Systemic Anti Cancer Treatment Protocol Carboplatin / Gemcitabine Gynaecological Cancer PROCTOCOL REF: MPHAGYNCAG (Version No: 1.0) Approved for use in: Recurrent/metastatic endometrial carcinoma Previously available as 2 nd line option for locally advanced or metastatic epithelial ovarian carcinoma in patients with relapsed disease following a recurrence-free interval of at least 6 months after platinum-based, first-line therapy no longer approved, see NICE appraisal TA389 Dosage Drug Dosage Route Frequency Gemcitabine 1000mg/m² day 1 and day 8 IV infusion 21 day cycle max 6 Carboplatin AUC 4 x (GFR + 25) IV infusion cycles Calvert formula for Carboplatin dosage Carboplatin dose in mg = AUC x (creatinine clearance + 25) If estimated GFR is used the Wright formula must be used for creatinine clearance. Creatinine clearance should be capped at 125ml/min for carboplatin Avoid the use of Cockcroft and Gault formulae as it is less accurate. Issue Date: May 2017 Page 1 of 7 Protocol reference: MPHAGYNCAG
Supportive Treatments: Dexamethasone 4mg tablets orally twice daily for three days Domperidone 10mg tablets, three times a day when required Interactions Aminoglycosides e.g. gentamicin increased risk of nephrotoxicity and ototoxicity with Carboplatin. Renal function should be well monitored and audiometric tests carried out. Phenytoin- carboplatin can cause a decrease in phenytoin serum levels. This may lead to re of seizures and may require an increase of phenytoin dosages. Extravasation risk Gemcitabine - neutral Carboplatin - irritant Administration Day Drug Dose Route Diluent and rate 1 Ondansetron 16mg PO 30 minutes before chemotherapy Dexamethasone 8mg PO 30 minutes before chemotherapy Gemcitabine 1000mg/m² IV Infusion Carboplatin AUC 4 IV Infusion 250mL sodium chloride 0.9% over 30 minutes 500mL glucose 5% over 30 to 60 minutes 8 Dexamethasone 8mg PO 30 minutes before chemotherapy Gemcitabine mg/m² IV Infusion 250mL sodium chloride 0.9% over 30 minutes Vein discomfort throughout infusion of gemcitabine may be eased using heat pack. Issue Date: May 2017 Page 2 of 7 Protocol reference: MPHAGYNCAG
Facilities to treat anaphylaxis must be present when administering carboplatin. If a patient experiences an infusion-related reaction, give future does with premedication cover of IV chlorphenamine 10mg and IV hydrocortisone 100mg. Main Toxicities Carboplatin and Gemcitabine Gastrointestinal Nausea, vomiting,diarrhoea, constipation, mucositis General disorders and Malaise, fever, chills, urticaria, flu-like syndrome, rash, administration site pruritus conditions Carboplatin: Decreases in serum electrolytes (sodium, magnesium, potassium and calcium) Hearing loss Gemcitabine: Oedema/peripheral oedema - including facial oedema. Oedema is usually reversible after stopping treatment Haematological Neutropenia, anaemia, thrombocytopenia Hepatobiliary Musculoskeletal Nervous system Respiratory Skin and subcutaneous tissue disorders Elevation of liver transaminases (AST and ALT), alkaline phosphatase and bilirubin. Gemcitabine: back pain, myalgia Carboplatin: Paraesthesia, decreased deep tendon reflexes. Gemcitabine: headache, insomnia, somnolence Gemcitabine can cause dyspnoea usually mild and passes rapidly without treatment, cough and rhinitis Alopecia Allergic skin rash frequently associated with pruritus Urological Carboplatin: Renal function impairment Gemcitabine: Haematuria, mild proteinuria Issue Date: May 2017 Page 3 of 7 Protocol reference: MPHAGYNCAG
Investigations Medical Assessment Nursing Assessment Pre Cycle 1 Cycle 2 Cycle 3 Cycle 4 Ongoing X X X As per management plan X X X X X Every cycle FBC X X X X X Every cycle U&E & LFT X X X X X Every cycle CrCl X X X X X Every cycle CA125* X X X X X CT scan Informed Consent X X Every cycle *ovarian patients only PS recorded X X X X X Every cycle Toxicities documented X X X X X Every cycle Weight recorded X X X X X Every cycle Dose Modifications and Toxicity Management Haematological Toxicity Proceed on day 1 if- Plt 100 x 10 9 /L ANC 1.0 x 10 9 /L Delay 1 week on day 1 if- Plt 99 x 10 9 /L ANC 0.9 x 10 9 /L Proceed on day 8 if- Plt 75 x 10 9 /L ANC 1.0 x 10 9 /L Omit on day 8 if- Plt 74 x 10 9 /L ANC 0.9 x 10 9 /L On day 8 of the cycle if blood results do not meet the above levels the patient will miss that dose and proceed to the next cycle. Issue Date: May 2017 Page 4 of 7 Protocol reference: MPHAGYNCAG
These haematological guidelines assume that patients are well with good performance status, that other acute toxicities have resolved and the patient has not had a previous episode of neutropenic sepsis. Dose modification of Gemcitabine Neutrophil count Platelet count Percentage of standard dose of Gemcitabine (%) > 1.5 and 100 100 1 to 1.5 or 75 to 100 50 < 1 or < 75 Omit dose* *Treatment omitted will not be re-instated within a cycle. Treatment will start on day 1 of the next cycle once the absolute neutrophil count reaches at least 1.5 and the platelet count reaches 100. Non-Haematological Toxicity Grading and Management of Toxicity Toxicity should be grading according to the CTCAEv4 criteria. Following assessment treatment should be withheld for any toxicity until resolved to grade 0/1. For dose modification, follow the general guidance below and discuss with treating clinician. 1 st Grade 2 Grade 3 Grade 4 Interrupt treatment until Interrupt treatment until Discontinue resolved to grade 0/1, then resolved to grade 0/1, then treatment continue at 100% of original continue at 75-80% of dose with prophylaxis where original dose with possible prophylaxis where possible 2nd 3rd 4th Interrupt treatment until resolved to grade 0/1, then continue at 75-80% of original dose Interrupt treatment until resolved to grade 0/1, then continue at 50% of original dose Discontinue treatment Interrupt treatment until resolved to grade0/1, then continue at 50% of original dose Discontinue treatment Issue Date: May 2017 Page 5 of 7 Protocol reference: MPHAGYNCAG
Hepatic Impairment Gemcitabine No safety data in patients with hepatic impairment. If bilirubin > 27 μmol/l, initiate treatment with dose of 800 mg/m 2. Renal Impairment Carboplatin Patients with creatinine clearance values of less than 60 ml/min are at greater risk to develop myelosuppression. Carboplatin is contraindicated if glomerular filtration rate is 20 ml/min. The optimal use of Carboplatin in patients presenting with impaired renal function requires adequate dosage adjustments and frequent monitoring of both haematological nadirs and renal function. In patients with impaired renal function, dosage of carboplatin should be reduced Gemcitabine CrCl < 30ml/min consider dose reduction clinical decision. References Dosage Adjustment for Cytotoxics in Hepatic Impairment. January 2009 UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Dosage Adjustment for Cytotoxics in Renal Impairment. January 2009 UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January 2009) Stockley s drug interactions. Ninth edition. Edited K. Baxter. Pharmaceutical press. London. 2010 Issue Date: May 2017 Page 6 of 7 Protocol reference: MPHAGYNCAG
www.medicines.org.uk Gemcitabine plus carboplatin compared with carboplatin in patients with platinum sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG Pfisterer J et al J Clin Oncol 2006 24(29):4699-4707 NICE TA 389 April 2016 Issue Date: May 2017 Page 7 of 7 Protocol reference: MPHAGYNCAG