Gemcitabine & Cisplatin Available for Routine Use in Burton in-patient Derby in-patient Burton day-case Derby day-case Burton community Derby community Burton out-patient Derby out-patient Indication Advanced or metastatic cholangiocarcinomas and other biliary tract tumours Treatment Intent Palliative Anti-Emetics Pre-chemotherapy Day 1 & 8 2 Post-chemotherapy Day 1 & 8 C Day 1 Sodium chloride 0.9% 1000ml Intravenous infusion over 1 hour Sodium chloride 0.9% 500ml Intravenous infusion over 30 (if urine output remains low) Provided urine output is satisfactory (see notes) Cisplatin 25mg/m 2 Intravenous infusion in 500ml sodium chloride 0.9% over 60 (protect infusion from light) Sodium chloride 0.9% + 1000ml Intravenous infusion over 2 hours 20mmol magnesium sulphate + 20 mmol potassium chloride Followed by Gemcitabine 1000mg/m 2 Intravenous infusion in 250ml sodium chloride 0.9% over 30 AUTHORISED BY: Dr K Shankland PAGE 1 of 5
Day 8 Sodium chloride 0.9% 1000ml Intravenous infusion over 1 hour Sodium chloride 0.9% 500ml Intravenous infusion over 30 (if urine output remains low) Provided urine output is satisfactory (see notes) Cisplatin 25mg/m 2 Intravenous infusion in 500ml sodium chloride 0.9% over 60 (protect infusion from light) Sodium chloride 0.9% + 1000ml Intravenous infusion over 2 hours 20mmol magnesium sulphate + 20 mmol potassium chloride Followed by Gemcitabine 1000mg/m 2 Intravenous infusion in 250ml sodium chloride 0.9% over 30 Frequency & duration: every 21 days for a maximum of 8 cycles (See notes below) Notes: 1. Prior to starting therapy, the following laboratory parameters must be met Haemoglobin 10g/dl (prior transfusions for patients with low haemoglobin are allowed) WBC 3.0 x 10 9 /L Absolute neutrophil count (ANC) 1.0 x 10 9 /L Platelet count 100 x 10 9 /L Adequate liver function a. Total bilirubin 1.5 x upper limit of normal (ULN) b. ALT, AST & alkaline phosphatase 3 x ULN (if liver metastases are present, they can be 5 x ULN) Adequate renal function with serum urea and serum creatinine < 1.5 times ULN and a calculated GFR 45 ml/min. a. If the calculated GFR is below 60ml/min, isotope EDTA confirmation of adequate renal function is required 2. Patients require a full blood count prior to every dose of gemcitabine. AUTHORISED BY: Dr K Shankland PAGE 2 of 5
3. If the Day 8 treatment is not given for any reason, omit it completely. Do not defer it by 1 week. 4. Prior to administration of cisplatin on day 1 & 8 of each cycle adequate renal function must be demonstrated with a calculated creatinine clearance 45 ml/min. Otherwise doses must be modified as follows Estimated GFR (ml/min) Cisplatin Dose Gemcitabine Dose 45 Full dose Full dose <45 * Omit Full dose * Repeat the creatinine clearance assessment (consider using the more accurate isotope GFR method) ensuring the patient is adequately hydrated prior to this test and further cisplatin administration. Proceed with cisplatin if the repeated reading is 60 ml/min, otherwise cisplatin is to be omitted until recovery of renal function. If cisplatin has to be omitted, continue with gemcitabine dosing according to FBC. If a sudden increase in creatinine occurs, haemolytic uraemic syndrome should be ruled out. 5. Accurate fluid balance sheet must be kept. 6. Urine output should be maintained at > 100 ml/hour before (for at least 4 hours), during and after chemotherapy (8 hours). 7. 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. Urine output should increase within 30 of commencing the infusion. If urine output remains <100ml/hr after 30, a 10 mg stat IV bolus of Furosemide may be given to increase urine output. If 30 after the furosemide dose urine output has still not improved, the Consultant should be contacted for advice. 8. If day case administration, ensure Cisplatin is commenced by 15.00 hours at the latest so an adequate renal output can be maintained. 9. If in-patient administration, ensure Cisplatin is commenced by 19.00 hours at the latest so an adequate renal output can be maintained. 10. Advise patients to drink at least 2 litres of fluid over next 24 hours. AUTHORISED BY: Dr K Shankland PAGE 3 of 5
11. Dose Adjustments Haematological toxicity Gemcitabine in both treatment arms will be dose-reduced if haematological toxicity occurs. The dose to be administered will depend on the FBC result on the day of treatment. WBC (x 10 9 /L) ANC (x 10 9 /L) Platelets (x 10 9 /L) Gemcitabine Dose 2 and/or 1 and/or 100 Full Full 1 1.9 0.5 50-99 75% Dose Full 0.9 Cisplatin Dose < 1 < 0.5 <50 Delay* Delay * If delay is > 3 weeks for haematological toxicity, the patient will be withdrawn from treatment NB: the dose of gemcitabine will be re-escalated to full dose upon recovery of haematological toxicity despite a previous dose reduction in order to maintain the dose-intensity of therapy. 12. Biliary Tract Obstruction During Treatment In the event of the development of obstructive jaundice due to biliary tract obstruction, appropriate measures will be undertaken to diagnose (e.g. by ultrasound and/or CT scan) and relieve the obstruction (e.g. by ERCP/PTC +/- stent insertion/drainage). Chemotherapy will be deferred until the Liver Function Tests have improved to the pre-treatment eligibility levels (i.e. total bilirubin 1.5 X ULN; ALT, AST & alkaline phosphatase 3 x ULN - unless liver metastases are present, when they can be 5 x ULN). Chemotherapy may then resume at the start of the next treatment cycle. Biliary tract obstruction by itself shall not constitute evidence of disease progression. CT or MRI/MRCP imaging will be performed at the planned time points (i.e. after 3 and 6 months of treatment). However, if there is radiological evidence of disease progression compared to baseline during the investigation of obstructive jaundice, the patient shall be withdrawn from the study. 13. If after the initial 4 cycle course, radiological reassessment demonstrates a response to treatment, a further 4 cycles of therapy should be offered (See protocol) AUTHORISED BY: Dr K Shankland PAGE 4 of 5
14. Alcohol content of gemcitabine Doses of gemcitabine not available as ready- made infusions contain up to approximately 11g of ethanol (1.5units). Patients should be advised not to drive on the day of treatment. Where alcohol content is a concern please contact pharmacy for advice about alternative formulations. References: 1. ABC-02 Trial Protocol; Final version 2.0 27 th June 2005 2. Valle J. et al; Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer; N Engl J Med 2010; 362:1273-1281 AUTHORISED BY: Dr K Shankland PAGE 5 of 5