Bevacizumab + Paclitaxel & Carboplatin Available for Routine Use in Not routinely commissioned, each case requires prior documented approval before offering & commencing therapy from NHS England Cancer Drug Fund Indication The first line treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer where the following criteria are met: 1. Chemotherapy naïve advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (not licensed at this dosage) 2. 1st line indication 3. Either FIGO stage III debulked but residual disease more than 1cm, or FIGO stage IV 4. Given with Carboplatin and Paclitaxel combination chemotherapy 5. Bevacizumab to start with: 1st or 2nd cycle of chemotherapy following debulking surgery or an attempt at debulking surgery (either performed prechemotherapy or after 3 cycles of neo-adjuvant chemotherapy), OR 1st or 2nd cycles of chemotherapy for those patients with stage IV disease OR inoperable disease Treatment Intent Radical Anti-Emetics Pre-chemotherapy 3 (During combination therapy) Post-chemotherapy C (During combination therapy) Day 1 Bevacizumab 7.5mg/kg Intravenous infusion in 100ml of Sodium Chloride 0.9% over 15 minutes (See note 2 below) Followed by: Sodium - Intravenous infusion to flush line Chloride 0.9% Dexamethasone 20mg Slow intravenous bolus (30 minutes prior to paclitaxel) Ranitidine 50mg Intravenous bolus over at least 2 minutes (30 minutes prior to paclitaxel) AUTHORISED BY: Dr M Persic PAGE 1 of 10
Chlorphenamine 10mg Paclitaxel 175mg/m 2 (MAXIMUM 350mg) Intravenous bolus (30 minutes prior to paclitaxel) Intravenous infusion in 500ml of Sodium Chloride 0.9% or Dextrose 5% Infusion in a PVC- Free infusion bag via a lowabsorption set using a 0.2micron end-line filter over 3 hours Carboplatin Dose = AUC * (GFR + 25) mg (See notes below) Intravenous infusion in 500ml Dextrose 5% over 30 minutes Frequency & duration: every 21 days for a maximum of 6 cycles (initial debulking surgery) every 21 days for a maximum of 3 cycles (delayed (interval) debulking surgery) Followed by Day 1 Bevacizumab 7.5mg/kg Intravenous infusion in 100ml of Sodium Chloride 0.9% over 15 minutes (or fastest rate given previously) Sodium Chloride 0.9%- Intravenous infusion to flush line Frequency & duration: every 21 days for a maximum of 18 cycles of bevacizumab (including combination with chemotherapy) Notes: 1. Patients should begin treatment no later than six weeks after surgery. 2. Bevacizumab can be omitted from the first post-operative cycle if cytotoxic chemotherapy must be started within 4 weeks of surgery. 3. During the cycles of chemotherapy, bevacizumab should be administered on the same day as chemotherapy. If the chemotherapy is delayed then the bevacizumab must also be delayed accordingly. 4. If bevacizumab is being given in combination with chemotherapy then it should be given before any chemotherapy drugs. No routine premedications, including antiemetics, are required. AUTHORISED BY: Dr M Persic PAGE 2 of 10
5. If a bevacizumab infusion is not tolerated well (e.g. fever, chills) then the next infusion should be given over 60-90 minutes +/- chlorphenamine cover. If this is tolerated, reduce the next doses in a step-wise fashion to a minimum time of 30 minutes, and maintain that infusion time for all remaining doses 6. As this dosage of Bevacizumab is not licensed in ovarian cancer it must be used within the treating Trust s governance framework 7. As a precautionary measure, it is recommended that an interval of 7 days is left between the insertion of any central venous access devices (CVADs) and the onset of bevacizumab treatment.. The status of the wound must be checked before treatment commences to ensure healing is occurring. 8. At each Cycle the following investigations are required:- FBC CA 125 U&Es LFTs BP Urinalysis 9. Following a toxicity assessment treatment may be given if: Neutrophils > 1.5 x 10 9 /L Platelets >100 x 10 9 /L BP < 150/100mmHg Proteinuria < 2+ (dipstick) see notes below for action if 2+ result 10. If the assessment takes place on a Friday i.e. 3 days pre treatment and blood results fall between the following parameters the patient must be re-bled on the day of treatment: Neutrophils 1.0-1.5 x 10 9 /L Platelets 80-100 x 10 9 /L Patients with blood results below the above parameters must be deferred by 1 week. 11. Frequent vital sign monitoring during the first hour of Paclitaxel administration is recommended. AUTHORISED BY: Dr M Persic PAGE 3 of 10
12. Whilst neurotoxicity is rare occasionally problems have been experienced in patients with diabetes or pre-existing occult neuropathic deficits. The following dose reductions are advised: Degree of neuropathy Paclitaxel Dose Neuropathy interfering with function 135mg/m 2 (CTC grade 2) Impairment of daily activities of daily Omit living (CTC grade 3) 13. Paclitaxel-related acute hypersensitivity reactions Despite routine prophylaxis with antihistamines and steroids etc., 2-4% of patients will suffer hypersensitivity reactions to paclitaxel. These usually occur in the first 5-10 minutes of the first or second infusion. Adrenaline (1ml/1:1000 IM) should be available, as should antihistamines, dexamethasone and oxygen. Whilst mild/moderate reaction may subside with further steroids and antihistamines, allowing successful re-challenge, this practice should be avoided if the severity of the initial reaction was such that adrenaline was required. Degree of reaction Mild symptoms Skin rash, flushing, localised pruritus Moderate symptoms Generalised pruritus or rash, mild dyspnoea, mild hypotension Severe symptoms Bronchospasm, generalised urticaria, angio-oedema, hypotension (systolic <80mmHg) Recommended Action Reduce infusion rate Treat with further IV chlorphenamine 10mg Monitor until recovery Then re-challenge Stop paclitaxel infusion Treat with IV hydrocortisone 100mg and IV chlorphenamine 10mg Re-challenge after recovery Stop paclitaxel infusion Treat with IM adrenaline (1ml 1:1000), IV hydrocortisone 100mg and IV chlorphenamine 10mg AUTHORISED BY: Dr M Persic PAGE 4 of 10
14. Alcohol content Paclitaxel contains up to 21g (approx. 2.5 units) of ethanol per maximum dose. Patients should be advised not to drive on the day of treatment. Consider alternative chemotherapy agents for patients where alcohol content is a concern. 15. Carboplatin dosage based on EDTA renogram prior to cycle 1. If the isotopic clearance is measured then the value uncorrected for body surface area (BSA) should be used in dose calculations. The Cockcroft Gault formula may be used to calculate at the Clinicians discretion. e.g. Cockcroft Gault Formula Females: 1.04 x (140 age) x weight (kg) serum creatinine (micromol/l) For patients with body mass index (BMI) of 30 kg/m2 with stable serum creatinine values, the adjusted body weight (ABW) should be used to estimate the GFR i.e. Ideal Body Weight Female IBW (kg) = Height in cm - 105 ABW = IBW + 0.4(actual weight IBW If the estimated serum creatinine clearance is <60 ml/minute, then a formal measurement of the GFR should be considered, using either a 24 hour urine collection or an isotopic clearance. If the isotopic clearance is measured then the value uncorrected for body surface area (BSA) should be used in dose calculations. 16. The GFR should be recalculated, or re-measured, for Renal toxicity (CTC Grade 2, serum creatinine >1.5 x ULN), Serum creatinine changes of 10% compared to baseline, or last creatinine value used to calculate carboplatin dose (whichever is most recent), Each dose modification of carboplatin, Cycle 2, if there has been significant doubt about the true GFR at cycle 1 (according to clinical judgement). 17. AUC = 5 AUTHORISED BY: Dr M Persic PAGE 5 of 10
18. BEVACIZUMAB Schedule Modification due to Adverse Events Event Venous Thrombosis Grade 3 or incidentally discovered pulmonary embolus first occurrence Grade 3 or incidentally discovered pulmonary embolus second occurrence, Grade 4 first occurrence Action to Be Taken Hold bevacizumab treatment If the planned duration of therapeutic dose anticoagulant (defined as a dose titrated to maintain an INR of at least 1.5 for warfarin or equivalent) therapy if 2 weeks, bevacizumab should be held until the period of therapeutic-dose anticoagulant therapy is over If the planned duration of therapeutic dose anticoagulant (defined as a dose titrated to maintain an INR of at least 1.5 for warfarin or equivalent) therapy if 2 weeks, bevacizumab should be held for 2 weeks and then may be resumed during the period of therapeutic dose anticoagulant as soon as all of the following are met: The subject must be on a stable dose of anticoagulant and, if on warfarin, have an INR within the target range (usually 2-3) prior to restarting study drug treatment The subject must not have had a grade 3 or 4 haemorrhagic event since entering the study The subject must not have had any evidence of tumour invading or abutting major blood vessels on any prior CT scan Discontinue bevacizumab In the case of an arterial thromboembolic event (e.g. angina, MI) treatment with bevacizumab must be discontinued Haemorrhage Grade 1 and 2 Grade 3 or 4 (First occurrence) Hypersensitivity Reaction Hypersensitivity reaction attributable to bevacizumab Grade 3 or 4 No dose modification Discontinue bevacizumab Treat with hydrocortisone, antihistamines and adrenaline if required (See Guidelines for the Treatment of Allergic Reactions for more details) Discontinue bevacizumab treatment Event Action to Be Taken Gastrointestinal perforation Gastrointestinal perforation or Discontinue bevacizumab treatment dehiscence Proteinuria (See algorithms overleaf) First occurrence of proteinuria <2+ (dipstick) Bevacizumab should be administered as scheduled No additional evaluation is required 2+ or 3+ (dipstick) Bevacizumab should be administered as scheduled Collect 24-hour urine for determination of total protein within 3 days before the next scheduled bevacizumab administration: AUTHORISED BY: Dr M Persic PAGE 6 of 10
If 24-hour protein 2g bevacizumab should be administered as scheduled If 24-hour protein >2g omit next scheduled bevacizumab dose and do 24-hour urine collection for determination of total protein within 3 days before the subsequently scheduled cycle. Delay bevacizumab treatment until proteinuria has decreased to 2 g. Do 24-hour urine before each scheduled dose until proteinuria has improved to 1 g/24 hours, but omit bevacizumab only if >2 g/24 hours Nephrotic syndrome Discontinue bevacizumab treatment permanently (CTCAE Grade 4) 2 nd and subsequent occurrence of proteinuria <3+ (dipstick) Bevacizumab should be administered as scheduled No additional evaluation is required 3+ (dipstick) Bevacizumab should be administered as scheduled and collect 24-hour urine for determination of total protein within 3 days before the next scheduled bevacizumab administration: If 24-hour proteinuria 2 g: administer next bevacizumab dose as scheduled. If 24-hour proteinuria >2 g: omit next scheduled bevacizumab dose and do 24-hour urine collection for determination of total protein within 3 days before the subsequently scheduled cycle. Delay bevacizumab treatment until proteinuria has decreased to 2 g. Do 24-hour urine before each scheduled dose until proteinuria has improved to 1 g/24 hours, but omit bevacizumab only if >2 g/24 hours Nephrotic syndrome Discontinue bevacizumab treatment permanently (CTCAE Grade 4) AUTHORISED BY: Dr M Persic PAGE 7 of 10
Event Hypertension Grade 1 Grade 2 Grade 3 Grade 4 Action to Be Taken Asymptomatic, transient (<24 hrs) increase by >20mmHg (diastolic) or to >150/100mmHg if previously within normal range. Intervention not indicated Recurrent or persistent (>24hrs) or symptomatic increase by >20mmHg (diastolic) or to >150/100mmHg if previously within normal range. Monotherapy of anti-hypertensive may be indicated. Once controlled <150/110mmHg, patients may continue bevacizumab therapy Requiring more than one anti-hypertensive or more intensive therapy than previously. Bevacizumab should be withheld for persistent or symptomatic hypertension and should be permanently discontinued if BP is not controlled. If not controlled with medication, discontinue bevacizumab Occurrence of grade 4 hypertension should lead to permanent discontinuation of bevacizumab. All doses of anti-hypertensive medicines should be recorded at all visits Due to the effect of bevacizumab on wound healing and the half-life of three weeks, it is recommended that elective major surgery should be postponed for at least 4-6 weeks after the last dose of bevacizumab has been administered. Emergency surgery should not be delayed. AUTHORISED BY: Dr M Persic PAGE 8 of 10
Algorithm for proteinuria (dipstick) 2+ Dipstick 2+ First occurrence: Give Bevacizumab and do 24-hour urine Second occurrence: Give Bevacizumab 2 g: Give next Bevacizumab dose as scheduled. > 2 g: Omit Bevacizumab dose. Do 24-hour urine before next scheduled dose 2 g: Give next Bevacizumab dose as scheduled and do 24-hour urine before each scheduled dose until 1g protein/24 hours > 2 g: Omit Bevacizumab dose Readminister only once protein < 2g and do 24-hour urine before each scheduled dose until 1g protein/24 hours Algorithm for proteinuria (dipstick) 3+ Dipstick 3+: Give Bevacizumab and do 24-hour urine collection before next scheduled dose 2 g: Give next Bevacizumab dose as scheduled. > 2 g: Omit Bevacizumab dose. Do 24-hour urine before next scheduled dose 2 g: Give next Bevacizumab dose as scheduled and do 24-hour urine before each scheduled dose until 1g protein/24 hours AUTHORISED BY: Dr M Persic PAGE 9 of 10 > 2 g: Omit Bevacizumab dose Readminister only once protein < 2g.and do 24-hour urine before each scheduled dose until 1g protein/24 hours
References: 1. ICON-7 Trial Protocol, Version 3.0 16.07.2007 2. Communication with ICON 7 Trial Physician, 16 th May 2007 3. Roche; Summary of Product Characteristics last updated on the emc: 30/03/2012 (Accessed 1/6/2012) 4. Communication with Pharmacy team, Royal Surrey Hospital AUTHORISED BY: Dr M Persic PAGE 10 of 10