Dr P Savage Date Review date: October Gemcitabine Regimens 1. Gemcitabine-1250/Cisplatin-70 D1+8 CTIS

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1 BLADDER CANCER / TRANSITIONAL CELL CARCINOMA Section by: Dr Philip Savage, Professor Jonathan Waxman, Dr Alison Falconer, Dr Simon Stewart. Version: Bladder Cancer/TCC Regimens Approved v7.01 NWLCN 15Oct13 Section last updated: 15 th October 2013 Section last corrected: 15 th October 2013 Approved by Urology Lead Oncology Clinician: Dr P Savage Date Review date: October 2015 I N D E X Page Gemcitabine Regimens 1. Gemcitabine-1250/Cisplatin-70 D1+8 CTIS Gemcitabine-1000/Carboplatin 5AUC D1+8 CTIS Taxane regimens 3. Paclitaxel-80 weekly CTIS Gemcitabine/Cisplatin/Paclitaxel D1+8 Additional private care CTIS Gemcitabine/Carboplatin/Paclitaxel D1+8 Additional private care CTIS Other regimens 6. CMV CTIS MVAC CTIS Vinflunine (Additional private care, no longer CDF) 14 Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 1 of 18

2 BLADDER CANCER / TRANSITIONAL CELL CARCINOMA Section by: Dr Philip Savage, Professor Jonathan Waxman,Dr Alison Falconer, Dr Simon Stewart. Version: Bladder Cancer-TCC Regimens Approved v7.01 NWLCN 15Oct13 Section last updated: 15 th October 2013 Section last corrected: 15 th October 2013 Approved by Urology Lead Oncology Clinician: October 2013 Review date: October 2015 Gemcitabine Regimens 1. Gemcitabine1250-Cisplatin70 D1+8 (CTIS: 1695) Gemcitabine 1250mg/m 2 IV over 30 mins Day 1 and 8 Prehydrations Day 1 Cisplatin 70mg/m 2 IV over 2 hrs Day 1 Post hydrations Day 1 Gemcitabine dose changed April 2011 October 2013; Some clinician dose in line with POUT Trial; Gemcitabine 1000mg/m 2 Day 1 and 8 October 2013; Some clinicians split Cisplatin dose in line with POUT trial ie for GFR 50-70mls/min administer cisplatin as split dose: ie Cisplatin 35mg/m 2 days 1 and 8 Interval between cycles: Repeat every 21 days Number of cycles: Neoadjuvant: 3 cycles Adjuvant: 4 cycles Metastatic: 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs, EDTA Adequate renal function (Crcl 60mls/min). Tests to OK/Confirm each cycle of chemo: Day 1; FBC, U&Es, LFTs, Crcl (calculated). Consider repeating EDTA cycle 3. Day 8 FBC, U&Es Supportive drugs with each cycle: Antiemetics as per NWLCN guidelines below or as per local policy; Day 1; Very high risk antiemetics Day 8; Low risk anti-emetics Chlorhexidine mouthwash 10ml qds prn. Patient information: Chemotherapy treatment booklet (local information/macmillan) Your chemotherapy record (NWLCN red book) NWLCN Chemotherapy alert card Macmillan drug specific information sheets and information prescriptions as appropriate NWLCN Neutropenia DVD Additional information: Administration notes: Gemcitabine: must be administered over 30 minutes. In case of injection site reaction/vein irritation, the infusion may be slowed down slightly, but must not be infused over more than one hour. Prolonged infusion increases the treatment toxicity and should be avoided. Peripheral venous comfort may be increased by warming the arm with a heat pad. Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 2 of 18

3 Cisplatin Weigh patient before and after cisplatin infusion or monitor urine output. If weight gain >1.5kg or symptomatic of fluid retention: inform doctor, patient may require diuretics Dose modifications: See table Gem-Cisp: Bladder below References: J. Clin Oncol 2000;18: Van der Maase et al EORTC protocol BC Cancer Agency Protocol summary GUAVPG March 2011 dose modifications Table: Gem-Cisp Bladder If day 8 chemo is delayed, omit day 8 chemo and restart day 22 once counts recovered. Side-effect Gem-Cisp Bladder Haematology Neutrophils Platelets x 10 9 L x10 9 /L Day and or <0.5 or <75 Day and or Dose Modification Source: GC vs MVAC Trial/BCCA all drugs Gemcitabine 25% dose reduction Cisplatin full dose Delay until recovered. Discuss with consultant. all drugs Gemcitabine 25% dose reduction <0.5 or <75 Neurotoxicity WHO Grade 0-1 Grade 2 Renal Toxicity Crcl Grade 3 Grade 4 60mls/min 50-59mls/min <50mls/min Do not give All drugs; Gemcitabine: Cisplatin: Gemcitabine: Cisplatin: Gemcitabine: Cisplatin: Cisplatin: Cisplatin: Cisplatin: 50% dose reduction 50% dose reduction or omit Omit 50% dose reduction or stop Stop Check with consultant. Consider split dose of cisplatin ie. administer 35mg/m 2 on day 1 and day 8 Omit Creatinine WHO grade (>5 x ULN) Ototoxicity Gemcitabine: Gemcitabine: Omit Tinnitus or significant clinical hearing loss: Reduce or stop Cisplatin. Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 3 of 18

4 2. Gemcitabine1000-Carboplatin 5AUC D1+8 (CTIS: 134) Gemcitabine 1000mg/m 2 IV over 30 mins Day 1 and 8 Carboplatin 5(GFR+25)mg IV over 1 hour Day 1 Interval between cycles: Repeat day 21 (for patients unable to tolerate Gemcitabine/cisplatin) Number of cycles: Neoadjuvant: 3 cycles Adjuvant: 4 cycles Metastatic: Tests before starting course of chemo: Tests to OK/Confirm each cycle of chemo: Supportive drugs with each cycle: Patient information: Additional information: Administration notes: Gemcitabine administration notes; see page 2 6 cycles FBC, U&Es, LFTs, EDTA, adequate renal function (Cr 50mls/min) or discuss with consultant. Day 1; FBC, U&Es, LFTs, Crcl (calculated), Consider repeating EDTA after cycle 3. Day 8: FBC, U&Es Antiemetics as per NWLCN guidelines as below or as per local policy; Day 1; High risk antiemetics Day 8; Low risk antiemetics Chemotherapy treatment booklet (local information/macmillan) Your chemotherapy record (NWLCN red book) NWLCN Chemotherapy alert card Macmillan drug specific information sheets and information prescriptions as appropriate NWLCN Neutropenia DVD Carboplatin Hypersensitivity Reactions Carboplatin may cause allergic reactions which can occur within minutes of administration. See below for SPC information. If any reaction occurs: stop the infusion and discuss with consultant. After discussion with consultant: Mild reactions eg rash: May consider re-challenge after discussion with consultant. Severe reactions Do not re-challenge. Discuss with consultant. Carboplatin SPC (Hospira (09 June 2009): Infrequent allergic reactions to carboplatin have been reported, e.g. erythematous rash, fever with no apparent cause or pruritus. Rarely, anaphylaxis, angio oedema and anaphylactoid reactions including bronchospasm, urticaria and facial oedema have occurred. These reactions are similar to those observed after administration of other platinum containing compounds and may occur within minutes. The incidence of allergic reactions may increase with previous exposure to platinum therapy; however, allergic reactions have been observed upon initial exposure to carboplatin. Patients should be observed carefully for possible allergic reactions and managed with appropriate therapy, including antihistamines, adrenaline and/or glucocorticoids. Dose modifications: See table Gem-Carbo Bladder table page 5 References: Carboplatin substitution. J. Clin Oncol 2000;18:3068 Van der Maase et al Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 4 of 18

5 Table: Gem-Carbo Bladder If day 8 chemo is delayed then omit day 8 chemo and restart next cycle day 22 once counts recovered Side-Effect Gem-Carbo Bladder Dose Modification (Dr P Savage) Haematology Neutrophils Platelets x10 9 /L x 10 9 /L Day and 100 <1.5 or <100 Day and 75 <1.5 or <75 Renal Function 30mls/min < 30mls/min all drugs Wait until recovery. Discuss with consultant. Consider Gemcitabine: 20% dose reduction day 1 and 8 Carboplatin: 20% dose reduction day 1 Wait until recovery and discuss with consultant Gemcitabine day 8 full dose Do not give day 8 and restart next cycle of chemotherapy on day 22 Dose as per Calvert formula Do not give. Discuss with consultant Taxane Regimens 3. Paclitaxel-80 Weekly (CTIS: 1698) Dexamethasone 8mg* IV bolus 30minutes before paclitaxel Day 1 Chlorphenamine 10mg IV bolus 30minutes before paclitaxel Day 1 Ranitidine 50mg IV bolus 30 minutes before paclitaxel Day 1 Paclitaxel 80mg/m 2 IV over 1 hour Day 1 *Cycle 2 onward dexamethasone may be reduced to 4mg if no problems with first cycle at 8mg Interval between cycles: Repeat every 7 days Number of cycles: Relapsed bladder 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Supportive drugs with each cycle: Moderate risk antiemetics as per NWLCN guidelines or as per local policy Dexamethasone pre-medication as above Patient information: Chemotherapy treatment booklet (local information/macmillan) Your chemotherapy record (NWLCN red book) NWLCN Chemotherapy alert card Macmillan drug specific information sheets and information prescriptions as appropriate NWLCN Neutropenia DVD Additional information: Administration notes: Paclitaxel: Use administration set (polyethylene lined with inline filter 0.22 microns) provided by pharmacy only for paclitaxel. Acute hypersensitivity reactions can occur, observe closely especially during the first two cycles. Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 5 of 18

6 Hypersensitivity Reactions Paclitaxel Hypersensitivity Reactions Paclitaxel may cause allergic reactions. See below for SPC information. If any reaction occurs: stop the infusion and discuss with consultant After discussion with consultant: Mild reactions e.g rash: May consider re-challenge after discussion with consultant. Severe reactions Do not re-challenge. Discuss with consultant. Paclitaxel SPC (Hospira 31 Nov 2010). Significant hypersensitivity reactions: As characterised by dyspnoea and hypotension requiring treatment, angioedema, and generalised urticaria have occurred in <1% of patient receiving paclitaxel after adequate premedication. These reactions are probably histamine-mediated. In the case of severe hypersensitivity reactions paclitaxel infusion should be discontinued immediately, symptomatic therapy should be initiated and the patient should not be re-challenged with paclitaxel. Macrogolglycerol ricinoleate (polyoxyl castor oil), an excipient in the medicinal product, can cause these reactions. Dose modifications: Table Paclitaxel below Reference: JCO 20 No (Feb 15 th ) p Table: Paclitaxel Weekly Side-effect Haematology Neutrophils Platelets x10 9 /L x10 9 /L 1.5 and 100 <1.5 or <100 Neutrophils 0.5x10 9 /L for 7 days or more (SPC/WWW) Platelets <25 x10 9 /L Dose Modification (Source: Will weekly win trial/). Do not treat below these levels Delay until recovery. Once recovered reduce dose according to nadir counts below. If delayed longer than 2 weeks discuss with consultant. Paclitaxel 20% dose reduction Paclitaxel 20% dose reduction Febrile neutropenia (ANC <1.0 and fever) or sepsis with neutrophils <1.0 Neurotoxicity Hepatic Function Bilirubin Paclitaxel 20% dose reduction Grade 2 Paclitaxel 20% dose reduction If still progressing stop paclitaxel < 21micromol/L 21-51micromol/L >51micromol/L Up to 50% dose reduction Omit paclitaxel Severe liver impairment Omit Paclitaxel Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 6 of 18

7 4. Gem/Cisp/Paclitaxel (BA11 Schedule) (CTIS 1696) For Additional Private Care unless local NDP approved Dexamethasone 8mg* IV bolus 30mins before paclitaxel Day 1 and 8 Chlorphenamine 10mg IV bolus 30mins before paclitaxel Day 1 and 8 Ranitidine 50mg IV bolus 30mins before paclitaxel Day 1 and 8 Paclitaxel 80mg/m 2 IV over 1 hour Day 1 and 8 Prehydrations Cisplatin 70mg/m 2 IV over 2 hours Day 1 Post hydrations Gemcitabine 1000mg/m 2 IV over 30mins Day 1 and 8 * Cycle 2 onwards dexamethasone may be reduced to 4mg if no problem with first cycle at 8mg Interval between cycles: 21 days Number of cycles: Palliative therapy after relapse on Gemcitabine/cisplatin 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs, EDTA 60mls/min Tests to OK/confirm each cycle of chemo: Day 1: FBC, U&Es, Crcl (calculated), LFTs. Consider repeat EDTA after cycle 3 or if rising creatinine. Day 8: FBC, U&Es FBC evaluations should be made weekly for at least the first 2 cycles. Adequate renal function (Crcl 60ml/min). Supportive drugs with each cycle: Antiemetics as per NWLCN guidelines below or as per local policy Day 1: Very high risk antiemetics Day 8: Moderate risk antiemetics If afebrile grade 4 neutropenia on day 15 give ciprofloxacin 500mg orally bd for 7 days. Chlorhexidine mouthwash 10mls QDS Patient information: Chemotherapy treatment booklet (local information/macmillan) Your chemotherapy record (NWLCN red book) NWLCN Chemotherapy alert card Macmillan drug specific information sheets and information prescriptions as appropriate NWLCN Neutropenia DVD Additional information: Administration notes: Gemcitabine see page 2 Cisplatin see page 3 Paclitaxel: Use administration set (polyethylene lined with inline filter 0.22 microns) provided by pharmacy only for paclitaxel. Acute hypersensitivity reactions can occur, observe closely especially during the first two cycles. Hypersensitivity Reactions Paclitaxel Hypersensitivity Reactions Paclitaxel may cause allergic reactions. See page 6 for SPC information. If any reaction occurs: stop infusion and discuss with consultant After discussion with consultant: Mild reactions e.g rash: May consider re-challenge after discussion with consultant. Severe reactions Do not re-challenge. Discuss with consultant Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 7 of 18

8 Reference: BA11 Clinical Trial (EORTC 30987) Table: Gem-Cisp-Paclitaxel-Bladder If day 8 chemo is delayed, then omit day 8 chemo and restart next cycle on day 22 once counts recovered. Side effect Gem-Cisp-Paclitaxel Haematology Neutrophils Platelets x10 9 /L x10 9 /L Day and 100 <1.5 or <100 Dose Modification (BA11) Delay until recovery. If recovery takes 2 weeks then treatment may be continued with 25% dose reduction of ALL drugs (gemcitabine, cisplatin, paclitaxel) provided WBC >2.0, Neutrophils >1.0, Platelets >75 Day and and or <0.5 or <50 all drugs (paclitaxel and gemcitabine) Paclitaxel and gemcitabine: 25% dose reduction Paclitaxel and gemcitabine: 50% dose reduction Delay until recovery and dose reduce If at any time Grade 4 Neutropenia (neutrophils <0.5 and fever >38.5 o C) Grade 4 Thrombocytopenia (<10) for more than 3 days or Thrombocytopenia with bleeding during the nadir Renal Toxicity Crcl <50mls/min Mucosal Toxicity Neurotoxicity Grade 3 or 4 Other Toxicities 60mls/min 50-59mls/min All drugs 25% dose reduction (unless larger reduction required above) for next cycle All drugs 25% dose reduction unless larger reduction required above for next cycle Cisplatin divide full dose over 2 days Gemcitabine and paclitaxel full dose Gemcitabine If serum creatinine <6xULN full dose If serum creatinine >6xULN do not give gemcitabine Cisplatin :Repeat IV hydrations (max 2 days) if then still <50mls/min do not give cisplatin Paclitaxel: Grade 3 or 4 All drugs (gemcitabine, cisplatin, paclitaxel) 25% dose reduction on Day 1 and 8 Stop cisplatin Gemcitabine and paclitaxel may continue after discussion with consultant. Grade 1-2 Grade 3 Grade 4 All drugs 50% dose reduction Consider stopping therapy or all drugs 50% dose reduction Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 8 of 18

9 5. Gem-Carbo-Paclitaxel (CTIS: 1697) For Additional Private Care unless local NDP approved Dexamethasone 20mg* IV bolus 30mins prior to paclitaxel Day 1 Ranitidine 50mg IV bolus 30mins prior to paclitaxel Day 1 Chlorphenamine 10mg IV bolus 30mins prior to paclitaxel Day 1 Paclitaxel 175mg/m 2 IV over 3 hours Day 1 Carboplatin 4x(GFR+25)mg IV over 1 hour Day 1 Gemcitabine 800mg/m 2 IV over 30mins Day 1 and 8 Interval between cycles: 21 days Number of cycles: Palliative therapy following relapse after Gemcitabine/cisplatin 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs EDTA. Crcl must 40mls/min or discuss with consultant Tests to OK/confirm each cycle of chemo: Day 1: FBC, U&Es, LFTs, Crcl (calculated). Consider repeating EDTA after cycle 3. Day 8: FBC, U&Es Supportive drugs with each cycle: Antiemetics as per NWLCN guidelines below or as per local policy Day 1: High risk antiemetics Day 8: Low risk antiemetics If afebrile grade 4 neutropenic day 15, give prophylactic ciprofloxacin 500mg BD for 7 days. Pre-med as above Patient information: Chemotherapy treatment booklet (local information/macmillan) Your chemotherapy record (NWLCN red book) NWLCN Chemotherapy alert card Macmillan drug specific information sheets and information prescriptions as appropriate NWLCN Neutropenia DVD Additional information: Administration notes Gemcitabine see page 2 Carboplatin see page 4 Paclitaxel: Use administration set (polyethylene lined with inline filter <0.22microns) provided by pharmacy only for paclitaxel. Paclitaxel should be administered prior to carboplatin. Vital signs should be monitored every 15 minutes for first hour of paclitaxel infusion on all cycles. Hypersensitivity Reactions Paclitaxel Hypersensitivity Reactions Paclitaxel may cause allergic reactions. See page 6 for SPC information. If any reaction occurs: stop infusion and discuss with consultant After discussion with consultant: Mild reactions e.g rash: May consider re-challenge after discussion with consultant. Severe reactions Do not re-challenge. Discuss with consultant. Carboplatin Hypersensitivity Reactions Carboplatin may cause allergic reactions which can occur within minutes of administration. See page 4 for SPC information. If any reaction occurs: stop the infusion and discuss with consultant. Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 9 of 18

10 After discussion with consultant: Mild reactions eg rash: May consider re-challenge after discussion with consultant. Severe reactions Do not re-challenge. Discuss with consultant Dose modifications: See table below Reference: J. Clin Oncol 2001;19(9): Modified from Hussain et al (see page 2529) Table: Gem/Carbo/Paclitaxel If day 8 chemo is delayed then omit day 8 chemo and restart next cycle on day 22 once counts recovered. Side effect : Gem/Carbo/Paclitaxel Haematology Neutrophils x10 9 /L Platelets x10 9 /L Day and 100 Dose Modification (BA11/plus Hussain) Continue with dose based on day 8/nadir counts. If day 8 neutrophils 0.5 and platelets 50: Give full dose If day 8 neutrophils <0.5 or platelets <50: Reduce dose to paclitaxel 135mg/m 2, carboplatin 3AUC and gemcitabine 800mg/m 2 Day 1 and 8 (full dose) <1.5 or <100 Day and 100 <1.0 or <100 If at any time Grade 4 Neutropenia (neutrophils <0.5 and fever >38.5 o C) Grade 4 Thrombocytopenia (<10) for more than 3 days or Thrombocytopenia with bleeding during the nadir Delay until recovered. If delay 2 weeks discuss with consultant If delay <2 weeks give doses based on day 8/nadir counts If day 8 neutrophils 0.5 and platelets 50: Give full dose If day 8 neutrophils <0.5 or platelets <50: Reduce dose to paclitaxel 135mg/m 2, carboplatin 3AUC and gemcitabine 800mg/m 2 Day 1 and 8 (full dose) gemcitabine Do not give day 8. Restart next cycle on day 22 if counts recovered with doses based on Day 8 FBC as detailed above All drugs 25% dose reduction (unless larger reduction required above) for next cycle All drugs 25% dose reduction unless larger reduction required above) for next cycle Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 10 of 18

11 Side effect : Gem/Carbo/Paclitaxel Renal Toxicity Crcl 40mls/min Non-Haematological Toxicities <40mls/min Grade 1-2 Grade 3 Dose Modification (BA11/plus Hussain) Carboplatin according to Calvert formula above Gemcitabine and paclitaxel full dose Discuss with consultant Delay until recovery to grade 1 or less, then dose reduce to Paclitaxel 135mg/m 2 (from 175mg) Carboplatin 3AUC (from 4AUC) Gemcitabine 800mg/m 2 Day 1 and 8 (full dose) If grade 3 recurs despite dose reduction discuss with consultant Other Regimens 6. CMV (CTIS: 187) Vinblastine 4mg/m 2 IV in minibag over 10mins Day 1 and 8 Methotrexate 30mg/m 2 IV bolus Day 1 and 8 Prehydrations Day 2 Cisplatin 100mg/m 2 IV over 4 hrs Day 2 Post hydrations Day 2 Interval between cycles: Repeat every 21 days Number of cycles: Neoadjuvant: 2-3 cycles Adjuvant therapy: 4 cycles Metastatic disease: 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs, EDTA Tests to OK/Confirm each cycle of chemo: Day 1; FBC, U&Es, LFTs, Crcl (calculated). Day 8; FBC, U&Es Consider repeating EDTA after cycle 3. Adequate renal function (Crcl 60ml/min). Caution if 3 rd space fluid present or renal impairment these reduce clearance of methotrexate so may require measurements of methotrexate levels and folinic acid rescue. Supportive drugs with each cycle: Antiemetics as per NWLCN guidelines or as per local policy Day 1: Very high risk antiemetics Day 8: Low risk antiemetics Chlorhexidine mouthwash 10ml qds prn. Patient information: Chemotherapy treatment booklet (local information/macmillan) Your chemotherapy record (NWLCN red book) NWLCN Chemotherapy alert card Macmillan drug specific information sheets and information prescriptions as appropriate Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 11 of 18

12 NWLCN Neutropenia DVD Additional information: Administration notes Weigh patient before and after cisplatin infusion or monitor urine output. If weight gain >1.5kg or symptomatic of fluid retention: inform doctor, patient may require diuretics Dose modifications: Table Bladder-CMV below References: J. Clin Oncol 1985;3:1463 Harker et al. Lancet 1999;354:533 International collaboration of trialists Table: Bladder-CMV Side-effect Haematology Day 1 or 8 Neutrophils Platelets x 10 9 /L x 10 9 /L 1.5 and 100 <1.5 or < 100 Renal Function Day 1 or 8 Crcl 60mls/min 46-59mls/min 45mls/min Dose Modification (Dr Savage) All drugs: Day 1 - Delay until recovered then discuss with consultant. Day 8 - Omit chemo, restart Day 1 chemo as planned on day 22 All drugs : Vinblastine : Methotrexate : Cisplatin : 50% dose reduction Consider alternative treatment 7. MVAC (CTIS: 682) Methotrexate 30mg/m 2 IV bolus Day 1, 15, 22 Vinblastine 3mg/m 2 (max 10mg) IV in minibag over 10mins Day 2, 15, 22 Doxorubicin 30mg/m 2 IV bolus Day 2 Prehydrations Day 2 Cisplatin 70mg/m 2 IV over 2 hrs Day 2 Post hydrations Day 2 Interval between cycles: Repeat Day 28 Number of cycles: Neoadjuvant: 3 cycles Adjuvant: 4 cycles Metastatic: 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs, EDTA, MUGA Tests to OK/Confirm each cycle of chemo: Day 1; FBC, U&Es, LFTs, Crcl (calculated), Day 15; FBC, U&Es Day 22; FBC, U&Es Consider repeating EDTA after cycle 3. Consider repeating MUGA after cycles 3 and 6. Adequate renal function (Crcl 60mls/min). Caution if 3 rd space fluid present or renal impairment these reduce clearance of methotrexate so may require measurement of methotrexate levels and Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 12 of 18

13 Supportive drugs with each cycle: Patient information: folinic acid rescue. Adequate cardiac function pre-treatment. Risk of cardiomyopathy increases with total doxorubicin dose >450mg/m 2. Antiemetics as per NWLCN guidelines below or as per local policy Day 1: No antiemetics Day 2: Very high risk antiemetics Day 15; Low risk antiemetics Day 22; Low risk antiemetics Chlorhexidine mouthwash 10ml qds. Chemotherapy treatment booklet (local information/macmillan) Your chemotherapy record (NWLCN red book) NWLCN Chemotherapy alert card Macmillan drug specific information sheets and information prescriptions as appropriate NWLCN Neutropenia DVD Additional information: Administration notes Weigh patient before and after cisplatin infusion or monitor urine output. If weight gain >1.5kg or symptomatic of fluid retention: inform doctor, patient may require diuretics Dose modifications: See table MVAC-Bladder below Reference: J. Clin Oncol 1992;10:1066 Loehrer et al J. Urol 1992;148:302 Stockle et al NEJM 2003;349:859 Grossman et al Table: MVAC - Bladder Side-effect MVAC Bladder Haematology Day 1 or 8 Neutrophils Platelets x 10 9 /L x 10 9 /L 1.5 and 100 <1.5 or < 100 Dose Modification (Source GC vs MVAC Trial/NLCN) All drugs: Day 1 - Delay until recovered then discuss with consultant. Day 8 - Omit chemo, restart Day 1 chemo as planned on day 22 Renal Toxicity Crcl 60ml/min 51-59ml/min <50ml/min All drugs: Cisplatin: Methotrexate: Cisplatin: but give over 2 days Hold drug until recovery Omit Neurotoxicity Cardiotoxicity WHO Grade 2-3 Vinblastine: Cisplatin: WHO Grade 3 Doxorubicin: Hold until recovered then reduce by 1mg/m 2 Hold drug until recovery Discontinue Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 13 of 18

14 Side-effect MVAC Bladder Dose Modification (Source GC vs MVAC Trial/NLCN) Hepatic Function (NLCN/DI Handbook) Bilirubin <20micromol/L micromol/l Mucositis 52-85micromol/L >85micromol/L WHO Grade 1-2 all drugs Doxorubicin: 50% dose reduction (NLCN) Vinblastine: 50% dose reduction (NLCN) Doxorubicin: 75% dose reduction (NLCN) Vinblastine: 75% dose reduction (DI Handbook) Methotrexate: 25% dose reduction (NLCN) Do not give regimen Methotrexate: Withhold until recovered Ototoxicity WHO Grade 3 Methotrexate: Reduce dose by 10mg/m 2 Folinic Acid: 15mg PO/IV every 6 hours for 4 doses starting 24 hours after start of methotrexate If tinnitus or significant hearing loss, reduce or stop Cisplatin Pleural Effusion /Ascites Drain or seek advice on dose of Methotrexate and Duration of folinic acid 7. Vinflunine-320 Vinflunine 320*mg/m 2 IV in minibag over 20minutes Day 1 Reduce starting dose if Performance Status <2 (SPC) *320mg/m 2 is the starting dose for patients with WHO/ECOG performance status 2 and aged less than 75 years. In case of WHO/ECOG PS of 0 or 1 and prior pelvic irradiation, treatment should be started at reduced dose 280mg/m 2. In the absence of any haematological toxicity during the first cycle causing dose delay or dose reduction, the dose may be increased to 320mg/m 2 every 3 weeks for subsequent cycles Reduce dose in patients aged over 75 years (SPC) *320mg/m 2 is the starting dose for patients aged less than 75years with PS 2. Patients aged 75 and less than 80years, the SPC starting dose is 280mg/m 2 every 21 days. Patients aged 80years and older, the SPC starting dose is 250mg/m 2 every 21 days. Doses in subsequent cycles should then be adjusted according to toxicity. Interval between cycles: Repeat every 21days Number of cycles: Treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of prior platinum containing chemotherapy 6cycles Tests before starting course of chemo: FBC, U&Es, LFTs, Crcl (Calculated), PS, Cardiac history (see SPC). Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs, Crcl (calculated). Supportive drugs with each cycle: Antiemetics as per NWLCN guidelines or as per local policy Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 14 of 18

15 Patient information: Laxatives (senna/docusate), dietary measures (fibre) and oral hydration day 1 to 5 of each cycle to prevent constipation. If at high risk of constipation (eg opiates or abdominal mass) then add lactulose Days 1 to 7 of each cycle to prevent constipation Chemotherapy treatment booklet (local information/macmillan) Your chemotherapy record (NWLCN red book) NWLCN Chemotherapy alert card Macmillan drug specific information sheets and information prescriptions as appropriate NWLCN Neutropenia DVD Additional information: Vinflunine is a new vinca alkaloid and must comply with NPSA dilution requirements. See SPC for interaction with Administration notes Dose modifications: See table below Dose level Zero 320mg/m 2 Starting dose patients aged 75 or less with PS 2. Dose level 1 280mg/m 2 Dose level mg/m 2 Reference: Javlor SPC. Pierre Fabre 30/07/2013 Table: Vinflunine Bladder Side-effect Vinflunine Bladder Dose Modification (Javlor SPC 30/07/13) Haematology Neutrophils Platelets x 10 9 /L x 10 9 /L 1.0 and 100 <1.0 or < 100 Delay until recovered to above these levels, thenreduce dose as below. If not recovered within 2 weeks discontinue vinflunine Neutropenia grade 4 (ANC <0.5x10 9 /L > 7 days) And/or Febrile neutropenia (ANC1.0x 10 9 /L & fever 38.5 o C ) Cardiac Disorders Cardiac ischaemia in patients with prior history of cardiac infarction or angina pectoris First Occurrence: Wait until recovered to above levels then reduce dose by one dose level ie if initial dose was 320mg/m 2 then reduce to 280mg/m 2 If initial dose was 280mg/m 2 then reduce to 250mg/m 2 If initial dose was 250mg/m 2 then reduce to 225mg/m 2 2 nd Consecutive Event Wait until recovered to above levels then reduce dose by one dose level ie If previous dose was 280mg/m 2 then reduce to 250mg/m 2 If previous dose was 250mg/m 2 then discontinue treatment If previous dose was 225mg/m 2 then discontinue treatment 3 rd Consecutive Event Discontinue treatment See SPC for information Discontinue vinflunine Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 15 of 18

16 Side-effect Vinflunine Bladder Dose Modification (Javlor SPC 30/07/13) Posterior Reversible Encephalopathy Syndrome (PRES) See SPC for signs and symptoms Discontinuation of vinflunine should be considered in patients who develop neurological signs of PRES. See SPC Hepatic Function (SPC ) Child Pugh Grade A Or Patients with Prothrombin time 60% NV and Bilirubin x ULN and transaminases >ULN and/or GGT > 5 x ULN Child Pugh Grade B Or Patients with Prothrombin time 50% NV and Bilirubin >3.0 x ULN and transaminases >ULN and GGT >ULN Child Pugh Grade C Renal Toxicity (SPC ) Crcl 60ml/min 40-59ml/min 20-39mls/min <20ml/min See also SPC for further information Recommended dose Vinflunine 250mg/m 2 every 21 days Recommended dose Vinflunine 200mg/m 2 every 21 days No dose recommendation. Vinflunine has not been evaluated in patients with severe hepatic impairment (Child Pugh grade C) or patients with prothrombin time <50% NV or with bilirubin >5.0xULN or with isolated transaminases >2.5xULN ( 5xULN only in cases of liver metastases) or with GGT >15xULN 280mg/m 2 every 21 days 250mg/m 2 every 21 days No data Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 16 of 18

17 Side-effect Vinflunine Bladder Dose Modification (Javlor SPC 30/07/13) Constipation (SPC NCI CTC v2.0) Grade 2 5 days (requiring laxatives) OR Grade 3 any duration (Constipation requiring manual evacuation or enema) Delay until recovered to baseline or Grade 1, then reduce dose as below. Discontinue if unresolved after 2 weeks First Occurrence: Wait until recovered to above levels then reduce dose by one dose level ie if initial dose was 320mg/m 2 then reduce to 280mg/m 2 If initial dose was 280mg/m 2 then reduce to 250mg/m 2 If initial dose was 250mg/m 2 then reduce to 225mg/m 2 2 nd Consecutive Event Wait until recovered to above levels then reduce dose by one dose level ie If previous dose was 280mg/m 2 then reduce to 250mg/m 2 If previous dose was 250mg/m 2 then discontinue treatment If previous dose was 225mg/m 2 then discontinue treatment Mucositis (SPC NCI CTC v2.0) Grade 2 5 days ( Moderate ) OR Grade 3 any duration ( Severe ) 3 rd Consecutive Event Discontinue treatment Delay until recovered to baseline or grade 1, then reduce dose as below. Discontinue if unresolved after 2 weeks First Occurrence: Wait until recovered to above levels then reduce dose by one dose level ie if initial dose was 320mg/m 2 then reduce to 280mg/m 2 If initial dose was 280mg/m 2 then reduce to 250mg/m 2 If initial dose was 250mg/m 2 then reduce to 225mg/m 2 2 nd Consecutive Event Wait until recovered to above levels then reduce dose by one dose level ie If previous dose was 280mg/m 2 then reduce to 250mg/m 2 If previous dose was 250mg/m 2 then discontinue treatment If previous dose was 225mg/m 2 then discontinue treatment Any other Toxicity Grade 3 (ie severe or life threatening, except grade 3 nausea/vomiting 3 rd Consecutive Event Discontinue treatment Delay until recovered to baseline then reduce dose as below. Discontinue if unresolved after 2 weeks. First Occurrence: Wait until recovered to above levels then reduce dose by one dose level ie if initial dose was 320mg/m 2 then reduce to 280mg/m 2 If initial dose was 280mg/m 2 then reduce to 250mg/m 2 If initial dose was 250mg/m 2 then reduce to 225mg/m 2 Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 17 of 18

18 Side-effect Vinflunine Bladder Dose Modification (Javlor SPC 30/07/13) 2 nd Consecutive Event Wait until recovered to above levels then reduce dose by one dose level ie If previous dose was 280mg/m 2 then reduce to 250mg/m 2 If previous dose was 250mg/m 2 then discontinue treatment If previous dose was 225mg/m 2 then discontinue treatment 3 rd Consecutive Event Discontinue treatment BLADDER CANCER/TRANSITIONAL CELL CARCINOMA Section by: Dr Philip Savage, Professor Jonathan Waxman, Dr Alison Falconer, Dr Simon Stewart. Version Control Sheet Version Date Author Status Comment Susan Whear Draft Susan Whear Replaced Previously approved version Susan Whear Draft Susan Whear Draft Susan Whear Replaced Previously approved version Susan Whear Draft Susan Whear Replaced Previously approved version Susan Whear Draft Susan Whear Replaced Previously approved version Susan Whear Draft Susan Whear Replaced Version control box added. Version approved Susan Whear Replaced Previously approved version Susan Whear Draft Added version control box Paclitaxel approval Susan Whear Draft Added Vinflunine additional private care Susan Whear Draft Amended title to include TCC Corrected page numbers Added information on reduced dose gemcitabine and split dose cisplatin in Gemcitabine/cisplatin regimen page APPROVED Section approved by Dr Philip Savage Lead clinician. Bladder Cancer-TCC Regimens v7.01 Approved NWLCN 15Oct13.doc Bladder page 18 of 18