Bevacizumab + Paclitaxel + Cisplatin Available for Routine Use in Not routinely commissioned, each case requires prior documented approval before offering & commencing therapy from the Cancer Drugs Fund Indication The first line treatment of recurrent or metastatic cervical cancer in combination with chemotherapy where intolerant to carboplatin and the following criteria are met 1. Histologically confirmed carcinoma of the cervix 2. Indication for 1st line palliative chemotherapy 3. Primary stage IVB, recurrent, or persistent disease not amenable to curative treatment with surgery and/or radiotherapy. 4. PS 0 or 1 5. No previous treatment with bevacizumab or other anti- VEGF therapy Treatment Intent Palliative Anti-Emetics Pre-chemotherapy Day 1 Ondansetron 8mg STAT (in view of pre-meds) Day 2 Netupitant/Palonosetron 1 capsule STAT (in view of pre-meds) Post-chemotherapy C Day -2 Ranitidine 150mg Oral TWICE daily for 5 days STARTING 3 DAYS BEFORE THE CISPLATIN DOSE Cetirizine 10mg Oral ONCE daily for 5 days STARTING 3 DAYS BEFORE THE CISPLATIN DOSE Dexamethasone 8mg Oral TWICE daily for 5 days STARTING 3 DAYS BEFORE THE CISPLATIN DOSE Day 1 Bevacizumab 15mg/kg Intravenous infusion in 100ml Sodium Chloride 0.9% over 30 minutes (see notes below) Dexamethasone 20mg Slow intravenous bolus (30 minutes prior to paclitaxel) Ranitidine 50mg Intravenous bolus over at least 2 minutes (30 minutes prior to paclitaxel) Chlorphenamine 10mg Intravenous bolus (30 minutes prior to paclitaxel) AUTHORISED BY: Dr M Persic PAGE 1 of 9
Day 2 Provided urine output is satisfactory (see notes) Paclitaxel 175mg/m 2 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 endline filter over 3 hours Sodium chloride 1000ml Intravenous infusion over 1 hour 0.9% Sodium chloride 500ml Intravenous infusion over 30 minutes 0.9% (if urine output remains low) Mannitol 10% 100ml Intravenous infusion over 10 minutes Cisplatin 80mg/m2 Intravenous infusion in 1000ml sodium chloride 0.9% over 2 hours (protect infusion from light) Mannitol 10% 100ml Intravenous infusion over 10 minutes Sodium chloride 0.9% + 20mmol magnesium sulphate + 20 mmol potassium chloride 1000ml Intravenous infusion over 2 hours Frequency & duration: every 21 days until excessive toxicity or disease progression, whichever occurs first Notes: 1. Bevacizumab is ONLY approved for use in combination with combination chemotherapy and is not approved for use as a single agent maintenance therapy 2. Bevacizumab will be dosed based upon the patient s weight at initiation will be used to dose the bevacizumab for the duration of treatment. If a patients weight changes by 10% during the course of treatment, the dose of bevacizumab will be recalculated. 3. At each Cycle the following investigations are required:- FBC CA 125 U&Es LFTs 4. Following a toxicity assessment treatment may be given if: Neutrophils > 1.5 x 10 9 /L AUTHORISED BY: Dr M Persic PAGE 2 of 9
Platelets >100 x 10 9 /L 5. 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. 6. Frequent vital sign monitoring during the first hour of Paclitaxel administration is recommended. 7. 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 living (CTC grade 3) (approx. 80% of full dose) Omit 8. 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. AUTHORISED BY: Dr M Persic PAGE 3 of 9
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 9. 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. 10. The GFR prior to the first treatment should routinely be > 60 ml/minute. Then prior to each cycle, GFR should be estimated or measured as deemed clinically appropriate e.g. Cockcroft Gault Formula Females: Males: 1.04 x (140 age) x weight (kg) serum creatinine (micromol/l) 1.23 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 Male IBW (kg) = Height in cm 100 ABW = IBW + 0.4(actual weight IBW AUTHORISED BY: Dr M Persic PAGE 4 of 9
If the estimated serum creatinine clearance is <60 ml/minute, then a formal measurement of the GFR is required, 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. 11. 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 (whichever is most recent), Cycle 2, if there has been significant doubt about the true GFR at cycle 1 (according to clinical judgement). 12. If creatinine clearance is < 60mls/min the Cisplatin dose is adjusted as follows: 60 ml/min FULL dose Cisplatin 40-59 ml/min 50% dose Cisplatin (i.e. 40mg/m 2 ) < 40 ml/min OMIT Cisplatin 13. Mannitol 10% infusion is the preferred diuretic. If urine output remains <100ml/hr, a further dose of 100ml may be given by intravenous infusion over 10 minutes. Urine output should increase within 30 minutes of commencing the infusion. If urine output remains <100ml/hr after 30 minutes, a 10 mg stat IV bolus of Furosemide may be given to increase urine output. If 30 minutes after the furosemide dose urine output has still not improved, the Consultant should be contacted for advice. 14. Ensure Cisplatin is commenced by 15.00 hours at the latest so an adequate renal output can be maintained. 15. Patients must be advised to drink 2 litres of fluid over next 24 hours. 16. Urine output should be maintained at > 100 ml/hour before (for at least 2 hours from commencing hydration), during and after chemotherapy (8 hours). 17. Accurate fluid balance sheet must be kept. 18. If cisplatin is contra-indicated, substitute Carboplatin, see separate QACS protocol 19. 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 AUTHORISED BY: Dr M Persic PAGE 5 of 9
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 BEVACIZUMAB Schedule Modification due to Adverse Events Event Venous Thrombosis Grade 3 or incidentally discovered pulmonary embolus 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 Grade 3 or incidentally discovered Discontinue bevacizumab pulmonary embolus second occurrence, Grade 4 first occurrence In the case of an arterial thromboembolic event (e.g. angina, MI) treatment with bevacizumab must be discontinued Haemorrhage Grade 1 and 2 No dose modification Grade 3 or 4 (First occurrence) Hypersensitivity Reaction Hypersensitivity reaction attributable to bevacizumab Grade 3 or 4 Gastrointestinal perforation Gastrointestinal perforation or dehiscence Discontinue bevacizumab Treat with hydrocortisone, antihistamines and adrenaline if required (See Guidelines for the Treatment of Allergic Reactions for more details) Discontinue bevacizumab treatment Discontinue bevacizumab treatment AUTHORISED BY: Dr M Persic PAGE 6 of 9
Event Action to Be Taken 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: 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 9
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 9
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 References: 1. Krishnansu S et al; Improved Survival with Bevacizumab in Advanced Cervical Cancer; N Engl J Med 2014; 370:734-743February 20, 2014 (Abstract accessed on-line 5/3/14) 2. Communication with Pharmacy team, Royal Surrey Hospital AUTHORISED BY: Dr M Persic PAGE 9 of 9 > 2 g: Omit Bevacizumab dose Readminister only once protein < 2g.and do 24-hour urine before each scheduled dose until 1g protein/24 hours