Mr Hrouda Date Review date: May 2014

Transcription

1 GERM CELL TUMOURS Section by: Dr Philip Savage, Dr Cathryn Brock and Professor Michael Seckl Version: Germ Cell Tumour Regimens v3.02 NWLCN 28May12 Section last updated: 28 th May 2012 Last Corrected 28 th May 2012 Approved by Oncology GCT Lead Clinician: Dr Philip Savage Date Approved by NWLCN Urology Tumour Group: Mr Hrouda Date Review date: May 2014 Page Treatment Options by IGCCC Prognostic Group Adjuvant Carboplatin 7AUC CTIS: BEP 5 day+d9+d16 CTIS: First Line Good prognosis BEP 5day+D8+D16 CTIS: EP 100/20 5day CTIS: Renal impairment CEB CTIS: Intermediate prognosis BEP 5day+D8+D16 CTIS: POMB/ACE CTIS: 60/ Poor prognosis BEP 5day+D8+D16 CTIS: POMB/ACE CTIS: 60/ Poor prognosis plus Cerebral mets EP/OMB/ITMTX CTIS: 63/62/ Emergency treatment EP 100/20 1 day CTIS: day CTIS: 66/ day CTIS: 69 8 Second/Subsequent Line TIP CTIS: PACE/PAC-PLAT CTIS: 648 / GCP (ovarian GCT) CTIS: VelP CTIS: Oxaliplatin-Gemcitabine CTIS: Etoposide 50mg/m 2 oral CTIS: Under Consultant Direction Only Etoposide 500/Cisplat60 CTIS: 17 Cisplatin weekly/etoposide CTIS: followed by Etoposide 50mg/m 2 oral CTIS: Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 1 of 20

2 GERM CELL TUMOURS Section by: Dr Philip Savage, Dr Cathryn Brock and Professor Michael Seckl Version: Germ Cell Tumour Regimens v3.02 NWLCN 28May12 Section last updated: 28 th May 2012 Last Corrected 28 th May 2012 Approved by Oncology GCT Lead Clinician: May 2012 Approved by NWLCN Urology Tumour Group: June 2012 Review date: May 2014 GERM CELL TUMOURS Teratoma/Seminoma 1. Carboplatin 7AUC (CTIS: 1103) Carboplatin 7x(GFR+25)mg IV over 1 hour Day 1 Interval between cycles: one cycle only. No repeats Number of cycles: Adjuvant seminoma: one cycle only. No repeats Tests prior to single cycle of chemo: FBC, U&Es, LFTs, EDTA, CT TAP; Sperm storage if wished. GFR 40mls/min. If < 40mls/min discuss with consultant. Neutrophils 1.0 x 10 9 /L and Platelets 80 x 10 9 /L. If below these levels discuss with consultant. Supportive drugs: High risk antiemetics as per NWLCN guidelines or as per local policy Dose modifications: Dose as per GFR. Do not give if GFR below 40mls/min Reference: Lancet 2005;366 (9482): Oliver RT et al 2. BEP 5day +D9 +D16 (CTIS: 817) Etoposide 100mg/m 2 IV over 1 hour Days 1 to 5 Prehydrations Days 1 to 5 Cisplatin 20mg/m 2 IV over 2 hours Days 1 to 5 Post hydrations Days 1 to 5 Bleomycin* 30,000iu IV over 6 hours Day 2, 9,16 Interval between cycles: Repeat every 21 days Number of cycles: Adjuvant: 2 cycles only Good prognosis: 3 cycles Intermediate prognosis: 4 cycles Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 2 of 20

3 Poor prognosis; 4 cycles Test prior to course of chemo: FBC, U&Es, Mg, LFTs, EDTA (repeat prior to cycle 3); Sperm storage if time permits; Respiratory function tests (and repeat prior to cycle 3); CT TAP; MRI brain. Aim to avoid routine antiemetic steroids, Tests to OK/Confirm each cycle of chemo: FBC, U&Es, Mg, LFTs. Repeat EDTA if Supportive drugs: High risk antiemetics as per NWLCN guidelines or as per local policy Additional Information: *Bleomycin may be administered either on day 1 or 2 If GCSF support is required with this regimen, GCSF should be started on day 6 (24hours after the end of day 5 chemotherapy) and should continue as prescribed. Bleomycin may be administered on day 9 even if GCSF has been or is still being prescribed Dose modifications: See BEP table below Reference: Advanced Disease. Lancet 2001;357: Toner GC et al Adjuvant: J.Clin Oncol 1996;14(2): Pont J et al Table: BEP Due to curative aim of treatment, dose modifications should be avoided and only made after discussion with and under direction of the consultant in charge. However, where a dose reduction is to be made the following may serve as guidance: Side effect Dose Modification (Source: ) Haematology Neutrophils Platelets x10 9 /L x10 9 /L 1.0 and 80 If counts below these limits delay and discuss with consultant. Consider GCSF to support subsequent cycles (discuss with consultant) Renal function 60mls/min EDTA <60ml/min <50ml/min <30ml/min Discuss with consultant, consider changing to carboplatin using the CEB regimen, or dose reduce Cisplatin. As above plus Omit bleomycin Discuss with consultant Hepatic Impairment Bilirubin 25micromol/L >25micromol/L Consider etoposide 25-50% dose reduction Pulmonary Toxicity If bleomycin pulmonary toxicity (BPT) is suspected, stop bleomycin. Whilst there is no accurate test to predict who is likely to get this problem, it is more likely to occur in smokers, those aged over 40 years, those with poor renal function and those with previous RT treatment. Generally BPT presents after the end of chemotherapy treatment. Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 3 of 20

4 3. CEB (CTIS: 1124) Etoposide 120mg/m 2 IV over 1 hour Days 1,2 and 3 Carboplatin 5x(GFR+25)mg* IV over 1 hour Day 1 Bleomycin 30,000iu IV over 6 hours Day 2 *5x(GFR+25) if EDTA or if calculated Crcl reduce dose by 10%. *Dose in original paper was escalated if Day 16 platelets >150 x 10 9 /L and WBC >1.5 x 10 9 /L. Inferior to cisplatin based BEP, only use if unable to tolerate cisplatin Interval between cycles: Repeat every 21 days Number of cycles: Poor renal function unable to tolerate cisplatin: 4 cycles Tests prior to course of chemo: FBC, U&Es, Mg, LFTs, EDTA (repeat prior to 3 rd cycle), CT TAP, MRI brain. Sperm storage if time permits. Respiratory function tests if indicated. Aim to avoid routine steroid anti-emetics, Tests to ok/confirm each cycle of chemo: FBC, U&Es, Mg, LFTs. Repeat EDTA if Supportive drugs: High risk antiemetics as per NWLCN guidelines or as per local policy Macmillan drug specific information sheet/information Dose modifications: See CEB table on GCT page 5 Reference: J. Clin Oncol 1997;15(5): Horwich A et al Table: CEB Due to curative aim of treatment, dose modifications should be avoided and only made after discussion with and under direction of the consultant in charge. However, where a dose reduction is to be made the following may serve as guidance: Side effect Dose Modification (Source: ) Haematology Neutrophils Platelets x10 9 /L x10 9 /L 1.0 and 80 If counts below these limits delay and discuss with consultant. Consider GCSF to support subsequent cycles/escalated back at full dose (discuss with consultant) Renal function EDTA Hepatic Impairment Bilirubin 60ml/min <60ml/min <50ml/min <30ml/min 25micromol/L >25micromol/L Calculate carboplatin dose using Calvert equation Omit bleomycin Carboplatin dose as above Discuss with consultant Consider etoposide 25-50% dose reduction Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 4 of 20

5 Side effect Dose Modification (Source: ) Pulmonary Toxicity If bleomycin toxicity (BPT) is suspected stop bleomycin. Whilst there is no accurate test to predict who is likely to get this problem, it is more likely to occur in smokers, those aged over 40 years, those with poor renal function and those with previous RT treatment. Generally BPT presents after the end of chemotherapy treatment. 4. EP-100/20 5 day (CTIS: 1106) Etoposide 100mg/m 2 IV over 1 hour Days 1,2,3,4,5 Prehydrations Days 1,2,3,4,5 Cisplatin 20mg/m 2 IV over 2 hours Days 1,2,3,4,5 Post hydrations Days 1,2,3,4,5 Interval between cycles: Repeat every 21 days Number of cycles: Good prognosis 4 cycles Tests prior to course of chemo: FBC, U&Es, Mg, LFTs; Crcl/EDTA (repeat prior to cycle 3); CT TAP; MRI brain. Sperm storage if time permits; Aim to avoid routine antiemetic steroids. Tests to ok/confirm each cycle of chemo: FBC, U&Es, Mg, LFTs. Repeat EDTA if Supportive drugs High risk antiemetics as per NWLCN guidelines or as per local policy Dose modifications: Discuss with consultant Reference: J. Clin Oncol 1988;6(8): Bosl GJ et al Table: EP-GCT Due to curative aim of treatment, dose modifications should be avoided and only made after discussion with and under direction of the consultant in charge. However, where a dose reduction is to be made the following may serve as guidance: Side effect Dose Modification Haematology Neutrophils Platelets x10 9 /L x10 9 /L 1.0 and 80 If counts below these limits delay and discuss with consultant. Consider GCSF to support subsequent cycles/escalated back at full dose (discuss with consultant) Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 5 of 20

6 Side effect Renal function EDTA Hepatic Impairment Bilirubin 60mls/min <60ml/min <50ml/min <30ml/min 25micromol/L >25micromol/L Dose Modification Consider changing to carboplatin calculating dose using Calvert equation or dose reduce cisplatin As above plus Etoposide: 25% dose reduction Discuss with consultant Consider etoposide 25-50% dose reduction 5. POMB/ACE Chemo every two weeks beginning with POMB, POMB, ACE, POMB, ACE etc. 5a. POMB (CTIS: 60) Vincristine 1mg/m 2 (max 2mg) IV in minibag over 10mins Day 1 Methotrexate 300mg/m 2 IV over 12 hours Day 1 Bleomycin 15,000iu IV over 12 hours Day 2 Bleomycin 15,000iu IV over 12 hours Day 2 Folinic acid 15mg Oral/IV at 24, 36, 48 and 60 hours after start of methotrexate Pre-hydrations Day 3 Cisplatin 40mg/m 2 IV over 4 hours Day 3 Cisplatin 40mg/m 2 IV over 4 hours Day 3 Cisplatin 40mg/m 2 IV over 4 hours Day 3 Post hydrations Day 3 5b. ACE (CTIS: 61) Etoposide 100mg/m 2 IV over 30mins-1 hour Day 1, 2, 3 Actinomycin-D 0.5mg IV bolus Day 1, 2, 3 Cyclophosphamide 500mg/m 2 IV over 30mins-1 hour Day 3 Interval between cycles: Chemo every 2 weeks beginning POMB, POMB, ACE POMB, ACE, POMB etc. Alternate every two weeks with ACE (see above) ie: POMB every 28 days Number of cycles: Intermediate prognosis: 5 cycles (ie P.P.A.P.A.) or to marker normalisation plus 2 cycles Poor prognosis: 7 cycles (ie. P.P.A.P.A.P.A.) or to Marker normalisation plus 2 cycles Tests before starting course of chemo: FBC, U&E, Mg, LFTs, EDTA (repeat prior to cycle 3); CT TAP; MRI brain; Sperm storage if time permits; Respiratory function tests (and repeat prior to cycle 3). Aim to avoid routine antiemetic steroids. Tests to ok/confirm each cycle of chemo: FBC, U&Es, Mg, LFTs. Repeat EDTA if Supportive drugs: Antiemetics below as per NWLCN guidelines or as per local policy POMB ; Very high risk anti-emetics ACE; Moderate risk anti-emetics. Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 6 of 20

7 Macmillan drug specific information sheets /information Dose modifications: Discuss with consultant Reference: Ann. Oncol. 1997;8(5): Bower M et al. 6. Poor Prognosis Plus Cerebral Metastases at Presentation EP/OMB MTX 1gram + Intrathecal Methotrexate EP 150/75 (CTIS: 63) Etoposide 150mg/m 2 IV over 30mins-1 hour Day 1 Cisplatin 25mg/m 2 IV over 4 hours Day 1 Cisplatin 25mg/m 2 IV over 4 hours Day 1 Cisplatin 25mg/m 2 IV over 4 hours Day 1 Post hydrations Day 1 OMB MTX 1gram (CTIS: 62) Vincristine 1mg/m 2 (max 2mg) IV in minibag over 10mins Day 1 Methotrexate 500mg/m 2 IV over 12 hours Day 1 Methotrexate 500mg/m 2 IV over 12 hours Day 1 Bleomycin 15,000iu IV over 12 hours Day 2 Bleomycin 15,000iu IV over 12 hours Day 2 Folinic acid 30mg IV bolus every 6 hours to a total of 12 doses, starting 32 hours after start of methotrexate Intrathecal Methotrexate (CTIS: 782) Given with EP in EP/OMB-CNS regimen Methotrexate 12.5mg intrathecal dose Folinic acid 7.5mg oral given at 24 and 48 hours post methotrexate Where folinic acid rescue is prescribed for both intrathecal and IV methotrexate omit rescue doses for intrathecal methotrexate. Interval between cycles: EP 150/75 alternates weekly with OMB-MTX 1gram if CNS disease. Intrathecal methotrexate given with EP 150/75. Alternating chemo every week Number of cycles: 8 cycles (ie. EP-OMB x 4) or to normalisation of markers plus 2 cycles. Tests before starting course of chemo: FBC, U&Es, Mg, LFTs, EDTA (repeat prior to cycle 3); Sperm storage if time permits; Respiratory function tests (and repeat prior to cycle 3) CT TAP; MRI brain. Aim to avoid routine antiemetic steroids. Test to ok/confirm each cycle of chemo: FBC, U&Es, Mg, LFTs. Repeat EDTA if Supportive drugs: Antiemetics below as per NWLCN guidelines or as per local policy EP: Very high risk antiemetics OMB: High risk antiemetics Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 7 of 20

8 Dose Modifications: Discuss with Consultant Reference: Cancer 1986;57(11): Rustin GJ et al 7. Emergency Treatment Sick Patients EP 100/20 (CTIS: 1day: 64, 2day: 66, 3day: 69, 2day emergency: 1513) Most commonly used as initial treatment in patients with very extensive disease particularly pulmonary disease. Same Chemotherapy is given on 1,2 or 3 consecutive days. Note: these doses are the same as days of BEP (but without bleomycin). Etoposide 100mg/m 2 IV over 30mins-1 hour Prehydrations Cisplatin 20mg/m 2 IV over 2 hours Post hydrations Interval between cycles: Repeat determined by consultant often weekly. Number of cycles: Depends on response, often change regimen once condition improves. Tests before starting course of chemo: FBC, U&Es, Mg, LFTs, EDTA (repeat prior to cycle 3) CT TAP; MRI brain; Sperm storage if time permits. Aim to avoid routine antiemetic steroids. Tests to ok/confirm each cycle of chemo: FBC, U&Es, Mg, LFTs. Repeat EDTA if Supportive drugs: High risk antiemetics as per NWLCN guidelines or as per local policy Dose modifications: Discuss with consultant Reference: Ann.Oncol. 2004;15(9): Rustin GJ et al Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 8 of 20

9 8. TIP (CTIS: 1120) Dexamethasone* 20mg Oral 12 hours pre paclitaxel Day 1 Dexamethasone* 20mg Oral 3-6 hours pre paclitaxel Day 1 Ranitidine 50mg IV bolus 30-60mins pre-paclitaxel Day 1 Chlorphenamine 10mg IV bolus 30-60mins pre-paclitaxel Day 1 Paclitaxel 175mg/m 2 IV over 3hrs Days 1 Prehydrations Days 1,2,3,4,5 Cisplatin 20mg/m 2 IV over 2 hrs Days 1,2,3,4,5 Mesna 340mg/m 2 IV over 20 mins Days 1,2,3,4,5 Ifosfamide 1200mg/m 2 }IV over 1hr Days 1,2,3,4,5 Mesna (in bag with Ifosfamide) 1200mg/m 2 } Days 1,2,3,4,5 Mesna 720mg/m 2 IV over 12hrs Days 1,2,3,4,5 Neulasta 6mg SC stat 24 hours after last dose of ifosfamide *Dexamethasone premed may be changed to a single dose dexamethasone 20mg IV bolus 30-60minutes pre paclitaxel Interval between cycles: Repeat every 21 days Number of cycles: Relapsed refractory disease: 3-4 cycles Tests before starting course of chemo: FBC, U&Es, Mg, LFTs, EDTA (repeat prior to cycle 3) CT TAP; MRI brain. Aim to avoid routine antiemetic steroids. Tests to ok/confirm each cycle of chemo: FBC, U&Es, Mg, LFTs. Repeat EDTA if Supportive drugs: High risk antiemetics as per NWLCN guidelines or as per local policy. GCSF support starting day 9 for 5 to 7 days Dose modifications: Table page 10 Reference: J. Clin Onc (12) Motzer RJ et al J. Clin Onc a(15S) abstract el6094. Mardiak J et al BCCA protocol adopted February 2012 Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 9 of 20

10 Table: TIP Due to curative aim of treatment, dose modifications should be avoided and only made after discussion with and under direction of the consultant in charge. However, where a dose reduction is to be made the following may serve as guidance: Side effect Dose Modification (Dr P Savage) Haematology Neutrophils Platelets X10 9 /L x10 9 /L 1.0 and 90 If counts below these limits, delay and discuss with consultant. Consider GCSF to support subsequent cycles escalated back to full dose Renal Function (PS/NLCN 2009) 60mls/min 40-59mls/min <40mls/min Hepatic Function (SPC) Ifosfamide SPC Bilirubin >17micromol/L Or Transaminases/ALP >2.5 x ULN all drugs Ifosfamide 30% dose reduction Redo EDTA. If still below 40mls/min Do not give cisplatin If renal function recovered above 40mls/min restart cisplatin with 25% dose reduction. If renal function recovers further to baseline, full dose cisplatin may be resumed after discussion with consultant. No reduction for cisplatin or paclitaxel Do not give ifosfamide Do not give ifosfamide 9 PAC-E PAC/PLAT Regimen used to determine if GCT is still chemosensitive. High dose therapy with stem cell rescue is considered in chemosensitive patients. 9a PAC-E (CTIS: 648) (New paclitaxel dose Oct 2005) Etoposide 150mg/m 2 IV over 1 hour Day 1 Dexamethasone* 20mg Oral 12 hours pre paclitaxel Day 1 Dexamethasone* 20mg Oral 3-6 hours pre paclitaxel Day 1 Ranitidine 50mg IV bolus 30-60mins pre-paclitaxel Day 1 Chlorphenamine 10mg IV bolus 30-60mins pre-paclitaxel Day 1 Paclitaxel 135mg/m 2 IV over 3 hours Day 1 9b PAC-PLAT (CTIS: 641) Dexamethasone* 20mg Oral 12 hours pre paclitaxel Day 1 Dexamethasone* 20mg Oral 3-6 hours pre paclitaxel Day 1 Ranitidine 50mg IV bolus 30-60mins pre-paclitaxel Day 1 Chlorphenamine 10mg IV bolus 30-60mins pre-paclitaxel Day 1 Paclitaxel 135mg/m 2 IV over 3 hours Day 1 Cisplatinum 60mg/m 2 IV over 2 hours Day 1 Post hydrations Day 1 *Dexamethasone premed may be changed to a single dose dexamethasone 20mg IV bolus 30-60minutes pre paclitaxel Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 10 of 20

11 Interval between cycles: PAC-E alternates with PAC/PLAT every 14 days ie. PAC-E repeated every 28 days Number of cycles: Relapsed refractory disease: 2-4 cycles (PACE-PAC/PLAT) x 2-4 Tests before starting course of chemo: FBC, U&Es, Mg, LFTs, EDTA (repeat prior to cycle 3) CT TAP; MRI brain. Aim to avoid routine antiemetic steroids. Tests to ok/confirm each cycle of chemo: FBC, U&Es, Mg, LFTs. Repeat EDTA if Supportive drugs: High risk anti-emetics below as per NWLCN guidelines or as per local policy PAC-E: High risk anti-emetics PAC-PLAT: Very high risk antiemetics Dose modifications: Table below Reference: Reprod. Med. 2004;49(8): Osbourne R et al Table: PAC/PLAT-PACE Due to curative aim of treatment, dose modifications should be avoided and only made after discussion with and under directions of the consultant in charge. However, where a dose reduction is to be made the following may serve as guidance: Side effect Dose Modification Haematology Neutrophils Platelets x10 9 /L x10 9 /L 1.0 and 80 If counts below these limits delay and discuss with consultant. Renal Function Crcl Hepatic Function 50mls/min <50mls/min all drugs Consider switching to carboplatin 4AUC Etoposide: 25% dose reduction Paclitaxel: Discuss with consultant Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 11 of 20

12 10. GCP (Hansen Regimen) (CTIS: 1104) Dexamethasone* 20mg Oral 12 hours pre paclitaxel Day 1 Dexamethasone* 20mg Oral 3-6 hours pre paclitaxel Day 1 Ranitidine 50mg IV bolus 30-60mins pre-paclitaxel Day 1 Chlorphenamine 10mg IV bolus 30-60mins pre-paclitaxel Day 1 Gemcitabine 800mg/m 2 IV over 1hr Day 1 and 8 Paclitaxel 175mg/m 2 IV over 3hrs Day 1 Carboplatin 5(GFR+25)mg IV over 1hr Day 1 *Dexamethasone premed may be changed to a single dose dexamethasone 20mg IV bolus 30-60minutes pre paclitaxel Interval between cycles: Repeat every 21 days Number of cycles: Relapsed/refractory ovarian Germ cell tumours: 2-4 cycles Tests before starting course of chemo: FBC, U&Es, LFTs, EDTA (repeat prior to cycle 3) CT TAP; MRI brain. Aim to avoid routine antiemetic steroids. Aim to avoid routine antiemetic steroids. Tests to ok/confirm each cycle of chemo: Day 1; FBC, U&Es, LFTs. Repeat EDTA if Day 8; FBC, U&Es Supportive drugs; Antiemetics below as per NWLCN guidelines or as per local policy Day 1; High risk antiemetics Day 8; Low risk antiemetics Dose modifications: Table below Reference: Gynecol.Oncol. 2005;96(2): Du Bois A. et al Table: GCP Due to curative aim of treatment, dose modifications should be avoided and only made after discussion with and under direction of the consultant in charge. However, where a dose reduction is to be made the following may serve as guidance: Side effect Dose Modification Haematology Neutrophils Platelets x10 9 /L x10 9 /L Day and 80 <1.0 or <80 Day and 80 <1.0 or <80 all drugs. Do not treat below these limits. Delay until recovery. Discuss doses with consultant gemcitabine Omit day 8 chemo and restart next cycle day 22 as planned Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 12 of 20

13 Side effect If Neutrophils <0.5 for 4 days Or Neutropenic sepsis Or Platelets <25 Or Platelets <50 for 5 days Renal Function 30mls/min <30mls/min Dose Modification } } Gemcitabine: Omit day 1 and 8 } } Carboplatin dose as Calvert equation. Paclitaxel: Gemcitabine: Discuss with consultant Hepatic Function Bilirubin <27micromol/L 27-50micromol/L >50micromol/L all drugs Gemcitabine: 25% dose reduction Paclitaxel: 25% dose reduction Gemcitabine: 25% dose reduction Paclitaxel: 50% dose reduction 11. VeIP (CTIS: 632) Vinblastine 0.11mg/kg (max 10mg) IV in minibag over 10mins Day 1and 2 Prehydrations Day 1,2,3,4,5 Cisplatin 20mg/m 2 IV over 2hrs Day 1,2,3,4,5 Mesna 240mg/m 2 IV over 20mins Day 1,2,3,4,5 Ifosfamide 1200mg/m 2 } IV over 1 hrs Day 1,2,3,4,5 Mesna (in bag with ifosfamide) 1200mg/m 2 } Day 1,2,3,4,5 Mesna 720mg/m 2 IV over 12hrs Day 1,2,3,4,5 Interval between cycles: Repeat every 21 days Number of cycles: Relapsed/refractory: 4 cycles Tests before starting course of chemo: FBC, U&Es, Mg, LFTs, EDTA (repeat prior to cycle 3) CT TAP; MRI brain. Aim to avoid routine antiemetic steroids. Tests to ok/confirm each cycle of chemo: FBC, U&Es, Mg, LFTs. Repeat EDTA if Supportive drugs: High risk antiemetics as per NWLCN guidelines or as per local policy Dose modifications: Table below Reference: Ann Inter Med 1988;109(10):846. Loehrer PJ et al Ann Inter Med 1988;109: Loehrer PJ et al Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 13 of 20

14 Table: VelP Due to curative aim of treatment, dose modifications should be avoided and only made after discussion with and under direction of the consultant in charge. However, where a dose reduction is to be made the following may serve as guidance: Side effect Dose Modification (Source: ) Haematology Neutrophils Platelets x10 9 /L x10 9 /L 1.0 and 80 If below these limits delay until recovered then full dose Renal Function (NLCN 2009) Hepatic Function 60mls/min <60mls/min 40-59mls/min <40mls/min <26micromol/L 26-51micromol/L >51micromol/L all drugs Cisplatin: consider swapping to carboplatin Ifosfamide 30% dose reduction Do not give. Discuss with consultant all drugs Vinblastine: 50% dose reduction Ifosfamide: 50% dose reduction Gemcitabine: 25% dose reduction Omit vinblastine 12. Oxaliplatin/Gemcitabine (CTIS: 1700) Request local approval before treatment commences Gemcitabine 1000mg/m 2 IV over 30mins Day 1 and 8 Oxaliplatin 130mg/m 2 IV over 2 hours Day 1 Interval between cycles: Repeat every 21 days Number of cycles: Relapsed/Refractory disease: 6 cycles Tests before starting course of chemo: FBC, U&Es, LFT, Crcl calculated. Do EDTA if Crcl <50mls/min Tests to ok/confirm each cycle of chemo: Day 1: FCB, U&Es, LFTs, Crcl (calculated) Day 8: FBC, U&Es Supportive drugs with each cycle: High risk antiemetics as per NWLCN guidelines or as per local policy Administration notes: Oxaliplatin is incompatible with normal saline, therefore, the venous access device and administration sets should be flushed with 5% glucose. Patients should be advised to keep warm as exposure to cold post oxaliplatin infusion may aggravate symptoms of peripheral neuropathy and laryngopharyngeal dysthesia. In the event of laryngopharyngeal symptoms during an oxaliplatin infusion, reassure the patient that the symptoms are likely to resolve. This must not be confused with an allergic response which requires emergency intervention. The patient who suffers from laryngopharyngeal spasm may be re-challenged with oxaliplatin at a slower infusion rate of up to 6 hours. On occasions pain may be experienced in the infusion arm, if so, slow infusion rate to a maximum 6 hours. Consider CVAD if problematic. Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 14 of 20

15 Hypersensitivity Reactions: Stop infusion and institute appropriate support. Discuss with consultant. Dose modifications: See table below Reference: J. Clin.Onc 22 No.1 (January) Table: Oxaliplatin/Gemcitabine Side Effects Dose Modifications Haematology Neutrophils Platelets x 10 9 /L x 10 9 /L Day and 75 <1.5 or <75 Day and or <1.0 or <50 If Neutropenic fever or Thrombocytopenia <50x10 9 /L Renal function Crcl 30mls/min < 30mls/min Hepatic Function Bilirubin >1.5 x ULN ALT/AST/ALP >3.0 x ULN Non haematological toxicities including Neurotoxicity; Cold related dysaethesia Parasthesia without pain Parasthesia with pain Parasthesia with functional impairment Laryngeal dysaesthesia Delay until recovered. Discuss dose with consultant. gemcitabine Discuss with consultant. Consider gemcitabine 25% dose reduction Omit day 8 chemotherapy and restart next cycle of gemcitabine and oxaliplatin on DAY 15. Discuss dose with consultant } Next cycle } Oxaliplatin full dose } Gemcitabine 25% dose reduction Do not give Do not give Do not give Discuss with consultant Administer oxaliplatin over 6 hours Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 15 of 20

16 Side Effects Allergic reactions to oxaliplatin Approximately 9.1% (SPC) incidence of acute hypersensitivity to oxaliplatin usually after more than 6 cycles have been administered. During administration patient may develop rash, fever, swollen mouth/tongue hyper or hypotension etc. This rarely develops to full blown anaphylaxis even with repeated treatment Dose Modifications Grade 1 and 2 If acute hypersensitivity occurs: Discontinue infusion Treat with IV corticosteroids and antihistamine Re-challenge at consultant s discretion with: (COIN) Dexamethasone 4mg orally every 6 hours starting 24 hours pre chemo Dexamethasone 8mg IV 30 minutes pre chemo Chlorphenamine 10mg IV bolus dose 30 mins pre chemo Ranitidine 50mg IV bolus dose 30mins pre chemo Continue dexamethasone, chlorphenamine and ranitidine for hours after oxaliplatin Grade 3 and 4 Treat for full anaphylaxis. DO NOT GIVE further oxaliplatin 13. Etoposide Oral (CTIS: 1699) Etoposide 50mg/m 2 Oral Once daily Day 1 to 21 (etoposide oral is available as 50mg or 100mg capsules) Interval between cycles: Repeat every 28 days (1 week break) Number of cycles: Relapsed/Refractory disease 3 cycles Tests before starting course of chemo: FBC, U&Es, LFTs Weekly FBC for first 8 weeks Tests to ok/confirm each cycle of chemo: FBC, U&Es, LFTs Supportive drugs with each cycle: None Dose modifications: Reference: J. Clin Onc 13 No.5 (May)1995; Table: Etoposide Oral Side Effects Haematology Neutrophils Platelets x10 9 /L x10 9 /L 1.0 and 80 <1.0 or <80 <0.5 or <50 Dose Modification Withhold treatment until recovered. Discuss with consultant. Withhold treatment for 1 week/until recovered then restart with 25% dose reduction Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 16 of 20

17 14. Escalated Dose EP for Relapsed GCT EP 500/60 1 day (CTIS: ) Etoposide 500mg/m 2 IV over 2 hours Day 1 Prehydrations Day 1 Cisplatin 60mg/m 2 IV over 2 hours Day 1 Post hydrations Day 1 Interval between cycles: Repeat every 21 days Number of cycles: For consultant use only Relapsed/Refractory disease: 4-6 cycles Tests prior to course of chemo: FBC, U&Es, Mg, LFTs; Crcl/EDTA (repeat prior to cycle 3); CT TAP; MRI brain. Aim to avoid routine antiemetics steroids. Tests to ok/confirm each cycle of chemo: FBC, U&Es, Mg, LFTs. Repeat EDTA if Supportive drugs: Very high antiemetics as per NWLCN guidelines or as per local policy Dose modifications: Discuss with consultant and see page 6 Reference: Professor M Seckl experience 15. Cisplatin weekly plus oral Etoposide (Van der Burg) Cisplatin plus oral etoposide (CTIS 1835 Cisp 50wk + Etop) weekly for maximum 6 weeks as below. Patients with a response or stable disease then receive oral etoposide (CTIS: 1699) for up to 3 cycles. 15a. Cisp50 wk + Etop (CTIS: 1835) Pre hydrations Days 1, 8, 15 Sodium Chloride 3% 250mls IV over 3 hours Days 1, 8, 15 Cisplatin 50mg/m 2 IV over 3 hours Days 1, 8, 15 Post hydrations Days 1, 8, 15 Etoposide 50mg Oral once a day Days 1 to 15 NB. Sodium chloride 3% and cisplatin to run simultaneously. 3% used to reduce renal complications in weekly cisplatin at this dose (Trial used doses up to cisplatin 70mg/m 2 ) Interval between cycles: Repeat day 29 maximum 2 cycles Maximum 2 cycles (total 6 cisplatin infusions). Patients with a response or stable disease receive oral etoposide 21 day (CTIS regimen 1699 on page 18) Number of cycles: For consultant use only Relapsed/Refractory disease Maximum 2 cycles Tests before starting course of chemo: FBC, U&Es, LFTs, EDTA, Crcl must be 60mls/min. Tests to Ok/Confirm each dose of chemo: Weekly FBC, U&Es, LFTs, Crcl (calculated) must be above 70mls/min if calculated. Supportive drugs with each cycle: High risk antiemetics as per NWLCN guidelines or as per local policy Sodium chloride 3% as above Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 17 of 20

18 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 Van der Berg Cisp 60wk/Etop Ovarian Cancer NB. Original paper administered cisplatin 70mg/m 2 weekly for maximum 6 weeks (2 cycles of above) Reference: B.J. Cancer Van der Burg Weekly cisplatin and daily etoposide is highly effective in platinum pre-treated ovarian cancer. Table: Cisp 50wk + Etop Side-effect Haematology WBC Platelets X10 9 /L x10 9 /L Day 8 (Cisplatin no.2) > 2.5 and >75 <2.5 or <75 Day 15 (Cisplatin no.3) >1.5 and >50 <1.5 or <50 Day 29 (Cisplatin no.4) >3.0 and >100 <3.0 or <100 Day 36 (Cisplatin no.5) >2.5 and >75 <2.5 or <75 Dose modification (Prof Seckl) Delay all drugs until recovery, then full dose. Omit cisplatin (Etoposide ends day 15 anyway) Delay all drugs until recovery, then full dose Delay all drugs until recovery, then full dose Day 43 (Cisplatin no.6) >1.5 and >50 <1.5 or <50 Renal function Crcl Neuropathy 60ml/min <60ml/min Omit cisplatin (Etoposide ends day 43 anyway) Stop cisplatin. Discuss with consultant > grade 2 Stop cisplatin Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 18 of 20

19 15b. Etop 21 day (CTIS: 1835) Follows 2 cycles of Cisp-50 wkly + Etop (CTIS: 1750) Etoposide 50mg/m 2 Oral once a day Days 1 to 21 (max 100mg) If heavily pretreated use max 50mg/day Interval between cycles: Repeat day 28 Number of cycles: Relapsed/Refractory GCT Usually up to 3 cycles following 2 cycles of Cisp-50 wkly. Further treatment only under direction of consultant in charge. Maximum 9 cycles Tests before starting course of chemo: FBC, U&Es, LFTs, Tests to Ok/Confirm each cycle of chemo: Weekly FBC (Day 1,8,15 of each cycle) Three weekly U&Es, LFTs. Supportive drugs with each cycle: Patient information: Dose modification: See table Etop 21day below Reference: B.J. Cancer 2002: 86, Low risk antiemetics Chemotherapy treatment booklet (local information/macmillan) Table: Etop-21 day Side-effect Etoposide 21 Day WBC Platelets x10 9 /L x10 9 /L Day and 100 <3.0 or <100 Day and 50 <2.0 or <50 Day and 50 <2.0 or <50 Dose modification (Prof Seckl) Continue full dose Delay until recovery then full dose Continue Discontinue etoposide until next cycle Continue Discontinue etoposide until next cycle Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 19 of 20

20 GERM CELL TUMOURS Section by: Dr Philip Savage, Dr Cathryn Brock and Professor Michael Seckl Version Control Sheet Version Date Author Status Comment Susan Whear Draft Susan Whear Replaced Previously approved version Susan Whear Replaced Previously approved version Susan Whear Draft Susan Whear Replaced Previously approved version Susan Whear Replaced Previously approved version Susan Whear Draft Susan Whear Draft Susan Whear APPROVED Version control box added. Version approved Germ Cell regimens v3.02 NWLCN 28May12.doc Urology GCT page 20 of 20