Thames Valley SACT Regimenstvscn.nhs.uk/wp-content/uploads/2019/02/Gynae-2.4-January-2019.pdf · BEP 5 day metastatic Non-seminomatous germ cell 22 BEP 3 day adjuvant Non-seminomatous

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Gynae SACT regimens 1

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SACT Regimens

Gynaecological Cancer

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Gynae SACT regimens Page 2 of 86

Notes from the editor Theseregimens are available on the Network website www.tvscn.nhs.uk. Any correspondence about the regimens should be addressed to: Sally Coutts, Cancer Pharmacist, Thames Valley email: [email protected] Tel: 01865 857166 Acknowledgements These regimens have been compiled by the Network Pharmacy Group in collaboration with the Gynae CAG with key contribution from Dr Bernadette Lavery, Consultant Oncologist, OUH Dr Clive Charlton, Consultant Oncologist, RBFT Dr Marcia Hall, Consultant Oncologist, HWP Prof Sean Kehoe, Consultant Gynaecologist, OUH Karen Carter, Oncology Pharmacist, RBFT

© Thames Valley Cancer Network. All rights reserved. Not to be reproduced in whole or in part without the permission of the copyright owner.

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Thames Valley SACT Regimens Gynaecological Cancer Theregimens listed below were approved for use within the Thames Valley Cancer Network by the Gynae CAG. Date published: January 2019 Date of review: January 2021

SACT Regimens Name of regimen Indication Page

List of modifications to this version 5

Bevacizumab 15mg/kg Cervical, 6

BIP inpatient Recurrent cervical carcinoma 8

Cisplatin 40 weekly with RT Advanced cervical carcinoma 11

Cisplatin 70 pre radiotherapy Advanced cervical carcinoma 13

Cisplatin 50 Recurrent cervical carcinoma 15

Topotecan Cisplatin Recurrent cervical carcinoma 17

BEP 3 day metastatic Non-seminomatous germ cell 19

BEP 5 day metastatic Non-seminomatous germ cell 22

BEP 3 day adjuvant Non-seminomatous germ cell 25

EMA / CO Gestational trophoblastic disease 28

Carboplatin AUC7 Dysgerminoma and seminoma 29

Methotrexate 50 Germ cell 30

Methotrexate weekly Germ cell 31

Bevacizumab 7.5mg/kg Ovarian, fallopian, peritoneal 32

Carboplatin desensitisation 34

Niraparib Ovarian, fallopian tube, peritoneal 36

Paclitaxel carboplatin 21 day Ovarian + endometrial + cervical 39

Paclitaxel cisplatin Ovarian 41

Carboplatin 21 day Ovarian 43

Carboplatin 28 day Ovarian 45

Cisplatin / oral etoposide Relapsed ovarian 47

Cisplatin weekly Relapsed ovarian 50

Cisplatin 21 day Recurrent ovarian 52

Etoposide IV Recurrent ovarian 54

Etoposide oral Recurrent ovarian 55

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Name of regimen cont. Indication Page

Gemcitabine Cisplatin Recurrent ovarian 56

Liposomal doxorubicin (Caelyx) Recurrent / resistant ovarian 59

Olaparib capsules Ovarian, Fallopian 61

Paclitaxel 3 weekly Recurrent / relapsed ovarian 63

Paclitaxel weekly Recurrent ovarian 65

Gemcitabine Carboplatin Ovarian cancer 67

Paclitaxel 7 day and carboplatin Advanced ovarian cancer 69

Paclitaxel 7 day and carboplatin 7 day Advanced ovarian cancer 71

Liposomal doxorubicin and carboplatin Advanced ovarian cancer 73

Doxorubicin Endometrial cancer 75

Doxorubicin + cisplatin Endometrial cancer 76

Doxorubicin + ifosfamide Adjuvant uterine sarcoma 78

Doxorubicin (30) + ifosfamide (3g) Metastatic uterine sarcoma 81

Ifosfamide nomogram 84

Hydration regimens 86

Carboplatin may be substituted with cisplatin in those patients hypersensitive to carboplatin, unless soecified in CDF or NICE criteria. Cisplatin may be substituted with carboplatin in those patients hypersensitive to cisplatin, unless soecified in CDF or NICE criteria.

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List of amendments in this version Regimen type: Gynae Tumours Date due for review: January 2021 Previous Version number: 2.3 This version number: 2.4 Table 1 Amendments

Page Action Type

Amendment Made/ asked by

Diluents amended as per national dose specifications

Table 2 New regimens to be approved and checked by CAG included in this version

Name of regimen Indication Reason / Proposer

Gemcitabine Cisplatin Ovarian Dr Nicum

Carboplatin desensitisation Desensitisation Dr Nicum

Bevacizumab CDF

Bevacizumab CDF

Olaparib NICE

Niraparib CDF

For anti-emetic guidelines: http://tvscn.nhs.uk/networks/cancer/cancer-topics/chemotherapy/ For dose banded chemotherapy standardized product specifications: www.england.nhs.uk/commissioning/spec-services/npc-crg/group-b/b02/dose-banded-chemotherapy-standardised-product-specifications/

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BEVACIZUMAB (15mg/kg) Indication: The first line palliative chemotherapy treatment of primary stage IVB recurrent or persistent disease not amenable to curative treatment with surgery and/or radiotherapy.cervical cancer in combination with Paclitaxel and either Cisplatin or Carboplatin chemotherapy, no previous treatment with bevacizumab or other anti-VEGF therapy. PS 0 or 1

DRUG REGIMEN Day 1 BEVACIZUMAB 15mg/kg IV in 100ml sodium chloride 0.9% infusion over 90* minutes. * The initial dose should be administered over 90 minutes, if tolerated well the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated all subsequent infusions may be administered over 30 minutes.

Cycle frequency: Repeat every 21 days until disease progression

DOSE MODIFICATIONS Renal impairment no studies have been conducted to investigate bevacizumab in renal impairment since the kidneys are not a major organ for bevacizumab metabolism or excretion. Clinical decision Hepatic impairment no studies have been conducted to investigate bevacizumab in hepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion. Clinical decision

INVESTIGATIONS Routine Blood tests 1. Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 2. Non-urgent Blood tests Tests relating to disease response/progression.

CONCURRENT MEDICATIONS

ANTI-EMETIC POLICY Minimal emetic risk

Bevacizumab cervical

Gynae CAG Chair Authorisation: Date:

Page 1 of 2 Published: January 2019 Review: January 2021

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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Gastrointestinal perforation Haemorrhage Arterial thromboembolism REFERENCES 1. Bevacizumab January 2005 www.medicines.org.uk 2. CDF

Bevacizumab cervical



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BIP inpatient (Cervix)

Indication: Recurrent cervical carcinoma

DRUG REGIMEN Day 1 BLEOMYCIN 30,000units in 1000ml sodium chloride 0.9% infusion over 24 hours Pre-hydration CISPLATIN 50mg/m2 in 1000ml sodium chloride 0.9% infusion over 4 hours

Post hydration Day 2 MESNA 1g/m2 IV bolus IFOSFAMIDE 1.7g/m2 and MESNA 1.7g/m2 in 1L sodium chloride 0.9% infusion over 8 hours IFOSFAMIDE 1.7g/m2 and MESNA 1.7g/m2 in 1L sodium chloride 0.9% infusion over 8 hours IFOSFAMIDE 1.7g/m2 and MESNA 1.7g/m2 in 1L sodium chloride 0.9% infusion over 8 hours

MESNA 3g/m2 in 1L sodium chloride 0.9% infusion over 12 hours Cycle Frequency: Every 21 days for 6 cycles

NB. Some evidence that IP is as good as BIP therefore bleomycin may be omitted at consultant’s discretion [1]. Cisplatin may be given on day 3 (instead of day 1) if the patient doesn’t have a line inserted.

DOSE MODIFICATIONS This regimen is ideally only given with normal renal function. Previous neutropenic sepsis, discuss with SpR or Consultant Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin [3] If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration.

Bleomycin: GFR > 50ml/min give 100% dose GFR 10-50ml/min give 75% dose GFR <10ml/min give 50% dose [3]

Ifosfamide: GFR 40-59ml/min give 70% dose GFR <40ml/min clinical decision. Creatinine >120micromol/L ifosfamide not recommended [3] Discuss if *Bilirubin >17micromol/L *AST and Alk Phos > 2.5 x upper limit of normal[3]

BIP Gynae CAG Chair Authorisation: Date:


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INVESTIGATIONS Routine Blood test 1) Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 Liver function tests (LFT) a. Monitor magnesium throughout treatment. b. Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion. c. If probability of remaining free from CNS toxicity <0.2 do not give (consider carefully). If probability of remaining free from CNS toxicity is between 0.2 and 0.5 monitor for signs of encephalopathy. d. Pulmonary function tests are indicated if patient complains of dyspnoea or there are changes on

x-ray. 2) Non-urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per inpatient schedule at the end of the TVCN protocols. If fluid balance is > 2L positive after 8 hours post hydration OR if patient gains >2kg in weight or urine output <100ml//hour during IV administration post Cisplatin give 20 - 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV Methylthioninium chloride (methylene blue) can be given as prophylaxis against, or treatment of, ifosfamide-induced encephalopathy (see details under regimen specific complications below).

ANTIEMETIC POLICY Highly emetogenic

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Neural Toxicity- refer to the ifosfamide-induced encephalopathy specific neural toxicity grade and nomogram (abridged below in full at the end of this document) Methylthioninium chloride (methylene blue) can be given as prophylaxis against, or treatment of, ifosfamide-induced encephalopathy. Dose: 50mg tds IV or orally. NB. 50mg = 5ml of 1% solution. 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. 53-97% oral absorption Nephrotoxicity-Irreversible renal failure and tubular damage can occur, and this is more frequent with cumulative doses over 25mg/m2. Dose reductions should be instituted for GFR and changes in fractional phosphate clearance (Tmp/GFR mmol/l). BIP Gynae CAG Chair Authorisation:

Date:


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Nephrotoxicity-Irreversible renal failure and tubular damage can occur, and this is more frequent with cumulative doses over 25 – 50g/m2

of Ifosfamide. Nephrotoxicity – ensure adequate pre and post hydration is prescribed Ototoxicity – assess patient for tinnitus or hearing abnormalities Pulmonary function tests (including transfer factor) prior to each cycle of BEP. If breathlessness or infiltrates appear not attributable to tumour or co-existence of lung disease bleomycin must be stopped immediately. Treat patients with corticosteroids and a broad-spectrum antibiotic. REFERENCES 1. Bloss, J.D., Blessing, J.A., Behrens, B.C., Mannel, R, S., Rader, J.S., Sood-Anil,

K., Markman, M., Benda, J. Randomised trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a gynaecological oncology group study. J Clin Oncol, 2002. 20(7):p. 1832-7.

2. COIN guidelines. Clin Oncol (R Coll Radiol), 2001. 13: p. S211-248. 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic

impairment. 2009, The North London Cancer Network. 4. Kupfer, A., C. Aeschlimann, et al., Prophylaxis and reversal of ifosfamide encephalopathy with

methylene blue. Lancet, 1994. 343(8900): p. 763-4. 5. Turner, A.R., C.D. Duong, et al., Methylene blue for the treatment and prophylaxis of

ifosfamide-induced encephalopathy. Clin Oncol (R Coll Radiol), 2003. 15(7): p. 435-9.

BIP Gynae CAG Chair Authorisation: Date:


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CISPLATIN 40 weekly with Radiotherapy (Cervix) Indication: Advanced cervical carcinoma, vulval and vaginal carcinoma

DRUG REGIMEN Day 1 Pre-hydration regimen

CISPLATIN 40mg/m2 (max 70mg) in 1000ml sodium chloride 0.9% infusion over 2 hours (daypatient) or 4 hours (inpatient) Post-hydration regimen

Cycle Frequency: Every 7 days whilst having external beam radiotherapy usually 5 cycles Last cycle may be delivered with intra-cavity treatment. NB. Cisplatin may also be started in advance of radiotherapy see cisplatin pre radiotherapy regimen (no more than 9 cycles of treatment to be given IN TOTAL). NB Ideally given early or middle part of the week, not Friday:

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with SpR or Consultant Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin [2]

If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration

INVESTIGATIONS Routine Blood test 1) Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5

a. Monitor magnesium throughout treatment. b. Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion. (Cisplatin) c. Consider transfusions to keep Hb >12g/dL 2) Non-urgent blood tests Tests relating to disease response/progression

Cisplatin + RT



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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 20 ¬ 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV

ANTI-EMETIC POLICY Highly emetogenic.

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Nephrotoxicity – ensure adequate pre and post hydration is prescribed Ototoxicity – assess patient for tinnitus or hearing abnormalities REFERENCES 1. COIN guidelines. Clin Oncol (R Coll Radiol), 2001. 13: p. S211-248. 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and

hepatic impairment. 2009, The North London Cancer Network.

Cisplatin + RT



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CISPLATIN 70 pre radiotherapy (Cervix) Indication: Advanced cervical carcinoma


CISPLATIN 70mg/m2 in 1000ml sodium chloride 0.9% infusion over 2 hours (daypatient) or 4 hours (inpatient) Post-hydration regimen

Cycle Frequency: 3 weekly (no more than 9 cycles of cisplatin to be given in TOTAL) NB. Dose may vary from 70-80mg/m2 in advance of radiotherapy (at the clinicians discretion) then use the cisplatin 40 weekly with radiotherapy regimen for later courses.

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with SpR or Consultant Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin [2]



a. Monitor magnesium throughout treatment. b. Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion. (Cisplatin) c. Consider transfusions to keep Hb >12g/dL 2) Non-urgent blood tests Tests relating to disease response/progression

Cisplatin + pre RT



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Cisplatin + pre RT



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CISPLATIN 50 (Cervix) Indication: Recurrent carcinoma of the cervix


CISPLATIN 50mg/m2 in 1000ml sodium chloride 0.9% infusion over 2 hours (daypatient) or 4 hours (inpatient)

Post-hydration regimen NB. In very fit patients dose may be increased up to 75mg/m2 (discuss with Consultant). Cycle Frequency: Every 21 days for 6 cycles

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <40ml/min consider carboplatin [2]



a. Monitor magnesium throughout treatment. b. Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion.

2) Non-urgent blood tests Tests relating to disease response/progression

Cisplatin 50 Gynae CAG Chair Authorisation: Date:


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Cisplatin 50 Gynae CAG Chair Authorisation: Date:


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#TOPOTECAN CISPLATIN (Cervix) Indication: Recurrent or stage IVB cervical cancer. Palliative NICE guidance: Topotecan in combination with cisplatin is recommended as a possible treatment for women with recurrent or stage IVB cervical cancer only if they have not received cisplatin before.

DRUG REGIMEN Day 1 TOPOTECAN 0.75mg/m2 in 50ml sodium chloride 0.9% infusion over 30 minutes Pre-hydration


Post-hydration Day 2 TOPOTECAN 0.75mg/m2 in 50ml sodium chloride 0.9% infusion over 30 minutes Day 3 TOPOTECAN 0.75mg/m2 in 50ml sodium chloride 0.9% infusion over 30 minutes Cycle Frequency: Every 21 days for 4 to 6 cycles

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. Topotecan: Delay treatment by 1 week if neutrophils < 1.5 x 109/L or platelets < 100 x 109/L. Grade 3 neutropenia - reduce dose to 3.5mg/m2 Grade 4 neutropenia - reduce dose to 3mg/m2 Hepatic impairment:

Bilirubin >170mol/L – clinical decision. Renal impairment: GFR 20-39ml/min give 50% dose GFR <20ml/min omit[4] Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 40ml/min consider carboplatin [2]


Topotecan cisplatin



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INVESTIGATIONS Routine Blood test 1) Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 GFR assessed using 51Cr-EDTA result or calculated creatinine clearance at the Consultant’s discretion. 2) Non-urgent blood tests Tests relating to disease response/progression

ANTI-EMETIC POLICY High emetic risk.

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS REFERENCES 1. Gordon, A.N., J.T. Fleagle, et al., Recurrent epithelial ovarian carcinoma: a randomized

phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol, 2001. 19(14): p. 3312-22.

2. Gore, M., W. ten Bokkel Huinink, et al., Clinical evidence for topotecan-paclitaxel non--cross-resistance in ovarian cancer. J Clin Oncol, 2001. 19(7): p. 1893-900.

3. ten Bokkel Huinink, W., M. Gore, et al., Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol, 1997. 15(6): p. 2183-93.

4. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London Cancer Network.

Topotecan cisplatin



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BEP 3 day metastatic (Germ cell tumour) Indication: Good prognosis metastatic non-seminomatous germ cell tumour

DRUG REGIMEN Day 1 ETOPOSIDE 166mg/m2 in 1000ml* sodium chloride 0.9% infusion over 2 hours Pre-hydration regimen


Post-hydration regimen Day 2 BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM injection (daypatient) or in 1000ml sodium

chloride 0.9% IV infusion over 12 hours (inpatient) ETOPOSIDE 166mg/m2 in 1000ml* sodium chloride 0.9% infusion over 2 hours Pre-hydration regimen


Post-hydration regimen Day 3 ETOPOSIDE 166mg/m2 in 1000ml* sodium chloride 0.9% infusion over 2 hours Day 9 HYDROCORTISONE 100mg in 2ml water for injection IM BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM Day 16 HYDROCORTISONE 100mg in 2ml water for injection IM BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM *doses 48mg to 88mg in 250ml, doses 96mg to 180mg in 500ml sodium chloride 0.9%

Cycle Frequency: Every 21 days for 3 cycles only (Good prognosis disease up to 4 cycles excluding bleomycin on the last cycle).

NB Day 9 may be given on day 8 instead. Day 16 may be given on day 15 instead (RBFT).

DOSE MODIFICATIONS Any delays with/without dose modification may cause treatment failure. Discuss with Consultant before delaying treatment or reducing doses of any drug.

Bleomycin: GFR >50ml/min give 100% dose GFR 10-50ml/min give 75% dose GFR <10ml/min give 50% dose.[1] Confirm with SpR or Consultant. If patient is breathless discuss with Consultant.

BEP 3 day medtastatic



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Etoposide: CrCl >50ml/min give 100% doseCrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose Bilirubin 26-51micromol/L or ALT/AST 60-180u/L give 50% dose Bilirubin >51micromol/L or ALT/AST >180u/L Clinical decision [1] Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin[1] If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration

INVESTIGATIONS Prior to first treatment check patient has had sperm banking and EDTA clearance Routine Blood test 1) Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 IM bleomycin usually administered despite neutropenia if platelets are >75 a. Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) b. Pulmonary function tests are indicated if patient complains of dyspnoea or there are changes on

x-ray.

2) Non-urgent blood tests -Tests relating to disease response/progression


ANTI-EMETIC POLICY Highly emetogenic days 1 and 2 Low emetogenic day 3 Minimal emetic risk days 8, 15

BEP 3 day metastatic



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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Pulmonary function tests (including transfer factor) prior to each cycle of BEP. If breathlessness or infiltrates appear not attributable to tumour or co-existence of lung disease bleomycin must be stopped immediately. Treat patients with corticosteroids and a broad spectrum antibiotic. 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 Cancer Network. 2. COIN guidelines. Clin Oncol (R Coll Radiol), 2001. 13: p. S211-248.

BEP 3 day metastatic



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BEP 5 day metastatic (Germ cell tumour)

Indication: Intermediate or poor prognosis metastatic non-seminomatous germ cell tumour



Post hydration regimen

Day 2 BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM injection (daypatient) or in 1000ml sodium chloride 0.9% IV infusion over 12 hours (inpatient)

ETOPOSIDE 100mg/m2 in 1000ml* sodium chloride 0.9% infusion over 2 hours Pre-hydration regimen


Post hydration regimen

Day 3 ETOPOSIDE 100mg/m2 in 1000ml* sodium chloride 0.9% infusion over 2 hours Pre-hydration regimen


Post-hydration regimen







Day 9 HYDROCORTISONE 100mg in 2ml water for injection IM BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM

Day 16HYDROCORTISONE 100mg in 2ml water for injection IM BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM *doses 48mg to 88mg in 250ml, doses 96mg to 180mg in 500ml sodium chloride 0.9%

Cycle Frequency: Every 21 Days for 4 cycles only.

NB Day 9 may be given on day 8 instead. Day 16 may be given on day 15 instead (RBFT)

BEP 5 day Gynae CAG Chair Authorisation: Date:


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DOSE MODIFICATIONS Any delays with/without dose modification may cause treatment failure. Discuss with Consultant before delaying treatment or reducing doses of any drug Bleomycin: GFR >50ml/min give 100% dose GFR 10-50ml/min give 75% dose GFR <10ml/min give 50% dose [1] Confirm with SpR or Consultant. If patient is breathless discuss with Consultant. 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 ALT/AST 60-180u/L give 50% dose Bilirubin >51micromol/L or ALT/AST >180u/L Clinical decision[1] Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <40ml/min consider carboplatin[1] If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration

INVESTIGATIONS Prior to first treatment check patient has had sperm banking and EDTA clearance as appropriate Routine Blood test 1) Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 a. Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion. (Cisplatin) b. Pulmonary function tests are indicated if patient complains of dyspnoea or there are changes on

x-ray. 2) Non-urgent blood tests Tests relating to disease response/progression



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ANTI-EMETIC POLICY Moderately emetogenic days 1 to 5 Low emetogenic risk days 8, 15

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Pulmonary function tests (including transfer factor) prior to each cycle of BEP. If breathlessness or infiltrates appear not attributable to tumour or co-existence of lung disease bleomycin must be stopped immediately. Treat patients with corticosteroids and a broad spectrum antibiotic. 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. 2009, The

North London Cancer Network. 2. COIN guidelines. Clin Oncol (R Coll Radiol), 2001. 13: p. S211-248.



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BEP 3 day adjuvant (Germ cell tumour) Indication: Adjuvant treatment of non-metastatic non-seminomatous germ cell tumour


CISPLATIN 50mg/m2 in 1000ml sodium chloride 0.9% infusion over 2 hours (daypatient) or 4 hours (inpatient) Post-hydration regimen

Day 2 BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM injection (daypatient) or in 1000ml sodium

chloride 0.9% IV infusion over 12 hours (inpatient) ETOPOSIDE 120mg/m2 in 1000ml* sodium chloride 0.9% infusion over 2 hours Pre-hydration regimen


Post hydration regimen Day 3 ETOPOSIDE 120mg/m2 in 1000ml* sodium chloride 0.9% infusion over 2 hours Day 9 HYDROCORTISONE 100mg in 2ml water for injection IM BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM Day 16HYDROCORTISONE 100mg in 2ml water for injection IM BLEOMYCIN 30,000units in 3ml Lidocaine 1% IM *doses 48mg to 88mg in 250ml, doses 96mg to 180mg in 500ml sodium chloride 0.9% Cycle Frequency: Every 21 days for 2 cycles only.

NB Day 9 may be given on day 8 instead. Day 16 may be given on day 15 instead (RBFT).

DOSE MODIFICATIONS Any delays with/without dose modification may cause treatment failure. Discuss with Consultant before delaying treatment or reducing doses of any drug.

Bleomycin: GFR > 50ml/min give 100% dose GFR 10-50ml/min give 75% dose GFR <10ml/min give 50% dose[1] Confirm with SpR or Consultant. If patient is breathless discuss with Consultant.

BEP 3 day adj



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Etoposide: CrCl >50ml/min give 100% doseCrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose Bilirubin 26-51micromol/L or ALT/AST 60-180u/L give 50% dose Bilirubin >51micromol/L or ALT/AST >180u/L Clinical decision [1] Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin (1) If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration

INVESTIGATIONS Prior to first treatment check patient has had sperm banking and EDTA clearance. Routine Blood test 1) Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 a. Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) b. Pulmonary function tests are indicated if patient complains of dyspnoea or there are changes on

x-ray.



ANTI-EMETIC POLICY Highly emetogenic days 1 and 2 Low emetogenic risk day 3, Minimal emetic risk days 8, 15

BEP 3 day adj



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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Pulmonary function tests (including transfer factor) prior to each cycle of BEP. If breathlessness or infiltrates appear not attributable to tumour or co-existence of lung disease bleomycin must be stopped immediately. Treat patients with corticosteroids and a broad spectrum antibiotic. 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. 2009, The North London Cancer Network. 2. COIN guidelines. Clin Oncol (R Coll Radiol), 2001. 13: p. S211-248.

BEP 3 day adj



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EMA / CO (Germ cell) Indications: High risk gestational trophoblastic disease[1]

DRUG REGIMEN EMA Day 1 DACTINOMYCIN 0.5mg IV bolus ETOPOSIDE 100mg/m2 in 1000ml* sodium chloride 0.9% infusion over 1 hour METHOTREXATE 300mg/m2 in 500ml sodium chloride 0.9% infusion over 12 hours

Folinic acid 15mg PO every 12 hours for 4 doses starting 24 hours after start of methotrexate

Day 2 DACTINOMYCIN 0.5mg IV bolus ETOPOSIDE 100mg/m2 in 1000ml* sodium chloride 0.9% infusion over 1 hour

CO Day 8 VINCRISTINE 0.8mg/m2 (max 2mg) in 50ml sodium chloride 0.9% infusion over 10 minutes CYCLOPHOSPHAMIDE 600mg/m2 in 250ml sodium chloride 0.9% infusion over 30 minutes *doses 48mg to 88mg in 250ml, doses 96mg to 180mg in 500ml sodium chloride 0.9%

Cycle Frequency: Every 14 days. Cycles of EMA/CO alternate weekly to marker CR plus a further 6-8 weeks of therapy.

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. CO: no specific recommendations for dose modification in renal or hepatic impairment in Charing Cross Hospital protocol, discuss with consultant.

INVESTIGATIONS 1) Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L >75 ≤75 Neutrophils x 109/L >1.5 ≤1.5 GFR 2) Non-urgent blood tests- tests relating to disease response/progression

ANTI-EMETIC POLICY Highly emetogenic

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cyclophosphamide may irritate bladder, drink copious volumes of water.

REFERENCES 1. Trophoblastic Tumour Screening and Treatment Centre, Gestational trophoblastic disease chemotherapy protocols, Charing Cross Hospital.

EMA / CO Gynae CAG Chair Authorisation: Date:


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CARBOPLATIN (Germ cell) Indication: Seminoma stage 1 and dysgerminoma

DRUG REGIMEN Day 1 CARBOPLATIN AUC = 7 in 500ml glucose 5% infusion over 30 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 SACT administration

Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Creatinine clearance (GFR) ideally measured by 51Cr-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 Cancer Network.

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METHOTREXATE 50 (Germ cell) Indication: Low risk gestational trophoblastic disease[1]

DRUG REGIMEN Day 1 METHOTREXATE 50mg IM at noon Day 2 FOLINIC ACID 15mg po 6pm (30 hrs later) Day 3 METHOTREXATE 50mg IM at noon Day 4 FOLINIC ACID 15mg po 6pm (30 hrs later) Day 5 METHOTREXATE 50mg IM at noon Day 6 FOLINIC ACID 15mg po 6pm (30 hrs later) Day 7 METHOTREXATE 50mg IM at noon Day 8 FOLINIC ACID 15mg po 6pm (30 hrs later) Cycle Frequency: Every 14 days Continue until hCG 4 or less and then further 3 cycles of treatment

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar.

a. If CrCl exceeds ULN, do EDTA before any methotrexate administered. If EDTA below predicted, request consultant in charge to advise on methotrexate and folinic acid dose.

b. Progressively increasing transaminases – discuss with consultant. c. Ascites/ pleural effusions – discuss dose of methotrexate and folinic acid with consultant.

INVESTIGATIONS Routine Blood test 1) Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L >75 ≤ 75 Neutrophils x 109/L >1.5 ≤1.5


ANTI-EMETIC POLICY Mildly emetogenic


REFERENCES 1. Trophoblastic Tumour Screening and Treatment Centre, Gestational trophoblastic disease

chemotherapy protocols, Charing Cross Hospital.

Methotrexate Gynae CAG Chair Authorisation: Date:


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METHOTREXATE weekly (Germ cell) Indication: Germ cell

DRUG REGIMEN Day 1 METHOTREXATE 40mg/m2 IV bolus Cycle Frequency: Every 7 days for 6 weeks in the first instance

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar GFR 60ml/min give 65% dose GFR 45ml/min give 50% dose GFR <30 mills/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 SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 2) Non-urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Folinic acid 15mg PO/IV every 6 hours for 6 doses starting 24 hours after Methotrexate if: * Pleural effusions/ascots * Previous mucositis * Serum creatinine >120 micromols/L

ANTI-EMETIC POLICY Mildly emetogenic

ADVERSE EFFECTS/REGIMEN SPECIFIC COMPLICATIONS Methotrexate induced mucositis - folinic acid (calcium folinate) rescue (see concurrent medication)

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BEVACIZUMAB (7.5mg/kg) Indication: The first line treatment of Chemotherapy naïve advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (not licensed at this dosage) of FIGO stage III debulked but residual disease more than 1cm OR Stage IV disease OR Stage III at presentation and requiring neo-adjuvant chemotherapy due to low likelihood of optimal primary surgical cytoreduction given with paclitaxel and carboplatin combination. Bevacizumab to start with 1st or 2nd cycle of chemotherapy following primary debulking surgery, OR 1st or 2nd cycle of chemotherapy following interval debulking surgery performed after 3-4 cycles of neo-adjuvant chemotherapy, OR 1st or 2nd cycles of chemotherapy for those patients with stage IV disease or inoperable disease, OR 1st cycle of neo-adjuvant chemotherapy. As this dosage of Bevacizumab is not licensed in ovarian cancer it must be used within the treating Trust’s governance framework. Note: This policy is NOT for patients with stage I-III disease who have had optimal debulking

DRUG REGIMEN Day 1 BEVACIZUMAB 7.5mg/kg IV in 100ml sodium chloride 0.9% infusion over 90* minutes. * The initial dose should be administered over 90 minutes, if tolerated well the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated all subsequent infusions may be administered over 30 minutes.

Cycle frequency: Repeat every 21 days for maximum 18 cycles

DOSE MODIFICATIONS Renal impairment no studies have been conducted to investigate bevacizumab in renal impairment since the kidneys are not a major organ for bevacizumab metabolism or excretion. Clinical decision Hepatic impairment no studies have been conducted to investigate bevacizumab in hepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion. Clinical decision

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INVESTIGATIONS Routine Blood tests 1. Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 2. Non-urgent Blood tests Tests relating to disease response/progression.


ANTI-EMETIC POLICY Minimal emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Gastrointestinal perforation Haemorrhage Arterial thromboembolism REFERENCES 1. Bevacizumab January 2005 www.medicines.org.uk 2. CDF

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CARBOPLATIN DESENSITISATION

Indication: Carboplatin esensitisation for Carboplatin AUC 5 IV CrCl

DRUG REGIMEN Day 1 Pre-medication CARBOPLATIN AUC 0.005 in 50ml Glucose 5% infusion over 30 minutes CARBOPLATIN AUC 0.05 in 50ml Glucose 5% infusion over 30 minutes CARBOPLATIN AUC 0.5 in 50ml Glucose 5% infusion over 30 minutes CARBOPLATIN AUC 4.445 in 500ml Glucose 5% infusion over 60 minutes

Dose (mg) = (GFR + 25) x AUC Cycle Frequency: 1 cycle Ideally GFR is measured using 51Cr-EDTA.

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. If GFR/ calculated CrCl = or < 20ml/min discuss with consultant.


GFR assessed using 51Cr-EDTA result or calculated creatinine clearance at the Consultant’s discretion.

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CONCURRENT MEDICATION Ensure pre-medication given prior to start of desensitisation PRIOR TO EACH CYCLE of Carboplatin DEXAMETHASONE 8MG BD –to be taken the night before and the morning of chemotherapy RANITIDINE 150MG OD- to be taken the night before chemotherapy CETIRIZINE 10MG OD- to be taken the night before chemotherapy PRIOR TO TREATMENT T-30 DEXAMETHASONE 8MG IV BOLUS T-30 ONDANSETRON 8MG IV BOLUS T-30 CHOLPHEAMINE 10MG IV BOLUS T-30 RANITIDINE 50MG IV BOLUS 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 (routinely dexamethasone and metoclopramide is adequate but 5HT3 antagonist may be required if there is inadequate control).

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Ototoxicity - monitor Neurotoxicity - monitor REFERENCES 1. Royal Marsden desensitisation regimen

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NIRAPARIB

Indication: Niraparib as maintenance treatment in patients with relapsed, platinum-sensitive and high grade serous ovarian, fallopian tube or primary peritoneal carcinoma who are in response following platinum-based SECOND line chemotherapy and who HAVE a germline BRCA mutation where the following criteria are met: 2. The prescribing clinicians is fully aware of the likely toxicities of niraparib, the associated monitoring required and the reasons why 48% of patients in the ENGOT-OV16/NOVA trial had dose interruptions in the 1st cycle and 47% commenced their 2nd cycle at a reduced niraparib dosage 3. Confirmed histological diagnosis of predominantly high grade serous epithelial ovarian, fallopian tube or primary peritoneal carcinoma 4. Patient has had a germline BRCA test and HAS a documented germline BRCA mutation 6. The patient relapsed following 1st line chemotherapy (ie the penultimate line of treatment) and had platinum-sensitive disease at this relapse, platinum sensitivity defined by a complete or partial remission which lasted for more than 6 months following completion of 1st line platinum-based chemotherapy (whether given pre- and/or post-operatively or if the patient did not have surgery) 7. The patient is in a complete or partial response following completion of 2nd line platinum-based chemotherapy (ie the most recent chemotherapy) and that the serum CA125 is either normal or has demonstrated a >90% decrease from before the initiation of 2nd line chemotherapy and is stable 8. The patient is less than 12 weeks since completing 2nd line chemotherapy 9. The patient has not previously received any PARP inhibitor 10. The patient has an ECOG PS of either 0 or 1. (PS of 2 or more is not eligible for niraparib 11. Continued until disease progression or unacceptable toxicity or patient choice to stop 12. A formal medical review as to whether maintenance treatment with niraparib should continue or not and at what dose will be scheduled to occur at least by the start of the second cycle of treatment 13. Niraparib will be used as monotherapy 14. No treatment breaks of more than 6 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or intercurrent comorbidities to improve) 15. Niraparib is to be otherwise used as set out in its SPC

DRUG REGIMEN NIRAPARIB capsules 300 mg once daily orally Cycle frequency: continuously as long as receiving clinical benefit and free of toxicity

Niraparib Gynae CAG Chair Authorisation: Date:


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DOSE MODIFICATIONS Dose adjustments for adverse reactions Recommendations for the management of adverse reactions are provided in Table 1. In general, it is recommended to first interrupt the treatment (but no longer than 28 consecutive days) to allow the patient to recover from the adverse reaction and then restart at the same dose. In the case that the adverse reaction recurs, it is recommended to reduce the dose. If adverse reactions persist beyond a 28-day dose interruption, it is recommended that Niraparib be discontinued. If adverse reactions are not manageable with this strategy of dose interruption and reduction, it is recommended that Niraparib be discontinued. Dose reductions may be implemented based on adverse reactions. The recommended dose reductions are first from three hard capsules daily (300 mg) to two hard capsules daily (200 mg). If further dose reduction is needed, a second dose reduction from two hard capsules daily (200 mg) to one capsule daily (100 mg) may be implemented. The recommended dose modifications for adverse reactions are listed below

Dose modifications for non-haematologic adverse reactions Non-haematologic CTCAE* ≥ Grade 3 treatment-related adverse reaction where prophylaxis is not considered feasible or adverse reaction persists despite treatment First occurrence: • Withhold Niraparib for a maximum of 28 days or until resolution of adverse reaction. • Resume Niraparib at a reduced dose (200 mg/day). Second occurrence: • Withhold Niraparib for a maximum of 28 days or until resolution of adverse reaction. • Resume Niraparib at a reduced dose (100 mg/day).

CTCAE ≥ Grade 3 treatment-related adverse reaction lasting more than 28 days while patient is administered Niraparib 100 mg/day. Discontinue treatment. Dose modifications for haematologic adverse reactions Haematologic adverse reactions have been observed during the treatment with Niraparib especially during the initial phase of the treatment. It is therefore recommended to monitor complete blood counts (CBCs) weekly during the first month of treatment and modify the dose as needed. After the first month, it is recommended to monitor CBCs monthly and periodically after this time. Based on individual laboratory values, weekly monitoring for the second month may be warranted. Haematologic adverse reaction requiring transfusion or haematopoietic growth factor support • For patients with platelet count ≤ 10,000/μL, platelet transfusion should be considered. If there are other risk factors for bleeding such as co-administration of anticoagulation or antiplatelet medicinal products, consider interrupting these substances and/or transfusion at a higher platelet count. • Resume Niraparib at a reduced dose.

Platelet count < 100,000/μL First occurrence: • Withhold Niraparib for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥ 100,000/µL. • Resume Niraparib at same or reduced dose based on clinical evaluation. • If platelet count is < 75,000/μL at any time, resume at a reduced dose.



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Second occurrence: • Withhold Niraparib for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥ 100,000/µL. • Resume Niraparib at a reduced dose. • Discontinue Niraparib if the platelet count has not returned to acceptable levels within 28 days of the dose interruption period, or if the patient has already undergone dose reduction to 100 mg QD.

Neutrophil < 1,000/µL or Haemoglobin < 8 g/dL • Withhold Niraparib for a maximum of 28 days and monitor blood counts weekly until neutrophil counts return to ≥ 1,500/µL or haemoglobin returns to ≥ 9 g/dL. • Resume Niraparib at a reduced dose. • Discontinue Niraparib if neutrophils and/or haemoglobin have not returned to acceptable levels within 28 days of the dose interruption period, or if the patient has already undergone dose reduction to 100 mg QD. Confirmed diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) • Permanently discontinue Niraparib.

Renal impairment No dose adjustment is necessary for patients with mild to moderate renal impairment. There are no data in patients with severe renal impairment or end stage renal disease undergoing haemodialysis; use with caution in these patients.

Hepatic impairment No dose adjustment is needed in patients with mild to moderate hepatic impairment. There are no data in patients with severe hepatic impairment; use with caution in these patients.

INVESTIGATIONS See SPC

ANTI-EMETIC POLICY Minimal emetogenic risk


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS MDS/AML Hypertension REFERENCES CDF 1/6/18 SPC 4/1/18



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PACLITAXEL CARBOPLATIN 21 day (Ovarian/Uterine/Cervix) Indications: First line treatment of ovarian cancer[1] Recurrent ovarian cancer[2] Advanced endometrial cancer Advanced, metastatic and recurrent cervical carcinoma Unknown primary if appropriate NICE guidance: It is recommended that paclitaxel in combination with a platinum-based compound or platinum-based therapy alone are offered as alternatives for first-line chemotherapy in the treatment of ovarian cancer. (Technology Appraisal Guidance No 55, 2003) Paclitaxel in combination with platinum-based therapy is now recommended as a treatment option for women whose disease relapses after 6 months of first-line platinum-based therapy. Within this recommendation, women who have received paclitaxel as part of their first-line treatment may receive paclitaxel as part of their second line (or subsequent) treatment. (Technology Appraisal Guidance No 91, 2005)

DRUG REGIMEN Day 1 PRE-MEDICATION 30 mins prior to paclitaxel DEXAMETHASONE 20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus

PACLITAXEL 175mg/m2 in 500ml* sodium chloride 0.9% infusion over 3 hours (PVC free) CARBOPLATIN AUC 5 in 500ml Glucose 5% infusion over 30 minutes Dose (mg) = (GFR + 25) x AUC *doses 84mg to 144mg in 250ml sodium chloride 0.9%

Cycle Frequency: Every 21 days for 6 cycles (may be given for 8 cycles in certain circumstances) until progression when in combination with bevacizumab in cervical cancer)

*NB Ideally GFR is measured using 51Cr-EDTA (AUC 6 at RBFT)

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. Carboplatin: If GFR/CrCl = or < 20ml/min discuss with consultant.

Paclitaxel: If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. If grade II or > neuropathy, consider using paclitaxel 135mg/m2. Bilirubin <1.25xULN and AST/ALT <10xULN dose at 175mg/m2 Bilirubin <26micromol/L give 135mg/m2 Bilirubin 27-51micromol/L give 75mg/m2 Bilirubin >51micromol/L give 50mg/m2 [3]

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a. Liver function tests (LFTs) b. GFR assessed using 51Cr-EDTA result or calculated creatinine clearance at the Consultant’s

discretion. (Carboplatin) c. Patients with hydronephrosis or serum creatinine > 100 micromol/L need a serum creatinine

checked every cycle. All patients have serum creatinine checked 1st and 4th cycle -Carboplatin. 2) Non-urgent blood tests Tests relating to disease response/progression

CONCURENT MEDICATIONS Paclitaxel – ensure pre medication is given Carboplatin - Anaphylaxis treatment should be prescribed if the patient has had an anaphylactic episode previously. Carboplatin should be given at a slower rate e.g. 2-4 hours.


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS 2% risk of severe hypersensitivity. Reactions to paclitaxel range from mild hypotension (light-headedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5-10mins), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment. Ototoxicity - monitor Neurotoxicity – monitor

REFERENCES 1. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent

carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet, 2002. 360(9332): p. 505-15.

2. Parmar, M.K., J.A. Ledermann, et al., Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet, 2003. 361(9375): p. 2099-106.


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PACLITAXEL CISPLATIN (Ovarian) Indications: First line treatment of ovarian cancer for carboplatin allergic patients[1] Recurrent ovarian cancer for carboplatin allergic patients[2] NICE guidance: It is recommended that paclitaxel in combination with a platinum-based compound or platinum-based therapy alone are offered as alternatives for first-line chemotherapy in the treatment of ovarian cancer. (Technology Appraisal Guidance No 55, 2003) Paclitaxel in combination with platinum-based therapy is now recommended as a treatment option for women whose disease relapses after 6 months of first-line platinum-based therapy. Within this recommendation, women who have received paclitaxel as part of their first-line treatment may receive paclitaxel as part of their second line (or subsequent) treatment. (Technology Appraisal Guidance No 91, 2005)

DRUG REGIMEN Day 1 PRE-MEDICATION 30 mins prior to Paclitaxel infusion: DEXAMETHASONE 20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 175mg/m2 in 500ml* sodium chloride 0.9% infusion over 3 hours (PVC free) Pre-hydration regimen


Post-hydration regimen FUROSEMIDE 40mg PO (after cisplatin to induce diuresis)

*doses 84mg to 144mg in 250ml sodium chloride 0.9%

Cycle Frequency: Every 21 days for 6 cycles subject to tolerance and response

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. Paclitaxel: If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. If grade II or > neuropathy, consider using paclitaxel 135mg/m2. Bilirubin <1.25xULN and AST/ALT <10xULN dose at 175mg/m2 Bilirubin <26micromol/L give 135mg/m2 Bilirubin 27-51micromol/L give 75mg/m2 Bilirubin >51micromol/L give 50mg/m2 [1]

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Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin[1]

INVESTIGATIONS Routine Blood test 1) Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 Liver function tests (LFTs) 2) Non-urgent blood tests Tests relating to disease response/progression

CONCURENT 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 20 ¬ 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV Paclitaxel ensure pre medication is given.


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS 2% risk of severe hypersensitivity. Reactions to paclitaxel range from mild hypotension (light-headedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5-10mins), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment. 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


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CARBOPLATIN 21 day (Ovarian / Uterine)

Indication: Frontline chemotherapy in ovarian carcinoma.[1-4] Relapsed ovarian carcinoma with a 1 year or greater progression free interval after 1st line platinum based chemotherapy.[5]

Endometrial carcinoma Serous papillary uternine cancer

DRUG REGIMEN Day 1 CARBOPLATIN AUC 5 in 500ml glucose 5% infusion over 30 minutes

Dose (mg) = (GFR + 25) x AUC Cycle Frequency: Every 21 days for 6 cycles depending on tolerance and response Ideally GFR is measured using 51Cr-EDTA. In very good performance status patients AUC 6 may be considered. In frail, elderly patients AUC 4 may be considered.




Patients with hydronephrosis or serum creatinine > 100 micromol/L need a serum creatinine checked every cycle. All patients have serum creatinine checked 1st and 4th cycle.


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. Carboplatin 21 day



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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Ototoxicity - monitor Neurotoxicity - monitor REFERENCES 1. Taylor, A.E., E. Wiltshaw, et al., Long-term follow-up of the first randomized study of

cisplatin versus carboplatin for advanced epithelial ovarian cancer. J Clin Oncol, 1994. 12(10): p. 2066-70.

2. Colombo, N., D. Guthrie, et al., International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst, 2003. 95(2): p. 125-32.

3. ICON2: randomised trial of single-agent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer. ICON Collaborators. International Collaborative Ovarian Neoplasm Study. Lancet, 1998. 352(9140): p. 1571-6.

4. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet, 2002. 360(9332): p. 505-15.


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CARBOPLATIN 28 day (Ovarian / Uterine)

Indication: Frontline chemotherapy in ovarian carcinoma.[1-4] Relapsed ovarian carcinoma with a 1 year or greater progression free interval after 1st line platinum based chemotherapy.[5]

Metastatic endometrial cancer

DRUG REGIMEN Day 1 CARBOPLATIN AUC 6 in 500ml glucose 5% infusion over 30 minutes Dose (mg) = (GFR + 25) x AUC Ideally GFR is measured using 51Cr-EDTA AUC = 6 In very good performance status patients AUC 7 may be considered. In frail, elderly patients AUC 5 may be considered.

Cycle Frequency: Every 28 days for 6 cycles depending on tolerance and response




Patients with hydronephrosis or serum creatinine >100 micromol/L need a serum creatinine checked every cycle. All patients have serum creatinine checked 1st and 4th cycle. 2) Non-urgent blood tests Tests relating to disease response/progression

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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Ototoxicity - monitor Neurotoxicity - monitor REFERENCES 1. Taylor, A.E., E. Wiltshaw, et al., Long-term follow-up of the first randomized study of

cisplatin versus carboplatin for advanced epithelial ovarian cancer. J Clin Oncol, 1994. 12(10): p. 2066-70.

2. Colombo, N., D. Guthrie, et al., International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst, 2003. 95(2): p. 125-32.

3. ICON2: randomised trial of single-agent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer. ICON Collaborators. International Collaborative Ovarian Neoplasm Study. Lancet, 1998. 352(9140): p. 1571-6.



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CISPLATIN / ORAL ETOPOSIDE (Ovarian) Indication:Treatment regimen for use in platinum resistant / relapsed ovarian cancer[1, 2] Results: Two phase II studies report response rate of 46% (29% CR) in platinum resistant patients

and up to 92% (63% CR) in patients with platinum free interval of > 12 months. Median overall survival of 13-26 months depending upon platinum sensitivity.

DRUG REGIMEN Day 1 ETOPOSIDE 50mg PO daily from days 1 to 14 inclusive Pre-hydration regimen


Post hydration regimen Day 8 Pre-hydration regimen


Post hydration regimen Day 15Pre-hydration regimen


Post hydration regimen NB. Consider using cisplatin 40mg/m2 in heavily pre-treated patients. Cycle Frequency: Every 28 days for 2 cycles only.

On completion of 2 cycles if stable or responsive disease, consider oral ETOPOSIDE (see oral etoposide regimen).

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. If prolonged neutropenia after cycle 1; consider reducing etoposide duration to 7 days.

Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin[3]

If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration.

In case of neuropathy/ototoxicity consider using cisplatin 50mg/m2.

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Etoposide: Note when dose reducing the etoposide capsules available as only 50 or 100mg strengths CrCl >50ml/min give 100% doseCrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose Bilirubin 26-51micromol/L or ALT/AST 60-180u/L give 50% dose Bilirubin >51micromol/L or ALT/AST >180u/L Clinical decision[3]

INVESTIGATIONS 1) Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5

Monitor magnesium throughout treatment.

GFR assessed using 51Cr-EDTA result or calculated creatinine clearance at the Consultant’s discretion. 51Cr-EDTA advised if patient has not had one previously, has a calculated creatinine clearance < 60ml/min or has ascites.

Ensure patient is passing urine well and calculated creatinine clearance is not falling with each cycle. (cisplatin)

Ototoxic. Patients may need baseline audiometry particularly if elderly. Repeat audiometry if patient complains of hearing loss or tinnitus. (cisplatin)

Neurotoxic. Monitor for signs of peripheral neuropathy. (cisplatin) 2) Non-urgent blood tests- Tests relating to disease response/progression Monitor CA125 every 3-4 weeks.


ANTI-EMETIC POLICY Highly emetogenic days 1, 8, 15 Low to moderate emetogenic risk other days




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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities.

REFERENCES 1. van der Burg, M.E., R. de Wit, et al., Weekly cisplatin and daily oral etoposide is highly

effective in platinum pre-treated ovarian cancer. Br J Cancer, 2002. 86(1): p. 19-25. 2. Meyer, T., A.E. Nelstrop, et al., Weekly cisplatin and oral etoposide as treatment for

relapsed epithelial ovarian cancer. Ann Oncol, 2001. 12(12): p. 1705-9. 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and





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CISPLATIN weekly (Ovarian) Indication:Treatment regimen for use in platinum resistant/relapsed ovarian cancer, in

patients that cannot tolerate oral etoposide (modification of cisplatin/oral etoposide regime).[1, 2]



Post hydration regimen NB Consider 40mg/ m2 in heavily pre-treated patients. Cycle Frequency: Every 7 days for 8 weeks. Thereafter at Consultant’s discretion.

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin[3] If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration. Consider dose reduction to cisplatin 50mg/m2.






Neurotoxic. Monitor for signs of peripheral neuropathy. (cisplatin)

Cisplatin weekly



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2) Non-urgent blood tests- Tests relating to disease response/progression Monitor CA125 every 3-4 weeks.

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 20 ¬ 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities. REFERENCES 1. van der Burg, M.E., R. de Wit, et al., Weekly cisplatin and daily oral etoposide is highly




Cisplatin weekly



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CISPLATIN 21 day (Ovarian) Indication: Treatment regimen for use in recurrent ovarian cancer, in patients that cannot

tolerate carboplatin



Post hydration regimen In previously treated patients consider 70mg/m2 cisplatin. Cycle Frequency: Every 21 days for 6 cycles

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin[3] If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration. Consider dose reduction to cisplatin 50mg/m2.






Neurotoxic. Monitor for signs of peripheral neuropathy. (cisplatin)

Cisplatin 3 weekly



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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities. REFERENCES 1. van der Burg, M.E., R. de Wit, et al., Weekly cisplatin and daily oral etoposide is highly




Cisplatin 3 weekly



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ETOPOSIDE IV (Ovarian) Indication: Recurrent ovarian cancer (as per oral etoposide regimen, used in patients that

cannot tolerate oral route)

DRUG REGIMEN Days 1 to 3 ETOPOSIDE 166mg/m2 in 1000ml* sodium chloride 0.9% infusion over 2 hours *doses 48mg to 88mg in 250ml, doses 96mg to 180mg in 500ml sodium chloride 0.9% Cycle frequency: Every 21 days for a maximum of 6 cycles

However if it follows 2 cycles of cisplatin / oral etoposide regimen is repeated every 21 days for a maximum 4 cycles.

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. CrCl >50ml/min give 100% doseCrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose Hepatic impairment:- Arguments for and against dose reduction - discuss with SpR or Consultant Bilirubin 26-51micromol/L or ALT/AST 60-180u/L give 50% dose Bilirubin >51micromol/L or ALT/AST >180u/L Clinical decision




ANTI-EMETIC POLICY Low emetogenic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS -

Etoposide IV Gynae CAG Chair Authorisation: Date:


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ETOPOSIDE oral (Ovarian) Indication: Recurrent ovarian cancer

DRUG REGIMEN Days 1 to 14 ETOPOSIDE 100mg od PO (Dose may be split to 50mg bd to improve tolerability.) Cycle frequency: Every 21 days for a maximum of 6 cycles

However if it follows 2 cycles of cisplatin / oral etoposide regimen is repeated every 21 days for a maximum 4 cycles.

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar.

CrCl >50ml/min give 100% doseCrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose

Hepatic impairment:- Arguments for and against dose reduction - discuss with SpR or Consultant Bilirubin 26-51micromol/L or ALT/AST 60-180u/L give 50% dose Bilirubin >51micromol/L or ALT/AST >180u/L Clinical decision

INVESTIGATIONS 1) Blood results required before SACT administration

Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5



ANTI-EMETIC POLICY Low emetogenic risk


REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London Cancer Network. Etoposide oral



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GEMCITABINE CISPLATIN (Ovarian)

Indications: For 2nd or 3rd line treatment relapsed ovarian cancer, with carboplatin sensitivity

DRUG REGIMEN Day 1 GEMCITABINE* 1000mg/m2

infusion in 250ml sodium chloride 0.9% over 30 minutes Prehydration CISPLATIN 75mg/m2 in 1000ml sodium chloride 0.9% IV infusion over 2 hours Post hydration

Day 8 GEMCITABINE* 1000mg/m2 infusion in 250ml sodium chloride 0.9% over 30 minutes NB * for elderly patients start at 750mg/m2 day 1 and 8 Cycle Frequency: Every 21 days for 6 cycles

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant. Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin [3] 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) If bilirubin > 27 μmol/L, initiate treatment with dose of 800 mg/m2. Neutrophils >1.5x109/L and platelets >100x109/L give 100% dose Neutrophils 0.5-1.5x109/L or platelets 50-100x109/L give 75% dose or delay based on clinical assessment Neutrophils <0.5x109/L or platelets <50x109/L delay treatment (Day 1) or omit treatment (Day 8) 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 25% dose reduction Grade 4 toxicity – omit until toxicity resolved then restart 50% dose reduction

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Haematological toxicity Gemcitabine D 1 Cisplatin D 1 Gemcitabine D 8 Day 1 Full blood count Delay until Delay until - Neutrophil <1.5 OR Plt <100 recovery then recovery then (Protocol Starting Dose) full dose then full dose Delay in Day 1 of >1 week or 800mg/m2 60mg/m2 800mg/m2 ≤2 weeks OR Neutropenic fever OR Grade IV thrombocytopenia Further occurrence despite 800mg/m2 50mg/m2 omit first dose reduction • Day 8 Gemcitabine – Dose modifications for Day 8 gemcitabine will be based on a full blood count taken within 24 hours of treatment. Day 8 blood count Gemcitabine dose Neutrophils ≥1.5 AND platelets ≥ 100 100% dose Neutrophils ≥1.0 to 1.4 AND/OR platelets 75-99 50% dose Neutrophils < 1.0 AND/OR platelets < 75 omit dose • Dose levels should be adjusted independently for each drug If there are still problems after 2 dose reductions then patients should be discussed on an individual basis with the Lead Chief Investigator or Trial Physician Patients should be treated for anaemia according to local practice.



2) Non-urgent blood tests- Tests relating to disease response/progression

CONCURRENT MEDICATION

ANTI-EMETIC POLICY Highly emetogenic day 1, moderately emetogenic day 8




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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Ototoxicity - monitor Neurotoxicity - monitor Diarrhoea – see dose modifications Mucositis – see dose modifications

REFERENCES 1. Pfisterer et al, Journal of Clinical Oncology 24, 4699-707, 2. Papadimitriou et al.Gynaecological Oncology 2004 , 92, page 152-9, 3. ICON 6 study




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LIPOSOMAL DOXORUBICIN (Caelyx) (Ovarian)

Indication: Treatment of recurrent /resistant ovarian cancer Metastatic endometrial cancer NICE guidance: Pegylated liposomal doxorubicin hydrochloride is recommended as an option for the second-line(or subsequent treatment of women with partially platinum-sensitive, platinum resistant or platinum refractory advanced ovarian cancer, and for women who are allergic to platinum-based compounds (Technology Appraisal Guidance No 91, 2005).

DRUG REGIMEN Cycle 1 Day 1 PEGYLATED LIPOSOMAL DOXORUBICIN 40mg/m2 in 500ml glucose 5% infusion at a

rate of 1mg/min. (If no infusion-related reactions, subsequent cycles over 1 hour.)

Cycle 2 onwards Day 1 PEGYLATED LIPOSOMAL DOXORUBICIN 40mg/m2 in 500ml glucose 5% infusion over 1

hour (If infusion-related reactions give at a rate of 1mg/min clinical decision)

Cycle Frequency: Every 28 days for a maximum of 6 cycles

NB if dose is less than 90mg give in 250ml glucose 5% due to stability as per SPC

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. Bilirubin 20-51micromol/L give 75% dose Bilirubin > 51micromol/L give 50% dose Maximum cumulative dose = 450-550 mg/m2

(in normal cardiac function) = 400 mg/m2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation) Palmar plantar erythema or stomatitis: (See SPC for further information) Delay for 1 week if grade 2 -4. Use steroids (e.g. prednisolone 30mg daily or Dexamethasone 8mg daily) for treatment. Anecdotally, pyridoxine 50mg tds can be used. Reduce dose to by 25% if > 2 week delay or if grade III or above.

INVESTIGATIONS 1) Blood results required before SACT administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 2) Non urgent blood tests - Tests relating to disease response/progression ECG monitoring (possibly ECHO), particularly if patient has pre-existing cardiac disease.

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CONCURRENT MEDICATION ANTIEMETIC POLICY Low emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity – use with caution in cardiac dysfunction. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Infusion related reactions – allergic or anaphylactic like reactions consider prophylaxis Palmar-plantar erythema treat with steroids prednisolone 30mg od or dexamethasone 8mg od. Consider pyridoxine.



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OLAPARIB capsules

Indication: for maintenance treatment of relapsed, platinum-sensitive, BRCA1 or BRCA2 mutation-positive ovarian, fallopian tube and peritoneal cancer after response to platinum based chemotherapy if they have had 3 or more courses of platinum based chemotherapy

DRUG REGIMEN OLAPARIB capsules 400 mg twice daily orally Cycle frequency: continuously as long as receiving clinical benefit and free of intolerable toxicity

DOSE MODIFICATIONS Treatment may be interrupted to manage adverse reactions such as nausea, vomiting, diarrhoea, and anaemia and dose reduction can be considered (see section 4.8 of SPC). The recommended dose reduction is to 200 mg twice daily (equivalent to a total daily dose of 400 mg). If a further final dose reduction is required, then reduction to 100 mg twice daily (equivalent to a total daily dose of 200 mg) could be considered. Patients with renal impairment The effect of renal impairment on exposure to Olapraib has not been studied. Olaparib can be administered in patients with mild renal impairment (creatinine clearance > 50 ml/min). Olaparib may only be used in patients with moderate or severe renal impairment if the benefit outweighs the potential risk, and the patient should be carefully monitored for renal function and adverse events. Patients with hepatic impairment The effect of hepatic impairment on exposure to Lynparza has not been studied. Therefore, Olaparib is not recommended for use in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal), as safety and efficacy have not been established.

INVESTIGATIONS PS 0-1 Normal organ and marrow function within 28 days of starting QTc <470 msec FBC and U&E'S at least monthly Clincal assessment , monthly CA125 and CT imaging every 12 weeks.

Olaparib Gynae CAG Chair Authorisation: Date:


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ANTI-EMETIC POLICY Minimal emetogenic risk


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Based upon experience from Phase I and II studies, olaparib is generally well tolerated. The safety concerns are primarily related to the risk of myelosupression. Supportive care should be provided therapeutically and prophylactically as deemed necessary by the treating physician REFERENCES SPC

Olaparib Gynae CAG Chair Authorisation: Date:


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PACLITAXEL 3 weekly (Ovarian)

Indication:Treatment for recurrent/relapsed ovarian cancer[1, 2] NICE guidance:

Single-agent paclitaxel is recommended as an option for the second line (or subsequent) treatment of women with platinum-refractory or platinum-resistant advanced ovarian cancer, and for women who are allergic to platinum-based compounds. (Technology Appraisal Guidance No 91, 2005)

DRUG REGIMEN Day 1 PRE-MEDICATION 30 mins prior to infusion: DEXAMETHASONE 20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus

PACLITAXEL 175mg/m2 in 500ml* sodium chloride 0.9% infusion over 3 hours (PVC free) * doses 84mg to 144mg in 250ml sodium chloride 0.9%

Cycle Frequency: Every 21 days up to a maximum of 6 cycles

DOSE MODIFICATIONS If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. If grade II or > neuropathy, consider using paclitaxel 135mg/m2.

Bilirubin <1.25xULN and AST/ALT <10xULN dose at 175mg/m2 Bilirubin <26micromol/L give 135mg/m2 Bilirubin 27-51micromol/L give 75mg/m2 Bilirubin >51micromol/L give 50mg/m2 Delay 1 week if day 1 neutrophil count <1.5x109/L and / or platelet count is <100x109/L. If more than two weeks delay or previous neutropenic sepsis consider reducing dose by 25%. If ANC < 0.5x109/L and /or platelet nadir count <50x109/L for 7 days or more, reduce dose from 175mg/m2 to 135mg/m2 or from 200mg/m2 to 175mg/m2.

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INVESTIGATIONS 1) Blood results required before SACT administration: Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 2) Liver function tests (LFTs). 3) Check CA125 each cycle. 4) Assess response every 3 cycles with CT.

ANTI-EMETIC POLICY Low emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS 2% risk of severe hypersensitivity. Reactions range from mild hypotension (light-headedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5-10mins), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment. REFERENCES 1. McGuire, W.P., W.J. Hoskins, et al., Cyclophosphamide and cisplatin compared with

paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med, 1996. 334(1): p. 1-6.



Paclitaxel 3 weekly



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PACLITAXEL weekly (Ovarian) Indication:Treatment option for recurrent ovarian cancer[1-4] Results: In phase II studies with patients previously treated with 3 weekly paclitaxel response rates of 29-47% with median durations of 2-7 months and 4.1months were noted. A randomised trial involving 208 patients that had not previously received paclitaxel showed no difference in response between 67mg/m2 per week and 200mg/m2 every 3 weeks. The weekly regime is much better tolerated, with less myelosuppression, neurotoxicity and alopecia. NICE guidance: Single-agent paclitaxel is recommended as an option for the second line (or subsequent) treatment of women with platinum-refractory or platinum-resistant advanced ovarian cancer, and for women who are allergic to platinum-based compounds. (Technology Appraisal Guidance No 91, 2005)

DRUG REGIMEN Day 1 PRE-MEDICATION 30 mins prior to infusion: DEXAMETHASONE 8mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 80mg/m2 in 250ml* sodium chloride 0.9% infusion over 1 hour (PVC free) * doses 162mg to 600mg in 500ml sodium chloride 0.9% NB. Dose escalation to 90mg/m2 possible on second and subsequent cycles - discuss with Consultant.

Cycle Frequency: Every 7 days for 8 weeks. May continue up to a maximum of 16 weeks in responding patients depending on side effects.

DOSE MODIFICATIONS

Previous neutropenic sepsis, discuss with Consultant or Registrar If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. If grade II or > neuropathy, consider using reducing dose of paclitaxel Delay 1 week if day 1 neutrophil count <1.5x109/L and / or platelet count is <100x109/L.

In the absence of Gilbert's syndrome: Bilirubin >51micromol/L stop treatment

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INVESTIGATIONS 1) Blood results required before SACT administration:


2) Liver function tests (LFTs). 3) Reassess 3 weekly with CA125.

ANTI-EMETIC POLICY Low emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS 2% risk of severe hypersensitivity. Reactions range from mild hypotension (light-headedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5-10mins), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment. REFERENCES 1. Abu-Rustum, N.R., C. Aghajanian, et al., Salvage weekly paclitaxel in recurrent ovarian

cancer. Semin Oncol, 1997. 24(5 Suppl 15): p. S15-62-S15-67. 2. Thirapakawong, C., S. Senapad, et al. Phase II study of weekly paclitaxel as a second line

chemotherapy in refractory epithelial ovarian cancer. in ASCO. 2001. 3. Rosenburg, P., H. Andersson, et al. A randomised multicenter study of single agent

paclitaxel (Taxol) given weekly versus every three weeks to patients (PTS) with ovarian cancer (OC) previously treated with platinum therapy. in ASCO. 1999.

4. Fennelly, D., C. Aghajanian, et al., Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol, 1997. 15(1): p. 187-92.

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GEMCITABINE CARBOPLATIN (Ovarian)

Indications: 3rd line treatment of ovarian cancer Unknown primary if appropriate

DRUG REGIMEN Day 1 GEMCITABINE* 1000mg/m2

infusion in 250ml sodium chloride 0.9% over 30 minutes CARBOPLATIN AUC 5 in 500ml glucose 5% infusion over 30 minutes

Dose (mg) = (GFR + 25) x AUC

Day 8 GEMCITABINE* 1000mg/m2

infusion in 250ml sodium chloride 0.9% over 30 minutes NB * for elderly patients start at 750mg/m2 day 1 and 8 Cycle Frequency: Every 21 days for 6 cycles NB ideally dosed on 51Cr-EDTA clearance, therefore should be done before starting chemotherapy

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant. Carboplatin: If GFR = or < 20ml/min discuss with consultant.

Gemcitabine: CrCl <30ml/min consider dose reduction (Clinical decision) If bilirubin > 27 μmol/L, initiate treatment with dose of 800 mg/m2. Neutrophils >1.5x109/L and platelets >100x109/L give 100% dose Neutrophils 0.5-1.5x109/L or platelets 50-100x109/L give 75% dose or delay based on clinical assessment Neutrophils <0.5x109/L or platelets <50x109/L delay treatment (Day 1) or omit treatment (Day 8) 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 25% dose reduction Grade 4 toxicity – omit until toxicity resolved then restart 50% dose reduction

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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Ototoxicity - monitor Neurotoxicity - monitor Diarrhoea – see dose modifications Mucositis – see dose modifications

REFERENCES 1. Pfisterer et al, Journal of Clinical Oncology 24, 4699-707, 2. Papadimitriou et al.Gynaecological Oncology 2004 , 92, page 152-9,

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PACLITAXEL 7 day and CARBOPLATIN (ovarian) Indication: 2nd and 3rd line treatment of advanced ovarian cancer

DRUG REGIMEN Day 1 PRE-MEDICATION 30 mins prior to infusion: DEXAMETHASONE 10-20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 80mg/m2 in 250ml* sodium chloride 0.9% infusion over 1 hour (PVC free) CARBOPLATIN AUC 5** in 500ml glucose 5% infusion over 30 minutes Dose (mg) = (GFR + 25) x AUC

Day 8 PRE-MEDICATION 30 mins prior to infusion: DEXAMETHASONE 10-20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 80mg/m2 in 250ml* sodium chloride 0.9% infusion over 1 hour (PVC free)

Day 15 PRE-MEDICATION 30 mins prior to infusion: DEXAMETHASONE 10-20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 80mg/m2 in 250ml* sodium chloride 0.9% infusion over 1 hour (PVC free) * doses 162mg to 600mg in 500ml sodium chloride 0.9%

**EDTA Ideally GFR is measured using 51Cr-EDTA then AUC =5

**Calculated CrCl If GFR is calculated from serum creatinine then AUC = 6

NB elderly, poor performance status and heavily pretreated patients should be started on 60mg/m2 paclitaxel.

Cycle Frequency: Every 21 days for 6 cycles. If required, can be dropped to every 28 days, giving patients a week off paclitaxel at the clinicians discretion

DOSE MODIFICATIONS

Previous neutropenic sepsis, discuss with Consultant or Registrar Paclitaxel: If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. If grade II or > neuropathy, consider using reducing dose of paclitaxel Delay 1 week if day 1 neutrophil count < 1.5x109/L and / or platelet count is < 100x 09/L. Myelosuppression is reasonably common consider dose reduction from 80 to 60mg/m2 In the absence of Gilbert's syndrome: Bilirubin >51micromol/L stop treatment

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Carboplatin: If GFR = or < 20ml/min discuss with consultant.



Liver function tests (LFTs).

GFR assessed using 51Cr-EDTA result or calculated creatinine clearance the Consultant’s discretion.




ANTI-EMETIC POLICY Moderately emetogenic day 1 (routinely dexamethasone and metoclopramide is adequate but 5HT3 antagonist may be required if there is inadequate control). Mildly emetogenic day 8 and 15

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS 2% risk of severe hypersensitivity. Reactions range from mild hypotension (light-headedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5-10mins), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment. Ototoxicity - monitor Neurotoxicity - monitor

REFERENCES 1. Rose et al, Gynaecological Oncology 2005, 96, page 296-300. 2. Leiser et al International Journal of Gynaecological Cancer 2007, 17, page 379-86.

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PACLITAXEL 7 day and CARBOPLATIN 7 day (Ovarian) Indication: Recurrent ovarian cancer previously treated.

DRUG REGIMEN Day 1 PRE-MEDICATION 30 mins prior to infusion: DEXAMETHASONE 10-20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 80mg/m2 in 250ml* sodium chloride 0.9% infusion over 1 hour (PVC free) CARBOPLATIN AUC 2** in 500ml glucose 5% infusion over 30 minutes Dose (mg) = (GFR + 25) x AUC

Day 8 PRE-MEDICATION 30 mins prior to infusion: DEXAMETHASONE 10-20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 80mg/m2 in 250ml* sodium chloride 0.9% infusion over 1 hour (PVC free) CARBOPLATIN AUC 2* in 500ml glucose 5% infusion over 60 minutes Dose (mg) = (GFR + 25) x AUC

Day 15 PRE-MEDICATION 30 mins prior to infusion: DEXAMETHASONE 10-20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 80mg/m2 in 250ml* sodium chloride 0.9% infusion over 1 hour (PVC free) CARBOPLATIN AUC 2* in 500ml glucose 5% infusion over 60 minutes Dose (mg) = (GFR + 25) x AUC * doses 162mg to 600mg in 500ml sodium chloride 0.9%

**EDTA Ideally GFR is measured using 51Cr-EDTA then AUC = 2 **Calculated CrCl If GFR is calculated from serum creatinine then AUC = 3

Cycle Frequency: Every 28 days for 2 to 4 cycles. Patient may be changed to 21 day Paclitaxel and carboplatin according to response

DOSE MODIFICATIONS

Previous neutropenic sepsis, discuss with Consultant or Registrar Paclitaxel: If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. If grade II or > neuropathy, consider using reducing dose of paclitaxel Delay 1 week if day 1 neutrophil count < 1.5x109/L and / or platelet count is < 100x109/L. Myelosuppression is reasonably common consider dose reduction from 80 to 60 mg/m2 In the absence of Gilbert's syndrome: Bilirubin >51micromol/L stop treatment

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Carboplatin: If GFR = or < 20ml/min discuss with consultant.




GFR assessed using 51Cr-EDTA result or calculated creatinine clearance the Consultant’s discretion.




ANTI-EMETIC POLICY Moderately emetogenic day 1 (routinely dexamethasone and metoclopramide is adequate but 5HT3 antagonist may be required if there is inadequate control). Mildly emetogenic day 8 and 15

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS 2% risk of severe hypersensitivity. Reactions range from mild hypotension (light-headedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5-10mins), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment. Ototoxicity - monitor Neurotoxicity - monitor

REFERENCES 1. Rose et al, Gynaecological Oncology 2005, 96, page 296-300. 2. Leiser et al International Journal of Gynaecological Cancer 2007, 17, page 379-86.

Paclitaxel carboplatin 7 day



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LIPOSOMAL DOXORUBICIN (Caelyx) and CARBOPLATIN (Ovarian)

Indication: 2nd and 3rd line treatment of advanced ovarian cancer

DRUG REGIMEN Cycle 1 Day 1 PEGYLATED LIPOSOMAL DOXORUBICIN 30mg/m2 in 250ml glucose 5% infusion at a

rate of 1mg/min (or over 1 hour, If infusion-related reactions clinical decision) CARBOPLATIN AUC 5 in 500ml glucose 5% infusion over 30 minutes Dose (mg) = (GFR + 25) x AUC

Cycle Frequency: Every 28 days for 6 cycles

NB ideally dosed on 51Cr-EDTA clearance, therefore should be done before starting chemotherapy

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. Liposomal doxorubicin: Bilirubin 20-51micromol/L give 75% dose Bilirubin > 51micromol/L give 50% dose Maximum cumulative dose = 450-550mg/m2

(in normal cardiac function) = 400 mg/m2(in patients with cardiac dysfunction or exposed to mediastinal irradiation) Palmar plantar erythema or stomatitis: (See SPC for further information) Delay for 1 week if grade 2 -4. Use steroids (e.g. prednisolone 30mg daily or Dexamethasone 8mg daily) for treatment. Anecdotally, pyridoxine 50mg tds can be used. Reduce dose to by 25% if > 2 week delay or if grade III or above. Carboplatin If GFR = or < 20ml/min discuss with consultant.



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2) Non-urgent blood tests- Tests relating to disease response/progression ECG monitoring (possibly ECHO), particularly if patient has pre-existing cardiac disease.


ANTI-EMETIC POLICY Moderately emetogenic

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity – use with caution in cardiac dysfunction. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Infusion related reactions – allergic or anaphylactic like reactions consider prophylaxis Palmar-plantar erythema treat with steroids prednisolone 30mg od or dexamethasone 8mg od. Consider pyridoxine. Ototoxicity - monitor Neurotoxicity - monitor


impairment. 2009, The North London Cancer Network. 2. BMC cancer 2006, 6 page 202, Pignata et al.

Liposomal doxorubicin / carboplatin



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DOXORUBICIN (Endometrial) Indication: Endometrial cancer

DRUG REGIMEN Day 1 DOXORUBICIN 70mg/m2

IV bolus

Cycle Frequency: Every 21 days for 6 cycles

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 = 450-550 mg/m2

(in normal cardiac function) = 400 mg/m2

(in patients with cardiac dysfunction or exposed to mediastinal irradiation)

INVESTIGATIONS Routine blood test 1) Blood results required before SACT administration

Give Discuss

Hb x g/dL ≥10 <10

Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5

2) Non urgent blood tests

Tests relating to disease response/progression

ECG (possible ECHO) required if patient has preexisting cardiac disease (Doxorubicin)


ANTIEMETIC POLICY Moderately emetogenic

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity – monitor cardiac function. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue.

Doxorubicin GynaeCAG Chair Authorisation: Date:


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Gynae SACT regimens 76

DOXORUBICIN + CISPLATIN Indication: Endometrial cancer

DRUG REGIMEN Day 1 DOXORUBICIN 50mg/m2 IV bolus Pre-hydration regimen


Post-hydration regimen NB. Doxorubicin 60mg/m2 can be used if patient not heavily pre-treated (d/w Consultant). NB. Cisplatin dose can be escalated to 60mg/m2 depending on renal function and how tolerated (d/w Consultant). Cycle Frequency: Every 21 days for 6 cycles subject to tolerance and response

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin [3] If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration. 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 [3] If AST is 2-3 x ULN give 75% dose If AST >3x ULN, give 50% dose [2] Maximum cumulative dose: 450-550mg/m2 (in normal cardiac function) 400mg/m2 (in combination with thoracic radiation treatment or cyclophosphamide or in patients with cardiac risk factors)

Doxorubicin + cisplatin



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Ensure patient is passing urine well (urine output >100ml/hour).and calculated creatinine clearance is not falling with each cycle.

Ototoxic. Patients may need baseline audiometry particularly if elderly. Repeat audiometry if patient complains of hearing loss or tinnitus.

Neurotoxic. Monitor for signs of peripheral neuropathy. 2) Non-urgent blood tests- Tests relating to disease response/progression ECG (possible ECHO) required if patient has pre-existing cardiac disease (doxorubicin)



ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities. Cardiotoxicity – monitor cardiac function. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. REFERENCES 1. COIN guidelines. Clin Oncol (R Coll Radiol), 2001. 13: p. S211-248. 2. Summerhayes, M. and S. Daniels, Dosage adjustment for cytotoxics in hepatic impairment,

in Practical Chemotherapy. 2003, Radcliffe Medical Press: Abingdon. p. 357-373. 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and


Doxorubicin + cisplatin



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DOXORUBICIN + IFOSFAMIDE (Uterine sarcoma)

Indication: Adjuvant uterine sarcoma

Results: Data comes from small phase II studies, no randomised data available. Ifosfamide alone gives response rates of 30% in carcinosarcoma and 17% in leiomyosarcoma. Ifosfamide with doxorubicin gave a response rate of 30.3% in 35 women with leiomyosarcoma: response duration averaged 4 months.

DRUG REGIMEN Day 1 DOXORUBICIN 25mg/m2 IV bolus MESNA 1g/m2 IV bolus IFOSFAMIDE 1.7g/m2 and MESNA 1.7g/m2 in 1L sodium chloride 0.9% infusion over 8 hours MESNA 1g/m2 in 1L sodium chloride 0.9% infusion over 8 hours Day 2 DOXORUBICIN 25mg/m2 IV bolus MESNA 1g/m2 IV bolus IFOSFAMIDE 1.7g/m2 and MESNA 1.7g/m2 in 1L sodium chloride 0.9% infusion over 8 hours MESNA 1g/m2 in 1L sodium chloride 0.9% infusion over 8 hours Day 3 MESNA 1g/m2 IV bolus IFOSFAMIDE 1.7g/m2 and MESNA 1.7g/m2 in 1L sodium chloride 0.9% infusion over 8 hours MESNA 1g/m2 in 1L sodium chloride 0.9% infusion over 8 hours NB. Doxorubicin 30mg/m2 can be used if patient not heavily pre-treated (d/w Consultant). An alternative regimen partly using ORAL mesna can be used: Cycle Frequency: Every 21 days for 3 cycles

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with SpR or Consultant 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 [3][1] Maximum cumulative dose: 450-550mg/m2 (in normal cardiac function) 400mg/m2 (in combination with thoracic radiation treatment or cyclophosphamide or in patients with cardiac risk factors)

Ifosfamide + doxorubicin



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Ifosfamide: GFR >60ml/min give 100% dose GFR 40-59ml/min give 70% dose GFR <40ml/min clinical decision (can switch to cyclophosphamide) Confirm with SpR or Consultant If creatinine >120mmol/L ifosfamide is contraindicated Confirm with SpR or Consultant.[2] Bilirubin >17 micromol/L is contraindicated AST and Alk Phos > 2.5 x upper limit of normal is contraindicated[3]


Liver function tests (LFTs)

Creatinine clearance (GFR)

ECG (possible ECHO) required if patient has pre-existing cardiac disease (doxorubicin) Neural Toxicity - Assess Probability of remaining free from severe CNS toxicity (ifosfamide) refer to the ifosfamide-induced encephalopathy specific neural toxicity grade and nomogram Give Discuss >0.5 <0.5 Careful consideration should be given if <0.2 2) Non-urgent blood tests Tests relating to disease response/progression


Ensure adequate pre-and post-hydration prescribed as per inpatient schedule at the end of the TVCN protocols. If fluid balance is > 2L positive (or gains >2kg) after 8 hours post hydration OR urine output <100ml//hour during IV administration post Cisplatin give 20 - 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV Methylthioninium chloride (methylene blue) can be given as prophylaxis against, or treatment of, ifosfamide-induced encephalopathy (see details below).





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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Urothelial toxicity (haemorrhagic cystitis) caused by acrolein and other urotoxic metabolites of ifosfamide can be prevented by the administration of mesna (included in the protocols). Neural Toxicity- refer to the ifosfamide-induced encephalopathy specific neural toxicity grade and nomogram (abridged below in full at the end of this document) Methylthioninium chloride (methylene blue) can be given as prophylaxis against, or treatment of, ifosfamide-induced encephalopathy. Dose: 50mg tds IV or orally. NB. 50mg = 5ml of 1% solution. 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. 53-97% oral absorption Nephrotoxicity-Irreversible renal failure and tubular damage can occur, and this is more frequent with cumulative doses over 25 – 50g/m2

of Ifosfamide. Cardiotoxicity – monitor cardiac function. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. REFERENCES 1. Summerhayes, M. and S. Daniels, Dosage adjustment for cytotoxics in hepatic impairment,

in Practical Chemotherapy. 2003, Radcliffe Medical Press: Abingdon. p. 357-373. 2. Ashley, C. and A. Currie, The Renal Drug Handbook. 2 ed. 2004, Oxford: Radcliffe Medical

Press. 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxic in hepatic impairment. 2009,

The North London Cancer Network. 4. Kupfer, A., C. Aeschlimann, et al., Prophylaxis and reversal of ifosfamide encephalopathy

with methylene blue. Lancet, 1994. 343(8900): p. 763-4. 5. Turner, A.R., C.D. Duong, et al., Methylene blue for the treatment and prophylaxis of





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DOXORUBICIN + IFOSFAMIDE (Uterine sarcoma)

Indication: Advanced uterine sarcoma

Results: Data comes from small phase II studies, no randomised data available. Ifosfamide alone gives response rates of 30% in carcinosarcoma and 17% in leiomyosarcoma. Ifosfamide with doxorubicin gave a response rate of 30.3% in 35 women with leiomyosarcoma: response duration averaged 4 months.

DRUG REGIMEN Day 1 DOXORUBICIN 30mg/m2 IV bolus MESNA 1g/m2 IV bolus IFOSFAMIDE 3g/m2 and MESNA 3g/m2 in 1L sodium chloride 0.9% infusion over 8 hours MESNA 1g/m2 in 1L sodium chloride 0.9% infusion over 8 hours Day 2 DOXORUBICIN 30mg/m2 IV bolus MESNA 1g/m2 IV bolus IFOSFAMIDE 3g/m2 and MESNA 3g/m2 in 1L sodium chloride 0.9% infusion over 8 hours MESNA 1g/m2 in 1L sodium chloride 0.9% infusion over 8 hours Day 3 MESNA 1g/m2 IV bolus IFOSFAMIDE 3g/m2 and MESNA 3g/m2 in 1L sodium chloride 0.9% infusion over 8 hours MESNA 1g/m2 in 1L sodium chloride 0.9% infusion over 8 hours Cycle Frequency: Every 21 days

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with SpR or Consultant 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 [3][1] Maximum cumulative dose: 450-550mg/m2 (in normal cardiac function) 400mg/m2 (in combination with thoracic radiation treatment or cyclophosphamide or in patients with cardiac risk factors)




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Ifosfamide: GFR >60ml/min give 100% dose GFR 40-59ml/min give 70% dose GFR <40ml/min clinical decision (can switch to cyclophosphamide) Confirm with SpR or Consultant If creatinine >120mmol/L ifosfamide is contraindicated Confirm with SpR or Consultant.[2] Bilirubin >17 micromol/L is contraindicated AST and Alk Phos >2.5 x upper limit of normal is contraindicated[3]


Liver function tests (LFTs)

Creatinine clearance (GFR)

ECG (possible ECHO) required if patient has pre-existing cardiac disease (doxorubicin) Neural Toxicity - Assess Probability of remaining free from severe CNS toxicity (ifosfamide) refer to the ifosfamide-induced encephalopathy specific neural toxicity grade and nomogram Give Discuss > 0.5 <0.5 Careful consideration should be given if <0.2 2) Non-urgent blood tests Tests relating to disease response/progression


Ensure adequate pre-and post-hydration prescribed as per inpatient schedule at the end of the TVCN protocols. If fluid balance is > 2L positive (or gains >2kg) after 8 hours post hydration OR urine output <100ml//hour during IV administration post Cisplatin give 20 - 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV Methylthioninium chloride (methylene blue) can be given as prophylaxis against, or treatment of, ifosfamide-induced encephalopathy (see details below).





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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Urothelial toxicity (haemorrhagic cystitis) caused by acrolein and other urotoxic metabolites of ifosfamide can be prevented by the administration of mesna (included in the protocols). Neural Toxicity- refer to the ifosfamide-induced encephalopathy specific neural toxicity grade and nomogram (abridged below in full at the end of this document) Methylthioninium chloride (methylene blue) can be given as prophylaxis against, or treatment of, ifosfamide-induced encephalopathy. Dose: 50mg tds IV or orally. NB. 50mg = 5ml of 1% solution. 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. 53-97% oral absorption Nephrotoxicity-Irreversible renal failure and tubular damage can occur, and this is more frequent with cumulative doses over 25 – 50g/m2

of Ifosfamide. Cardiotoxicity – monitor cardiac function. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. REFERENCES 1. Summerhayes, M. and S. Daniels, Dosage adjustment for cytotoxics in hepatic impairment,

in Practical Chemotherapy. 2003, Radcliffe Medical Press: Abingdon. p. 357-373. 2. Ashley, C. and A. Currie, The Renal Drug Handbook. 2 ed. 2004, Oxford: Radcliffe Medical

Press. 3. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxic in hepatic impairment. 2009,

The North London Cancer Network. 4. Kupfer, A., C. Aeschlimann, et al., Prophylaxis and reversal of ifosfamide encephalopathy

with methylene blue. Lancet, 1994. 343(8900): p. 763-4. 5. Turner, A.R., C.D. Duong, et al., Methylene blue for the treatment and prophylaxis of





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Ifosfamide-induced encephalopathy specific neural toxicity grade and nomogram 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.) 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. 53-97% oral absorption Nephrotoxicity-Irreversible renal failure and tubular damage can occur, and this is more frequent with cumulative doses over 25 – 50g/m2 of Ifosfamide. Dose reductions should be instituted for GFR and changes in fractional phosphate clearance (Tmp/GFR mmol/l). Urothelial toxicity (haemorrhagic cystitis) caused by acrolein and other urotoxic metabolites of ifosfamide can be prevented by the administration of mesna (included in the protocols). Neural toxicity grade Classify toxicity as grade 0-1, 2 or 3-4 and adjust ifosfamide treatment as indicated if either GFR or Tp/Ccrea (Tmp/GFR) or HCO3 is reduced.

Toxicity Grade* GFR (ml/min/1.73m2)

Tp/Ccrea (Tmp/GFR) (mmol/l)

HCO3** (mmol/l)

Action (apply worst grade)

Grade 0/1 ≥60 ≥1.00 ≥17.0 Ifos dose 100%

Grade 2 40-59 0.8-0.99 14.0-16.9 Ifos dose 70% of total

Grade 3/4 ≤40 ≤0.8 ≤14.0 ***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 HCO3 should be re-checked when the patientis 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/m2/day

Ifos Neural toxicity



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Fractional phosphate clearance calculated as below Tp/Ccrea = Phosphateserum – Phosphateurine x creatinineserum Creatinineurine [mmol/ml] Neural toxicity nomogram

Ifos Neural toxicity



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Pre-hydration and post-hydration regimens

Ensure adequate diuresis is obtained prior to administration and maintained during and after administration. 1. Inpatient

Pre 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours Give cisplatin in 1000ml volume over 4 hours Post 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours

NB 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 6 hours if oral intake is inadequate

2. Day case Pre 1L sodium chloride 0.9% + 20 mmol KCl + 8mmol MgSO4 infusion over 2 hours 200ml mannitol 10% infusion over 30 minutes Give cisplatin in 1000ml volume over 2 hours Post 1L sodium chloride 0.9% + 20 mmol KCl + 8mmol MgSO4 infusion over 2 hours

NB Furosemide 40mg may be added if required

Hydration Gynae CAG Chair Authorisation: Date


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