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DERBY-BURTON LOCAL CANCER NETWORK FILENAME DA-EPOCH_R.DOC HCCPG B52 CONTROLLED DOC NO: CSIS Regimen Name: DA_EPOCH_R DA-EPOCH-R Available for Routine Use in Derby in-patient Derby day-case Derby community Derby out-patient Burton in-patient Burton day-case Burton community Burton out-patient Indication Treatment Intent Anti-Emetics Frequency & Duration First line treatment of primary mediastinal B-cell lymphoma Radical Pre-chemotherapy Day 1-5 3 Post-chemotherapy A Every 21 days for 6 to 8 cycles. Restage after 4 and 6 cycles. If tumour masses shrink>20% between cycles 4 and 6, continue for a further 2 cycles. ** DOSES FOR THE FIRST CYCLE (DOSE LEVEL 1) ARE SHOWN BELOW. DOSES MAY BE ADJUSTED FROM CYCLE 2 BASED ON THE PREVIOUS CYCLE’S NADIR (see haematological toxicity)** Day 1 Allopurinol 300mg Prednisolone 60 mg/m2 Paracetamol 1g Chlorphenamine 10mg Hydrocortisone 100mg Rituximab 375mg/m2 Cotrimoxazole Aciclovir Fluconazole Omeprazole Metoclopramide Ondansetron 480mg 400mg 50mg 20mg 10mg 8mg DATE OF ISSUE: 25.08.16 REVIEWED BY: C.WARD REVIEW DATE: 25.08.18 Oral once daily for 7 days for 1- 2 cycles. Consider pre-hydration with IV fluids for bulky disease Oral twice daily for 5 days (give 1st dose 30 minutes pre rituximab) Orally as a single dose 30 minutes pre rituximab Intravenous injection 30 minutes pre rituximab Intravenous injection 30 minutes pre rituximab Intravenous infusion in 500ml sodium chloride 0.9% as per rate calculator Oral once daily for 21 days Oral twice daily for 21 days Oral once daily for 21 days Oral once daily for 5 days Oral four times daily as needed Oral as a single dose prior to chemotherapy, then twice daily as needed AUTHORISED BY: Dr J Addada *** VALID ON DATE OF PRINTING ONLY *** VERSION 2 PAGE 1 of 6 DERBY-BURTON LOCAL CANCER NETWORK FILENAME DA-EPOCH_R.DOC HCCPG B52 CONTROLLED DOC NO: CSIS Regimen Name: DA_EPOCH_R Ctd overleaf 2 Day 1-4 Doxorubicin Vincristine 10 mg/m /day 0.4mg/m2/day (no cap) Day 1-4 Etoposide 50 mg/m2/day Ondansetron Day 5 8mg Cyclophosphamide 750 mg/m GCSF (Biosimilar) Day 6 2 300 micrograms Intravenous infusion in an elastomeric infusor in sodium chloride 0.9% via a central line over 96 hours Intravenous infusion in 500ml sodium chloride 0.9% over 24 hours via a central line Oral as a single dose prior to chemotherapy Intravenous bolus Subcutaneous injection once daily until neutrophil recovery (supply 7 doses) Notes: Doses are based on actual body weight and should not be routinely capped. Consider omitting Rituximab in the first cycle if bulky disease. Consider intrathecal prophylaxis for patients with >1 extranodal site and elevated LDH Rituximab This section should be read in conjunction with the ‘Guidelines for the administration of Rituximab’. 1. The day 1 dose of prednisolone should be given 30 mins prior to receiving rituximab. Premedication consisting of analgesia and an antihistamine and an intravenous corticosteroid should always be administered 30 minutes before each infusion of rituximab. (e.g. paracetamol 1g oral STAT and chlorphenamine 4mg oral or 10mg IV bolus STAT and hydrocortisone 100mg IV STAT). In addition pethidine 25mg IV should be available in case of a severe infusion reaction. 2. Rituximab doses should be rounded to the nearest 100mg. Use rituximab rate calculator to assist with rate escalation of rituximab infusion. 3. Occurrence of an Infusion Related Event or Hypersensitivity: Stop the infusion and contact a doctor. When symptoms improve, continue the infusion at half the rate prior to the reaction. Accelerate the infusion rate more slowly as tolerated by the patient. DATE OF ISSUE: 25.08.16 REVIEWED BY: C.WARD REVIEW DATE: 25.08.18 AUTHORISED BY: Dr J Addada *** VALID ON DATE OF PRINTING ONLY *** VERSION 2 PAGE 2 of 6 DERBY-BURTON LOCAL CANCER NETWORK FILENAME DA-EPOCH_R.DOC HCCPG B52 CONTROLLED DOC NO: CSIS Regimen Name: DA_EPOCH_R Dose modifications and toxicities 1. Pre-treatment tests FBC, U&Es, LFTs. Urate, bone profile prior to 1st cycle and as clinically indicated. Patients at high risk of tumour lysis refer to tumour lysis protocol. Consider ECHO/MUGA to assess LV function in patients over 65 years or with cardiac risk factors. Double lumen central venous access required. 2. Haematological toxicity Cycles should be repeated on day 22 provided the neutrophil count > 1x109/l and the platelet count >75x109/l, otherwise repeat FBC daily until recoveryadminister filgrastim as necessary. Patients with bone marrow involvement should be treated on time irrespective of counts if safe to do so. Consider support with platelet transfusions. Dose Adjustments according to nadir Doxorubicin, Etoposide and Cyclophosphamide ONLY: Doses may be adjusted from Cycle 2 based on the previous cycle’s neutrophil (ANC) nadir. This is monitored by obtaining TWICE WEEKLY FBC, i.e. days 9, 12, 15,18: If nadir ANC ≥0.5x109/l: increase by 1 dose level If nadir ANC <0.5x109/l on 1 or 2 measurements: same dose as last Cycle If nadir ANC <0.5x109/l on at least 3 measurements: decrease by 1 dose level If platelet nadir <25x109/l: reduce by 1 dose level regardless of ANC Life threatening infections: decrease by 1 dose level There is no maximum number of dose escalations. Please see Table 1. overleaf: DATE OF ISSUE: 25.08.16 REVIEWED BY: C.WARD REVIEW DATE: 25.08.18 AUTHORISED BY: Dr J Addada *** VALID ON DATE OF PRINTING ONLY *** VERSION 2 PAGE 3 of 6 DERBY-BURTON LOCAL CANCER NETWORK FILENAME DA-EPOCH_R.DOC HCCPG B52 CONTROLLED DOC NO: CSIS Regimen Name: DA_EPOCH_R Table 1: Drug Dose Adjustments Drugs Drug Doses per Dose Levels -2 -1 1 2 3 CYCLE 1 Prednisolone (mg/m2 twice daily) Rituximab 2 (mg/m /day) Doxorubicin (mg/m2/day) Vincristine (mg/m2/day) Etoposide (mg/m2/day) Cyclophosphamide (mg/m2/day) 64% (64%x0.8) 80% (100%x0.8) 100% (starting dose) 120% (100%x1.2) 144% (120%x1.2) 60 60 60 60 60 375 375 375 375 375 10 10 10 12 14.4 0.4 0.4 0.4 0.4 0.4 50 50 50 60 72 480 600 750 900 1080 3. Non-haematological toxicity Neurotoxicity: If the patient complains of significant constipation or sensory loss in fingers and/or toes, consider dose reduction of vincristine: Reduce by 25% for grade 2 motor neuropathy Reduce by 50% for grade 3 motor or sensory neuropathy For patients who develop ≥ grade 3 ileus, treatment should be delayed until recovery and vincristine introduced at 75% of the normal dose thereafter. If ≥ grade 3 ileus recurs, vincristine should be discontinued. Infections: Consider reducing by one dose level for life threatening infections associated with organ failure or prolonged morbidity. 4. Renal impairment Cyclophosphamide- clinical decision. Consider whether patient is being treated with high dose. Creatinine Clearance Dose Modification ml/min 10-20 75% dose of cyclophosphamide <10 50% dose of cyclophosphamide DATE OF ISSUE: 25.08.16 REVIEWED BY: C.WARD REVIEW DATE: 25.08.18 AUTHORISED BY: Dr J Addada *** VALID ON DATE OF PRINTING ONLY *** VERSION 2 PAGE 4 of 6 DERBY-BURTON LOCAL CANCER NETWORK FILENAME DA-EPOCH_R.DOC HCCPG B52 CONTROLLED DOC NO: CSIS Regimen Name: DA_EPOCH_R Etoposide Creatinine Clearance ml/min 15-50 <15 Dose Modification 75% dose of etoposide 50% dose of etoposide Doxorubicin Clinical decision-discuss with Consultant if renal impairment severe. Vincristine No dose reduction required. 5. Hepatic impairment Cyclophosphamide No dose reductions are required for for hepatic impairment. These are recommended doses although it should always be considered whether liver impairment is disease related. Doxorubicin Bilirubin micromol/L 20-51 51-85 >85 AST Units/L 2-3xULN >3xULN Etoposide Bilirubin micromol/L 26-51 >51 AST/ALT Units/L 60-180 >180 DATE OF ISSUE: 25.08.16 REVIEWED BY: C.WARD REVIEW DATE: 25.08.18 Dose Modification 50% dose of doxorubicin 25% dose of doxorubicin omit Dose Modification 75% dose 50% dose Dose Modification 50% dose of etoposide Clinical decision regarding further reduction of etoposide Dose Modification 50% dose of etoposide Clinical decision regarding further reduction of etoposide AUTHORISED BY: Dr J Addada *** VALID ON DATE OF PRINTING ONLY *** VERSION 2 PAGE 5 of 6 DERBY-BURTON LOCAL CANCER NETWORK FILENAME DA-EPOCH_R.DOC Vincristine Bilirubin micromol/L 26-51 >51 AST/ALT Units/L 60-180 >180 HCCPG B52 CONTROLLED DOC NO: CSIS Regimen Name: DA_EPOCH_R Dose Modification 50% dose of vincristine 50% dose of vincristine if AST/ALT normal, (if AST/ALT>180 consider omission) Dose Modification 50% dose of vincristine Consider omission of vincristine 6. Drug Interactions Itraconazole, posaconazole and voriconazole inhibit the metabolism of vincristine increasing neurotoxicity, therefore are contraindicated. Supportive care 1. Allopurinol 300mg once daily (100mg if creatinine clearance <20mls/min) for 12 cycles. Consider rasburicase for patients at high risk of tumour lysis. Refer to tumour lysis protocol. 2. Co-trimoxazole 480mg once daily. In cases of allergy to co-trimoxazole, consider dapsone 100mg daily. 3. 4. 5. 6. 7. Aciclovir 400mg twice daily. Fluconazole 50mg daily. Omeprazole 20mg once daily for 5 days (i.e. concurrently with prednisolone) All patients receive primary prophylaxis with GCSF (filgrastim). Consider mesna if high dose cyclophosphamide prescribed on dose escalation (>1.5g/m2) References 1. Dunleavy D, et al. Dose-Adjusted EPOCH-Rituximab Therapy in Primary Mediastinal B-Cell Lymphoma. N Engl J Med 2013; 368:1408-16. 2. The North London Cancer Network- Dose Adjustment for Cytotoxics in Renal Impairment. Jan 2009 3. The North London Cancer Network- Dose Adjustment for Cytotoxics in Hepatic Impairment. Jan 2009 4. SPC Vincristine accessed online on 18/9/15 at www.medicines.org.uk DATE OF ISSUE: 25.08.16 REVIEWED BY: C.WARD REVIEW DATE: 25.08.18 AUTHORISED BY: Dr J Addada *** VALID ON DATE OF PRINTING ONLY *** VERSION 2 PAGE 6 of 6