Regimen: Pegylated Liposomal Doxorubicin Hydrochloride (PLDH) (Caelyx ) and Carboplatin ( CALYPSO regimen)

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1 Regimen: Pegylated Liposomal Doxorubicin Hydrochloride (PLDH) (Caelyx ) and Carboplatin ( CALYPSO regimen) Indications This is NOT a NICE-approved treatment. Please ensure that this regimen is locally funded before prescribing this treatment or discussing with patients. Palliative therapy for relapsed ovarian, fallopian tube or primary peritoneal cancer with late relapse (> 6 months) after prior platinum-based treatment. Regimen details Day(s) Drug Dose Route 1 Pegylated Liposomal Doxorubicin 30mg/m 2 IV Hydrochloride (PLDH) 1 Carboplatin AUC = 5 or 6* IV Carboplatin Dose=Target AUC x (GFR*+25) * Measured GFR (calculated using a patient specific method such as a 24- hour urine sample or 51 Cr-EDTA/ DTPA) is preferred whenever feasible, particularly in circumstances of co-morbidity that could affect renal function such as dehydrated patients or patients with a either a high or low weight. Alternatively the Cockcroft & Gault Method can also be used to estimate a patient s GFR. If using 24-hour urine or 51 Cr-EDTA/DTPA is used, consider dosing at AUC 5. If using Cockcroft and Gault, consider dosing at AUC 6 Administration Pegylated Liposomal Doxorubicin Hydrochloride is administered in 250ml glucose 5% infusion bag. Pegylated Liposomal Doxorubicin Hydrochloride should be given over 60 minutes or at 1mg/minute (whichever is longer) for the first cycle. If well tolerated then subsequent doses can be administered over 60 minutes. Infusions of Pegylated Liposomal Doxorubicin Hydrochloride must not be filtered. Carboplatin is administered in ml glucose 5% over minutes Avoid any device containing aluminium that may come in contact with Carboplatin. Patients should be observed closely for hypersensitivity reactions, particularly during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of carboplatin. Facilities for the treatment of hypotension and bronchospasm must be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require discontinuation of therapy. The infusion may be temporarily interrupted and when symptoms improve re-started at a slower infusion rate. Chlorphenamine 10mg iv may be administered. Severe reactions, such as hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of carboplatin and appropriate therapy. Page 1 of 6

2 Frequency Every 28 days for a maximum of 6 cycles Extravasation Pegylated Liposomal Doxorubicin Hydrochloride is an exfoliant (Group 4) Carboplatin is an irritant (Group 3) Premedication Emetogenicity Additional recommended supportive medication Pre- treatment evaluations None usually required. Pegylated Liposomal Doxorubicin Hydrochloride can be associated with an infusion reaction, which usually occurs during the first cycle. Carboplatin can also be associated with an infusion reaction, particularly if patients have previously received carboplatin. If a reaction occurs, the infusion should be stopped until symptoms have cleared and can be recommenced at a slower rate. Hydrocortisone 100mg IV bolus and chlorphenamine 10mg IV bolus may be administered if appropriate. If a reaction occurs to carboplatin, hydrocortisone 100mg IV bolus and chlorphenamine 10mg IV bolus should be given minutes prior to all subsequent infusions. As both agents have the potential to cause infusion-related reactions, consideration should be given to leaving an interval between administering the Pegylated Liposomal Doxorubicin Hydrochloride and Carboplatin. This regimen has moderate-high emetic potential - refer to local protocol Loperamide 4mg po stat then 2mg prn if diarrhoea develops. Mouthwashes as per local policy To minimise the risk of PPE for the first week after Pegylated Liposomal Doxorubicin Hydrochloride infusion: Keep hands and feet as cool as possible. Avoid tight-fitting gloves, sock, footwear and high-heeled shoes. Avoid exposing the skin to very hot water. Avoid vigorous rubbing of skin-pat skin dry after washing. Avoid use of topical anaesthetics as these can worsen skin reactions. FBC LFT U&E (inc. SrCr) Ca125 ECHO Baseline - results valid for 28 days Baseline - results valid for 28 days Baseline - results valid for 28 days Pre D1 results valid for 28 days Only required if clinically indicated Regular investigations FBC Pre D1 results valid for 72 hours LFT Pre D1 results valid for 7 days U&E (inc. SrCr) Pre D1 results valid for 7 days Ca125 Pre D1 results valid for 7 days Clinical Assessment Clinically assess patient prior to each cycle, particularly focusing on whether the patient has developed renal dysfunction, ototoxicity, marked stomatitis, Palmar-Plantar Erythrodysaesthesia or neurotoxicity Page 2 of 6

3 Standard limits for administration to go ahead if blood results not within range, authorisation to administer must be given by prescriber/consultant Dose modifications Haematological toxicity Neutrophil count 1.0x 10 9 /L Platelet count 100 x 10 9 /L Creatinine Clearance > 30ml/min & <10% change in GFR from previous cycle Bilirubin < 20micromol/L ALT/AST < 1.5 x ULN Defer therapy for 1 week if: Neutrophils <1.0 x 10 9 /L or Platelets < 100 x 10 9 /L Renal impairment GFR Carboplatin Dose >30ml/min 100% 20-30ml/min <20ml/min Consider alternative, nonnephrotoxic regimen Contraindicated If the calculated GFR falls by more than10% from the previous cycle then consider a dose alteration. Dose modifications should not be required for Pegylated Liposomal Doxorubicin Hydrochloride in patients with renal impairment. Hepatic impairment Serum bilirubin (micromol/l) Pegylated Liposomal Doxorubicin Hydrochloride Dose <20 100% %* %* >68 Avoid * If the first dose is tolerated without an increase in bilirubin or LFTs, the second dose can be increased to the next dose increment and then titrated to full dose on subsequent cycles if again tolerated. Carboplatin: Transient increases in liver enzymes have been seen although no dose reduction is usually required. In severe hepatic dysfunction consider a dose reduction after discussing with the consultant. NCI Common Toxicity Criteria Toxicity Definition Dose adjustment Febrile neutropenia ANC <0.5 x 10 9 /l plus fever requiring IV antibiotics +/- hospitalisation Reduce all future doses of Pegylated Liposomal Doxorubicin Hydrochloride to 20mg/m 2 and reduce all future doses of carboplatin by 1 AUC. Stomatitis Grade 2 (painful erythema, oedema or ulcers, but can eat) Grade 3 (painful erythema, edema or Treat symptomatically and/or delay until recovered to Grade 1. If symptoms continue, reduce dose of Pegylated Liposomal Doxorubicin Hydrochloride to 20mg/m 2 Treat symptomatically and delay until recovered to Grade 1 and Page 3 of 6

4 Adverse effects the contents of the table indicate the adverse effects that should be documented on consent to treatment forms Significant drug interactions For full details consult product literature/ reference texts PPE (Hand- Foot Syndrome) Other toxicities ulcers, and cannot eat) then continue Pegylated Liposomal Doxorubicin Hydrochloride at a reduced dose of 20mg/m 2. Grade 4 (requires Discontinue treatment parenteral or enteral support) Grade 2 Grade 3 or 4 Grade III toxicity (except alopecia, nausea & vomiting) Grade IV toxicity (except alopecia, nausea & vomiting) Treat symptoms until recovered to Grade 1. If patient not recovered to Grade 1 by 42 days after previous dose, discontinue treatment Discontinue treatment Reduce dose of Pegylated Liposomal Doxorubicin Hydrochloride to 20mg/m 2 and/or reduce dose of carboplatin to AUC 4 provided toxicity has resolved to Grade 1. If further toxicity occurs, an additional reduction may be made after discussion with consultant Withhold treatment and discuss with consultant If a delay of more than 3 weeks is required for recovery, or more than 2 dose reductions are necessary, the patient should discontinue treatment. Rare or Serious Side Effects Febrile neutropenia Myelosuppression Peripheral neuropathy Convulsions Thromboembolism Secondary leukaemias Optic neuritis Acute Hypersensitivity reactions (first infusion) Cardiac toxicity Pulmonary Fibrosis (very rare) Frequently occurring Side Effects Nausea and vomiting Alopecia (reversible) Possible diarrhoea or constipation Fatigue / asthenia Stomatitis and mucositis Allergic reactions such as rash and pruritus Palmar-Plantar Erythrodyaesthesia (PPE) / Hand-Foot Syndrome (HFS) Discoloured urine For full details of adverse effects and contraindications, see the Summary of product characteristics (SPC) of each component of the regimen Carboplatin: Warfarin/coumarin anticoagulants: increased or fluctuating anticoagulant effects. Avoid if possible: in the first instance, consider switching patient to a low molecular weight heparin during treatment or if the patient continues taking an oral anticoagulant monitor the INR at least once a week and adjust dose accordingly. Aminoglycoside antibiotics: increased risk of nephrotoxicity and Page 4 of 6

5 Comments Cumulative Doses References ototoxicity Clozapine: increased risk of agranulocytosis, avoid concomitant use Diuretics: increased risk of nephrotoxicity and ototoxicity Nephrotoxic drugs: increased nephrotoxicity ; not recommended Phenytoin: reduced absorption of the antiepileptic Pegylated Liposomal Doxorubicin Hydrochloride: Ciclosporin: giving doxorubicin with high doses of ciclosporin can lead to neurotoxicity. N/A Use Pegylated Liposomal Doxorubicin Hydrochloride in caution at cumulative doses in excess of 450mg/m 2 (or equivalent antracycline dosage). Consider previous anthracycline exposure. National Institute for Health and Clinical Excellence. Technology Appraisal 91. Paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan for second-line or subsequent treatment of advanced ovarian cancer. [internet] accessed 09/12/2010, available at Pujade-Lauraine E, Uwe Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, Vasey PA, et al. Pegylated Liposomal Doxorubicin and Carboplatin Compared With Paclitaxel and Carboplatin for Patients With Platinum-Sensitive Ovarian Cancer in Late Relapse. J Clin Oncol (20): Pujade-Lauraine E, Mahner S, Kaern J, Gebski V, Heywood M, Vasey P, et al. A randomized, phase III study of carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in relapsed platinum-sensitive ovarian cancer (OC): CALYPSO study of the Gynecologic Cancer Intergroup (GCIG). J Clin Oncol 2009;27:18s: abstr LBA5509 Rose PG. Pegylated liposomal doxorubicin: optimizing the dosing schedule in ovarain cancer. The Oncologist. 2004;10 (3): Sehouli J, Camara O, Schmidt M, Mahner S, Seipelt G, Otremba B, et al. North-Eastern German Society of Gynecological Oncology. Pegylated liposomal doxorubicin (CAELYX ) in patients with advanced ovarian cancer: results of a German multicenter observational study. Cancer Chemother Pharmacol (3): Daniels S. North London Cancer Network. Dose adjustment for cytotoxics in hepatic impairment [internet]. accessed 09/12/2010 available at Daniels S. North London Cancer Network. Dose adjustment for cytotoxics in renal impairment [internet]. accessed 09/12/2010 available at Summary of Product Characteristics Caelyx (Pegylated Liposomal Doxorubicin Hydrochloride) 2mg/ml concentrate for solution for infusion (Schering-Plough) [internet], accessed 10/09/2010 available from Summary of Product Characteristics Carboplatin 10mg/ml Intravenous Infusion (Hospira) [monograph on the Internet].accessed 09/12/2010 available from Baxter K, editor. Stockley s Drug Interactions. Pharmaceutical Press; Accessed on line on 09/12/2010 available at Trissel LA. Handbook of Injectable Drugs, 15 th edition. American Society for Health-Systems Page 5 of 6

6 Pharmacists Accessed on line on 09/12/2010 available at Allwood M, Stanley A, Wright P, editors. The cytotoxics handbook. 4 th ed. Radcliffe Medical Press Document title Pegylated Liposomal Doxorubicin Hydrochloride PLDH (Caelyx ) and Carboplatin chemotherapy for ovarian cancer Document number Approval date 11/12/2011 Written by Dr Paul Cornes, Consultant Clinical Oncologist, BHOC Jarrod Dunn Cancer Services Pharmacist, TST Checked by James Carr, Network Pharmacist, ASWCS Authorised by Jeremy Braybooke, Chair, ASWCS Network Chemotherapy Group Review date December 2013 Document reviewed by Version number Summary of changes Version Page 6 of 6