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Systemic Anti Cancer Treatment Protocol

VACA

( ) Sarcoma

PROTOCOL REF: MPHAVACA (Version No: 1.0)

Approved for use in: Ewings sarcoma as alternative VIDE in older patients Palliative Ewings

Dosage:

Schedule VACA x 6 then surgery (21 days after finish of cycle 6 or as soon as recovery occurs) followed by consolidation (possibly further 6 cycles of VACA) and/or radiotherapy

Or in palliative patients – up to 12 cycles

Cycles 1, 3 and 5 (7, 9 and 11) Drug Dosage Route Frequency Vincristine 1.5mg/m2 (max 2mg) day 1 IV Every 21 days Doxorubicin 20mg/m2 days 1, 2 and 3 IV Every 21 days Cyclophosphamide 1200mg/m2 day 1 IV Every 21 days Mesna See administration below

Cycles 2, 4 and 6 (8, 10 and 12) Drug Dosage Route Frequency Vincristine 1.5mg/m2 (max 2mg) day 1 IV Every 21 days Dactinomycin 0.5mg/m2 (max 1mg) days 1, 2 and 3 IV Every 21 days Cyclophosphamide 1200mg/m2 day 1 IV Every 21 days Mesna See administration below

Supportive treatments: Dexamethasone tablets, 4mg twice daily for 3 days Domperidone 10mg oral tablets, up to 3 times a day or as required Filgrastim 30MU or 48MU by subcutaneous injection for 7 days followed by FBC and continuation if neutrophil count has not recovered

Issue Date: 10th June 2016 Page 1 of 5 Protocol reference: MPHAVACA Authorised by: : Drugs and Therapeutics Author: Anne Hines/Helen Flint Committee & Dr N Ali Version No: 1.0

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST

Extravasation risk: Vincristine – vesicant – follow trust /network policy, specific antidote may apply Dactinomycin – vesicant – follow trust /network policy, specific antidote may apply Doxorubicin – vesicant – follow trust /network policy, specific antidote may apply Cyclophosphamide – Non vesicant

Administration:

Cycles 1, 3 and 5

Day Drug Dosage Route Diluent and Rate 1 Dexamethasone 8mg PO 30 mins before chemotherapy 1 Ondansetron 16mg PO 30 mins before chemotherapy 1 Vincristine 1.5 mg/m2 IV In 50mL sodium chloride (max 2mg) 0.9% over 15 minutes 1 Doxorubicin 20mg/m2 IV IV bolus 1 Mesna 500mg/m2 IV In 500mL sodium chloride 0.9% over 60 minutes 1 Cyclophosphamide 1200mg/m2 IV In 1000mL sodium chloride + mesna + 1200mg/m2 0.9% over 3 hours 1 Mesna 1200mg/m2 IV In 1000mL sodium chloride 0.9% over 8 hours 2 Dexamethasone 8mg PO 24 hours after day 1 dose 2 Ondansetron 16mg PO 24 hours after day 1 dose 2 Doxorubicin 20mg/m2 IV IV bolus 3 Dexamethasone 8mg PO 24 hours after day 2 dose 3 Ondansetron 16mg PO 24 hours after day 2 dose 3 Doxorubicin 20mg/m2 IV IV bolus 6 Filgrastim 30MU or 48MU SC By subcutaneous injection daily for 7 days, followed by FBC

Issue Date: 10th June 2016 Page 2 of 5 Protocol reference: MPHAVACA Authorised by: : Drugs and Therapeutics Author: Anne Hines/Helen Flint Committee & Dr N Ali Version No: 1.0

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST

Cycles 2, 4 and 6

Day Drug Dosage Route Diluent and Rate 1 Dexamethasone 8mg PO 30 mins before chemotherapy 1 Ondansetron 16mg PO 30 mins before chemotherapy 1 Vincristine 1.5 mg/m2 IV In 50mL sodium chloride (max 2mg) 0.9% 1 Dactinomycin 0.5mg/m2 IV In 100mL sodium chloride (max 1mg) 0.9% over 30 minutes 1 Mesna 500mg/m2 IV In 500mL sodium chloride 0.9% over 60 minutes 1 Cyclophosphamide 1200mg/m2 IV In 1000mL sodium chloride + mesna + 1200mg/m2 0.9% over 3 hours 1 Mesna 1200mg/m2 IV In 1000mL sodium chloride 0.9% over 8 hours 2 Dexamethasone 8mg PO 24 hours after day 1 dose 2 Ondansetron 16mg PO 24 hours after day 1 dose 2 Dactinomycin 0.5mg/m2 IV In 100mL sodium chloride (max 1mg) 0.9% over 30 minutes 3 Dexamethasone 8mg PO 24 hours after day 2 dose 3 Ondansetron 16mg PO 24 hours after day 2 dose 3 Dactinomycin 0.5mg/m2 IV In 100mL sodium chloride (max 1mg) 0.9% over 30 minutes 6 Filgrastim 30MU or 48MU SC By subcutaneous injection daily for 7 days, followed by FBC

Notes: Dactinomycin and doxorubicin are alternated in each cycle.

Hydration Ensure adequate hydration with appropriate electrolyte supplementation if needed. Monitor blood pressure, cardiac functions, and respiratory frequencies, body weight and diuresis regularly throughout treatment. If oedma or hypertension occurs, treatment with diuretics may be necessary

Doxorubicin Maximum cumulative dose of doxorubicin: 450 to 550mg/m2 Perform baseline MUGA if patient is considered at risk of significantly impaired cardiac contractility. Substitute dactinomycin 1.5mg/m2 if cardiac ejection fraction < 40% Repeat MUGA during treatment if there is any suspicion of cardiac impairment

Issue Date: 10th June 2016 Page 3 of 5 Protocol reference: MPHAVACA Authorised by: : Drugs and Therapeutics Author: Anne Hines/Helen Flint Committee & Dr N Ali Version No: 1.0

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST

Filgrastim dose: For patients under 70kg: 30MU subcutaneous injection daily For patients 70kg and above: 48MU subcutaneous injection daily

Main Toxicities: Vincristine – neurotoxicity, Dactinomycin - Myelosuppression, alopecia, mucositis, diarrhoea, liver changes (rare) ovarian failure / infertility Doxorubicin - Myelosuppression, alopecia, mucositis, cardiomyopathy (see notes and treatment plan), ovarian failure / infertility Cyclophosphamide – Myelosuppression, alopecia, mucositis, diarrhoea, haemorrhagic cystitis

Investigations and treatment plan

Cycle Cycle Cycle Cycle Cycle Cycle Pre Comments 1 2 3 4 5 6 Medical X X X X X X Assessment Nursing X X X X X X X Every cycle Assessment As clinically ECHO/ECG X indicated FBC X X X X X X X Every cycle

U&E & LFT X X X X X X X Every cycle CrCl (Cockroft and X X X X X X X Gault) As clinically CT scan X X indicated Informed X Consent Blood Every cycle and pressure X X X X X X X during measurement chemotherapy PS recorded X X X X X X X Every cycle Toxicities X X X X X X X Every cycle documented Weight X X X X X X X Every cycle recorded Urine dipstick for protein / X X X X X X X Every cycle blood

Issue Date: 10th June 2016 Page 4 of 5 Protocol reference: MPHAVACA Authorised by: : Drugs and Therapeutics Author: Anne Hines/Helen Flint Committee & Dr N Ali Version No: 1.0

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Dose Modifications and Toxicity Management:

Haematological toxicity Dose intensity is important for surgical patients; discuss any deferrals with medical team

Proceed on day 1 if:- ANC ≥ 1.0 x 109/L Platelets ≥ 100 x 109/L

Delay 1 week on day 1 if:- ANC ≤ 0.9 x 109/L Platelets ≤ 99 x 109/L

In palliative patients 1st Occurrence 2nd Occurrence Delayed recovery > 6 Reduce cyclophosphamide, Reduce cyclophosphamide, days OR neutropenic dactinomycin and doxorubicin dactinomycin and doxorubicin sepsis grade 3 or 4 to 80% of original dose to 60% of original dose

Non-haematological toxicity

Renal Monitor serum creatinine before each cycle of chemotherapy. Calculate CrCl each time. Routine adjustment of cyclophosphamide is not needed as it is altered hepatically although most sources suggest

CrCl Cyclophosphamide dose ≥10mL/min 100%

<10mL/min 75% 2 GFR < 60mL/min/1.73m -

Hepatic Doxorubicin Bilirubin (µmol/L) Doxorubicin dose 20 to 50 50% 51 to 85 25% Above 85 omit No specific guidance but consider dose reductions of dactinomycin in severe hepatic dysfunction Gastric Grade 3 or 4 mucositis or GI toxicity – reduce dactinomycin, cyclophosphamide and doxorubicin to 80% of original dose for first occurrence and 60% or original dose for second occurrence Haematuria or Grade Action haemorrhagic Microscopic during Give additional bolus doses of Mesna then a cystitis cyclophosphamide continuous infusion at double dose infusion Grade 2 Discontinue cyclophosphamide, continue with double dose continuous Mesna and hydration for 24 hours after cyclophosphamide stopped

Issue Date: 10th June 2016 Page 5 of 5 Protocol reference: MPHAVACA Authorised by: : Drugs and Therapeutics Author: Anne Hines/Helen Flint Committee & Dr N Ali Version No: 1.0