Cisplatin + Etoposide IV / Oral therapy followed by Chemo-radiotherapy in Small Cell Carcinoma of the Cervix Indication: Neoadjuvant chemotherapy followed by Chemo-radiotherapy in Small Cell Carcinoma of the Cervix Regimen details: Cycles 1 to 4 of Chemotherapy: Etoposide 100mg/m 2 IV Cycles 5 and 6 of Chemo-radiotherapy: (*) Patients with reduced performance status, change Cisplatin to Carboplatin AUC 5 Etoposide 100mg/m 2 IV (*) Patients with reduced performance status, change Cisplatin to Carboplatin AUC 5 Radiotherapy (RT): Administration: Day 1 Days 2 and 3 50.4 Gy over 28 fractions (1.8 Gy/#) on Mondays to Fridays over 5 ½ weeks OR 45 Gy over 25 fractions (1.8 Gy/#) on Mondays to Fridays over 5 weeks Radiotherapy is delivered over 5 5 ½ weeks on weekdays only, with concurrent chemotherapy during the first and fourth week Furosemide 40mg orally Etoposide in Sodium Chloride 0.9% IV over 60 minutes Etoposide infusion should have maximum concentration of 0.2 0.35 mg/ml (PVC free) Monitor Etoposide infusion for the first 15 minutes for signs of hypotension 1litre Sodium Chloride 0.9% + 20mmol KCl + 1g MgSO 4 IV infusion over 60 minutes Cisplatin in 1 litre Sodium Chloride 0.9% IV over 2 hours 1litre Sodium Chloride 0.9% + 40mmol KCl + 1g MgSO 4 IV infusion over 2 hours Then either 500ml Sodium Chloride 0.9% IV infusion over 60 minutes or 500ml drinking water *Follow guidance protocol for Hydration schedules & fluid balance monitoring for outpatient Cisplatin regimens Any device containing aluminium that may come in contact with Cisplatin must be avoided Etoposide capsules, to be swallowed whole on an empty stomach, 30 minutes before or 2 hours after a meal. Daily dose of capsules can be divided in two, if necessary. Available as 50mg and 100mg capsules Page 1 of 6
Frequency: Extravasation: Anti- emetics: Every 21 days for 6 cycles Cisplatin and Etoposide: Non-vesicants Highly emetogenic. Follow Local Anti-emetic policy Regular investigations: FBC U&Es LFTs Mg 2+ and Ca 2+ EDTA Audiogram CT scan (disease evaluation) Prior to 1 st cycle Prior to 1 st cycle, if clinically indicated After 3 cycles Comments: Missed dose Etoposide capsules Do not take double next dose, inform clinical team and keep to normal dosing schedule Post dose vomiting Etoposide capsules Inform clinical team as soon as possible; do not take another capsule without consulting doctor GFR should be calculated using the Cockcroft & Gault equation in all patients; if the calculated GFR < 60 OR > 120ml/min, measure EDTA clearance or creatinine clearance before prescribing.monitor trends in serum creatinine between treatments: if > 20% from baseline value, recalculate GFR using the Cockcroft & Gault equation Hydration - Cisplatin Encourage oral hydration during treatment; for instance, drink a glass of water every hour during treatment, and at least a further 2 litres over the 24 hours following treatment Weight should be recorded prior to and at the end of Cisplatin treatment, and a strict fluid balance chart should be maintained. An average urine output of at least 100ml/hr must be maintained throughout treatment, and Cisplatin infusion should not be commenced unless this urine output is achieved. For low urine output, consider increasing the pre-hydration and diuretic regimen. Consider adding diuretics in weight-gain of 1.5 kg, or symptoms of fluid overload Electrolyte disturbances Cisplatin Disturbances in electrolytes can be a long term manifestation due to the Cisplatin induced renal tubular dysfunction. Check electrolytes- additional supplementation of magnesium, calcium or potassium may be required Allergy Cisplatin Anaphylactic-like reactions to Cisplatin have been reported. Facial edema, bronchoconstriction, tachycardia and hypotension may occur within minutes of Cisplatin administration. Adrenaline, corticosteroids and antihistamines have been effectively employed to alleviate symptoms Page 2 of 6
DOSE MODIFICATIONS Haematological Toxicity In the neoadjuvant setting, dose reduction and delays can compromise outcome. G-CSF should be considered in cycles 1 to 4 if more than one delay and / or before dose reduction. Start G-CSF support at least 24 hours post chemotherapy following the local Guidelines for the use of Colony Stimulating Factors to Manage Neutropenia. If in doubt, contact the relevant Consultant. G-CSF should NOT be given with cycles 5 and 6 Day 1 WBC < 3.0 x 10 9 / L or Neutrophils < 1.5 x 10 9 / L or Platelets < 100 x 10 9 / L Delay for 1 week. Repeat FBC - If within normal parameters, resume treatment at full doses Subsequent cycles If Neutrophils < 0.5 x 10 9 / L for 7 days, OR Febrile neutropenia is diagnosed OR Platelets < 50x 10 9 / L, Seek Consultant advice and consider reducing Etoposide dose to 75% and Cisplatin dose to 80% from previous doses (do not escalate for subsequent cycles) Renal Impairment: Cisplatin induces nephrotoxicity, which is cumulative. It is therefore contraindicated in patients with renal impairment. Consider dose reduction following the table below: CrCl (ml/min) Cisplatin Dose > 60 Give 100% 50 60 Give 80% < 50 Contraindicated Change to Carboplatin Etoposide dose should be adjusted as follows: CrCl (ml/min) Etoposide Dose > 60 Give 100% dose 40 60 Give 75% dose < 40 Give 50% dose Subsequent doses are based on clinical response Page 3 of 6
Hepatic Impairment: Cisplatin: No dose reduction necessary Etoposide dose should be adjusted as follows: Bilirubin (µmol / L) AST (units / L) Etoposide Dose < 26 or < 60 Give 100% 26 51 or 60 180 Give 50 % > 51 or > 180 Omit DOSE MODIFICATIONS FOR OTHER TOXICITIES AS APPROPRIATE PERIPHERAL NEUROPATHY/OTOTOXICITY CISPLATIN Cisplatin induced neuropathy is cumulative : Grade Neuropathy-sensory Ototoxicity Cisplatin Dose 1 Paresthesia (including tingling) but not --------- Give 100% interfering with function 2 Paresthesia interfering with function, Tinnitus not interfering with Give 80% (*) but not interfering with activities of daily living activities of daily living 3 Paresthesia interfering with activities of Tinnitus interfering with Omit Cisplatin daily living activities of daily living Change to Carboplatin AUC 5 4 Disabling Disabling Omit therapy (*) If Grade 2 neuropathy/ototoxicity persists, despite Cisplatin dose reduction, consider changing to Carboplatin AUC 5 Toxicities: Myelosuppression; fatigue ; nausea; vomiting; constipation; diarrhoea; stomatitis; nephrotoxicity; neurotoxicity / ototoxicity; taste disturbance; electrolyte disturbances; allergic reactions; alopecia Anaphylactic reactions have been reported following Etoposide administration Drug interactions: Cisplatin -Allopurinol, colchicine, probenecid, sulfinpyrazone : increase in serum uric acid concentration -Cephalosporins, aminoglycosides, amphotericin B : increase nephrotoxic and ototoxic effects of Cisplatin in these organs -Ciclosporine : excessive immunosuppression, with risk of lymphoproliferation -Cyclizine, phenothiazines : may mask ototoxicity symptoms -Furosemide, hydralazine, diazoxide and propranolol : intensify nephrotoxicity Page 4 of 6
-Oral anticoagulants : require an increased frequency of the INR monitoring -Penicillamine : may diminish the effectiveness of Cisplatin -Phenytoin : reduced epilepsy control Etoposide -Aprepitant : elevated Etoposide plasma levels -Ciclosporin (high doses) : increased plasma concentration of Etoposide, increased risk of toxicity -Coumarins : enhanced anticoagulant effect -Glucosamine ; St John s Wort : possible reduced Etoposide effectiveness -Grapefruit juice : reduced Etoposide plasma levels -Phenytoin : reduced absorption of the antiepileptic References: www.medicines.org.uk Summary of Product Characteristics. Etoposide. Bristol-Myers Pharmaceuticals. Sept 07 Summary of Product Characteristics. Cisplatin. Wockhardt UK Ltd. September 2006 Hoskins PJ et al. JCO (2003), Vol 21, Issue 18 (September): 3495-3501 Cisplatin dosage adjustment in Renal Impairment. Personal communication with Dr. A. Winship. Aug 09 UCLH-Dosage Adjustment for Cytotoxics in Hepatic Impairment. November 2003 UCLH-Dosage Adjustment for Cytotoxics in Renal Impairment. November 2003 GSTT Guidelines for treating Nausea and Vomiting in adult patients. September 2007 SELCN Cytotoxic Extravasation Guidelines (draft). July 2008 Stockley s Drug Interactions. Interactions search: Cisplatin and Etoposide. May 2009 CTCAE v3.0. August 2006 Appendix 1 Treatment summary Cycles 1 to 4 of Chemotherapy: Etoposide 100mg/m 2 IV (*) Patients with reduced performance status, change Cisplatin to Carboplatin AUC 5 Followed by cycles 5 and 6 of Chemo-radiotherapy: Etoposide 100mg/m 2 IV Page 5 of 6
(*) Patients with reduced performance status, change Cisplatin to Carboplatin AUC 5 Radiotherapy (RT): 50.4 Gy over 28 fractions (1.8 Gy/#) on Mondays to Fridays over 5 ½ weeks OR 45 Gy over 25 fractions (1.8 Gy/#) on Mondays to Fridays over 5 weeks CHEMOTHERAPY (i.e. 2 cycles) Week 1 2 3 4 5 6 Days 1-7 8-14 15-21 22-28 29-35 36-42 Cisplatin Etoposide IV Etoposide PO After 4 cycles of chemotherapy, 3 week gap then Chemo-radiotherapy : CHEMO-RADIOTHERAPY (cycles 5 and 6) Week 1 2 3 4 5 6 Days 1-7 8-14 15-21 22-28 29-35 36-42 Radiotherapy Cisplatin Etoposide IV Etoposide PO Page 6 of 6