BEACOPP-14/ BEACOPP- Escalated

Transcription

1 BEACOPP-14/ BEACOPP- Escalated INDICATION Early Stage Classical Hodgkin Lymphoma with positive interim PET-CT (Deauville 3 or more) Advanced Classical Hodgkin lymphoma This protocol should normally be restricted to patients with WHO performance status 0-2, and aged 60 or younger. Initiation of a BEACOPP protocol should only be undertaken after discussion at the lymphoma MDT. Refer to the Bleomycin supportive care document. Placement of a central line / PICC is highly recommended. TREATMENT INTENT Curative PRE-ASSESSMENT 1. Ensure histology is confirmed prior to administration of chemotherapy and document in notes. 2. Record stage of disease - CT scan (neck, chest, abdomen and pelvis) and / or PET-CT scan, presence or absence of B symptoms and clinical extent of disease. If PET-CT scan is performed at diagnosis, routine bone marrow is generally not required. Pulmonary function tests before course one, if history of respiratory disease or heavy smoker, and as clinically indicated (see bleomycin supportive care document) 3. Blood tests - FBC, ESR, U&Es, LDH, urate, calcium, magnesium, creatinine, LFTs, glucose, Igs, Hep B&C, EBV, CMV, VZV, HIV 1+2 after consent. 4. Send a "group and save" sample to transfusion and inform patient and transfusion laboratory that they will require irradiated blood products for all future transfusions. Ensure irradiation card is attached to the patient's notes. See Guidelines for the use of blood components in adult haematology. 5. Urine pregnancy test - before each course of chemotherapy for women of child-bearing age unless they are postmenopausal, have been sterilised or undergone a hysterectomy. 6. ECG +/- Echo - if clinically indicated. 7. Record performance status (WHO/ECOG). 8. Record height and weight. 9. Consent - ensure patient has received adequate verbal and written information regarding their disease, treatment and potential side effects. Document in medical notes all information that has been given. Obtain written consent prior to treatment. 10. Fertility - it is very important the patient understands the potential risk of reduced fertility. All patients should be offered fertility advice by referring to the Oxford Fertility Unit. 11. Hydration - in patients with bulky disease pre-hydrate with sodium chloride 0.9% 1 litre over of 7

2 hours. For patients at high risk of tumour lysis, refer to tumour lysis protocol. 12. Consider dental assessment / Advise dental check is carried out by patient's own dental practitioner before treatment starts. DRUG REGIMEN BEACOPP-14 Day 1 DOXORUBICIN 25mg/m 2 IV bolus OD Day 1 CYCLOPHOSPHAMIDE 650mg/m 2 IV bolus OD Days 1-3 ETOPOSIDE 100mg/m 2 IVI in 1000mL 0.9% Sodium Chloride Days 1-7 PROCARBAZINE 100mg/m 2 PO OD (50 mg capsules). Days 1-7 PREDNISOLONE 80mg/m 2 PO OD Day 8 BLEOMYCIN 10,000units/m 2 IVI in 100mL 0.9% Sodium Chloride Day 8 VINCRISTINE 1.4mg/m 2 (max. 2mg) IVI in 50mL 0.9% Sodium Chloride over 15mins OD Day 9-13 FILGRASTIM 30 MU SC OD or equivalent G-CSF as per local formulary BEACOPP-escalated Day 1 DOXORUBICIN 35mg/m 2 IV bolus OD Day 1 CYCLOPHOSPHAMIDE 1250mg/m 2 IV bolus or IVI in 250mL 0.9% Sodium Chloride over 30 minutes OD Day 1 MESNA 250mg/m 2 IV bolus OD. See Concurrent Medication. Days 1-3 ETOPOSIDE 200mg/m 2 IVI in 1000mL 0.9% Sodium Chloride Days 1-7 PROCARBAZINE 100mg/m 2 PO OD (50 mg capsules). Days 1-14 PREDNISOLONE 40mg/m 2 PO OD Day 8 BLEOMYCIN 10,000units/m 2 IVI in 100mL 0.9% Sodium Chloride Day 8 VINCRISTINE 1.4mg/m 2 (max. 2mg) IVI in 50mL 0.9% Sodium Chloride over 15mins OD Day 9 FILGRASTIM 30 MU SC OD until count recovered or equivalent G-CSF as per local formulary Patients should also drink 3L of fluid on the day of Cyclophosphamide treatment. CYCLE FREQUENCY BEACOPP-14 repeated every 14 days for 4 to 6 cycles BEACOPP-escalated repeated every 21 days for 2 to 6 cycles 2 of 7

3 INVESTIGATIONS FBC, U&Es, LFTs prior to Days 1 and 8. Closer monitoring is often necessary during BEACOPP-escalated therapy as profound cytopaenias are not uncommon. RESTAGING Clinical assessment prior to each course. When used after a positive interim PET with ABVD, further PET recommended after 4 cycles of BEACOPP-14 or 3 cycles of BEACOPP-escalated. If negative, recommend 2 further cycles of BEACOPP-14 or 1 further cycle of BEACOPP-escalated. Optimum timing of the scan is D11 or more after the start of the cycle. Alternatively, escalated BEACOPP can be used as frontline therapy for 6 cycles after a discussion with the patient regarding risk versus benefit. In this case, an interim PET is NOT recommended. An end of treatment PET should be performed in order to guide possible radiotherapy. DOSE MODIFICATIONS : HAEMATOLOGICAL TOXICITY Cycle 1: Full dose chemotherapy should be given. Cycle 2: Day 1 and subsequent courses: BEACOPP-14 Cycles should be repeated on Day 15 provided the white cell count > 2.5x10 9 /L and the platelet count > 80x10 9 /L. Day 8 drugs should be given on schedule and at full dose regardless of blood counts Delay in white cell count or platelet recovery < 1 week 1-2 weeks > 2 weeks Dose Modification None 75% dose of Cyclophosphamide, Doxorubicin, Etoposide, and Procarbazine 50% dose of Cyclophosphamide, Doxorubicin, Etoposide, and Procarbazine (Continued on next page) 3 of 7

4 BEACOPP-escalated Cycles should be repeated on Day 22 provided the white cell count > 2.5x10 9 /L and the platelet count > 80x10 9 /L. Day 8 drugs should be given on schedule and at full dose regardless of blood counts. Doses should be reduced in subsequent cycles if predefined toxic effects: CTCAE (v3.0) Grade 4 leucopenia (<1.0 x 10 9 /L) for more than four days; CTCAE Grade 4 thrombocytopenia (<25 x 10 9 /L), infection, or mucositis; or an adverse effect that requires a twoweek delay in treatment occur in a given cycle. After each such event, the doses of Cyclophosphamide and Etoposide should be reduced by one level on a five-level scale from escalated to standard doses as shown below. If toxic effects occur in two successive cycles, standard doses should be used for all subsequent cycles Level 1 escalated dose Level 2 Level 3 Level 4 Level 5 standard dose Cyclophosphamide 1250mg/m mg/m 2 950mg/m 2 800mg/m 2 650mg/m 2 Etoposide 200mg/m 2 175mg/m 2 150mg/m 2 125mg/m 2 100mg/m 2 DOSE MODIFICATIONS : NON-HAEMATOLOGICAL TOXICITY Neurotoxicity If the patient complains of significant constipation or sensory loss in fingers and/or toes, consider possible dose reduction of Vincristine. 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. Pulmonary toxicity All patients complaining of shortness of breath should have a CXR (also consider HRCT chest) and pulmonary function tests prior to further administration of Bleomycin. Bleomycin should be discontinued if any clinical signs or CXR evidence of pulmonary infiltration/fibrosis develop, or if the transfer factor is <50% of the predicted value. Renal / Hepatic Impairment Doxorubicin No dose reduction required. Clinical Bilirubin micromol/l 50% dose decision in severe impairment. Bilirubin micromol/l 25% dose Bilirubin > 85 micromol/l omit AST 2-3 x ULN 75% dose AST >3 x ULN 50% dose Doxorubicin maximum cumulative dose (additive to other anthracyclines): mg/m 2 (in normal cardiac function) 400 mg/m 2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation) 4 of 7

5 Cyclophosphamide Clinical decision - consider whether patient is being treated with high dose. GFR > 20 ml/min 100% dose GFR ml/min 75% dose GFR < 10 ml/min 50% dose Etoposide CrCl >50 ml/min 100% dose CrCl ml/min 75% dose CrCl <15 ml/min 50% dose Subsequent doses should be based on clinical response. Consider 75% dose if bilirubin >53 micromol/l (SPC recommendations); however, exposure to active metabolites may not be increased, suggesting that dose reduction may not be necessary. Clinical decision. - discuss with consultant Arguments for and against dose reduction. Bilirubin 26-51micromol/L or AST u/L -50% dose Bilirubin >51micromol/L or AST >180u/L -clinical decision Procarbazine Lack of available information Serum creatinine >177micromol/L give 50% dose Severe renal impairment not recommended. Bilirubin > 50 micromol/l consider a dose reduction. Bilirubin > 85 micromol/l or AST > 180 units then contraindicated Bleomycin CrCl > 50 ml/min CrCl ml/min CrCl < 10 ml/min Vincristine 100% dose 75% dose 50% dose Clinical decision Bilirubin 26-51micromol/L OR ALT/AST u/L -50% dose Bilirubin > 51micromol/L & normal ALT/AST -50% dose Bilirubin > 51micromol/L & ALT/ AST > 180 u/l -omit INVESTIGATIONS FBC, renal and liver profiles, only FBC result essential prior to administration of chemotherapy. 5 of 7

6 CONCURRENT MEDICATION Allopurinol Ranitidine Fluconazole Aciclovir Mesna 300mg daily for the first 4 weeks, starting hours prior to chemotherapy Daily for the duration of treatment (or PPI if specifically indicated - discuss with consultant) 50mg daily for the duration of treatment 200mg three times a day for duration of treatment and for 3 months after completion Routinely required for escalated BEACOPP (not BEACOPP-14). The oral dose of Mesna is 40% of the intravenous dose of the Cyclophosphamide given on 3 occasions at intervals of 4 hours beginning 2 hours before the Cyclophosphamide injection; thus a total dose of Mesna equivalent to 120% of the Cyclophosphamide is given. In patients at high-risk of urothelial toxicity a shorter interval may be left between oral Mesna doses, or the number of doses increased, or both. Alternatively, the initial dose of Mesna (20% of the dose of the Cyclophosphamide) may be given intravenously at the same time as the antineoplastic, followed by two oral doses (each 40% of the dose of the Cyclophosphamide) given 2 and 6 hours after the intravenous dose. Co-trimoxazole 480mg OD on Mon / Wed / Fri for duration of treatment and for 3 months afterwards (consider reducing the dose to 480 mg twice weekly during neutropenic periods) ANTI-EMETICS Day 1 Days 2-7 Day 8 High emetic risk Moderate emetic risk Low emetic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS For full exhaustive detailed descriptions, visit Compared with ABVD this regimen is associated with more profound cytopenias, higher rates of febrile neutropenia, increased rates of infertility and a roughly 2% risk of secondary MDS / AML. Escalated BEACOPP is considered high risk for infertility. Bleomycin is a component of this treatment and can cause pneumonitis refer to bleomycin supportive care document. 6 of 7

7 TREATMEMT RELATED MORTALITY 1-2% (although age-dependent) REFERENCES 1. University College London. RATHL study protocol /01/ Johnson P, Federico M, Kirkwood A, Fosså A, Berkahn L, Carella A, d'amore F, Enblad G, Franceschetto A, Fulham M, Luminari S, O'Doherty M, Patrick P, Roberts T, Sidra G, Stevens L, Smith P, Trotman J, Viney Z, Radford J, Barrington S. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma. N Engl J Med Jun 23;374(25): André MP, Girinsky T, Federico M, Reman O, Fortpied C, Gotti M, Casasnovas O, Brice P, van der Maazen R, Re A, Edeline V, Fermé C, van Imhoff G, Merli F, Bouabdallah R, Sebban C, Specht L, Stamatoullas A, Delarue R, Fiaccadori V, Bellei M, Raveloarivahy T, Versari A, Hutchings M, Meignan M, Raemaekers J. Early Positron Emission Tomography Response-Adapted Treatment in Stage I and II Hodgkin Lymphoma: Final Results of the Randomized EORTC/LYSA/FIL H10 Trial. J Clin Oncol. Mar 14:JCO ASCO 2006 Update of Recommendations for the Use of Hematopoietic Colony-Stimulating Factors. 5. Dosage Adjustment for Cytotoxics in Hepatic Impairment. University College London Hospitals NHS Foundation Trust. 3. Updated January Dosage Adjustment for Cytotoxics in Renal Impairment. University College London Hospitals NHS Foundation Trust. 3. Updated January of 7