Carboplatin + Paclitaxel Cancer of the Cervix

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1 Carboplatin + Paclitaxel Cancer of the Cervix Background: Topotecan in combination with cisplatin is recommended as a treatment option for women with recurrent or stage IVB cervical cancer only if they have not received prior cisplatin chemotherapy. (NICE TA 183) In patients who have had prior chemoradiotherapy or have impaired renal function, carboplatin and paclitaxel is an effective alternative. Patient group: Patients with metastatic or recurrent carcinoma of the cervix who are fit for combination chemotherapy, or if renal function precludes the use of cisplatin plus topotecan. ECOG PS 0-2 Pre-treatment assessment: Weight, FBC, U&E s, LFT s and creatinine clearance (calculated) CT scan and Histology Treatment Threshold WBC > 3 x 10 9 /L Platelets > 100 x 10 9 /L ANC > 1.5 x 10 9 /L Bilirubin < 1.25 x ULN and ALT/AST< 10 x ULN Creatinine Clearance > 20mL/min Pre-Meds: To be administered 30 minutes prior to paclitaxel Ondansetron 8mg PO Dexamethasone 16mg IV/PO bolus over 3-5 minutes Ranitidine 50mg IV in 50mL sodium chloride 0.9% infused over 20 minutes. Chlorphenamine 10mg IV bolus over 3-5 minutes

2 Regimen Details: Day 1 Paclitaxel 175mg/m 2 IV in 500mL 0.9% sodium chloride infused over 3 hours through non-pvc giving set and a 0.22 micron in-line filter. Carboplatin AUC 5 IV in 500ml glucose 5% infused over 60 minutes. Cycles are repeated at intervals of 21 days for 6 cycles Administration: Paclitaxel is administered through a non-pvc giving set with a 0.22 micron in-line filter. Paclitaxel must be administered before Carboplatin. Hypersensitivity reactions to Paclitaxel: dyspnoea and hypotension requiring treatment, angioedema, and generalised urticaria have occurred in <1% of patients receiving paclitaxel after adequate premedication. These reactions are probably histamine-mediated. In the case of severe hypersensitivity reactions, paclitaxel infusion should be discontinued immediately, symptomatic therapy should be initiated and the patient should not be re-challenged with paclitaxel. Blood pressure and pulse rate monitoring during infusion, cardiac monitoring with prior arrhythmia Extravasation (Paclitaxel) Care needed to avoid extravasation. Intravenous administration may lead to localised oedema, pain, erythema, and induration; on occasion, extravasation can result in cellulitis. Skin sloughing and/or peeling has been reported, sometimes related to extravasation. Skin discoloration may also occur. Rarely anaphylaxis, angio-oedema and anaphylactoid reactions including bronchospasm, urticaria and facial oedema can occur with carboplatin. These reactions are similar to those observed after administration of other platinum containing compounds and may occur within minutes. The incidence of allergic reactions may increase with previous exposure to platinum therapy; however, allergic reactions have been observed upon initial exposure to Carboplatin. Patients should be observed carefully for possible allergic reactions and managed with appropriate supportive therapy, including antihistamines, adrenaline and/or glucocorticoids.

3 Anti-emetics: Highly emetic day 1 Additional Medication: Paracetamol PO, Chlorphenamine IV and Hydrocortisone IV for administration related reactions. Monitoring and Assessment: FBC, U&E, LFTs and creatinine clearance calculated prior to each cycle Clinical assessment (medical review) - prior to each cycle Radiology to confirm response to treatment after 2 nd or 3 rd cycle Dose Modifications: Haematological Toxicity WBC < 3 x 10 9 /L Neutrophils < 1.5 x 10 9 /L or Platelets < 100 x 10 9 /L Delay treatment for 1 week Repeat FBC - If within normal parameters, resume treatment with Carboplatin and Paclitaxel at 100% doses. For subsequent cycles: If Neutrophils < 0.5 x 10 9 /L for 7 days, OR febrile neutropenia is diagnosed OR Platelets < 50 x 10 9 /L for 7 days then reduce doses by 20%. If myelosuppression continues despite the use of lower doses, discontinue therapy. Non Haematological Toxicity Severe cardiac conduction abnormalities have been reported rarely with paclitaxel. If patients develop significant conduction abnormalities during paclitaxel administration, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel. The occurrence of peripheral neuropathy is frequent with paclitaxel; the development of severe symptoms is rare. In severe cases, a dose reduction of 20% is recommended for all subsequent courses of paclitaxel. Renal Impairment The dose of carboplatin should remain the same throughout treatment. It should only be recalculated if the serum creatinine increases by 15% from baseline. Adjust dose using Calvert formula. Carboplatin is contraindicated if creatinine clearance is < 20ml/min.

4 Hepatic Impairment Paclitaxel is not recommended in severe hepatic impairment Bilirubin (µmol/l) Paclitaxel Dose (mg/m 2 ) > Pharmaceutical Care: The creatinine clearance should be calculated using the Cockcroft & Gault Formula Females: 1.04 x (140 age) x weight (kg) Serum creatinine (micromol/l) Males: 1.23 x (140 age) x weight (kg) Serum creatinine (micromol/l) The dose of Carboplatin should be calculated using the Calvert Formula. Dose mg = AUC * (GFR + 25) A second pharmacist check is required for all calculations. Carboplatin may interact with aluminium to form a black precipitate. Needles, syringes, catheters or IV administration sets that contain aluminium parts which may come into contact with carboplatin, should not be used for the preparation or administration of the drug. A decrease in phenytoin serum levels has been observed in case of concurrent administration of carboplatin and phenytoin. This may lead to reappearance of seizure and may require an increase of phenytoin dosages. Concurrent therapy with nephrotoxic or ototoxic drugs such as aminoglycosides, vancomycin, capreomycin and diuretics, may increase or exacerbate toxicity due to carboplatin induced changes in renal clearance. Final paclitaxel concentration should be in the range mg/mL Caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g. erythromycin, fluoxetine, gemfibrozil) or induce (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) either CYP2C8 or 3A4.

5 Most Common Toxicities: Myelosuppression +/- infection Nausea and vomiting Fatigue Asthenia Constipation Diarrhoea Mucositis Nephrotoxicity Neurotoxicity Ototoxicity Arthralgia/myalgia Taste disturbance Rash Alopecia Hypersensitivity reactions References: 1. SPC Carboplatin 10 mg/ml concentrate for solution for infusion. Accord Healthcare Limited [accessed 2 nd July 2014] 2. SPC Paclitaxel 6 mg/ml concentrate for solution. Hospira UK Ltd [accessed 2 nd July 2014] 3. Pectasides D, et al. Carboplatin and paclitaxel in metastatic or recurrent cervical cancer. Int J Gynecol Cancer May; 19(4): North London Cancer Network guidelines for dosage adjustment for cytotoxics in renal and hepatic impairment. NLCN 2009.