof. Dr. Khaled Abulkhair, PhD Medical Oncology SCE, royal College, UK Ass. Professor of Clinical Oncology Mansoura University

Outlines Extravasation and its management Specific Chemotherapy Toxicities and Chemo-protectants Management of Diarrhoea Dose Adjustments.

Extravasation Inadvertent administration of a vesicant solution into surrounding tissue. Vesicant is a fluid or medication that on extravasation can cause tissue necrosis. Best Example is Anthracyclines. Extravasations related to: – Double puncture of the distal wall – Mechanical friction – Dislodgement of the catheter

Extravasations Signs and Symptoms – Complaints of pain or burning – Swelling proximal to or distal to the IV site – Puffiness of the dependent part of the limb – Skin tightness at the venipuncture site – Blanching and coolness of the skin – Slow or stopped infusion – Damp or wet dressing

First signs are often subtle.

May be mild, blotchy redness, subtle swelling or change in infusion rate.

Within days brawny discoloration, indurations, dry desquamation, blistering with discomfort and/or pain.

Full thickness skin necrosis that involves underlying tendons and neurovascular structures that leads to permanent damage.

MyelosuppressionInfection

Managing Extravasation Stop infusion at once Withdraw the drug Leave cannula insitu Elevate limb to reduce oedema Apply heat for Vinca Alkaloids/and cold pack for others including Anthracyclines Why? Subsequent management depends upon drug involved and degree of damage. Maybe local extravasation policy i.e. use of antidote.

Antidotes DrugAntidote MechlorethamineNa thiosulfate Anthracyclines (Doxu, Dauno, Idaru, Epirubi) Dexrazoxane / +\- topical Dimethyl Sulfoxide Vinca AlkaloidsHyalourinidase

Preventing Complications Ensure staff are trained and supervised Supervised practice and competence assessed Practice continually updated Ensure correct preparation of patient, equipment and environment Aseptic non touch technique Managed aftercare Documentation

Specific chemotherapy Toxicities and Chemoprotectants Each drug can cause a common and specific toxicity that is unique to its family. ChemotherapyType of ToxicityChemoprotectant AnthracyclinesCardiotoxicityDexrazoxane CisplatinNephrotoxicity/OtotoxicityAmifostine Ifosfamide / Cyclophosphamide Haemorrhagic CystitisMESNA MethotrexateMucositis/NephrotoxicityGlucarpidase Leucovorin

Chemoprotectant Is a drug used to ameliorate specific toxicity from chemo and or radiotherapy Characteristics: Easy to administer Safe with no side effects Prevents all toxicity Doesn't interfere with the efficacy of chemotherapy Till date no this magic drug was not found

Dexrazoxane Acts as intracellular chelating agent thus decrease Anthracyclines free radical damage. Approved in metastatic breast cancer to minimize Cardiotoxicity if Anthracyclines cumulative doses exceeds 300 mg. It may increase hematologic toxicity. Controversial data about decreasing Anthracyclines effects, however, it is still indicated for early curable breast cancer patients. Recently approved as an antidote in case of Anthracyclines extravasation.

Amifostine It is used to decrease Cisplatin induced nephrotoxicity. Also approved to decrease Xerostomia with radiation therapy to H&N. Many side effects including allergic reactions, nausea and vomiting and more importantly hypotension.

Mesna (sodium di mercaptoethane sulfonate) Detoxifies Acrolein by combining to it and prevents it damaging the host cells. Acrolein is the active metabolite of both Cyclophosphamide and Ifosfamide that causes cystitis. Always given with Ifosfamide and may be used with Cyclophosphamide if doses higher than 1500 mg/m2. Oral and injection formula are available; whatever, the method to give should start before or with the chemotherapy and ends few hours after it

Glucarpidase A carboxypeptidase enzyme, is now approved and indicated for the treatment of toxic methotrexate concentrations (greater than 1 μmol/L) in patients with delayed methotrexate clearance due to renal function. Administered as a single intravenous dose of 50 units/kg. Continue leucovorin until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. However, caution must be used with administering leucovorin in conjunction with glucarpidase. Leucovorin should not be administered within 2 hours before or after a dose of glucarpidase.

Management of Diarrhoea Intensive loperamide therapy using doses higher than the recommended dose was initially described for irinotecan- induced diarrhoea. Atropine is used for the prevention of cholinergic activity of acute irinotecan-induced diarrhea. There is no maximal dose of loperamide when using for delayed diarrhea in this setting. The recommended dosing of loperamide is 4 mg P.O followed by 2 mg every 2 hours until diarrhea free. Intensive antidiarrhea treatment is also used for other agents (e.g., fluorouracil, epidermal growth factor receptor inhibitors).

CASES

A patient is receiving chemotherapy for limited-stage small cell lung carcinoma. After the third cycle of chemotherapy, she is hospitalized with febrile neutropenia. She recovers, and today, she is scheduled to receive the fourth cycle of chemotherapy. Which statement is the best treatment course for this patient? A.The patient should receive filgrastim 250 mcg/ m2/day subcutaneously for 10 days. B.The patient should receive filgrastim 5 mcg/kg/ day subcutaneously, starting today. C.The patient should receive pegfilgrastim 1 mg/ day subcutaneously for 6 days. D.The patient should receive filgrastim 5 mcg/kg/ day subcutaneously for 7 days, given at least 24 hours after chemotherapy

Which is the best sequence for administering Mesna and Ifosfamide? A.Mesna before ifosfamide and then at 4 and 8 hours after ifosfamide. B.Ifosfamide before mesna and then at 4 and 8 hours after mesna. C.Mesna and ifosfamide beginning and ending at the same time. D.Mesna on day 1 and ifosfamide on days 2–5.

A 38-year-old woman has a history of Hodgkin lymphoma. Two years ago, she completed six cycles of ABVD chemotherapy (i.e., doxorubicin, bleomycin, vinblastine, and dacarbazine). Each cycle included doxorubicin 50 mg/m2. Recently, she was given a diagnosis of stage IV breast cancer. She will be initiated on doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for four cycles. Which statement is most applicable? A.The patient has not reached the appropriate cumulative dose of doxorubicin to consider Dexrazoxane. B.The patient has reached the appropriate cumulative dose of doxorubicin to consider dexrazoxane. C.The patient should not receive any more doxorubicin because she is at an increased risk of cardiotoxicity. D.The patient should not receive dexrazoxane because of the possibility of increased myelosuppression.

Sometimes, extravasation is not immediately evident when it occurs. Immediately after administering CHOP-R to patient 1 H earlier, an extravasation is suspected. Which is the best treatment recommendation for the patient’s extravasation? A.Application of a warm pack for suspected extravasation of doxorubicin. B.Application of a cold pack for suspected extravasation of vincristine. C.Application of dimethyl sulfoxide and intravenous dexrazoxane for suspected extravasation of doxorubicin. D.Application of sodium thiosulfate for suspected extravasation of cyclophosphamide.

A 40-year-old man is about to begin R-CHOP chemotherapy for large cell non-Hodgkin lymphoma. The patient asks how long the treatment will take and whether he can be treated as an outpatient. Which is the best answer? A.Administration of this regimen is expected to be complete in 1 hour, but because the regimen is highly emetogenic, it is usually given to patients while in the hospital. B.Administration of this regimen may take as long as 6 hours because the rituximab infusion rate is slowly increased, but the regimen is usually given to outpatients. C.Administration of this regimen may take as long as 6 hours because the vesicants doxorubicin and vincristine should be infused over several hours, but the regimen is usually given to outpatients. D.Administration of this regimen is expected to be complete in 1 hour, but because of the risk of TLS, it is usually given to patients in the hospital.

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