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Network Chemotherapy Protocols Sarcoma Notes from the editor Thames Valley Cancer Network These protocols are available on the Network website Any correspondence about the protocols should
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Network Chemotherapy Protocols Sarcoma Notes from the editor Thames Valley Cancer Network These protocols are available on the Network website Any correspondence about the protocols should be addressed to: Sally Coutts, Lead Pharmacist, Thames Valley Cancer Network Tel: Acknowledgements These protocols have been compiled by the Network Pharmacy Group in collaboration with key contribution from Prof Bass Hassan, Medical Oncologist, OUH Dr Sally Trent, Clinical Oncologist, OUH Dr James Gildersleve, Clinical Oncologist, RBFT Thames Valley Cancer Network. All rights reserved. Not to be reproduced in whole or in part without the permission of the copyright owner. Network Chemotherapy Protocols Sarcoma 2 of 75 Network Thames Valley Cancer Network Chemotherapy Protocols Sarcoma Network Chemotherapy Protocols used in the management of Sarcoma Date published: May 2012 Date of review: May 2014 Chemotherapy Protocols Name of protocol Indication Page List of amendments to this version 5 Imatinib GIST, DFSP, PVNS and Chordoma 6 Sunitinib GIST 8 Paclitaxel weekly (Taxol) Angiosarcoma 10 AC Operable osteosarcoma 12 Doxorubicin Sarcoma 15 Liposomal doxorubicin Sarcoma 17 Gemcitabine / docetaxel Sarcoma 19 Ifosfamide 3G / doxorubicin 30 Sarcoma 21 Ifosfamide / etoposide +/- high dose Second Line osteosarcoma 24 methotrexate APMM (MAP) (offstudy EURAMOS1) Operable Osteosarcoma 29 AMM (MAP) (offstudy EURAMOS1) Operable Osteosarcoma 34 AMM Ifn (MAP Ifn) (offstudy EURAMOS1) Operable Osteosarcoma 38 MAPIE (offstudy EURAMOS1) Operable Osteosarcoma 45 Mifamurtide Osteosarcoma 54 Ifosfamide infusional Soft tissue, retoperitoneal, 56 de-differentiated sarcoma Trabectedin Soft tissue sarcoma 58 Irinotecan Temozolomide Ewing s, high grade sarcoma 60 VAC (offstudy EUROEWING-99) Ewing s, high grade sarcoma 62 VAI (offstudy EUROEWING-99) Ewing s, high grade sarcoma 64 VIDE (offstudy EUROEWING-99) Ewing s, high grade sarcoma, soft 66 tissue sarcoma Denosumab Giant cell tumours 69 Network Chemotherapy Protocols Sarcoma 3 of 75 Name of protocol (cont.) Indication Page Ifosfamide-induced encephalopathy specific 71 neural toxicity grade and nomogram Pre post hydration regimens 73 Common Toxicity Criteria 74 Network Chemotherapy Protocols Sarcoma 4 of 75 List of amendments in this version Protocol type: Sarcoma Tumours Date due for review: May 2014 Previous number: 2.0 This version number: Table 1 Amendments Page Action Type Amendment Made/ asked by Table 2 New protocols to be approved and checked by TSSG included in this version Name of protocol Indication Reason / Proposer Denosumab Giant cell Prof Hassan Mifamurtide Osteosarcoma Prof Hassan Ifosfamide infusional Soft tissue, Prof Hassan retoperitoneal, dedifferentiated sarcoma Irinotecan temozolomide Ewing s, high grade sarcoma Prof Hassan Network Chemotherapy Protocols Sarcoma 5 of 75 IMATINIB Thames Valley Cancer Network Indications: Gastrointestinal Stromal Tumours, Pigmented villonodular synovitis, Dermatofibrosarcoma protuberans, and Chordoma DRUG REGIMEN IMATINIB MESYLATE 400mg po once daily (may be increased to 800mg daily) Cycle Frequency: Every 3 months until disease progression (4 cycles initially) NB tablets available as 100 or 400mg strengths. DOSE MODIFICATIONS Use with caution in severe hepatic or renal impairment and in patients with a history of cardiac dysfunction. If Platelets 75, no treatment delay 7day ± 25% dose reduction or neutrophils 0.75, no treatment delay. Dose reduction of imatinib (glivec) may be necessary in selected patients but should be avoided where possible. If there is insufficient response after at least 3 months consider increased dose up to 800mg per day (400mg bd) maximum. Dose increases may be associated with more adverse effects. NB. Dose adjustments must be performed by Consultant in line with NICE guidelines and mutation testing INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 10 Plt x 10 9 /L 100 75 and 100 ( 75 no treatment) Neutrophils x 10 9 /L 1.5 0.75 and 1.5 ( 0.75 no treatment) Liver function tests and renal function (note electrolyte disturbances with Imatinib) 2) Non urgent tests Tests relating to disease response/progression Record all clinically assessable disease Investigations will usually include CT scan staging every 3 months PET-CTI of primary tumour site Record of WHO performance status, current height, weight and surface area FBC, U&E, creatinine, Liver function tests. Creatinine clearance 55mls/min, Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. Imatinib Page 1 of 2 Published: May 2012 Network Chemotherapy Protocols Sarcoma 6 of 75 DRUG INTERACTIONS Concomitant use of CYP3A4 inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St John s Wart) as they may significantly reduce exposure to Glivec, potentially increasing the risk of therapeutic failure. Caution should be taken when co-administering Glivec with CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, erythromycin, clarithromycin), as they could increase Glivec exposure Glivec can also increase the plasma concentration of other CYP3A4 metabolised drugs (statins, benzodiazepines, dihydropyridine calcium channels blockers [e.g. amlodipine, nifedipine] cyclosporin), therefore caution is recommended Concomitant use of strong CYP2D6 inducers should be avoided (e.g. rifampicin). Patients requiring anticoagulation should receive heparin-formulations rather than warfarin. In patients treated with metoprolol clinical monitoring should be considered. Caution should therefore be exercised when using Glivec and paracetamol concomitantly, especially with high doses of paracetamol. In thyroidectomy patients, plasma exposure to levothyroxine may be decreased when Glivec is co-administered. Caution is therefore recommended. However, the mechanism of the observed interaction is presently unknown. ANTIEMETIC POLICY None required ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Relapsed disease Neutropenia, thrombocytopenia, anaemia, Headache, mild nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, fluid retention, dermatitis, muscle cramps, muscle pain. Electrolyte disturbances REFERENCES 1. Glivec. Summary of product characteristics. November Imatinib Page 2 of 2 Published: May 2012 Network Chemotherapy Protocols Sarcoma 7 of 75 Sunitinib (GIST) Thames Valley Cancer Network NICE: Sunitinib is recommended as a treatment option for people with unresectable and/or metastatic malignant gastrointestinal stromal tumours if: imatinib treatment has failed because of resistance or intolerance. Indication: Treatment of unresectable and / or metastatic malignant gastrointestinal stromal tumour (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance. DRUG REGIMEN Day 1 Sunitinib 50mg orally daily for 4 weeks Cycle Frequency: Daily for 4 weeks then a 2 week rest period (6 week cycle) DOSE MODIFICATIONS Sunitinib: Renal impairment No starting dose adjustment required with mild severe or with end-stage renal disease (ESRD) on haemodialysis. Subsequent dose adjustments should be based on individual safety and tolerability. Hepatic impairment No starting dose adjustment is recommended with mild or moderate hepatic impairment. It has not been studied in subjects with severe. Tolerability Consider 37.5mg or 25mg daily continuously. Sunitinib Page 1 of 2 Published: May 2012 Network Chemotherapy Protocols Sarcoma 8 of 75 INVESTIGATIONS Routine Blood test 1) Blood results required before drug administration Give Discuss Hb x g/dl 10 10 Plt x 10 9 /L 100 100 Neutrophils x 10 9 /L 1.5 1.5 Thames Valley Cancer Network Blood tests should initially be performed 4 weekly, but later in the treatment course can be done less often in stable patients. Creatinine Liver function tests (LFT) Consider thyroid function tests 2) Non urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. CONCURRENT MEDICATION ANTIEMETIC POLICY ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Skin - skin discolouration and depigmentation of the hair and skin may occur. Palmar / plantar syndrome Neutropenia Mouth pain / irritation / sensitivity may occur Haemorrhage an increased risk of bleeding may occur. Hypertension treatment induced hypertension. Sunitinib treatment should temporarily be suspended until hypertension is controlled. Gastrointestinal serious gastrointestinal complications including gastrointestinal perforation have occurred rarely. Hypothyroidism RERERENCES 1. SPC July 2010 Sunitinib Page 2 of 2 Published: May 2012 Network Chemotherapy Protocols Sarcoma 9 of 75 PACLITAXEL weekly (Taxol) Thames Valley Cancer Network Indication: Angiosarcoma DRUG REGIMEN Days 1, 8, 15 PREMEDICATION 30 mins prior to infusion: DEXAMETHASONE 20 mg IV bolus RANITIDINE 50 mg IV bolus CHLORPHENAMINE 10 mg IV bolus PACLITAXEL 50mg/m 2 in 500ml sodium chloride 0.9% infusion over 3 hours (PVC free) Cycle Frequency: Every 28 days up to 6 cycles depending on tolerance and response NB Paclitaxel dose may be increased to 80mg/m 2 each day DOSE MODIFICATIONS If patient complains of tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. If Platelets 75, no treatment delay 7day ± give 75% dose or Neutrophils 0.75, no treatment delay. Bilirubin 1.25xULN and AST 10xULN dose at 100% Bilirubin 17micromol/L dose reduction required AST and Alk phos 3x normal dose reduction required INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 10 Plt x 10 9 /L 100 75 and 100, ( 75 no treatment) Neutrophils x 10 9 /L 1.5 0.75 and 1.5 ( 0.75 no treatment) 2) Non urgent tests Tests relating to disease response/progression Record all clinically assessable disease Investigations will usually include CT scan of site of measurable disease MRI of primary tumour site Record of WHO performance status, current height, weight and surface area FBC, U&E, creatinine, LFTs. Creatinine clearance 55mls/min, ECG, consider ECHO Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. Paclitaxel weekly Angiosarcoma Page 1 of 2 Published: May 2012 Network Chemotherapy Protocols Sarcoma 10 of 75 CONCURENT MEDICATIONS Ensure pre-medication is given. ANTIEMETIC POLICY Low emetic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS (2% risk of severe hypersensitivity) Reactions range from mild hypotension (light-headedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5-10 minutes), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment. REFERENCES 1. Penel et al 2007, JCO Vol25, 18S (June 20 supplement): Paclitaxel weekly Angiosarcoma Page 1 of 2 Published: May 2012 Network Chemotherapy Protocols Sarcoma 11 of 75 AC Thames Valley Cancer Network Indication: Neoadjuvant and adjuvant osteosarcoma adjuvant for de-differentiated chondrosarcoma and palliative therapy for selected patients (see EURAMOS 1 for trial protocols) DRUG REGIMEN Day 1 DOXORUBICIN 25mg/m 2 in 100ml sodium chloride 0.9% IV infusion over 4 hours Pre-hydration CISPLATIN 50mg/m 2 in 1000ml sodium chloride 0.9% IV infusion over 8 hours Post-hydration Day 2 DOXORUBICIN 25mg/m 2 in 100ml sodium chloride 0.9% IV infusion over 4 hours Pre-hydration CISPLATIN 50mg/m 2 in 1000ml sodium chloride 0.9% IV infusion over 8 hours Post-hydration Day 3 DOXORUBICIN 25mg/m 2 in 100ml sodium chloride 0.9% IV infusion over 4 hours Day 4 Prophylactic GCSF as per local policy (may be considered until WCC 5.0x10 9 /l pegylated give stat dose or standard GCSF continue for 7 days) Cycle Frequency: Every 21 days for maximum 6 cycles (3 cycles before surgery and 3 cycles post surgery) DOSE MODIFICATIONS If Platelets 75, no treatment delay 7day ± give 75% dose or Neutrophils 0.75, no treatment delay. Cisplatin If patient complains of tinnitus, tingling of fingers and/or discuss with Consultant or Registrar before administration GFR 60ml/min give 100% dose GFR 50-60ml/min give 75% dose GFR 40-50ml/min give 50% dose GFR 40ml/min omit dose Doxorubicin Dose reduce in severe renal impairment. Bilirubin 20-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin 85micromol/L omit If AST is 2-3 x ULN give 75% dose If AST is 3 x ULN give 50% dose Mucositis Grade 3 or 4- reduce Doxorubicin to 20mg/m 2 /day AC osteosarcoma Page 1 of 3 Published: May 2012 Network Chemotherapy Protocols Sarcoma 12 of 75 Maximum cumulative dose = 450 mg/m 2 (in normal cardiac function) = 400 mg/m 2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation) INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 10 Plt x 10 9 /L 100 75 and 100 ( 75 no treatment) Neutrophils x 10 9 /L 1.5 0.75 and 1.5 ( 0.75 no treatment) GFR 70 55 and 70ml Electrolytes+Mg If abnormal due to cisplatin Cr-EDTA clearance or serum Creatinine with a clearance to limit above (Consider formal measurement of creatinine clearance in patients with low surface area) Liver function tests (LFTs) to limits in dose modifications 2) Non urgent tests Tests relating to disease response/progression Essential pre-treatment investigations Record all clinically assessable disease Investigations will usually include CT scan of chest and isotope bone scan MRI of primary tumour site ECG, Echocardiogram (+LVEF) Audiometry Record of WHO performance status, current height, weight and surface area FBC, U&E Give adequate verbal and written information for patients and relatives concerning patient s disease, treatment strategy and side effects / mortality risk. If appropriate, discuss potential risk of infertility / early menopause with patient and relatives Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed If fluid balance 2L positive after 8 hours post hydration or urine output is 100ml/hr during IV administration post cisplatin give 200ml mannitol 10% (preferred) or 20-40mg furosemide po/iv. ANTIEMETIC POLICY High emetic risk days 1 and 2 including aprepitant Moderate emetic risk day 3 AC osteosarcoma Page 2 of 3 Published: May 2012 Network Chemotherapy Protocols Sarcoma 13 of 75 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity monitor cardiac function. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Note risk of delayed cardiomyopathy- if 20% reduction in LVEF after 300mg/m 2 - omit doxorubicin. Nephrotoxicity ensure adequate pre and post hydration is prescribed. Ototoxicity assess patient for tinnitus or hearing abnormalities, stop cisplatin if hearing loss extends to 2kHz. REFERENCES 1. ASWCS Chemotherapy handbook Jan 2005 update 2. Souhami et al. Lancet 1997 Sep 27;350: AC osteosarcoma Page 3 of 3 Published: May 2012 Network Chemotherapy Protocols Sarcoma 14 of 75 DOXORUBICIN Thames Valley Cancer Network Indication: Palliative sarcoma DRUG REGIMEN Day 1 DOXORUBICIN 60mg/m 2 IV bolus Cycle Frequency: Every 21 days for 6 cycles subject to tolerance and response NB Doxorubicin dose may be increased to 75mg/m 2 in younger patients DOSE MODIFICATIONS Dose reduce in severe renal impairment. Bilirubin 20-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin 85micromol/L omit If AST is 2-3 x ULN give 75% dose If AST is 3 x ULN give 50% dose Maximum cumulative dose = mg/m 2 (in normal cardiac function) = 400 mg/m 2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation) INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 10 Plt x 10 9 /L 100 100 Neutrophils x 10 9 /L 1.5 1.5 Liver function tests (LFTs) to limits in dose modifications 2) Non urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. 3) Pre-treatment Assess cardiac risk factors Consider ECG and ECHO Consider scalp cooling Doxorubicin Page 1 of 2 Published: May 2012 Network Chemotherapy Protocols Sarcoma 15 of 75 CONCURRENT MEDICATION ANTIEMETIC POLICY Moderate emetic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity monitor cardiac function. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Note risk of delayed cardiomyopathy- if 20% reduction in LVEF after 300mg/m 2 - omit doxorubicin. REFERENCES 1. Jensen et al 2002, Annals of Oncology 13: Lorigan P et al European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol Jul 20;25(21): Doxorubicin Page 2 of 2 Published: May 2012 Network Chemotherapy Protocols Sarcoma 16 of 75 LIPOSOMAL DOXORUBICIN (Caelyx) Indication: Sarcoma DRUG REGIMEN Day 1 Pegylated liposomal DOXORUBICIN *50mg/m 2 in 500ml glucose 5% infusion at a rate of 1mg/min on cycle 1 If no infusion-related reactions, subsequent cycles over 1 hour. NB *It is preferable to consider using 40mg/m 2 especially if heavily pre-treated and in view of toxicity. NB maybe used in combination with Ifosfamide see Doxorubicin/ Ifosfamide protocol. NB if dose is less than 90mg give in 250ml glucose 5% due to stability Cycle Frequency: Every 28 days for a maximum 6 cycles DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. Bilirubin 20-51micromol/L give 50% dose Bilirubin 51micromol/L give 25% dose Maximum cumulative dose = mg/m 2 (in normal cardiac function) = 400 mg/m 2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation) Palmar plantar erythema or stomatitis: (See SPC for further information) Delay for 1 week if grade 2-4. Use steroids (e.g. prednisolone 30mg daily or Dexamethasone 8mg daily) for treatment. Anecdotally, pyridoxine 50mg tds can be used. Reduce dose by 25% if 2 week delay or if grade III or above. Withdraw patient if 2 week delay grade III of above INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 10 Plt x 10 9 /L 100 100 Neutrophils x 10 9 /L 1.5 1.5 2) Non urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. Liposomal Doxorubicin Page 1 of 2 Published: May 2012 Network Chemotherapy Protocols Sarcoma 17 of 75 CONCURRENT MEDICATION Thames Valley Cancer Network ANTIEMETIC POLICY Moderate emetic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity use with caution in cardiac dysfunction. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Infusion related reactions allergic or anaphylactic like reactions consider prophylaxis Palmar-plantar erythema treat with steroids prednisolone 30mg od or dexamethasone 8mg od. Consider pyridoxine. REFERENCES 1. Nielsen OS et al. Phase 1 European Organisation for Research and Treatment of Cancer study determining safety of pegylated liposomal doxorubicin (Caelyx) in combination with ifosfamide in p
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