DRUG ADMINISTRATION SCHEDULE Day Drug Dose Route Diluent Rate 1* to 5 Prednisolone 40mg/m 2 Oral Once Daily For 5 days 1 Paracetamol 1gram Oral Once Only Chlorphenamine 10mg IV bolus Ondansetron 8mg IV bolus Rituximab 375mg/m 2 IV infusion Vincristine 1.4mg/m 2 (Max: 2mg) IV infusion Doxorubicin 50mg/m 2 IV bolus Cyclophosphamide 750mg/m 2 IV bolus **250ml 0.9% Sodium Chloride 50ml Sodium Chloride 0.9% * Ensure first dose of steroid is taken before commencing rituximab. ** Some centres may supply rituximab in 500ml on the first cycle to make the infusion rates easier to work with. See below 5 minutes CYCLE LENGTH AND NUMBER OF DAYS 21 Day cycle, usually given for 6 cycles, APPROVED INDICATIONS Induction therapy for High Grade (Diffuse Large B Cell) Non Hodgkin s Lymphoma (NHL) Relapsed Low Grade NHL Mantle Cell Lymphoma Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) In combination with salvage chemotherapy for patients relapsing > 12 month post 1 st line therapy with R-CHOP RECOMMENDED TAKE HOME MEDICATION Ondansetron 8mg twice daily for 3 days Allopurinol 300mg daily for 1-2 cycles Consider Stimulant Laxative Gastro Prophylaxis (H2 Antagonist or Proton Pump Inhibitor) during steroid treatment Primary prophylaxis with GCSF should be considered for patients with a greater than 20% risk of neutropenic sepsis and who would have compromised treatment outcomes through dose reduction. INVESTIGATIONS / MONITORING REQUIRED Prior to first cycle: CT Scan, FBC, U&E s, LFT s, LDH, Calcium, Uric Acid, ECG, Consider ECHO. Prior to each cycle: U&E s, LFT s, FBC ASSESSMENT OF RESPONSE R-CHOP NECN protocol CRP08 H033 (updated) Page 1 of 5
Measure palpable disease during clinical review prior to each cycle. CT scan at midpoint in treatment and on completion of treatment. REVIEW BY CLINICIAN Prior to each cycle (unless being reviewed by Nurse / Pharmacist see below) NURSE / PHARMACIST LED REVIEW Nurse or pharmacist led review, within a locally agreed protocol, is acceptable on day 1 for all cycles except the first, and middle cycle. ADMINISTRATION NOTES Risk of hypersensitivity and anaphylaxis particularly during the first cycle for the first two hours of administration. Monitor patient every 15 minutes for first hour then every 30minutes. Symptoms usually resolve with interruption of rituximab and administration of antipyretic and antihistamines. Some patients will require oxygen, intravenous fluids (0.9% Sodium Chloride), bronchodilators (e.g. nebulised salbutamol), and glucocorticoids (e.g. IV hydrocortisone). Risk of severe hypersensitivity (cytokine release syndrome) increases when Peripheral Lymphocytes > 25 cells x10 9 /l treatment should only proceed with caution in this setting. Reducing the infusion rate or using a different therapy first line may be appropriate. Doxorubicin may discolour urine (red) Risk of peripheral neuropathy (commonly presenting as ileus) with vincristine. May require reduction in vincristine dose, omission of vincristine, or substitution of vinblastine (6mg/m 2, Max: 10mg) or vindesine. Diabetic patients should increase frequency of monitoring of blood glucose while taking high dose steroids. Doxorubicin is cardiotoxic and has a cumulative lifetime dose of 450-550mg/m 2. Patients with prior anthracycline exposure, or under-lying cardiac disease should be considered for ECHO/MUGA. Vincristine is for intravenous administration only. Administration by other routes may be fatal. Prior to starting vincristine ensure the venous access device is sufficiently patent by flushing well with Sodium Chloride 0.9%. If there is doubt about the patency of the access device it must not be used. Vincristine is to be given by intravenous infusion in 50ml of Sodium Chloride 0.9% over 5 minutes. (Rate: 600ml/hr = about 200 drops per minute on a standard 20drop per ml IV giving set.). Administration should normally be free-flow rather than via a volumetric pump. Vincristine is highly vesicant during administration a nurse should remain with the patient and observe the infusion site carefully for signs of extravasation. In the event that extravasation is suspected the infusion must immediately be stopped and appropriate treatment started (according to the extravasation policy). Following administration of vincristine flush well with Sodium Chloride 0.9% R-CHOP NECN protocol CRP08 H033 (updated) Page 2 of 5
Previous neutropenic sepsis - consider GCSF. Primary prophylaxis for patients over 65years of age is appropriate if dose reduction to prevent neutropenia would compromise treatment outcome. (Patients over 65 years of agea have greater than 20% risk of developing neutropenic fever). Some clinicians may modify the protocol to use mitoxantrone 10mg/m 2 (R- CNOP) instead of doxorubicin for patients with cardiac toxicity, however, this practice lacks an evidence base. Rituximab Infusion Rates: First cycle of rituximab should commence at 50mg/hour and increase in rate by 50mg/hour every 30 minutes (to a maximum of 400mg/hour) provided the patient does not develop any signs of infusion reaction. Subsequent cycles (provided the previous cycle has been tolerated well) can start at 100mg/hour and increase by 100mg/hour every 30 minutes to a maximum of 400mg/hour. (Rapid infusion see below) The infusion rate can be calculated by: InfusionVolume[ ml] Rate[ mg / hour] InfusionRate[ ml / hour] = TotalDose[ mg] Blood Pressure, Pulse and Respiration rate should be measured every 15 minutes for the first hour of infusion, and then every 30 minutes subsequently. Rapid Infusion: a few small studies have demonstrated that it is possible to give rituximab at a faster rate for the second or third cycle. This practice is unlicensed and clinicians wishing to follow this practice should check with their own trust prior to adopting this practice. The unlicensed nature of the infusion rate should be explained to patients at the time of consent. The rapid infusion rate used is 20% of the dose over 30 minutes (100ml/hour), followed by the remaining 80% over just 60minutes (200ml/hour). Rapid infusion should only be considered for patients who have shown no signs of adverse reaction during previous infusions, and is contra-indicated in patients with high tumour bulk/burden or with high circulating lymphocyte counts. TOXICITIES Common: Hypersensitivity Reactions, Nausea, Alopecia, Constipation (including paralytic ileus), Peripheral Neuropathy, Discolouration of Urine, Lethargy Less Common: Cardiomyopathy, Arrhythmia, Diarrhoea, DOSE MODIFICATION / TREATMENT DELAYS Haematological Toxicity: (Note: where haematological disease is affecting bone marrow function, lower treatment parameters may be acceptable. This should be clearly documented for the specific patient.) Delay treatment on Day 1 if ANC < 1.5 x 10 9 cells/l or PLT < 100 x 10 9 cells/l R-CHOP NECN protocol CRP08 H033 (updated) Page 3 of 5
If Grade IV Neutropenia for 7 days or more reduce CHOP doses by 20% or add GCSF prophylaxis. Grade IV thrombocytopenia reduce CHOP doses by 20% Non-Haematological Toxicity: Constipation / Peripheral Neuropathy: Consider reducing dose of vincristine to 1mg, withholding vincristine altogether or switching to vinblastine or vindesine. Renal Function: If Cr > 300 µmol/l withhold cyclophosphamide. Hepatic Function: m l / m i n CrCl (or GFR) Cyclophosphamide Dose > 20 100% 10-20 ml/min 75% <10 ml/min 50% Bilirubin Vincristine Dose Doxorubicin Dose < 20 µmol/l 100% 100% 20 51 µmol/l 100% 50% >51 µmol/l 50% 25% TREATMENT LOCATION Suitable for administration in chemotherapy day units, under the supervision of haematology teams from Level 1 4 Haematology Services. REFERENCES: Roche. Summary of product Characteristics Mabthera. October 2006 National Institute for Clinical Excellence. Rituximab for aggressive non- Hodgkin s lymphoma TA 65. September 2003. Coiffier, B., Lepage, E., Briere, J., Herbrecht, R., Tilly, H., Bouabdallah, R., Morel, P., Van den Neste, E., Salles, G., Gaulard, P., Reyes, F., and Gisselbrecht, C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-b-cell lymphoma. New England Journal of Medicine 2002; 346 235-242. R-CHOP NECN protocol CRP08 H033 (updated) Page 4 of 5
Document Title: Document No: Author: Approved by: NECN CHEMOTHERAPY HANDBOOK PROTOCOL Document Control R-CHOP NECN protocol CRP08 H033 CRP08 H033 Due for Review: Fen 2015 Summary of Changes Calum Polwart, Network Pharmacist NECN Diane Plews / Anne Lennard 1.0a Final Version Approved Current Version: Approval Signature* Date Approved: 4.2 06/02/2015 2.0a Vincristine amended in line with NPSA guidance. 3.0a Updated to 6 + 2 schedule 4.0 Updated to add mantle cell indication and remove 6 +2 therapy 4.1 Protocol reviewed. Cyclophosphamide in renal impairment advice amended 4.2 Addition with salvage chemotherapy, and Primary GCSF for patients over 65 years (in line with GCSF policy) R-CHOP NECN protocol CRP08 H033 (updated) Page 5 of 5