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1 Thames Valley Network Chemotherapy Regimens Urological Cancer Network Chemotherapy Protocols Urological Cancer 1

2 Notes from the editor Thames Valley These protocols are available on the Network website Any correspondence about the protocols should be addressed to: Sally Coutts, Lead Pharmacist, Thames Valley Tel : Acknowledgements These protocols have been compiled by the Network Pharmacy Group in collaboration with the Urology TSSG with key contribution from Karen Carter, Senior Oncology Pharmacist, RBFT Dr Andrew Protheroe, Consultant Oncologist, OUH Dr Nicola Stoner, Principal Oncology Pharmacist, OUH Sandra Harding- Brown, Formerly Specialist Principal Pharmacist, Cancer Directorate, OUH Alison Ashman, Formerly Lead Pharmacist Thames Valley Thames Valley. All rights reserved. Not to be reproduced in whole or in part without the permission of the copyright owner. Network Chemotherapy Protocols Urological Cancer 2

3 Network Thames Valley Chemotherapy Regimens Urological Cancer Network Chemotherapy Protocols approved for use within the Thames Valley by the Urology TSSG Date published: October 2012 Date of review: October 2014 Chemotherapy Protocols Name of protocol Indication Page List of amendments to this version 5 Abiraterone Prostate 6 Cabazitaxel Prostate 8 Mitoxantrone Prostate 10 Docetaxel Prostate 11 Docetaxel Weekly Advanced Prostate 12 CMV Bladder 14 Gemcitabine / Cisplatin Bladder 16 Gemcitabine / Carboplatin Bladder 18 MVAC Bladder 20 MVAC accelerated Bladder 22 BEP 3 day (adjuvant) Non-seminomatous germ cell tumour 24 BEP 3 day (metastatic) Non-seminomatous germ cell tumour 26 BEP 5 day metastatic) Non-seminomatous germ cell tumour 28 Carboplatin AUC 7 Non-seminomatous germ cell tumour 31 Paclitaxel / ifosfamide / cisplatin (TIP) Salvage therapy 32 POMB / ACE Germ cell 36 PEC Relapsed germ cell 39 EP (seminoma) Seminoma 41 BEP (3 day) Adenocarcinoma of unknown primary 43 Axitinib Renal cell 45 Everolimus Renal cell 47 Interferon (Roferon) Renal cell 49 Pazopanib Renal cell 50 Sunitinib Renal cell 52 Network Chemotherapy Protocols Urological Cancer 3

4 Thames Valley Name of protocol Indication Page Mitomycin C bladder installation weekly Bladder 54 Mitomycin C bladder installation 14 day Bladder 55 Mitomycin C bladder installation post op Bladder 56 BCG bladder installation Bladder 57 Pre and post hydration 58 Common toxicity criteria 59 Network Chemotherapy Protocols Urological Cancer 4

5 Thames Valley List of amendments in this version Protocol type: Urology Tumours Date due for review: October 2014 Previous Version number: 3.1 This version number: 3.2 Table 1 Amendments Page Action Type Amendment Made/ asked by All All Dose modifications updated Cisplatin inpatient duration removed Table 2 New protocols to be approved and or checked by TSSG included in this version Name of protocol Indication Reason / Proposer Abiraterone Prostate cancer NICE approved Cabazitaxel Prostate cancer CDF Everolimus Kidney CDF Network Chemotherapy Protocols Urological Cancer 5

6 ABIRATERONE (Prostate) Thames Valley Indication: Advanced or metastatic castration resistant prostate cancer, previously treated with docetaxel, with PSA and / or radiographic evidence of disease progression. DRUG REGIMEN Day 1 Abiraterone 1000mg orally once daily Prednisolone 5mg orally twice daily Cycle Frequency: Daily until progression DOSE MODIFICATIONS Abiraterone: Any dose modifications should be discussed with a Consultant. Renal impairment No dose adjustment necessary. Caution advised in patients with severe renal impairment. Hepatic impairment For patients who develop hepatotoxicity during treatment, suspension of treatment and dose adjustment may be required. No dose adjustment is required in pre-existing mild hepatic impairment. Moderate (Child-Pugh class B) give 250mg daily. Elevations in ALT or AST >5xULN or bilirubin >3xULN in patients with moderate hepatic impairment discontinue abiraterone. Abiraterone should be avoided in severe hepatic impairment. 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 Blood tests should be performed 2 weekly for 3 months for transaminases, but later in the treatment course can be done less often in stable patients. Creatinine Liver function tests (LFT) 2) Non urgent tests Tests relating to disease response/progression Abiraterone Page 1 of 2 Published: October 2012 Version 3.2 Network Chemotherapy Protocols Urological Cancer 6

7 CONCURRENT MEDICATION Thames Valley ANTIEMETIC POLICY Minimal emetic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Hypertension, hypokalaemia and fluid retention use with caution Adrenocortical insufficency Hepatotoxicity REFERENCES SPC September 2011 Abiraterone Page 2 of 2 Published: October 2012 Version 3.2 Network Chemotherapy Protocols Urological Cancer 7

8 CABAZITAXEL (Prostate) Thames Valley Indication: 2 nd line treatment of hormone refractory metastatic prostate cancer following docetaxel based therapy Ensure funding is available for each patient before prescribing. DRUG REGIMEN Day 1 Cabazitaxel 25mg/m2 in 250ml sodium chloride 0.9% IV infusion over 1 hour Prednisolone 10mg orally daily Cycle Frequency: Every 21 days for 6 cycles DOSE MODIFICATIONS Cabazitaxel: Hepatic impairment Cabazitaxel is extensively metabolised by the liver. As a precautionary measure, cabazitaxel should not be given to patients with hepatic impairment (bilirubin 1 x ULN, or AST and/or ALT 1.5 x ULN). Renal impairment Mild renal impairment (creatinine clearance (CL CR ): 50 to 80 ml/min) no dose adjustment necessary. Moderate (CL CR : 30 to 50 ml/min) limited data available Severe renal impairment (CL CR <30 ml/min) or end stage renal disease treat with caution and monitor carefully during treatment. Dose modifications should be made if patients experience the following adverse reactions: Adverse reactions Dose modification Prolonged grade 3 neutropenia (longer than Delay treatment until neutrophil count is 1 week) despite appropriate treatment >1.5x109/L, then reduce cabazitaxel dose including G-CSF from 25 mg/m 2 to 20mg/m2. Febrile neutropenia or neutropenic infection Delay treatment until improvement or resolution, and until neutrophil count is >1.5x109/L, then reduce cabazitaxel dose from 25 mg/m 2 to 20 mg/m 2. Cabazitaxel Page 1 of 2 Published: October 2012 Version 3.2 Network Chemotherapy Protocols Urological Cancer 8

9 Grade >=3 diarrhoea or persisting diarrhoea Despite appropriate treatment, including fluid and electrolytes replacement Thames Valley Delay treatment until improvement or resolution, then reduce cabazitaxel dose from 25 mg/m 2 to 20mg/m2. Grade >= 2 peripheral neuropathy Delay treatment until improvement, then reduce cabazitaxel dose from 25 mg/m 2 to 20 mg/m 2. The treatment should be discontinued if a patient continues to experience any of these reactions at 20 mg/m 2. 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. Creatinine Liver function tests (LFT) 2) Non urgent tests Tests relating to disease response/progression CONCURRENT MEDICATION ANTIEMETIC POLICY Low emetic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Hypersensitivity reactions Peripheral neuropathy REFERENCES SPC April 2011 Cabazitaxel Page 2 of 2 Published: October 2012 Review: October 2012 Version 3.2 Network Chemotherapy Protocols Urological Cancer 9

10 MITOXANTRONE (Prostate) Thames Valley Indication: Hormone refractory metastatic prostate cancer DRUG REGIMEN Day 1 MITOXANTRONE 12mg/m 2 IV in 50ml sodium chloride 0.9% infusion over 15 minutes Cycle Frequency: Every 21 days maximum 9 cycles DOSE MODIFICATIONS Mitoxantrone: Bilirubin >60micromol/L and good performance status give 60% dose Bilirubin >60micromol/L and poor performance status omit Maximum cumulative dose = 110 mg/m 2 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 Cardiac function if required. 2) Non-urgent tests Tests relating to disease response/progression CONCURRENT MEDICATION Prednisolone 5mg bd (or 10mg od) orally continuously ANTI-EMETIC POLICY Low emetogenic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity monitor cardiac function. Mitoxantrone may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London. Mitoxantrone Page 1 of 1 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 10

11 DOCETAXEL Thames Valley Indications: Hormone refractory prostate cancer NICE recommend docetaxel as a possible treatment for men with hormone-refractory metastatic prostate cancer. DRUG REGIMEN Day 1 PREMEDICATION: DEXAMETHASONE DOCETAXEL 75mg/m 2 in 250ml sodium chloride 0.9% infusion over 1 hour Cycle Frequency: Every 21 days maximum 10 cycles NB It is recommended that the treatment should be stopped at a MAXIMUM of 10 cycles, if adverse events occur or in the presence of disease progression. DOSE MODIFICATIONS Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Hepatic impairment: Patients who have both elevations of transaminases (ALT and/or AST) > 1.5 x ULN and ALP > 2.5 x ULN: give 75% dose Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated. 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 CONCURRENT MEDICATION Prednisolone 5mg bd po continuously. ANTIEMETIC POLICY Low emetogenic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Ensure pre-medication is given Dermatology hand-foot syndrome Docetaxel Page 1 of 1 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 11

12 DOCETAXEL weekly Thames Valley Indications: Advanced prostate cancer NICE recommend docetaxel as a possible treatment for men with hormone-refractory metastatic prostate cancer. DRUG REGIMEN Day 1 PREMEDICATION: DEXAMETHASONE DOCETAXEL 30mg/m 2 in 250ml sodium chloride 0.9% infusion over 1 hour Day 8 PREMEDICATION: DEXAMETHASONE DOCETAXEL 30mg/m 2 in 250ml sodium chloride 0.9% infusion over 1 hour Day 15 PREMEDICATION: DEXAMETHASONE DOCETAXEL 30mg/m 2 in 250ml sodium chloride 0.9% infusion over 1 hour Day 22 PREMEDICATION: DEXAMETHASONE DOCETAXEL 30mg/m 2 in 250ml sodium chloride 0.9% infusion over 1 hour Day 29 PREMEDICATION: DEXAMETHASONE DOCETAXEL 30mg/m 2 in 250ml sodium chloride 0.9% infusion over 1 hour Cycle Frequency: Every 42 days for 2 cycles DOSE MODIFICATIONS Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Hepatic impairment: Patients who have both elevations of transaminases (ALT and/or AST) > 1.5 x ULN and ALP > 2.5 x ULN: Give 75% dose. Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated. 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 CONCURRENT MEDICATION Prednisolone 5mg bd po continuously. Docetaxel weekly Page 1 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 12

13 ANTIEMETIC POLICY Low emetogenic risk Thames Valley ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Ensure pre-medication is given Dermatology hand-foot syndrome REFERENCES 1. Tax 327 trial. NEJM, 2004, Vol 351, No. 15, Hainsworth et al. Weekly Docetaxel/estramustine for prostate cancer: a phase II trial. Clin Genitourin Cancer, 2006, 4 (4): Joshua et al. Weekly Docetaxel as second-line treatment after Mitoxantrone for androgen independent prostate cancer. Intern Med J. 2005, 35 (8): Bertelli et al. Weekly Docetaxel and zoledronic acid every four weeks in hormone refractory prostate cancer. Cancer Chemother Pharmacol. 2006, 57 (1) Di Lorenzo et al, Weekly docetaxel and vinorelbine as first line treatment in patients with hormone refractory prostate cancer. Eur Urol, 2004, 46 (6): Ferrero et al. A weekly schedule for docetaxel for metastatic hormone refractory prostate cancer. Oncology, 2004, 66 (4): Beer et al. Weekly docetaxel in elderly patients with prostate cancer. Clin Prostate Cancer, 2003, 2 (3): Gravis et al. Weekly Docetaxel for symptomatic metastatic hormone refractory prostate cancer. Cancer 2003, 98 (8), Petrioli et al. Weekly low dose docetaxel in advanced hormone resistant prostate cancer patients previously exposed to chemotherapy. 2003, Oncology, 64 (4): Beer et al, Weekly high dose calcitriol and docetaxel in metastatic androgen independent prostate cancer. 2003, 21 (1): Beer et al. Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Ann Oncol, 2001, 12 (9): Docetaxel weekly Page 1 of 1 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 13

14 CMV (Bladder) Thames Valley Indications Metastatic bladder cancer and adjuvant bladder cancer DRUG REGIMEN Day 1 Pre-hydration regimen METHOTREXATE 30mg/m 2 IV bolus VINBLASTINE 4mg/m 2 (Max. 10mg) in 50ml sodium chloride 0.9% IV infusion over 10 minutes CISPLATIN 100mg/m 2 in 1000ml sodium chloride infusion over 2 hours Post-hydration regimen Day 8 METHOTREXATE 30mg/m 2 IV bolus VINBLASTINE 4mg/m 2 (Max. 10mg) in 20ml sodium chloride 0.9% IV over 10 minutes Cycle Frequency: Every 21 days maximum 6 cycles DOSE MODIFICATIONS Cisplatin: GFR > 60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes discuss with Consultant or Registrar before administration Methotrexate: GFR 60ml/min give 65% dose GFR 45ml/min give 50% dose GFR <30 ml/min omit Bilirubin 51-85micromol/L or AST>180 give 75% dose Bilirubin >85micromol/L omit Vinblastine: Bilirubin micromol/l or AST/ALT>60-80 give 50% dose Bilirubin >51 micromol/l and AST/ALT normal give 50% dose Bilirubin >51 micromol/l and AST/ALT >180 omit CMV Page 1 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 14

15 Thames Valley 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 Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) 2) Non-urgent tests Tests relating to disease response/progression CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV For patient requiring Folinic acid support the dose is Folinic acid 15mg PO/IV every 6 hours for 6 doses starting 24 hours after Methotrexate especially if:. Pleural effusions/ascites. Previous mucositis. Serum creatinine > 120micromols/L ANTI-EMETIC POLICY Highly emetogenic day 1 Minimal emetogenic risk day 8 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Methotrexate induced mucositis - folinic acid (calcium folinate) rescue (see concurrent medication) Nephrotoxicity ensure adequate pre and post hydration is prescribed. Caution with furosemide. Ototoxicity assess patient for tinnitus or hearing abnormalities. REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London. CMV Page 2 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 15

16 CISPLATIN / GEMCITABINE (Bladder) Thames Valley Indications: Metastatic bladder cancer and neoadjuvant or adjuvant bladder cancer DRUG REGIMEN Day 1 Pre-hydration regimen GEMCITABINE 1000mg/ m 2 in 250ml sodium chloride 0.9% infusion over 30 minutes CISPLATIN 70mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Post-hydration regimen Day 8 GEMCITABINE 1000mg/ m 2 in 250ml sodium chloride 0.9% infusion over 30 minutes Cycle Frequency: Every 21 days (6 cycles for metastatic disease, 4 cycles for adjuvant) DOSE MODIFICATIONS Cisplatin: GFR > 60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration Gemcitabine: CrCl <30ml/min consider dose reduction (Clinical decision) Neutrophils >1.0x10 9 /L and platelets >100x10 9 /L give 100% dose Neutrophils x10 9 /L or platelets x10 9 /L give 75% dose or delay based on clinical assessment Neutrophils <0.5x10 9 /L or platelets <50x10 9 /L delay treatment Diarrhoea and/or mucositis Grade 2 toxicity omit until toxicity resolved then restart at 100% dose Grade 3 toxicity omit until toxicity resolved then restart at 75% dose Grade 4 toxicity omit until toxicity resolved then restart at 50% dose Omit if treatment is delayed for more than 4 weeks but continue with Cisplatin Gemcitabine / cisplatin Page 1 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 16

17 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 Thames Valley Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion. (Cisplatin) 2) Non-urgent tests Tests relating to disease response/progression CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV ANTI-EMETIC POLICY Highly emetogenic day 1 Low emetogenic risk days 8, 15 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Diarrhoea see dose modifications Mucositis see dose modifications Nephrotoxicity ensure adequate pre and post hydration is prescribed. Ototoxicity assess patient for tinnitus or hearing abnormalities. REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London. Gemcitabine / cisplatin Page 2 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 17

18 Thames Valley GEMCITABINE / CARBOPLATIN (Bladder) Indications: Metastatic bladder cancer when cisplatin is contra-indicated or unsuitable DRUG REGIMEN Day 1 GEMCITABINE 1000mg/m 2 in 250ml sodium chloride 0.9% infusion over 30 minutes CARBOPLATIN (AUC= 4.5) in 500ml glucose 5% infusion over 1 hour Dose = (25 + GFR) x AUC Day 8 GEMCITABINE 1000mg/m 2 in 250ml sodium chloride 0.9% infusion over 30 minutes Cycle Frequency: Every 21 days for 6 cycles NB Ideally GFR should be measured using EDTA If not it may be calculated DOSE MODIFICATIONS Carboplatin: Discuss if patient has a serum creatinine > 150 micromol/l Contraindicated if CrCl<20ml/min Gemcitabine: If CrCl <30ml/min consider dose reduction (Clinical decision) Neutrophils >1.0x10 9 /L and platelets >100x10 9 /L give 100% dose Neutrophils x10 9 /L or platelets x10 9 /L give 75% dose or delay based on clinical assessment Neutrophils <0.5x10 9 /L or platelets <50x10 9 /L delay treatment Diarrhoea and/or mucositis Grade 2 toxicity omit until toxicity resolved then restart at 100% dose Grade 3 toxicity omit until toxicity resolved then restart at 75% dose Grade 4 toxicity omit until toxicity resolved then restart at 50% dose Omit if treatment is delayed for more than 4 weeks but continue with Cisplatin Gemcitabine / carbo Page 1 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 18

19 Thames Valley 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 (LFT) Creatinine clearance (GFR) ideally measured by 51 Cr-EDTA or calculated at the Consultants discretion (Carboplatin). 2) Non-urgent tests Tests relating to disease response/progression CONCURRENT MEDICATION Carboplatin- Anaphylaxis treatment should be prescribed if the patient has had an anaphylactic episode previously. DEXAMETHASONE 20mg IV bolus CHLORPHENAMINE 10mg IV bolus RANITIDINE 50mg IV bolus Carboplatin should be given at a slower rate e.g. 2-4 hours. ANTI-EMETIC POLICY Moderately emetogenic day 1 Low emetic risk day 8 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Diarrhoea see dose modifications Mucositis see dose modifications REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London. Gemcitabine / carbo Page 2 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 19

20 MVAC (Bladder) Thames Valley Indications: Metastatic bladder cancer and adjuvant bladder cancer DRUG REGIMEN Day 1 Pre-hydration regimen METHOTREXATE 30mg/m 2 IV bolus VINBLASTINE 3mg/m 2 in 50ml sodium chloride 0.9% IV infusion over 10 minutes DOXORUBICIN 30mg/m 2 IV bolus CISPLATIN 70mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Post-hydration regimen Day 15 METHOTREXATE 30mg/m 2 IV bolus VINBLASTINE 3mg/m 2 in 50ml sodium chloride 0.9% IV infusion over 10 minutes Day 22 METHOTREXATE 30mg/m 2 IV bolus VINBLASTINE 3mg/m 2 in 50ml sodium chloride 0.9% IV infusion over 10 minutes Cycle Frequency: Every 28 days (6 cycles for metastatic disease, 4 cycles for adjuvant) DOSE MODIFICATIONS 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 ALT/AST is 2-3 x ULN give 75% dose If ALT/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) Cisplatin: GFR > 60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes discuss with Consultant or Registrar before administration Vinblastine: Bilirubin micromol/l or AST/ALT>60-80 give 50% dose Bilirubin >51 micromol/l and AST/ALT normal give 50% dose Bilirubin >51 micromol/l and AST/ALT >180 omit MVAC Page 1 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 20

21 Methotrexate: GFR 60ml/min give 65% dose GFR 45ml/min give 50% dose GFR < 30 ml/min omit Bilirubin 51-85micromol/L or AST>180 give 75% dose Bilirubin >85micromol/L omit Thames Valley 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 Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) 2) Non-urgent tests; tests relating to disease response/progression CONCURRENT MEDICATION For patient requiring Folinic acid support the dose is Folinic acid 15mg PO/IV every 6 hours for 6 doses starting 24 hours after Methotrexate especially if:. Pleural effusions/ascites. Previous mucositis. Serum creatinine >120 micromols/l Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV ANTI-EMETIC POLICY Highly emetogenic day 1 Minimal emetogenic risk days 15, 22 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Methotrexate induced mucositis - folinic acid (calcium folinate) rescue (see concurrent medication) Nephrotoxicity ensure adequate pre and post hydration is prescribed. Ototoxicity assess patient for tinnitus or hearing abnormalities. Cardiotoxicity monitor cardiac function REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London. MVAC Page 2 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 21

22 Thames Valley MVAC ACCELERATED (Bladder) Indications: Neoadjuvant bladder cancer pre surgery and metastatic bladder cancer DRUG REGIMEN Day 1 Pre-hydration regimen METHOTREXATE 30mg/m 2 IV bolus VINBLASTINE 3mg/m 2 in 50ml sodium chloride 0.9% IV infusion over 10 minutes DOXORUBICIN 30mg/m 2 IV bolus CISPLATIN 70mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Post-hydration regimen Days 4 to 10 GCSF as per local policy Cycle Frequency: Every 14 days for 3 cycles pre-surgery neoadjuvant, 6 cycles for metastatic disease DOSE MODIFICATIONS 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 ALT/AST is 2-3 x ULN give 75% dose If ALT/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) Cisplatin: GFR > 60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes discuss with Consultant or Registrar before administration Vinblastine: Bilirubin micromol/l or AST/ALT>60-80 give 50% dose Bilirubin >51 micromol/l and AST/ALT normal give 50% dose Bilirubin >51 micromol/l and AST/ALT >180 omit MVAC accelerated Page 1 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 22

23 Methotrexate: GFR 60ml/min give 65% dose GFR 45ml/min give 50% dose GFR < 30 ml/min omit Bilirubin 51-85micromol/L or AST>180 give 75% dose Bilirubin >85micromol/L omit 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 Thames Valley Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) 2) Non-urgent tests; tests relating to disease response/progression CONCURRENT MEDICATION For patient requiring Folinic acid support the dose is Folinic acid 15mg PO/IV every 6 hours for 6 doses starting 24 hours after Methotrexate especially if:. Pleural effusions/ascites. Previous mucositis. Serum creatinine >120 micromols/l Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV ANTI-EMETIC POLICY Highly emetogenic day 1 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Methotrexate induced mucositis - folinic acid (calcium folinate) rescue (see concurrent medication) Nephrotoxicity ensure adequate pre and post hydration is prescribed. Ototoxicity assess patient for tinnitus or hearing abnormalities. Cardiotoxicity monitor cardiac function REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London. MVAC accelerated Page 2 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 23

24 Thames Valley BEP (3 day) adjuvant (NSGCT) Indications: Adjuvant treatment for non-metastatic non-seminomatous germ cell tumour (stage 1 only) in patients with vascular or lymphatic invasion (risk of relapse up to 40% without treatment). Consider for patients who are unable to attend for intensive outpatient surveillance. DRUG REGIMEN Day 1 Pre-hydration regimen ETOPOSIDE 120mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours CISPLATIN 50mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Post-hydration regimen Day 2 Pre-hydration regimen ETOPOSIDE 120mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours CISPLATIN 50mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM injection (daypatient) or in 1000ml sodium chloride 0.9% IV infusion over 12 hours (inpatient) Post-hydration regimen Day 3 ETOPOSIDE 120mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Day 9 HYDROCORTISONE 100mg IM BLEOMYCIN 30,000units in 3ml 1% lidocaine IM Day 16 HYDROCORTISONE 100mg IM BLEOMYCIN 30,000units in 3ml 1% lidocaine IM Cycle Frequency: Every 21 days for TWO cycles ONLY DOSE MODIFICATIONS Any delays with/without dose modification may cause treatment failure. Discuss with Consultant before delaying treatment or reducing doses of any drug Cisplatin: GFR > 60ml/min give 100% dose GFR ml/min give 75% dose (to be discussed with consultant, consider full dose) GFR < 45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes discuss Consultant before administration Bleomycin: GFR > 50ml/min give 100% dose GFR 10-50ml/min give 75% dose GFR <10ml/min give 50% dose BEP 3 day adjuvant Page 1 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 24

25 Etoposide: CrCl > 50ml/min give 100% dose CrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose Bilirubin 26-51micromol/L or AST u/L 50% give dose Bilirubin >51micromol/L or AST >180u/L Clinical decision Thames Valley INVESTIGATIONS Check patient has had sperm-banking prior to starting first treatment 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 Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) 2) Non-urgent tests relating to disease response/progression CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 200ml Mannitol 10% IV or consider 20-40mg Furosemide PO/IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give 200ml Mannitol 10% IV or consider mg Furosemide PO/IV ANTI-EMETIC POLICY Highly emetogenic. days 1, 2 Low emetogenic risk day 3 Minimal emetogenic risk days 8, 15 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Pulmonary function tests (including transfer factor) prior to commencement of BEP. If breathlessness or infiltrates appear not attributable to tumour or co-existence of lung disease bleomycin must be stopped immediately. Consider treatment with corticosteroids and a broad spectrum antibiotic and / referral to chest team. Investigation of choice high resolution CT chest. Nephrotoxicity ensure adequate pre and post hydration is prescribed. Ototoxicity assess patient for tinnitus or hearing abnormalities. REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London. BEP 3 day adjuvant Page 2 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 25

26 Thames Valley BEP (3 day) metastatic (NSGCT) Indications: Good prognosis metastatic non-seminomatous germ cell tumour (3 cycles only) DRUG REGIMEN Day 1 Pre-hydration regimen ETOPOSIDE 166mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours CISPLATIN 50mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Post-hydration regimen Day 2 Pre-hydration regimen ETOPOSIDE 166mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours CISPLATIN 50mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM injection (daypatient) or in 1000ml sodium chloride 0.9% IV infusion over 12 hours (inpatient) Post-hydration regimen Day 3 ETOPOSIDE 166mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Day 9 HYDROCORTISONE 100mg IM BLEOMYCIN 30,000units in 3ml 1% lidocaine IM Day 16 HYDROCORTISONE 100mg IM BLEOMYCIN 30,000units in 3ml1% lidocaine IM NB Day 9 may be given on day 8 instead. Day 16 may be given on day 15 instead (RBH). NB Day 9 and 16 are given as outpatient treatments Cycle Frequency: Every 21 days for THREE cycles ONLY can give 4 cycles (good prognosis metastatic germ cell tumour, 4th cycle excluding bleomycin) DOSE MODIFICATIONS Any delays with/without dose modification may cause treatment failure. Discuss with Consultant before delaying treatment or reducing doses of any drug. Cisplatin: GFR > 60ml/min give 100% dose GFR ml/min give 75% dose (to be discussed with consultant, consider full dose) GFR < 45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes discuss with Consultant before administration Bleomycin: GFR > 50ml/min give 100% dose GFR 10-50ml/min give 75% dose GFR <10ml/min give 50% dose BEP 3 day metastatic Page 1 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 26

27 Etoposide: CrCl > 50 ml/min give 100% dose CrCl 15-50ml/min give 75% dose CrCl<15 ml/min give 50% dose Confirm with Consultant Bilirubin micromol/l or ALT/AST u/l give 50% dose Bilirubin >51 micromol/l or ALT/AST >180 u/l Clinical decision Thames Valley INVESTIGATIONS Check patient has had sperm banking prior to first treatment. 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 EDTA or Creatinine clearance (GFR) calculated at the Consultants discretion (Cisplatin) 2) Non-urgent tests Tests relating to disease response/progression CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 200ml Mannitol 10% IV or consider 20-40mg Furosemide PO/IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give 200ml Mannitol 10% IV or consider 20-40mg Furosemide PO/IV ANTI-EMETIC POLICY Highly emetogenic days 1, 2 Low emetogenic risk day 3 Minimal emetogenic risk days 9, 16 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Pulmonary function tests (including transfer factor) prior to commencement of BEP. If breathlessness or infiltrates appear not attributable to tumour or co-existence of lung disease bleomycin must be stopped immediately. Consider treatment with corticosteroids and a broad spectrum antibiotic and / referral to chest team. Investigation of choice high resolution CT chest. Nephrotoxicity ensure adequate pre and post hydration is prescribed. Ototoxicity assess patient for tinnitus or hearing abnormalities. REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London. BEP 3 day metastatic Page 2 of 2 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 27

28 Thames Valley BEP (5 day) metastatic (NSGCT) Indication: Intermediate or poor prognosis non-seminomatous germ cell tumour DRUG REGIMEN Day 1 Pre-hydration regimen ETOPOSIDE 100mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours CISPLATIN 20mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Post-hydration regimen Day 2 Pre-hydration regimen ETOPOSIDE 100mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours CISPLATIN 20mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM injection (daypatient) or in 1000ml sodium chloride 0.9% IV infusion over 12 hours (inpatient) Post-hydration regimen Day 3 Pre-hydration regimen ETOPOSIDE 100mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours CISPLATIN 20mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Post-hydration regimen Day 4 Pre-hydration regimen ETOPOSIDE 100mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours CISPLATIN 20mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Post-hydration regimen Day 5 Pre-hydration regimen ETOPOSIDE 100mg/m 2 in 1000ml sodium chloride infusion over 2 hours CISPLATIN 20mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Post-hydration regimen Day 9 HYDROCORTISONE 100mg in 2ml water for injection IM BLEOMYCIN 30,000 units in 3ml Lidocaine 1% IM Day 16 HYDROCORTISONE 100mg in 2ml water for injection IM BLEOMYCIN 30,000 units in 3ml Lidocaine 1% IM NB Day 9 may be given on day 8 instead. Day 16 may be given on day 15 instead (RBFT) NB Day 9 and 16 are given as daypatient treatments Cycle Frequency: Every 21 days for FOUR cycles ONLY BEP 5 day Page 1 of 3 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 28

29 Thames Valley DOSE MODIFICATIONS Any delays with/without dose modification may cause treatment failure. Discuss with Consultant before delaying treatment or reducing doses of any drug Cisplatin: GFR > 60ml/min give 100% dose GFR ml/min give 75% dose (to be discussed with consultant, consider full dose) GFR < 45ml/min consider carboplatin If patient complains of tinnitus, tingling of fingers and/or toes, discuss. Bleomycin: GFR > 50ml/min give 100% dose GFR ml/min give 75% dose GFR < 10 ml/min give 50% dose Confirm with SpR or Consultant If patient is breathless discuss with Consultant Etoposide: CrCl > 50 ml/min give 100% dose CrCl ml/min give 75% dose CrCl <15ml/min give 50% dose Bilirubin micromol/l or ALT/AST u/l give 50% dose Bilirubin >51 micromol/l or ALT/AST >180 u/l omit dose INVESTIGATIONS Check patient has had sperm-banking prior to first cycle of chemotherapy 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 Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) 2) Non-urgent tests Tests relating to disease response/progression BEP 5 day Page 2 of 3 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 29

30 Thames Valley CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV Consider GCSF for next cycle if patient experiences an episode of neutropenic sepsis ANTI-EMETIC POLICY Highly emetogenic days 1, 2, 3, 4, 5 Minimal emetogenic risk days 9, 16 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Pulmonary function tests (including transfer factor) prior to commencement of BEP. If breathlessness or infiltrates appear not attributable to tumour or co-existence of lung disease bleomycin must be stopped immediately. Consider treatment with corticosteroids and a broad spectrum antibiotic and / referral to chest team. Investigation of choice high resolution CT chest. Nephrotoxicity ensure adequate pre and post hydration is prescribed. Ototoxicity assess patient for tinnitus or hearing abnormalities. REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London. BEP 5 day Page 3 of 3 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 30

31 CARBOPLATIN (Seminoma) Thames Valley Indication: Seminoma stage 1 (adjuvant single dose) DRUG REGIMEN Day 1 CARBOPLATIN (AUC = 7) in 500ml glucose 5% infusion over 60 minutes Dose = (25 + GFR) x AUC Cycle Frequency: ONCE only DOSE MODIFICATIONS Discuss if patient has a serum creatinine > 150 micromol/l Contraindicated if CrCl<20ml/min 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 Creatinine clearance (GFR) ideally measured by 51 Cr-EDTA (or calculated) at the Consultants discretion (Carboplatin). 2) Non-urgent tests Tests relating to disease response/progression CONCURRENT MEDICATION Anaphylaxis treatment should be prescribed if the patient has had an anaphylactic episode previously. DEXAMETHASONE 20mg IV bolus CHLORPHENAMINE 10mg IV bolus RANITIDINE 50mg IV bolus Carboplatin should be given at a slower rate e.g. 2-4 hours. ANTI-EMETIC POLICY Moderately emetogenic ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London. Carboplatin seminoma Page 1 of 1 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 31

32 Thames Valley PACLITAXEL / IFOSFAMIDE / CISPLATIN (TIP) Indications: Salvage for metastatic germ cell DRUG REGIMEN Days 1 PRE-MEDICATION 30 mins prior to infusion: DEXAMETHASONE 20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 175mg/m 2 in 500ml sodium chloride 0.9% infusion over 3 hours (PVC free) Days 1 to 5 MESNA 200mg/m 2 in 250ml sodium chloride 0.9% infusion over 30 minutes IFOSFAMIDE 1g/m 2 with MESNA 1g/m 2 in 1L sodium chloride 0.9% infusion over 1 hour MESNA 600mg/m 2 in 500ml sodium chloride 0.9% over 12 hours Pre-hydration CISPLATIN 20mg/m 2 IV in 1000ml sodium chloride 0.9% infusion over 2 hours Post hydration Cycle Frequency: Every 21 days for 4 to 6 cycles DOSE MODIFICATIONS If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness or has/had previous neutropenic sepsis, discuss with Consultant or Registrar before administration. Cisplatin: GFR > 60ml/min give 100% dose GFR ml/min give 75% dose GFR < 45ml/min consider carboplatin Ifosfamide: GFR >60ml/min give 100% dose GFR 40-59ml/min give 70% dose GFR <40ml/min clinical decision. Creatinine >120micromol/L ifosfamide not recommended Discuss if *Bilirubin >17 micromol/l *AST and Alk Phos > 2.5 x upper limit of normal Paclitaxel: Bilirubin <1.25xULN and AST <10xULN dose at 175mg/m 2 Bilirubin <26micromol/L give 135mg/m 2 Bilirubin 27-51micromol/L give 75mg/m 2 Bilirubin >51micromol/L give 50mg/m 2 TIP Page 1 of 4 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 32

33 Thames Valley INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 9 < 9 Plt x 10 9 /L 100 < 100 WBC x 10 9 /L 3.0 < 3.0 Bilirubin 25 <25 Creatinine clearance (GFR) ideally measured by 51 Cr-EDTA or calculated at the Consultants discretion Neurological assessment and neurological toxicity 2) Non urgent tests. Tests relating to disease response/progression CONCURRENT MEDICATION Ensure Pre medication given with paclitaxel Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is <100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV ANTIEMETIC POLICY High emetic risk all days ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cisplatin Nephrotoxicity ensure adequate pre and post hydration is prescribed. Ototoxicity assess patient for tinnitus or hearing abnormalities. Paclitaxel- (2% risk of severe hypersensitivity) Reactions range from mild hypotension (lightheadedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5 10mins), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment. Ensure pre-medication is given. Ifosfamide encephalopathy - methylene blue and supportive therapy Methylthioninium chloride (methylene blue) Methylthioninium chloride (methylene blue) can be given as prophylaxis against, or treatment of, ifosfamide-induced encephalopathy (See specific neural toxicity grade and nomogram below). This should be started on the day of ifosfamide administration and continued for 24 hours after administration or until neurotoxic symptoms subside. Other risk factors include cisplatin, brain irradiation, hepatic failure and advancing age. Dose: 50mg tds IV or orally. (NB. 50mg = 5ml of 1% solution.) TIP Page 2 of 4 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 33

34 Thames Valley Administration IV: administer 50mg in 50 to 100ml sodium chloride 0.9% or glucose 5%, over 15 to 30 minutes Orally: use injection for oral administration. Dilute one ampoule in 100ml water before taking orally to minimise GI effects. Drink through a straw to avoid staining teeth % oral absorption Nephrotoxicity-Irreversible renal failure and tubular damage can occur, and this is more frequent with cumulative doses over 25 50g/m 2 of Ifosfamide. Dose reductions should be instituted for GFR and changes in fractional phosphate clearance (Tm p /GFR mmol/l). Neural toxicity grade Classify toxicity as grade 0-1, 2 or 3-4 and adjust ifosfamide treatment as indicated if either GFR or Tp/C crea (Tm p /GFR) or HCO 3 is reduced. Toxicity Grade* GFR (ml/min/1.73m 2 ) Tp/C crea (Tm p /GFR) (mmol/l) HCO3** (mmol/l) Action (apply worst grade) Grade 0/ Ifos dose 100% Grade Ifos dose 70% of total Grade 3/ ***Switch to Cyclophosphamide *Toxicity is scored from 0-4, analogous to the CTC system, but for the purpose of modifying treatment grades 0-1 and 3-4 are considered together. ** Low values of HCO 3 should be re-checked when the patient is clinically stable (to rule out infection as a cause, etc) before modifying treatment ***Discuss with consultant before and to confirm substitution of ifosfamide with cyclophosphamide 1500mg/m 2 /day Fractional phosphate clearance calculated as below Tp/C crea = Phosphate serum Phosphate urine x creatinine serum Creatinine urine [mmol/ml] TIP Page 3 of 4 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 34

35 Thames Valley Neural toxicity nomogram REFERENCES 1. ASWCS Chemotherapy handbook Jan Mead G et al on behalf of the MRC Testicular tumour working party. A phase 2 trial of TIP given as second line (post BEP) 3. Salvage chemotherapy for patients with metastatic germ cell cancer: a medical research council trial. British Journal of Cancer (2005) 93, Motzer RJ et al Paclitaxel, ifosfamide and cisplatin second line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 18: TIP Page 4 of 4 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 35

36 POMB / ACE (Germ cell) Thames Valley Indication: Metastatic germ cell DRUG REGIMEN POMB Day 1 VINCRISTINE 1mg/m 2 (max 2mg) IV infusion in 50ml sodium chloride 0.9% METHOTREXATE 300mg/m 2 in 1000ml sodium chloride 0.9% over 12 hours 1000ml sodium chloride 0.9% + 20mmol KCl over 4 hours Day 2 BLEOMYCIN 30,000iu in 2000ml sodium chloride 0.9% infusion over 24 hours FOLINIC ACID 15mg qds PO for 6 doses starting 24 hours after methotrexate Day 3 Pre-hydration regimen CISPLATIN 60mg/m 2 in 500ml sodium chloride 0.9% infusion over 4 hours CISPLATIN 60mg/m 2 in 500ml sodium chloride 0.9% infusion over 4 hours Post-hydration regimen Cycle Frequency: Every 14 days alternating with ACE (see regimen sequence below) ACE Day 1 DACTINOMYCIN 500micrograms IV bolus ETOPOSIDE 100mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Day 2 DACTINOMYCIN 500micrograms IV bolus ETOPOSIDE 100mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Day 3 CYCLOPHOSPHAMIDE 500mg/m 2 IV bolus DACTINOMYCIN 500micrograms IV bolus ETOPOSIDE 100mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Cycle frequency: Every 14 days alternating with POMB (see regimen sequence below) Regimen sequence: POMB POMB ACE POMB ACE POMB ACE POMB-ACE Page 1 of 3 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 36

37 Thames Valley DOSE MODIFICATIONS POMB Bleomycin: GFR >50ml/min give 100% dose GFR ml/min give 75% dose GFR < 10 ml/min give 50% dose Vincristine: Bilirubin or AST u/Lgive 50% dose Bilirubin >51 micromol/l and normal AST give 50% dose Bilirubin >51micromol/L and AST >180u/L omit Methotrexate: CrCl 60 ml/min give 65% dose CrCl 45 ml/min give 50% dose CrCl < 30 ml/min omit dose Bilirubin micromol/l or AST >180 u/l give 75% dose Bilirubin >85micromol/L omit Cisplatin: GFR > 60ml/min give 100% dose GFR ml/min give 75% dose GFR < 45ml/min consider carboplatin ACE Etoposide: CrCl > 50ml/min give 100% dose CrCl ml/min give 75% dose CrCl < 15 ml/min give 50% dose Bilirubin micromol/l or AST u/l give 50% dose Bilirubin >51micromol/L or AST >180u/L Clinical decision Cyclophosphamide: GFR >20ml/min give 100% dose GFR ml/min give 75% dose GFR < 10 ml/min give 50% dose Dactinomycin: Consider dose reduction in severe hepatic disease. POMB-ACE Page 2 of 3 Published: October 2012 Network Chemotherapy Protocols Urological Cancer 37