5-Fluorouracil & Radiotherapy for Adjuvant Oesophageal or Gastric Cancer (Modified Macdonald Protocol)

Transcription

1 5-Fluorouracil & Radiotherapy for Adjuvant Oesophageal or Gastric Cancer (Modified Macdonald Protocol) Indication: Adjuvant Chemo-radiotherapy for patients with resectable adenocarcinoma of the stomach or gastroesophageal junction Regimen details: Weeks 1-12 Continuous infusion 5-Fluorouracil during which there will be 5 weeks of concurrent Radiotherapy. The timing of the Radiotherapy 5-week block will vary through the 12 weeks according to clinical evaluation. For patients of poor performance status (particularly if they have received neo-adjuvant chemotherapy) consider concurrent chemoradiotherapy only for a total of 5 weeks. 7 Weeks of Chemotherapy ONLY: 5-Fluorouracil () 300mg/m 2 /day IV 5 Weeks of Chemo-radiotherapy: 5-Fluorouracil () 200mg/m 2 /day IV Radiotherapy (RT): Administration: Frequency: Extravasation: Anti- emetics: Supportive medication: 45Gy given over 25 fractions (1.8Gy) on weekdays only, for 5 weeks infusion, via central venous catheter and ambulatory infusion device The Protracted Venous Infused (PVI) is continued for a total of 12 weeks For up to 12 weeks continuous infusion. See also Appendix 1 Treatment summary, on page 4 : Non-vesicant Minimal emetogenic Follow local Anti-emetic Policy Metoclopramide is required before each fraction, and when required, throughout Radiotherapy Loperamide tablet/caps 4mg stat, then 2mg PRN for diarrhoea Pyridoxine tablets 50mg po tds, if required for palmar-plantar erythema (PPE) Advice on mouthcare and use of prophylactic mouthwashes should be given. If significant mucositis, consider use of ice chips (ice sucked by patient, starting 5 minutes before chemotherapy given and continued during administration) as an adjunct to dose reduction specified by Consultant Pre-treatment investigation: MAG3 or DMSA renal scan prior to 1 st cycle for differential renal function assessment Regular investigations: FBC LFTs U&Es Clinical review Weekly during RT, and D1 of each course of chemotherapy 4 weekly 4 weekly Weekly during RT Page 1 of 5

2 Comments: Cardiotoxicity 5-Fluorouracil Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiographic changes. These adverse events may be more common in patients with a prior history of coronary artery disease. Caution must be exercised in patients with history of significant cardiac disease, arrhythmias and angina pectoris Coronary artery spasm is more common in patients receiving continuous infusions of and is usually reversible on discontinuing the infusion. Should a patient receiving present with chest pains, stop the. Standard investigation and treatment of angina may be required. If rechallenge is necessary, this can be performed under Consultant supervision, but should symptoms redevelop, the should be withdrawn permanently DPD deficiency- 5-Fluorouracil Dihydropyrimidine dehydrogenase (DPD) deficiency can result in severe toxicity secondary to reduced metabolism of fluorouracil, usually manifest as severe toxicity within days of administration. If patients complain of toxicity very soon after administration, it is important to ensure supportive measures are implemented as soon as possible and Consultant consulted before further doses prescribed DOSE MODIFICATIONS Haematological Toxicity Day 1 of week when chemotherapy due: Neutrophils 1.0 x 10 9 /L or Platelets < 100 x 10 9 /L Delay chemotherapy for 1 week or until completely recovered Discuss with Consultant a dose reduction before re-challenge Renal Impairment: 5FU: Consider dose reduction in severe renal impairment (GFR < 10ml/min) only Hepatic Impairment Fluorouracil should be used with caution in patients with reduced liver function or jaundice: Bilirubin (µmol/l) AST 5FU Dose < 85 < 180 Give 100% > 85 or > 180 Contraindicated Page 2 of 5

3 DOSE MODIFICATIONS FOR OTHER TOXICITIES AS APPROPRIATE PALMAR/PLANTAR ERYTHEMA (PPE)/ MUCOSITIS/ DIARRHOEA FLUOROURACIL Patients with any grade PPE should receive Pyridoxine 50mg po tds throughout remainder of treatment For Grade 2 and above toxicities, should be discontinued until healing has occurred, and then recommence with dose reduction according to toxicity grading: Grade Palmar-plantar Erythema Mucositis Diarrhoea 5FU Dose 1 Minimal skin changes Erythema of the mucosa < 4 stools / day Give 100% (erythema) without pain but normal diet 2 Skin changes (peeling, Patchy ulcerations, can eat 4 6 stools / day Give 75% blisters, edema) or pain, and swallow modified diet not interfering with function 3 Ulcerative dermatitis or skin Confluent ulcerations; bleeding 7 stools / day Give 50% changes with pain interfering with minor trauma. Unable to with function adequately eat or hydrate orally Tissue necrosis; significant Life-threatening Give 25% spontaneous bleeding consequences Discuss with Life-threatening consequences Consultant Once dose reduction has been made, all subsequent treatment should remain at reduced dose. If patient not fit to receive chemotherapy on Week 5 of Chemo-radiotherapy, Radiotherapy should continue as planned, with Week 5 chemotherapy omitted completely i.e. not deferred. Toxicities: Myelosuppression; fatigue; nausea; vomiting; diarrhoea; mucositis; stomatitis; palmar-plantar erythema (PPE); ovarian failure; infertility; sensitivity of the skin to sunlight; alopecia (reversible) Drug interactions: 5-Fluorouracil is a known radiation-sensitizer. Patients should be carefully monitored for gastrointestinal toxicity when they are receiving concurrent & Radiation therapy Fluorouracil -Allopurinol : avoid concomitant use -Clozapine : increased risk of agranulocytosis, avoid concomitant use -Coumarins : enhanced anticoagulant effect -Digoxin tablets : reduced absorption (resolved by giving the digoxin in liquid) -Leucovorin : increased cytotoxic and toxic effects of Fluorouracil -Metronidazole ; Cimetidine : inhibit metabolism of fluorouracil (increased toxicity) -Phenytoin : reduced absorption of the antiepileptic -Sorivudine : marked and rapidly fatal fluorouracil toxicity Page 3 of 5

4 References: Summary of Product Characteristics. Fluorouracil. Medac GmbH.February 2007 Personal communication with Dr. D.Landau. October 2008 Macdonald JS et al. N Engl J Med (2001); vol 345 (10): SWSHCN- Approved Network Upper GI Regimen. May 2005 CCO Formulary- FULV-RT. October 2004 UCLH- Dosage Adjustment for Cytotoxics in Renal Impairment. November 2003 UCLH- Dosage Adjustment for Cytotoxics in Hepatic Impairment. November 2003 GSTT guidelines for treating nausea and vomiting in adult patients. September 2007 SELCN Cytotoxic Extravasation Guidelines (Draft). July 2008 Stockley s Drug Interactions. Interactions search: Fluorouracil. Sept 08 CTCAE v3.0. August 2006 APPENDIX 1 Treatment summary A. Example for patient undergoing RT during weeks 5 to 9 Week Therapy Dose RT Dose (Mon-Fri) 1-4 Chemotherapy ONLY 300mg/m 2 /day Chemo-radiotherapy 200mg/m 2 /day 45Gy, over 25 fractions (1.8Gy / day) Chemotherapy ONLY 300mg/m 2 /day Week Days (300mg/m 2 Week Days (200mg/m 2 RT Week Days (300mg/m 2 : Give RT on that day : Give chemotherapy on that day Page 4 of 5

5 B. Example for patient undergoing chemoradiotherapy only in total of 5 weeks. Week Days (200mg/m 2 RT : Give RT on that day : Give chemotherapy on that day Page 5 of 5