Regimen: Carboplatin + Paclitaxel

Regimen: Carboplatin + Paclitaxel Indications Regimen details Administration 1. Post surgical adjuvant or neoadjuvant (as in the EORTC 55791 trial) or relapse therapy for stage IC to IV ovarian, fallopian tube or primary peritoneal cancer 2. First line or relapse therapy for advanced cervix, vaginal or vulval cancer not amenable to definitive radiotherapy or radio-chemotherapy 3. First line or relapse therapy for advanced inoperable for uterine papillary serous carcinoma or carcino-sarcoma (Malignant Mixed Mullerian Tumors) of the endometrium 4. First line adjuvant therapy for endometrial cancers (maximum 4 cycles) or neoadjuvant or relapse therapy for advanced endometrial cancers 5. First line therapy for adenocarcinoma or undifferentiated cancers of uncertain primary site (particularly in those tumours presenting in women with peritoneal carcinomatosis of uncertain primary site) Day Drug Dose Route 1 Paclitaxel 175mg/m 2 IV 1 Carboplatin AUC 5 or 6* IV *Dose (mg) = target AUC (mg/ml.min) x [GFR (ml/min) + 25] Measured GFR (e.g. calculated using a patient specific method such as a 24-hour urine sample or 51 Cr-EDTA/ DTPA measurement) 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 Paclitaxel is administered in a 250-500ml sodium chloride 0.9% non-pvc infusion bag with a 0.22 micron in-line filter over 3 hours. Paclitaxel should be diluted to a concentration of 0.3-1.2mg/ml. Blood pressure & pulse should be monitored regularly (e.g. every 30 minutes) during paclitaxel infusion Carboplatin should be given in 250-500ml glucose 5% over 60 minutes. 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 infusions. Facilities for the treatment of anaphylaxis, 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, dyspnoea, bronchospasm, angioedema or generalised rash/erythema require immediate discontinuation of infusion and appropriate therapy. Avoid any device containing aluminium that may come into contact with Carboplatin. NB: Paclitaxel should always be administered before the carboplatin. Page 1 of 6

Frequency Every 21 days. First line adjuvant therapy for endometrial cancers: maximum of 4 cycles Other indications: maximum of 6 cycles Neoadjuvant chemotherapy 3 cycles prior to surgery then a further 3 cycles commencing within 6 weeks of surgery. (In a small number of patients, it may be appropriate to debulk after 6 cycles; in these cases, a further 2 cycles may be given post-surgery) Extravasation Paclitaxel is a vesicant (Group 5) Carboplatin is an irritant (Group 3) Premedication Dexamethasone 20mg PO 12hours and 6 hours before paclitaxel (OR 16-20mg IV 30 minutes before paclitaxel) PLUS Chlorphenamine 10mg IV 30 minutes before paclitaxel PLUS Ranitidine 50mg IV 30 minutes before paclitaxel Emetogenicity Additional recommended supportive medication This regimen has moderate to high emetogenic potential refer to local protocol. Loperamide 4mg po stat then 2mg prn if diarrhoea develops. Mouthwashes as per local policy Pre- treatment evaluation FBC LFT U&E (inc. SrCr, Ca & Mg) Ca125 EDTA/DTPA assessment 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 Baseline if significant/suspected renal dysfunction Regular investigation 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 Ca & Mg) 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, neurotoxicity or ototoxicity Standard limits for administration to go ahead if blood results not within range, authorisation to administer must be given by prescriber/consultant WBC count 2.5 x 10 9 /L Neutrophil count 1 x 10 9 /L Platelet count 100 x 10 9 /L Creatinine Clearance > 30ml/min & <10% change in GFR from previous cycle Bilirubin 17 micromol/l ALT/AST <5 x ULN Page 2 of 6

Dose modifications Haematological toxicity Dose modifications based on neutrophil and/or platelet count on day of treatment (day 1). Platelet count Action Dose modification once count recovery (x 10 9 /L) Paclitaxel Carboplatin Dose Dose 1 AND 100 Go ahead Full dose Full dose ANC (x 10 9 /L) <1 OR <100 Delay 1 week until count recovery <1 AND <100 Delay 1 week until count recovery No dose reduction necessary Give a 25% dose reduction Reduce dose by 1 AUC Reduce dose by 1 AUC Renal impairment Hepatic impairment NCI Common Toxicity Criteria If the calculated GFR falls by more than10% from the previous cycle then consider a dose alteration. GFR ml/min Carboplatin dose 30 Use AUC as per protocol 20-30 EDTA then use AUC as per protocol. Or consider alternative non-nephrotoxic regimen* <20 Contra-indicated *Clinical decision AST / ALT Bilirubin Paclitaxel Carboplatin (tranaminases) (micromol/l) dose dose* <5x ULN AND <17 175mg/m 2 100% <5 x ULN AND 17-26 135 mg/m 2 100% <5 x ULN AND 27-51 75 mg/m 2 100% <5 x ULN AND 52-85 50 mg/m 2 80-100% 5 x ULN OR >85 Not recommended. Consultant decision Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance and nadir blood counts. *Transient increases in liver enzymes have been seen in patients being treated with carboplatin although no dose reduction is usually required. Toxicity Definition Dose adjustment Febrile neutropenia ANC <0.5 x 10 9 /l plus fever requiring IV antibiotics +/- hospitalisation Reduce all future doses: give a 20% reduction for carboplatin and dose paclitaxel at 135mg/m 2 Fatigue Grade 3 1 st occurrence give 25% dose reduction; if persistent 50% or omit paclitaxel only Neuropathy Grade 2 Reduce paclitaxel to 135mg/m 2 in all subsequent cycles. If persistent 90mg/m 2 or omit Grade 3 Withhold paclitaxel until <grade 1; Page 3 of 6

Arthralgia and/or mylagia Grade 2 toxicity reinstate at 90mg/m 2. Discontinue if no recovery. If not contraindicated, consider giving diclofenac 50mg tds for 5 days +/- cocodamol 8-30/500 ii qds prn. Alternatively, consider prednisolone 10mg bd for 5 days starting 24 hours post-paclitaxel. If arthralgia and/or mylagia persists reduce subsequent paclitaxel doses to 135mg/m 2 Other toxicities Grade 3 toxicity (except alopecia, nausea & vomiting) Grade 4 toxicity (except alopecia, nausea & vomiting) Continue with 20% dose reduction of carboplatin and/or paclitaxel at 135mg/m 2 provided toxicity has resolved to Grade 1 or less. 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 Adverse effects the contents of the table indicate the adverse effects that should be documented on consent to treatment forms Rare or Serious Side Effects Febrile neutropenia Myelosuppression Nephrotoxicity U & E disturbances (especially hypomagnesiumaemia, hypokalaemia & hypocalcaemia) Neurotoxicity (including ototoxicity) Pulmonary fibrosis Risk of second malignancy e.g. leukaemia Teratogenicity Long term risk of early menopause, reduced fertility Arrhythmias Cardiac failure Frequently occurring Side Effects Nausea and vomiting Alopecia Diarrhoea or constipation Fatigue / asthenia Stomatitis and mucositis Sore veins (phlebitis) Allergic reactions Myalgia and/or arthralgia Oedema Other side effects include: flu-like symptoms, dyspnoea, taste changes, headaches, abdominal pain, bradycardia, hypotension, altered liver function. For full details of adverse effects and contraindications, see the Summary of product characteristics (SPC) of each component of the regimen Page 4 of 6

Significant drug interactions For full details consult product literature/ reference texts Warfarin/coumarin anticoagulants Avoid if possible as use often causes an elevation or fluctuation in the INR 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. Clozapine : increased risk of agranulocytosis, avoid concomitant use. Comments Cumulative Doses References Paclitaxel only: Concomitant administration of inducers or inhibitors of cytochrome P450 isoenzymes (CYP2C8 and 3A4) e.g. erythromycin, fluoxetine, gemfibrozil, rifampicin, carbamazepine, phenytoin, phenobarbital etc, may alter the pharmacokinetics of paclitaxel presenting a theoretical interaction. Carboplatin only: Aminoglycoside antibiotics : increased risk of nephrotoxicity and ototoxicity Diuretics : increased risk of nephrotoxicity and ototoxicity Nephrotoxic drugs : increased nephrotoxicity ; not recommended Phenytoin : reduced absorption of the antiepileptic In patients with significant frailty or co-morbidity where chemotherapy is nevertheless deemed appropriate, consider strategies to minimise toxicity such as reducing the carboplatin dose to AUC 3 and paclitaxel to 135mg/m 2 None. Trimbos JB, Parmar M, Vergote I, Guthrie D, Bolis G, Colombo N, et al. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 2003 95 (2): 105-12. ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003 361 (9375): 2099-2106. Pfisterer J, Ledermann JA. Management of platinum-sensitive recurrent ovarian cancer. Semin Oncol 2006 33 (Suppl 6): S12-16. Tinker AV, Bhagat K, Swenerton KD, Hoskins PJ. Carboplatin and paclitaxel for advanced and recurrent cervical carcinoma: the British Columbia Cancer Agency experience. Gynecologic Oncology July 2005, 98: 54-58. Hogberg T, Rosenberg P, Kristensen G, de Oliveira CF, de Pont Christensen R, Sorbe B, et al. J Clin Oncol A randomized phase-iii study on adjuvant treatment with radiation (RT) ± chemotherapy (CT) in early-stage high-risk endometrial cancer (NSGO-EC-9501/EORTC 55991) 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 25, No 18S (June 20 Supplement), 2007: 5503 Hoskins PJ, Swenerton KD, Pike JA, Wong F, Lim P, Acquino-Parsons C, Lee N. Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. J Clin Oncol 2001 19(20):4048-53. Shechter-Maor G, Bruchim I, Ben-Harim Z, Altaras M, Fishman A. Combined chemotherapy regimen of carboplatin and paclitaxel as adjuvant treatment for papillary serous and clear cell endometrial cancer. Int J Gynecol Cancer 2009 19(4):662-4. Arimoto T, Nakagawa S, Yasugi T, Yoshikawa H, Kawana K, Yano T, Taketani Y.Treatment with paclitaxel plus carboplatin, alone or with irradiation, of advanced or recurrent endometrial Page 5 of 6

carcinoma. Gynecol Oncol. 2007 104(1):32-5. Pectasides D, Xiros N, Papaxoinis G, Pectasides E, Sykiotis C, Koumarianou A et al. Carboplatin and paclitaxel in advanced or metastatic endometrial cancer. Gynecol Oncol 2008 109(2):250-4. Pectasides D, Fountzilas G, Papaxoinis G, Pectasides E, Xiros N, Sykiotis C, et al. Carboplatin and paclitaxel in metastatic or recurrent cervical cancer. Int J Gynecol Cancer. 2009 19(4):777-81. Hoskins PJ, Le N, Ellard S, Lee U, Martin LA, Swenerton KD, Tinker AV. Carboplatin Plus Paclitaxel for Advanced or Recurrent Uterine Malignant Mixed Mullerian Tumors : The British Columbia Cancer Agency Experience. Gynecol Oncol 2008 108 (1): 58-62. Duska LR, Garrett A, Eltabbakh GH, Oliva E, Penson R, Fuller AF. Paclitaxel and Platinum Chemotherapy for Malignant Mixed Müllerian Tumors of the Ovary. Gynecol Oncol 2002 85 (3), 459-463. Huebner G, Link H, Kohne CH, Stahl M, Kretzschmar A, Steinbach S, et al. German CUP Study Group. Paclitaxel and carboplatin vs gemcitabine and vinorelbine in patients with adeno- or undifferentiated carcinoma of unknown primary: a randomised prospective phase II trial. Br J Cancer 2009 100(1):44-9. Summary of Product Characteristics Paclitaxel 6mg/ml concentrate for solution for infusion (Hospira) [internet], accessed 07/10/2010 available from http://www.medicines.org.uk/emc/medicine/15842/spc Summary of Product Characteristics Carboplatin 10mg/ml Intravenous Infusion (Hospira) [internet] accessed 11/11/2010, available at http://www.medicines.org.uk/emc/medicine/622/spc Daniels S. North London Cancer Network. Dose adjustment for cytotoxics in hepatic impairment [internet]. accessed 15/12/2010 available at http://www.bopawebsite.org/tikidownload_file.php?fileid=621 Daniels S. North London Cancer Network. Dose adjustment for cytotoxics in renal impairment [internet]. accessed 11/11/2010 available at http://www.bopawebsite.org/tikidownload_file.php?fileid=620 Document title Carboplatin&Paclitaxel 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 Braybrooke, Chair ASWCS Network Chemotherapy Group Review date December 2013 Document reviewed by Version number Summary of changes Version Page 6 of 6