Thames Valley. Thames Valley Chemotherapy Regimens Upper Gastrointestinal Cancer

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1 Chemotherapy Regimens Upper Gastrointestinal Cancer

2 Notes from the editor These regimens are available on the Network website Any correspondence about the regimens should be addressed to: Sally Coutts, Cancer Pharmacist, Acknowledgements These regimens have been compiled by the Network Pharmacy Group in collaboration with the Upper GI CAG with key contribution from Dr Kinnari Patel, Consultant Oncologist, OUHFT Dr James Gildersleve, Consultant Oncologist, RBFT Dr Nicola Warner, Consultant Oncologist, OUHFT Dr Claire Blesing, Consultant Oncologist, OUHFT Karen Carter, Pharmacist, RBFT Jane Gibbard, Pharmacist, OUHFT Alison Ashman, Formerly Lead Pharmacist Cancer Network Cancer Network. All rights reserved. Not to be reproduced in whole or in part without the permission of the copyright owner. Chemotherapy Regimens Upper GI Cancer 2

3 Chemotherapy Regimens Upper Gastrointestinal Cancer Network Chemotherapy regimens used in the management of Upper Gastrointestinal Cancer Date published: January 2019 Date of review: January 2021 Chemotherapy Regimens Name of regimen Indication Page List of amendments to this version 5 Cisplatin + Fluorouracil (CF 80 pre-op) infusor Oesophagus 6 Docetaxel Fluorouracil Oxaliplatin (FLOT) if local Gastric and oesophagus 8 Trust funding agreed ECF Gastric and oesophagus 10 EC capecitabine (ECX) Gastric and oesophagus 12 Epirubicin, oxaliplatin and capecitabine (EOX) Gastric and oesophagus 17 Epirubicin, oxaliplatin and fluorouracil (EOF) Gastric and oesophagus 20 Paclitaxel Carboplatin 21 day Oesophagus 23 Trastuzumab, capecitabine and cisplatin Gastric oesophageal junction 25 Cisplatin + Fluorouracil (CF 75 RT) + RT infusor Oesophagus 26 Cisplatin + Capecitabine + RT Oesophagus 28 Cisplatin + Capecitabine Oesophagus 31 Docetaxel 75 Gastric and oesophagus 34 Mitomycin + Fluorouracil (MF) Gastric and oesophagus 36 Paclitaxel 7 day Carboplatin 7 day + RT Oesophagus 38 Capecitabine + RT Pancreas 40 Gemcitabine Pancreas 43 Gemcitabine + RT Pancreas 45 Gemcitabine and capecitabine Pancreas 47 Fluorouracil continuous + RT Pancreas 50 FOLFIRINOX if local Trust funding agreed for Pancreas 51 adjuvant use Oxaliplatin and capecitabine Pancreas 53 Gemcitabine + Paclitaxel albumin bound Pancreas 56 Capecitabine if local Trust funding agreed Gallbladder cholangiocarcinoma 58 Cisplatin + Modified De Gramont infusor Gallbladder 61 Gemcitabine (1000) + Cisplatin (25) Gallbladder cholangiocarcinoma 65 Lenvatinib Hepatocellular 67 Chemotherapy Regimens Upper GI Cancer 3

4 Name of regimen Indication Page Regorafenib Hepatocellular 70 Sorafenib Hepatocellular 72 Pre and post-hydration regimen 74 Carboplatin may be substituted with cisplatin in those patients hypersensitive to carboplatin and cisplatin may be substituted with carboplatin in those patients hypersensitive to cisplatin, unless otherwise specified by NICE or CDF. Chemotherapy Regimens Upper GI Cancer 4

5 List of amendments in this version Regimen type: Upper GI Tumours Date due for review: January 2021 Previous Version number: 4.4 and 4.5 This version number: 4.5a Table 1 Amendments Page Action Type Amendment Made/ asked by FOLFIRINOX adjuvant use indication added for private patients and Trusts that have agreed to fund locally Table 2 New protocols to be approved and checked by CAG included in this version Name of regimen Indication Reason / Proposer Docetaxel Fluorouracil Oxaliplatin FLOT Gastric Oesophagus For private patients and Trusts that have agreed to fund locally Capecitabine Cholangiocarcinoma For private patients and Trusts that have agreed to fund locally Lenvatinib Hepatocellular CDF Regorafenib Hepatocellular CDF For anti-emetic guidelines: For dose banded chemotherapy standardized product specifications: Chemotherapy Regimens Upper GI Cancer 5

6 CISPLATIN + FLUOROURACIL (CF 80 pre-op) infusor Indication: Pre-operative chemotherapy for cancer of the oesophagus DRUG REGIMEN Day 1 Pre hydration CISPLATIN 80mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours (daypatient) FLUOROURACIL 4000mg/m 2 infusion over 96 hours via an infusor Post hydration Cycle Frequency: Repeat day 21 (2 cycles only) DOSE MODIFICATIONS Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin or switch to an appropriate oxaliplatin containing regimen Discuss with Consultant re omission / substitution If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration. Fluorouracil: Not to go ahead if cisplatin is contra-indicated/discontinued Consider dose reduction in severe renal impairment only. Bilirubin <85micromol/L or ALT/AST <180 give 100% dose Bilirubin >85micromol/L or ALT/AST >180 omit Treatment delays If Neutrophils <1.5x10 9 /L and/or the platelet count <100x10 9 /L delay the second course by one week, recheck blood count. If satisfactory (>1.5x10 9 /L and >100x10 9 /L) give 75% dose Cisplatin and 5FU. If not satisfactory delay by a further week and recheck blood count, if satisfactory (>1.5x10 9 /L and >100x10 9 /L) then give 50% dose Cisplatin and 5FU. If still unsatisfactory after 2 week delay chemotherapy should be discontinued. CF infusor Page 1 of 2 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 6

7 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 <10 Plt x 10 9 /L 100 <100 Neutrophils x 10 9 /L 1.5 <1.5 WBC x 10 9 /L 3.5 <3.5 Creatinine clearance (GFR) calculated or EDTA or 24 hour urine collection at the Consultant discretion. (Cisplatin) 2) Non-urgent blood tests Tests relating to disease response/progression CONCURRENT MEDICATION Ensure adequate pre and post hydration prescribed as per inpatient schedule at the end of TVCN protocols. If fluid balance is > 2L positive after 8 hours post hydration OR if patient gains >2kg in weight or urine output <100ml//hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV ANTI-EMETIC POLICY Highly emetogenic day 1 Low emetogenic risk days 2, 3, 4 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds Mucositis use routine mouthcare Diarrhoea treat with codeine or loperamide Nephrotoxicity ensure adequate pre and post hydration is prescribed Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease or those who develop chest pain during treatment with fluorouracil. REFERENCES 1. Lancet May 18; 359 (9319): CF infusor Page 2 of 2 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 7

8 DOCETAXEL FLUOROURACIL OXALIPLATIN (FLOT) Indication: Peri-operative use in resectable gastric or gastro-oesophageal junction adenocarcinoma Suitable for fit patients only, with PS 0 1 Not NHSE commissioned regimen - Trust to fund locally, and not charge to NHSE DRUG REGIMEN Day 1 DOCETAXEL 50mg/m 2 in 250ml sodium chloride 0.9% IV infusion over 60 minutes Flush with glucose 5% after infusion CALCIUM LEVOFOLINATE* 175mg in glucose 5% infusion over 2 hours concurrently with oxaliplatin via a Y site placed immediately before the injection site. OXALIPLATIN 85mg/m 2 in 250ml glucose 5% infusion over 2 hours FLUOROURACIL 2600mg/m 2 continuous infusion over 24 hours via an infusor Cycle Frequency: Every 14 days for 4 cycles before surgery, plus a further 4 cycles after surgery. NBCalcium levofolinate is not the same as calcium folinate (calcium leucovorin). Calcium levofolinate is a single isomer of folinic acid and the dose is generally half that of calcium folinate. If calcium levofolinate is not available calcium folinate (leucovorin) may be used instead. DOSE MODIFICATIONS Symptoms including diarrhoea, mucositis and leucopenia, discuss with Registrar or Consultant. If neutrophils<1.5x10 9 /L or platelets<100x10 9 /L delay 1 week, only treat when neutrophils and platelets are above these limits. If >1 delay or 1 delay >or= 2 weeks reduce all the 5FU doses to 80% for future cycles. A further dose reduction may be made at the Clinician s discretion. Fluorouracil: Consider dose reduction in severe renal impairment only. Bilirubin <85micromol/L or ALT/AST <180 give 100% dose Bilirubin > 85micromol/L or ALT/AST >180 omit Oxaliplatin: If persistent peripheral sensory symptoms occur, withdraw treatment GFR >20ml/min give 100% dose and adjust according to toxicity GFR <20ml/min dose reduce Hepatic impairment: Probably no dose reduction necessary Clinical decision If patients develop acute laryngopharyngeal dysaesthesia infuse the next cycle over 6 hours. If symptoms persist reduce dose to 65mg/m 2 Docetaxel Fluorouracil Oxaliplatin Page 1 of 2 Published: January 2019 Version 4.5a Chemotherapy Regimens Upper GI Cancer 8

9 Docetaxel: Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Hepatic impairment: Patients who have both elevations of transaminase (ALT and/or AST) > 1.5 x ULN and ALP > 2.5 x UL give 75% dose. Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated. INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Serum creatinine - GFR should be calculated or measured using EDTA 2) Non urgent blood tests Tests relating to disease response/progression CONCURRENT MEDICATION Patients who experience delayed diarrhoea will require loperamide 2mg every 2 hours to continue for 12 hours after the last loose stool. This high dose should be discontinued after 48 hours ANTIEMETIC POLICY Moderately emetogenic day 1 Low emetogenic risk day 2 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds Diarrhoea treat with loperamide or codeine Peripheral sensory neuropathy and laryngeal spasm avoid cold drinks and touching cold items. Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease or those who develop chest pain during treatment with fluorouracil. Docetaxel Fluorouracil Oxaliplatin Page 2 of 2 Published: January 2019 Version 4.5a Chemotherapy Regimens Upper GI Cancer 9

10 ECF Indication: Advanced gastric, oesophageal cancer, adjuvant gastric cancer and unknown adenocarcinoma. Neoadjuvant gastric cancer if capecitabine contraindicated. Unknown primary if appropriate DRUG REGIMEN Day 1 EPIRUBICIN 50mg/m 2 IV bolus Pre-hydration CISPLATIN 60mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Post hydration FLUOROURACIL 200mg/m 2 /24 hours continuous infusion for 7 days, Day 8 FLUOROURACIL 200mg/m 2 /24 hours continuous infusion for 7 days Day 15 FLUOROURACIL 200mg/m 2 /24 hours continuous infusion for 7 days and continue for 21 days after last Epirubicin / Cisplatin admission. Note on cycle 1 Fluorouracil should start 4 hours prior to cisplatin. Cycle Frequency: Every 21 days up to 6 cycles Adjuvant 3 cycles pre-op and 3 cycles post-op DOSE MODIFICATIONS Platelets x 10 9 /L <25 Neutrophils x 10 9 /L <0.5 WBC x 10 9 /L <1.0 Dose modification Full dose Stop 5FU, delay Cisplatin and epirubicin until recovery. Restart give 75% epirubicin dose on subsequent cycles Stop 5FU, delay Cisplatin and epirubicin until recovery. Restart 5FU at full dose, give 50% epirubicin dose on subsequent cycles Stop 5FU, delay Cisplatin and epirubicin until recovery. Restart 5FU at full dose BUT omit epirubicin from subsequent cycles ECF Page 1 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 10

11 Epirubicin: Bilirubin 24-51micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit Dose reduce in severe renal impairment. Neutropenia / fever infection Neutrophils give 75% dose of epirubicin for subsequent cycles Neutrophils <0.5 give 50% dose of epirubicin for subsequent cycles Maximum lifetime dose = 650mg/m2 (in combination with thoracic radiotherapy or previous anthracyclines = 1000 mg/m 2 (with normal cardiac function) Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin or switch to an appropriate oxaliplatin containing regimen Discuss with Consultant re omission / substitution Consider substitution with carboplatin AUC 4 or 5 every 4 weeks if cisplatin is contra-indicated If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration. Fluorouracil: Consider dose reduction in severe renal impairment only. Bilirubin <85micromol/L or ALT/AST <180 give 100% dose Bilirubin > 85micromol/L or ALT/AST >180 omit Diarrhoea and/or mucositis Grade 2 toxicity 1 week break from 5FU then restart at 150mg/m 2 /day Grade 3 toxicity stop 5FU until symptoms resolve, then restart at 100mg/m 2 /day Grade 4 toxicity stop 5FU until symptoms resolve, then restart at 50mg/m 2 /day ECF Page 2 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 11

12 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Creatinine clearance (GFR) calculated or EDTA or 24 hour urine collection at the Consultant discretion. (Cisplatin) 2) Non-urgent blood tests Tests relating to disease response/progression CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV ANTI-EMETIC POLICY Highly emetogenic day 1 Low emetogenic risk days 2 to 21 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds if symptoms fail to improve then stop 5FU for 1 week then restart at 150mg/m 2 /day. Mucositis see dose modifications use routine mouthcare Diarrhoea see dose modifications treat with loperamide or codeine Nephrotoxicity ensure adequate pre and post hydration is prescribed Cardiotoxicity monitor cardiac function. To minimise risk of anthracycline induced cardiac failure signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease or those who develop chest pain during treatment with fluorouracil. REFERENCES 1. Waters JS et al. Br J Cancer 1999; 80: ECF Page 3 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 12

13 EC CAPECITABINE (ECX) Indication: Advanced gastric, oesophageal cancer, adjuvant and neoadjuvant gastric cancer and unknown adenocarcinoma, adjuvant gastric and type 3 gastro oesophageal junction cancer. Unknown primary if appropriate DRUG REGIMEN Day 1 EPIRUBICIN 50mg/m 2 IV bolus Pre-hydration CISPLATIN 60mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Post hydration CAPECITABINE 1250mg/m² daily in 2 divided doses for 21 days Cycle frequency: Every 21 days (up to 6 cycles). Adjuvant chemo, give 3 cycles pre-op and 3 cycles post-op Note: Tablets are only available as 150mg and 500mg tablets Note: on cycle 1 capecitabine should start prior to cisplatin. DOSE MODIFICATIONS Platelets x 10 9 /L <25 Neutrophils x 10 9 /L <0.5 WBC x 10 9 /L <1.0 Dose modification Full dose Stop capecitabine, delay Cisplatin and epirubicin until recovery. Restart capecitabine at full dose, give 75% epirubicin dose on subsequent cycles Stop capecitabine, delay Cisplatin and epirubicin until recovery. Restart capecitabine at full dose, give 50% epirubicin dose on subsequent cycles Epirubicin: Bilirubin micromol/l give 50% dose Bilirubin micromol/l give 25% dose Bilirubin >85 micromol/l omit Dose reduce in severe renal impairment. Neutropenia / fever infection Neutrophils give 75% dose of epirubicin for subsequent cycles Neutrophils <0.5 give 50% dose of epirubicin for subsequent cycles Stop capecitabine, delay Cisplatin and epirubicin until recovery. Restart capecitabine at full dose BUT omit epirubicin from subsequent cycles Maximum lifetime dose = 1000mg/m 2 (with normal cardiac function) = 650mg/m 2 (in combination with thoracic radiotherapy or previous anthracyclines EC capecitabine Page 1 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 13

14 Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin or switch to an appropriate oxaliplatin containing regimen Discuss with Consultant re omission / substitution Consider substitution with carboplatin AUC 4 or 5 every 4 weeks if cisplatin is contra-indicated If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration. Capecitabine: Check CrCl prior to every cycle CrCl (ml/min) > 50 give 100% dose CrCl (ml/min) give 75% dose CrCl (ml/min) < 30 contraindicated (2) Hepatic impairment SPC recommends interruption of capecitabine therapy if treatment related elevations in bilirubin of > 3 x ULN or ALT/AST > 2.5 x ULN occur. Treatment may be resumed when bilirubin decreases to < 3 x ULN or hepatic aminotransferases decrease to < 2.5 x ULN. Please refer to summary of product characteristics for detailed guidance on dose modification due to toxicity (including plantar palmar, erythema and gastrointestinal toxicity). Brief guidance on initial dose modifications at the first appearance of toxicity is given below. the Summary of Product Characteristics (SPC) which can be viewed at This includes details on how to manage 2nd and subsequent appearance of toxicities. Toxicity can be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced it should not be increased at a later time. Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and handfoot syndrome. EC capecitabine Page 2 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 14

15 Toxicity Grades Dose changes within Dose adjustment for next a treatment cycle cycle/dose (% of starting dose) * Grade 1 Maintain dose level Maintain dose level * Grade 2-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Interrupt until resolved to grade % - 4th appearance Discontinue treatment permanently Not applicable * Grade 3-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Discontinue treatment permanently Not applicable * Grade 4-1st appearance Discontinue permanently OR 50% If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade nd appearance Discontinue permanently Not applicable INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Creatinine clearance (GFR) calculated or EDTA or 24 hour urine collection at the Consultant discretion. (Cisplatin) 2) Non-urgent blood tests Tests relating to disease response/progression CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations. Capecitabine enhances the anticoagulant effects of warfarin. Patients taking warfarin concomitantly with capecitabine must have regular monitoring of INR. EC capecitabine Page 2 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 15

16 ANTI-EMETIC POLICY Highly emetogenic day 1 Low emetogenic risk days 2 to 21 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds Mucositis see dose modifications Diarrhoea see dose modifications Nephrotoxicity ensure adequate pre and post hydration is prescribed Cardiotoxicity monitor cardiac function. To minimise risk of anthracycline induced cardiac failure signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. REFERENCES 1. REAL 2 trial (arm 3) 2. ST03 trial EC capecitabine Page 3 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 16

17 EPIRUBICIN, OXALIPLATIN and CAPECITABINE (EOX) Indication: Advanced gastric, oesophageal cancer, adjuvant gastric cancer and unknown adenocarcinoma Unknown primary if appropriate DRUG REGIMEN Day 1 EPIRUBICIN 50mg/m 2 IV bolus OXALIPLATIN 130mg/m 2 in 500ml* glucose 5% infusion over 2 hours Flush with glucose 5% after infusion CAPECITABINE 1250mg/m² daily in 2 divided doses for 21 days *oxaliplatin doses 55mg to 200mg in 250ml sodium chloride 0.9% Cycle frequency: Every 21 days (up to 6 cycles). Note: Tablets are only available as 150mg and 500mg tablets therefore dose must be rounded appropriately Oxaliplatin should always be administered before fluoropyrimidines. DOSE MODIFICATIONS Refer to the REAL-2 protocol Previous neutropenic sepsis, discuss with SpR or Consultant, Symptoms including diarrhoea, mucositis and leucopenia, discuss with SpR or Consultant. Epirubicin: Bilirubin micromol/l give 50% dose Bilirubin micromol/l give 25% dose Bilirubin >85 micromol/l omit Neutropenia / fever infection Neutrophils give 75% dose of epirubicin for subsequent cycles Neutrophils <0.5 give 50% dose of epirubicin for subsequent cycles Maximum lifetime dose = 1000mg/m 2 (with normal cardiac function) = 650mg/m 2 (in combination with thoracic radiotherapy or previous anthracyclines Oxaliplatin: If persistent sensory symptoms occur, withdraw treatment GFR >20ml/min give 100% dose and adjust according to toxicity GFR <20ml/min dose reduce [4] Hepatic impairment: Probably no dose reduction necessary Clinical decision If patients develop acute laryngopharyngeal dysaesthesia infuse the next cycle over 6 hours. If symptoms persist give 80% dose. EOX cape Page 1 of 3 Published: January 2019 Version 4.5a Chemotherapy Regimens Upper GI Cancer 17

18 Capecitabine: Check CrCl prior to every cycle CrCl (ml/min) >50 give 100% CrCl (min/min) give 75% dose CrCl (ml/min) <30 capecitabine is contraindicated (2) Hepatic impairment SPC recommends interruption of capecitabine therapy if treatment related elevations in bilirubin of > 3 x ULN or ALT/AST > 2.5 x ULN occur. Treatment may be resumed when bilirubin decreases to < 3 x ULN or hepatic aminotransferases decrease to < 2.5 x ULN. Please refer to summary of product characteristics for detailed guidance on dose modification s due to toxicity (including plantar palmar, erythema and gastrointestinal toxicity). Brief guidance on initial dose modifications at the first appearance of toxicity is given below. the Summary of Product Characteristics (SPC) which can be viewed at This includes details on how to manage 2nd and subsequent appearance of toxicities. Toxicity can be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced it should not be increased at a later time. Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and handfoot syndrome. Toxicity Grades Dose changes within Dose adjustment for next a treatment cycle cycle/dose (% of starting dose) * Grade 1 Maintain dose level Maintain dose level * Grade 2-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Interrupt until resolved to grade % - 4th appearance Discontinue treatment permanently Not applicable * Grade 3-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Discontinue treatment permanently Not applicable * Grade 4-1st appearance Discontinue permanently OR 50% If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade nd appearance Discontinue permanently Not applicable EOX cape Page 2 of 3 Published: January 2019 Version 4.5a Chemotherapy Regimens Upper GI Cancer 18

19 INVESTIGATIONS Routine Blood tests 1. Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 <10 Plt x 10 9 /L 75 <75 Neutrophils x 10 9 /L 1.5 < GFR assessed using 51 Cr-EDTA result or calculated creatinine clearance at the Consultant s discretion. 3. LFTs Non-urgent Blood tests Tests relating to disease response/progression. CONCURRENT MEDICATIONS Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations. Capecitabine enhances the anticoagulant effects of warfarin. Patients taking warfarin concomitantly with capecitabine must have regular monitoring of INR. ANTI-EMETIC POLICY Highly emetogenic day 1 Low emetogenic risk days 2 to 21 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds. Diarrhoea treat with loperamide or codeine Peripheral sensory neuropathy and laryngeal spasm avoid cold drinks and touching cold items Cardiotoxicity monitor cardiac function. To minimise risk of anthracycline induced cardiac failure signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease or those who develop chest pain during treatment with fluorouracil. REFERENCES 1. REAL 2 trial (arm 4) 2. REAL 3 standard arm EOX cape Page 3 of 3 Published: January 2019 Version 4.5a Chemotherapy Regimens Upper GI Cancer 19

20 EPIRUBICIN OXALIPLATIN FLUOROURACIL (EOF) Indication: Advanced gastric, oesophageal cancer, adjuvant gastric cancer and unknown adenocarcinoma for patients with poor renal function. Neoadjuvant gastric cancer if poor renal function and capecitabine contraindicated. DRUG REGIMEN Day 1 EPIRUBICIN 50mg/m 2 IV bolus OXALIPLATIN 130mg/m 2 in 500ml glucose 5% infusion over 2 hours FLUOROURACIL 200mg/m 2 /24 hours continuous infusion for 7 days, Day 8 FLUOROURACIL 200mg/m 2 /24 hours continuous infusion for 7 days Day 15 FLUOROURACIL 200mg/m 2 /24 hours continuous infusion for 7 days and continue for 21 days after last Epirubicin / Oxaliplatin admission. Fluorouracil should start prior to oxaliplatin. Cycle Frequency: Every 21 days up to 6 cycles Adjuvant 3 cycles pre-op and 3 cycles post-op DOSE MODIFICATIONS Platelets x 10 9 /L <25 Neutrophils x 10 9 /L <0.5 WBC x 10 9 /L <1.0 Dose modification Full dose Stop 5FU, delay Cisplatin and epirubicin until recovery. Restart give 75% epirubicin dose on subsequent cycles Stop 5FU, delay Cisplatin and epirubicin until recovery. Restart 5FU at full dose, give 50% epirubicin dose on subsequent cycles Epirubicin: Bilirubin 24-51micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit Dose reduce in severe renal impairment. Neutropenia / fever infection Neutrophils give 75% dose of epirubicin for subsequent cycles Neutrophils <0.5 give 50% dose of epirubicin for subsequent cycles Stop 5FU, delay Cisplatin and epirubicin until recovery. Restart 5FU at full dose BUT omit epirubicin from subsequent cycles Maximum lifetime dose = 650mg/m2 (in combination with thoracic radiotherapy or previous anthracyclines = 1000 mg/m 2 (with normal cardiac function) EOF Page 1 of 2 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 20

21 Oxaliplatin: If persistent sensory symptoms occur, withdraw treatment GFR > 30ml/min give 100% dose and adjust according to toxicity Omit if GFR <30ml/min [4] If bilirubin >50 micromol/l give 50% dose If patients develop acute laryngopharyngeal dysaesthesia infuse the next cycle over 6 hours. If symptoms persist give 80% dose. Fluorouracil: Consider dose reduction in severe renal impairment only. Bilirubin <85micromol/L or ALT/AST <180 give 100% dose Bilirubin > 85micromol/L or ALT/AST >180 omit Diarrhoea and/or mucositis Grade 2 toxicity 1 week break from 5FU then restart at 150mg/m 2 /day Grade 3 toxicity stop 5FU until symptoms resolve, then restart at 100mg/m 2 /day Grade 4 toxicity stop 5FU until symptoms resolve, then restart at 50mg/m 2 /day INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Creatinine clearance (GFR) calculated or EDTA or 24 hour urine collection at the Consultant discretion. (Cisplatin) 2) Non-urgent blood tests Tests relating to disease response/progression ANTI-EMETIC POLICY Highly emetogenic day 1 Low emetogenic risk days 2 to 21 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds if symptoms fail to improve then stop 5FU for 1 week then restart at 150mg/m 2 /day. Mucositis see dose modifications use routine mouthcare Diarrhoea see dose modifications treat with loperamide or codeine Nephrotoxicity ensure adequate pre and post hydration is prescribed Cardiotoxicity monitor cardiac function. To minimise risk of anthracycline induced cardiac failure signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease or those who develop chest pain during treatment with fluorouracil. REFERENCES 1. REAL 2 study EOF Page 2 of 2 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 21

22 PACLITAXEL CARBOPLATIN 21 day Indications: Oesophageal with contraindication to fluoropyramidines DRUG REGIMEN Day 1 PRE-MEDICATION 30 mins prior to paclitaxel DEXAMETHASONE 20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 175mg/m 2 in 500ml* sodium chloride 0.9% infusion over 3 hours (PVC free) CARBOPLATIN AUC 5 in 500ml Glucose 5% infusion over 60 mins Dose (mg) = (GFR + 25) x AUC *doses 84mg to 144mg in 250ml sodium chloride 0.9% Cycle Frequency: Every 21 days for 6 cycles (may be given for 8 cycles in certain circumstances) *NB Ideally GFR is measured using 51 Cr-EDTA DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar. Carboplatin: If GFR/CrCl = or < 20ml/min discuss with consultant. Paclitaxel: If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. If grade II or > neuropathy, consider using paclitaxel 135mg/m 2. Bilirubin <1.25xULN and AST/ALT <10xULN dose at 175mg/m 2 Bilirubin <26micromol/L give 135mg/m 2 Bilirubin 27-51micromol/L give 75mg/m 2 Bilirubin >51micromol/L give 50mg/m 2 [3] Carboplatin + paclitaxel Page 2 of 2 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 22

23 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 <10 Plt x 10 9 /L 100 <100 Neutrophils x 10 9 /L 1.5 <1.5 a. Liver function tests (LFTs) b. GFR assessed using 51 Cr-EDTA result or calculated creatinine clearance at the Consultant s discretion. (Carboplatin) c. Patients with hydronephrosis or serum creatinine > 100 micromol/l need a serum creatinine checked every cycle. All patients have serum creatinine checked 1st and 4th cycle -Carboplatin. 2) Non-urgent blood tests Tests relating to disease response/progression CONCURENT MEDICATIONS Paclitaxel ensure pre medication is given Carboplatin - Anaphylaxis treatment should be prescribed if the patient has had an anaphylactic episode previously. Carboplatin should be given at a slower rate e.g. 2-4 hours. ANTI-EMETIC POLICY Moderately emetogenic (routinely dexamethasone and metoclopramide is adequate but 5HT 3 antagonist may be required if there is inadequate control). ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS 2% risk of severe hypersensitivity. Reactions to paclitaxel range from mild hypotension (lightheadedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5-10mins), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment. Ototoxicity - monitor Neurotoxicity monitor REFERENCES Carboplatin + paclitaxel Page 2 of 2 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 23

24 TRASTUZUMAB, CISPLATIN and CAPECITABINE Indication: HER2+ve metastatic adenocarcinoma of stomach or gastrointestinal oesophageal junction. NICE guidance - Trastuzumab, in combination with cisplatin and capecitabine or 5-fluorouracil, is recommended as an option for the treatment of people with human epidermal growth factor receptor 2 (HER2)- positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who: have not received prior treatment for their metastatic disease and have tumours expressing high levels of HER2 as defined by a positive immunohistochemistry score of 3 (IHC3 positive). DRUG REGIMEN Day 1 Pre-hydration CISPLATIN 80mg/m2 in 1000ml sodium chloride 0.9% IV infusion over 2 hours Post hydration Days 1 to 14 CAPECITABINE 1000mg/m2 po twice daily Cycle Frequency: Every 21 days for 6 cycles Day 2 TRASTUZUMAB 8mg/kg in 250ml sodium chloride 0.9% IV infusion cycle 1 Day 1 TRASTUZUMAB 6mg/kg in 250ml sodium chloride 0.9% IV infusion cycles 2 to 18 Cycle Frequency: Every 21 days until disease progression starting on cycle 1 of cisplatin and capecitabine DOSE MODIFICATIONS Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin or switch to an appropriate oxaliplatin containing regimen Discuss with Consultant re omission / substitution If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration. Trastuzumab cisplatin capecitabine Page 1 of 4 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 24

25 Capecitabine: Check CrCl prior to every cycle CrCl (ml/min) >50 give 100% dose CrCl (ml/min) give 75% dose CrCl (ml/min) <30 contraindicated Hepatic impairment SPC recommends interruption of capecitabine therapy if treatment related elevations in bilirubin of > 3 x ULN or ALT/AST > 2.5 x ULN occur. Treatment may be resumed when bilirubin decreases to < 3 x ULN or hepatic aminotransferases decrease to < 2.5 x ULN. Please refer to summary of product characteristics (SPC) for detailed guidance on dose modifications due to toxicity (including plantar palmar, erythema and gastro-intestinal toxicity). Toxicity can be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced it should not be increased at a later time. Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and handfoot syndrome. Toxicity Grades Dose changes within Dose adjustment for next a treatment cycle cycle/dose (% of starting dose) * Grade 1 Maintain dose level Maintain dose level * Grade 2-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Interrupt until resolved to grade % - 4th appearance Discontinue treatment permanently Not applicable * Grade 3-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Discontinue treatment permanently Not applicable * Grade 4-1st appearance Discontinue permanently OR 50% if physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade nd appearance Discontinue permanently Not applicable Trastuzumab cisplatin capecitabine Page 2 of 4 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 25

26 Trastuzumab: No dose reduction or cessation of Trastuzumab is required if patient has acute reversible neutropenia. If trastuzumab infusion is delayed by more than 7 days the patient should be reloaded at 8mg/kg. Continuation and discontinuation of trastuzumab based on interval LVEF assessment If LVEF <44 hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF and >10 points from baseline then stop trastuzumab. If repeat LVEF and <10 points from baseline or LVEF >49 resume trastuzumab. If LVEF and >10 EF points from baseline hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF and >10 points from baseline stop trastuzumab. If repeat LVEF and <10 points from baseline or LVEF >49 resume trastuzumab. If LVEF > 50 or LVEF and <10 EF points from baseline continue trastuzumab. New LVEF assessment results should be available by the day of the next scheduled trastuzumab administration and a decision to give or hold the dose must be made based on this algorithm. INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 <10 Plt x 10 9 /L 100 <100 Neutrophils x 10 9 /L 1.5 <1.5 Creatinine clearance (GFR) calculated or EDTA or 24 hour urine collection at the Consultant's discretion. (Cisplatin) 2) Non-urgent blood tests - Tests relating to disease response / progression - Baseline weight and every 3 months - Monitor cardiac function (ECG/ECHO/MUGA) of all patients before and during treatment, aiming for assessments every 3 months. CONCURRENT MEDICATION Trastuzumab infusion related chills and/or fevers treat with paracetamol and chlorphenamine. Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations. Capecitabine enhances the anticoagulant effects of warfarin. Patients taking warfarin concomitantly with capecitabine must have regular monitoring of INR Give mouthcare and bowel support regimen as per Upper GI protocol Trastuzumab cisplatin capecitabine Page 2 of 4 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 26

27 ANTI-EMETIC POLICY High emetic risk day 1 cycles 1 to 6 Low emetic risk days 2 to 13 cycles 1 to 6 Minimal emetic risk cycles 7 to 18 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity - monitor cardiac function. Special attention is advisable in treating patients with a history of heart disease, arrhythmias or angina pectoris or those who develop chest pain during treatment with capecitabine. Trastuzumab infusion related chills and/or fevers are commonly observed during the first infusion (but infrequently with subsequent infusions). Other symptoms may include nausea, hypertension, vomiting, pain, rigors, headache, cough, dizziness, rash, and asthenia. Some adverse reactions to trastuzumab infusion including dyspnoea, hypotension, wheezing, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation and respiratory distress can be serious and potentially fatal. If symptoms of back ache, nausea or vomiting, do a set of obs. Give hydrocortisone 100mg IV, chlorphenamine 10mg IV. Hand foot syndrome: Palmer Plantar causing red palms and soles - treat with pyridoxine 50mg tds Diarrhoea - treat with loperamide or codeine Mucositis - see dose modifications Nephrotoxicity - ensure adequate pre- and post- hydration is prescribed REFERENCES Trastuzumab cisplatin capecitabine Page 2 of 4 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 27

28 CISPLATIN + FLUOROURACIL (CF 75 RT) concurrent with radical radiotherapy infusor Indication: Localised oesophageal carcinoma DRUG REGIMEN Day 1 Prehydration CISPLATIN 75mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours FLUOROURACIL 4000mg/m 2 over 96 hours via an infusor Posthydration Cycle Frequency: Week 1, 5 (with radiotherapy week 1 to 5 inc) and then week 9 and 13 DOSE MODIFICATIONS Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR <45ml/min consider carboplatin or switch to an appropriate oxaliplatin containing regimen If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration Fluorouracil: Discuss with consultant whether 5FU to go ahead if cisplatin is contra-indicated/discontinued. Consider dose reduction in severe renal impairment only. Bilirubin <85micromol/L or ALT/AST <180 give 100% dose Bilirubin > 85micromol/L or ALT/AST >180 omit Treatment delays If Neutrophils <1.5x10 9 /L and/or the platelet count <100x10 9 /L delay the second course by one week, recheck blood count. If satisfactory (>1.5x10 9 /L and >100x10 9 /L) give 75% dose Cisplatin and 5FU If not satisfactory delay by a further week and recheck blood count, if satisfactory (>1.5x10 9 /L and >100x10 9 /L) then give 50% dose Cisplatin and 5FU. If still unsatisfactory after 2 week delay chemotherapy should be discontinued. CF + RT infusor Page 1 of 2 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 28

29 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Creatinine clearance (GFR) calculated or EDTA or 24 hour urine collection at the Consultant discretion. (Cisplatin) 2) Non-urgent blood tests Tests relating to disease response/progression CONCURRENT MEDICATION Prescribe mouth and bowel support. Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV ANTI-EMETIC POLICY Highly emetogenic. day 1 Low emetogenic risk days 2, 3, 4 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds Mucositis use routine mouthcare. Discuss dose reduction if severe. Diarrhoea treat with codeine or loperamide, Discuss dose reduction if severe Nephrotoxicity ensure adequate pre and post hydration is prescribed Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease, arrhythmias or angina pectoris or those who develop chest pain during treatment with fluorouracil. REFERENCES 1. J Clin Onc 1997; 5 (No 1): CF + RT infusor Page 2of 2 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 29

30 CISPLATIN + CAPECITABINE concurrent with radical radiotherapy Indication: Oesophageal carcinoma (SCOPE-1 control arm) DRUG REGIMEN Day 1 Prehydration CISPLATIN 60mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours CAPECITABINE 625mg/m 2 po twice daily for 21 days Posthydration Cycle Frequency: every 21 days, 2 cycles followed by 2 cycles with concurrent RT DOSE MODIFICATIONS Cisplatin: GFR >60ml/min give 100% dose GFR 45-60ml/min give 50% dose GFR <45ml/min Consider carboplatin or switch to an appropriate oxaliplatin containing regimen If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration Capecitabine: GFR >51ml/min give 100% dose GFR 30-50ml/min give 75% dose GFR < 30ml/min omit dose Haematological The FBC should be taken and reviewed (up to 3 days) prior to Day 1 of each cycle of chemotherapy. Day 1: ANC > = 1x 10^9/L and/or plts > = 75 x 10^9/L -> Full dose drugs ANC x 10^9/L and/or plts x 10^9/L OR any episode of neutropenic sepsis during the previous cycle -> Stop chemotherapy until recovery. Restart with 75% dose cisplatin and capecitabine (or 5FU) ANC <0.5 x 10^9/L and/or plts <50 x 10^9L > Stop chemotherapy until recovery. Restart with 50% dose cisplatin and capecitabine (or 5FU) Cisplatin capecitabine RT Page 1 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 30

31 Treatment delays Capecitabine dose reduction schedule for non-haematological toxicities. Grade 1: during a course -> Maintain dose level, for next cycle -> Maintain dose level Grade 2 1st appearance: during a course interrupt until resolved to grade 0-1, for next cycle -> 100% dose 2nd appearance: during a course interrupt until resolved to grade 0-1, for next cycle -> 75% dose 3rd appearance: during a course interrupt until resolved to grade 0-1, for next cycle -> 50% dose 4th appearance: during a course discontinue treatment permanently Grade 3 1st appearance: during a course interrupt until resolved to grade 0-1, for next cycle -> 75% dose 2nd appearance: during a course interrupt until resolved to grade 0-1, for next cycle -> 50% dose 3rd appearance: during a course discontinue treatment permanently Grade 4 1st appearance: during a course discontinue permanently or If physician deems it to be in the patient s best interest to continue, interrupt until resolved to grade 0-1after discussion with Chief Investigator, for next cycle -> 50% dose INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Creatinine clearance (GFR) calculated or EDTA or 24 hour urine collection at the Consultant discretion. (Cisplatin) 2) Non-urgent blood tests Tests relating to disease response/progression CONCURRENT MEDICATION Prescribe mouth and bowel support. Ensure adequate pre-and post-hydration prescribed as per TVCN protocols. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV Cisplatin capecitabine RT Page 2 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 31

32 ANTI-EMETIC POLICY Highly emetogenic day 1 Low emetogenic risk days 2 to 21 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds Mucositis use routine mouthcare. Discuss dose reduction if severe. Diarrhoea treat with codeine or loperamide, Discuss dose reduction if severe Nephrotoxicity ensure adequate pre and post hydration is prescribed Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease, arrhythmias or angina pectoris or those who develop chest pain during treatment with fluorouracil. Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease, arrhythmias or angina pectoris or those who develop chest pain during treatment with capecitabine. REFERENCES 1. J Clin Onc 1997; 5 (No 1): SCOPE 1 version 5.0 December 2010 Cisplatin capecitabine RT Page 3 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 32

33 CISPLATIN + CAPECITABINE Indication: Neoadjuvant gastro-oesophageal carcinoma DRUG REGIMEN Day 1 Prehydration CISPLATIN 80mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours CAPECITABINE 1000mg/m 2 po twice daily for 14 days Posthydration Cycle Frequency: Every 21 days for 2 cycles prior to surgery DOSE MODIFICATIONS Cisplatin: Cisplatin produces cumulative nephrotoxicity. If a baseline estimate of renal function predicts the GFR to be > = 60ml/min full dose cisplatin should be used. If the estimate is <60mls/min an EDTA Creatinine clearance should be performed and the appropriate cisplatin dose used (see below). In the case of a 25% deterioration in estimated renal function on pre-treatment blood samples an EDTA Creatinine clearance should be performed and pending this an appropriate dose reduction in cisplatin should be made. The EDTA Creatinine clearance result, when available, takes precedent over estimated GFR for subsequent cisplatin dose calculations. GFR > =60mls/min -> Continue full dose GFR mls/min -> Cisplatin 50% dose at Consultants discretion GFR 40-49mls/min -> Cisplatin 50% dose, Capecitabine 75% dose GFR mls/min -> Stop cisplatin, use carboplatin AUC 5, Capecitabine 50% dose GFR < 30mls/min -> Stop cisplatin, use carboplatin AUC 5, Stop capecitabine Consider dose reduction of 5FU in cases of severe renal impairment (i.e. GFR < = 10mL/min.) If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration Capecitabine: GFR >51ml/min give 100% dose GFR 30-50ml/min give 75% dose GFR < 30ml/min omit dose Cisplatin capecitabine Page 1 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 33

34 Haematological The FBC should be taken and reviewed (up to 3 days) prior to day 1 of each cycle of chemotherapy. Day 1: ANC > = 1x10 9 /L and/or plts > = 75 x 10 9 /L -> Full dose drugs ANC x 10 9 /L and/or plts x 10 9 /L OR any episode of neutropenic sepsis during the previous cycle -> Stop chemotherapy until recovery. Restart with 75% dose cisplatin and capecitabine (or 5FU) ANC <0.5 x 10 9 /L and/or plts <50 x 10 9 L > Stop chemotherapy until recovery. Restart with 50% dose cisplatin and capecitabine (or 5FU) Treatment delays Capecitabine dose reduction schedule for non-haematological toxicities. Grade 1: during a course -> Maintain dose level, for next cycle -> Maintain dose level Grade 2 1st appearance: during a course interrupt until resolved to grade 0-1, for next cycle -> 100% dose 2nd appearance: during a course interrupt until resolved to grade 0-1, for next cycle -> 75% dose 3rd appearance: during a course interrupt until resolved to grade 0-1, for next cycle -> 50% dose 4th appearance: during a course discontinue treatment permanently Grade 3 1st appearance: during a course interrupt until resolved to grade 0-1, for next cycle -> 75% dose 2nd appearance: during a course interrupt until resolved to grade 0-1, for next cycle -> 50% dose 3rd appearance: during a course discontinue treatment permanently Grade 4 1st appearance: during a course discontinue permanently or If physician deems it to be in the patient s best interest to continue, interrupt until resolved to grade 0-1after discussion with Chief Investigator, for next cycle -> 50% dose Cisplatin capecitabine Page 2 of 3 Published: January 2019 Chemotherapy Regimens Upper GI Cancer 34