Rituximab, Gemcitabine, Dexamethasone and Cisplatin RGDP Regimen Available for Routine Use in Burton in-patient N/A Derby in-patient Burton day-case Derby day-case Burton outreach chemotherapy clinic N/A Derby outreach chemotherapy clinic Burton out-patient Derby out-patient Indication Treatment Intent Anti-Emetics Frequency & Duration Relapsed/refractory CD20+ve lymphoma Salvage Prechemotherapy Day 1 3 + Akynzeo 1hour prechemo Postchemotherapy Day 8 2 Day 1 C Day 8 B Every 21 days for a maximum of 6 cycles After 2 cycles responding patients may be considered for high dose chemotherapy and autologous stem cell transplant. Day 1 Paracetamol 1g As a single oral dose 30 minutes prior to rituximab Chlorphenamine 10mg As a single intravenous bolus 30 minutes prior to rituximab Dexamethasone 40mg Oral once daily for 4 days. Give 1 st dose 30 mins before Rituximab Rituximab 375mg/m 2 Intravenous infusion in 500ml sodium chloride 0.9% Akynzeo 300mg/0.5mg Oral as a single dose 1 hour before cisplatin chemotherapy Gemcitabine 1000mg/m 2 intravenous infusion in 250ml sodium chloride 0.9% infused over 30 minutes Sodium chloride 1000ml Intravenous infusion over 1 hour 0.9% Sodium chloride 0.9% 500ml Intravenous infusion over 30 minutes (if urine output remains low) Mannitol 10% 100ml Intravenous infusion over 10 minutes REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 1 of 7
Provided urine output is satisfactory (see notes) Cisplatin 75mg/m 2 Intravenous infusion in 500ml sodium chloride 0.9% over 1 hour (protect infusion from light) Mannitol 10% 100ml Intravenous infusion over 10 minutes Sodium chloride 0.9% + 20mmol magnesium sulphate + 20 mmol potassium chloride 1000ml Intravenous infusion over 2 hours Drinking water 2000ml Oral over the next 24 hours Allopurinol 300mg Oral once a day for 14 days for 1-2 cycles (reduce to 100mg if CrCl<20ml/min) Fluconazole 100mg Oral once a day for 21 days Aciclovir 400mg Oral twice daily for 21 days Cotrimoxazole 480mg Oral once daily for 21 days Omeprazole 20mg Oral once a day for 4 days Metoclopramide 10mg Oral four times daily for 4 days, then as required Day 8 Ondansetron 8mg As a single oral dose Dexamethasone 8mg As a single oral dose Gemcitabine 1000mg/m 2 Intravenous infusion in 250ml sodium chloride 0.9% infused over 30 minutes Dexamethasone 4mg Oral twice daily for 2 days Metoclopramide 10mg Oral four times daily for 2 days, then as required For mobilising cycles: Day 9 Lenograstim 263mcg (BSA<1.8m 2 ) OR 368mcg (BSA>1.8m 2 ) Subcutaneous injection ONCE daily (in the evening) until adequate stem cell harvest. Supply 7 doses. REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 2 of 7
Notes: Rituximab This section should be read in conjunction with the Guidelines for the administration of Rituximab. 1. The day 1 dose of dexamethasone should be given 30 mins prior to receiving rituximab. Premedication consisting of analgesia and an antihistamine and 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. Pre-treatment investigations Day 1: FBC, U&Es, measured or calculated CrCl and LFTs. Day 8: FBC Consider audiology testing in patients with impaired hearing at baseline. Dose modifications and toxicities 1. Haematological toxicity Day 1: Delay until neutrophils 1x10 9 /l and platelets (unsupported) 100x10 9 /l, unless cytopenias are disease related. Consider GCSF(filgrastim biosimilar 300mcg sc) to maintain dose intensity for patients with prolonged neutropenia resulting in delays to chemotherapy, or a prior episode of febrile neutropenia. The schedule of GCSF will depend on the timing of neutropenia but typically alternate day dosing starting on Day 9 for 4 doses is used. GCSF should not be given within 24 hours of chemotherapy. REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 3 of 7
Day 8: Neutrophil count Platelet % Gemcitabine dose counts 1x10 9 /l and 100x10 9 /l 100% 0.5-1 or 50-100 75% (or 100% with GCSF for isolated low neutrophils). Note GCSF should not be given within 24 hours of chemotherapy. <0.5 or <50 OMIT; or delay 1 week 2. Renal impairment Cisplatin Creatinine Clearance Dose % ml/min 60 100 45-59 75 <45 Omit, consider carboplatin Gemcitabine Creatinine Clearance Dose % ml/min 30 100 <30 Consider dose reduction- clinical decision Ensure cisplatin is commenced by 14.00 hours at the latest so an adequate renal output can be maintained. The urine output should be kept at > 100 ml/hour before (for at least 2 hours from commencing hydration), during and after chemotherapy (8 hours). Accurate fluid balance sheet must be kept. Mannitol 10% infusion is the preferred diuretic. If urine output remains <100ml/hr, a further dose of 100ml may be given by intravenous infusion over 10 minutes. Urine output should increase within 30 minutes of commencing the mannitol infusion. If urine output remains <100ml/hr after 30 minutes, a 20 mg stat IV bolus of furosemide may be given to increase urine output. If 30 minutes after the furosemide dose urine output has still not improved, the Consultant should be contacted for advice. REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 4 of 7
Patients must be advised to drink 2 litres of fluid in the 24 hours after administration of cisplatin. 3. Hepatic impairment Gemcitabine Bilirubin Dose % micromol/l 27 80% of dose initially and increase if tolerated. Raised transaminases do not seem to cause dose limiting toxicity. Cisplatin- no dose reduction necessary for hepatic impairment. 4. Neurotoxicity/ Ototoxicity Cisplatin can cause peripheral neuropathy and ototoxicity. These should be graded accordingly. Grade Toxicity 1 2 3 4 Neuropathy (motor) Paralysis Neuropathy (sensory) Subjective weakness but no objective findings Loss of deep tendon reflexes or parasthesia (including tingling) but not interfering with function Mild objective weakness function, but not interfering Objective sensory loss or parasthesia (including tingling) function, but not interfering Objective weakness interfering Sensory loss or parasthesia interfering Permanent sensory loss that interferes with function REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 5 of 7
Grade Toxicity 1 2 3 4 Hearing - Hearing loss not requiring intervention and not Hearing loss requiring hearing aid / intervention, i.e. Profound bilateral hearing loss (>90dB) Tinnitus - Tinnitus not Tinnitus Disabling 5. Alcohol content of gemcitabine Doses of gemcitabine not available as ready- made infusions contain up to approximately 11g of ethanol (1.5units). Patients should be advised not to drive on the day of treatment. Where alcohol content is a concern please contact pharmacy for advice about alternative formulations. 5. Other toxicities If there is any grade 2 toxicity (or above) proceed as follows: Cisplatin Grade 2 toxicity Dose % 1 st occurrence 80 2 nd occurrence 60 Unresolved or omit recurrent tinnitus Gemcitabine should be discontinued at the first sign of microangiopathic haemolytic anaemia (e.g. rapidly falling Hb with thrombocytopaenia, elevated bilirubin, creatinine, blood urea nitrogen or LDH). Supportive Care 1. Consider GCSF to maintain dose intensity for patients with febrile neutropenia or prolonged neutropenia. 2. Allopurinol 300mg once daily for the 1-2 cycles. (Reduce dose to 100mg if GFR < 10ml/min). 3. Co-trimoxazole 480mg ONCE daily. In cases of allergy to co-trimoxazole, consider dapsone 100mg daily. 4. Aciclovir 400mg twice daily. 5. Omeprazole 20mg daily for 4 days. 6. Fluconazole 100mg daily. REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 6 of 7
References 1. Crump, M. et al (2013). Randomised Comparison of Gemcitabine, dexamethasone and Cisplatin Versus Dexamethasone, Cytarabine and Cisplatin Chemotherapy Before Autologous Stem-Cell Transplantation for Relapsed and Refractory Aggressive Lymphomas: NCIC-CTG LY12. Journal of Clinical Oncology. 2013.53.9593. 2. The North London Cancer Network. Dosage Adjustment for Cytotoxics in Liver and Renal Impairment. Jan 2009 REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 7 of 7