Thames Valley Chemotherapy...

Thames Valley

Thames Valley Chemotherapy

Regimens Upper Gastrointestinal Cancer

Thames Valley

Chemotherapy Regimens – Upper GI Cancer 2

Notes from the editor These regimens are available on the Network website www.tvscn.nhs.uk. Any correspondence about the regimens should be addressed to: Sally Coutts, Cancer Pharmacist, Thames Valley email: [email protected] 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 Thames Valley Cancer Network

© Thames Valley Cancer Network. All rights reserved. Not to be reproduced in whole or in part without the permission of the copyright owner.

http://www.tvscn.nhs.uk/

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Thames Valley 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 Trust funding agreed

Gastric and oesophagus 8

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 adjuvant use

Pancreas 51

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

Thames Valley


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.

Thames Valley


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: http://tvscn.nhs.uk/networks/cancer/cancer-topics/chemotherapy/ For dose banded chemotherapy standardized product specifications: www.england.nhs.uk/commissioning/spec-services/npc-crg/group-b/b02/dose-banded-chemotherapy-standardised-product-specifications/

Thames Valley


CISPLATIN + FLUOROURACIL (CF 80 pre-op) infusor Indication: Pre-operative chemotherapy for cancer of the oesophagus

DRUG REGIMEN Day 1 Pre hydration

CISPLATIN 80mg/m2

in 1000ml sodium chloride 0.9% infusion over 2 hours (daypatient) FLUOROURACIL 4000mg/m2

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 <1.5x109/L and/or the platelet count <100x109/L delay the second course by one week, recheck blood count. If satisfactory (>1.5x109/L and >100x109/L) give 75% dose Cisplatin and 5FU. If not satisfactory delay by a further week and recheck blood count, if satisfactory (>1.5x109/L and >100x109/L) then give 50% dose Cisplatin and 5FU. If still unsatisfactory after 2 week delay chemotherapy should be discontinued.

CF infusor Upper GI CAG Chair Authorisation: Date:

Page 1 of 2 Published: January 2019 Review: January 2021

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INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration

Give Discuss

Hb x g/dL ≥10 <10

Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 WBC x 109/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 20 - 40 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 2002. May 18; 359 (9319): 1727-33

CF infusor Upper GI CAG Chair Authorisation: Date:


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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/m2 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/m2

in 250ml glucose 5% infusion over 2 hours FLUOROURACIL 2600mg/m2

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<1.5x109/L or platelets<100x109/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/m2

Docetaxel Fluorouracil Oxaliplatin

Upper GI CAG Chair Authorisation: Date:


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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



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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/m2

IV bolus Pre-hydration CISPLATIN 60mg/m2

in 1000ml sodium chloride 0.9% infusion over 2 hours Post hydration

FLUOROURACIL 200mg/m2/24 hours continuous infusion for 7 days, Day 8 FLUOROURACIL 200mg/m2/24 hours continuous infusion for 7 days Day 15 FLUOROURACIL 200mg/m2/24 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 109/L 100 50-100 25-49 <25

Neutrophils x 109/L 1.5 0.5-1.5 <0.5

WBC x 109/L 2.0 1.0-1.9 <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 Upper GI CAG Chair Authorisation: Date:


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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 0.5-1.0 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/m2

(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/m2/day Grade 3 toxicity – stop 5FU until symptoms resolve, then restart at 100mg/m2/day Grade 4 toxicity – stop 5FU until symptoms resolve, then restart at 50mg/m2/day



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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 20 ¬ 40 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/m2/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: 269-72



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Thames Valley


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


IV bolus Pre-hydration CISPLATIN 60mg/m2

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.


Neutrophils x 109/L 1.5 0.5-1.5 <0.5

WBC x 109/L 2.0 1.0-1.9 <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

Stop capecitabine, delay Cisplatin and epirubicin until recovery. Restart capecitabine at full dose BUT omit epirubicin from subsequent cycles

Epirubicin: Bilirubin 24-51 micromol/L give 50% dose Bilirubin 51-85 micromol/L give 25% dose Bilirubin >85 micromol/L omit Dose reduce in severe renal impairment. Neutropenia / fever infection Neutrophils 0.5-1.0 give 75% dose of epirubicin for subsequent cycles Neutrophils <0.5 give 50% dose of epirubicin for subsequent cycles Maximum lifetime dose = 1000mg/m2

(with normal cardiac function) = 650mg/m2

(in combination with thoracic radiotherapy or previous anthracyclines

EC capecitabine



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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) 30 - 50 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 www.medicines.org.uk. 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



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http://www.medicines.org.uk/

Thames Valley


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 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75% - 3rd appearance Interrupt until resolved to grade 0-1 50% - 4th appearance Discontinue treatment permanently Not applicable * Grade 3 - 1st appearance Interrupt until resolved to grade 0-1 75% - 2nd appearance Interrupt until resolved to grade 0-1 50% - 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 0-1 - 2nd appearance Discontinue permanently Not applicable



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 20 ¬ 40 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



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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



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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/m2

IV bolus OXALIPLATIN 130mg/m2 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 24-51 micromol/L give 50% dose Bilirubin 51-85 micromol/L give 25% dose Bilirubin >85 micromol/L omit Neutropenia / fever infection Neutrophils 0.5-1.0 give 75% dose of epirubicin for subsequent cycles Neutrophils <0.5 give 50% dose of epirubicin for subsequent cycles Maximum lifetime dose = 1000mg/m2

(with normal cardiac function) = 650mg/m2

(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 Upper GI CAG Chair Authorisation: Date:


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Capecitabine: Check CrCl prior to every cycle CrCl (ml/min) >50 give 100% CrCl (min/min) 30 - 50 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 modifications 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 www.medicines.org.uk. 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 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75% - 3rd appearance Interrupt until resolved to grade 0-1 50% - 4th appearance Discontinue treatment permanently Not applicable * Grade 3 - 1st appearance Interrupt until resolved to grade 0-1 75% - 2nd appearance Interrupt until resolved to grade 0-1 50% - 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 0-1 - 2nd appearance Discontinue permanently Not applicable



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INVESTIGATIONS Routine Blood tests 1. Blood results required before chemotherapy administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥75 <75 Neutrophils x 109/L ≥1.5 <1.5 2. GFR assessed using 51Cr-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.


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



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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.


IV bolus OXALIPLATIN 130mg/m2

in 500ml glucose 5% infusion over 2 hours FLUOROURACIL 200mg/m2/24 hours continuous infusion for 7 days,

Day 8 FLUOROURACIL 200mg/m2/24 hours continuous infusion for 7 days Day 15 FLUOROURACIL 200mg/m2/24 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


Neutrophils x 109/L 1.5 0.5-1.5 <0.5

WBC x 109/L 2.0 1.0-1.9 <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

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 0.5-1.0 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/m2

(with normal cardiac function)

EOF Upper GI CAG Chair Authorisation: Date:


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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/m2/day Grade 3 toxicity – stop 5FU until symptoms resolve, then restart at 100mg/m2/day Grade 4 toxicity – stop 5FU until symptoms resolve, then restart at 50mg/m2/day


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


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/m2/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 Upper GI CAG Chair Authorisation: Date:


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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/m2 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 51Cr-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/m2. Bilirubin <1.25xULN and AST/ALT <10xULN dose at 175mg/m2 Bilirubin <26micromol/L give 135mg/m2 Bilirubin 27-51micromol/L give 75mg/m2 Bilirubin >51micromol/L give 50mg/m2 [3]

Carboplatin + paclitaxel



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INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5

a. Liver function tests (LFTs) b. GFR assessed using 51Cr-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 5HT3 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 (light-headedness) 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



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TRASTUZUMAB, CISPLATIN and CAPECITABINE Indication: HER2+ve metastatic adenocarcinoma of stomach or gastro-intestinal oesophageal junction. NICE guidance - www.nice.org.uk 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.

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Capecitabine: Check CrCl prior to every cycle CrCl (ml/min) >50 give 100% dose CrCl (ml/min) 30 -50 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 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75% - 3rd appearance Interrupt until resolved to grade 0-1 50% - 4th appearance Discontinue treatment permanently Not applicable * Grade 3 - 1st appearance Interrupt until resolved to grade 0-1 75% - 2nd appearance Interrupt until resolved to grade 0-1 50% - 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 0-1 - 2nd appearance Discontinue permanently Not applicable




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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 45-49 and >10 points from baseline then stop trastuzumab. If repeat LVEF 45-49 and <10 points from baseline or LVEF >49 resume trastuzumab.

If LVEF 45-49 and >10 EF points from baseline hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF 45-49 and >10 points from baseline stop trastuzumab. If repeat LVEF 45-49 and <10 points from baseline or LVEF >49 resume trastuzumab.

If LVEF > 50 or LVEF 45-49 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.


Give Discuss

Hb x g/dL ≥10 <10

Plt x 109/L ≥100 <100 Neutrophils x 109/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




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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




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CISPLATIN + FLUOROURACIL (CF 75 RT) concurrent with radical radiotherapy infusor Indication: Localised oesophageal carcinoma

DRUG REGIMEN Day 1 Prehydration

CISPLATIN 75mg/m2

in 1000ml sodium chloride 0.9% infusion over 2 hours FLUOROURACIL 4000mg/m2

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 <1.5x109/L and/or the platelet count <100x109/L delay the second course by one week, recheck blood count. If satisfactory (>1.5x109/L and >100x109/L) give 75% dose Cisplatin and 5FU If not satisfactory delay by a further week and recheck blood count, if satisfactory (>1.5x109/L and >100x109/L) then give 50% dose Cisplatin and 5FU. If still unsatisfactory after 2 week delay chemotherapy should be discontinued.

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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 20 ¬ 40 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): 277-284

CF + RT infusor


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CISPLATIN + CAPECITABINE concurrent with radical radiotherapy Indication: Oesophageal carcinoma (SCOPE-1 control arm)


CISPLATIN 60mg/m2

in 1000ml sodium chloride 0.9% infusion over 2 hours CAPECITABINE 625mg/m2

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 0.5-0.99 x 10^9/L and/or plts 50-74 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)

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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







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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): 277-284 2. SCOPE 1 version 5.0 December 2010




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CISPLATIN + CAPECITABINE Indication: Neoadjuvant gastro-oesophageal carcinoma


CISPLATIN 80mg/m2

in 1000ml sodium chloride 0.9% infusion over 2 hours CAPECITABINE 1000mg/m2

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 50-59 mls/min -> Cisplatin 50% dose at Consultants discretion GFR 40-49mls/min -> Cisplatin 50% dose, Capecitabine 75% dose GFR 30-39 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

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Haematological The FBC should be taken and reviewed (up to 3 days) prior to day 1 of each cycle of chemotherapy. Day 1: ANC > = 1x109/L and/or plts > = 75 x 109/L -> Full dose drugs ANC 0.5-0.99 x 109/L and/or plts 50-74 x 109/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 109/L and/or plts <50 x 109L > 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




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ANTI-EMETIC POLICY Highly emetogenic. day 1 Low emetogenic risk days 2 to 14

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. Neurotoxicity / Ototoxicity - appears to be cumulative. Prior to each course, any new or progressive symptoms of peripheral neuropathy should be established. In the occurrence of > = Grade 2 ototoxicity and/or other neurotoxicity cisplatin should be replaced by carboplatin AUC 5.

REFERENCES




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DOCETAXEL (75)

Indication: Second line therapy for oesophago-gastric carcinoma

DRUG REGIMEN Day 1 PREMEDICATION: DEXAMETHASONE 8 mg BD starting 24 hours before chemotherapy

(or 20mg IV on day of chemotherapy) and 8mg bd post-chemotherapy for 2 days (for patients who are unable to tolerate high doses of steroids 4mg doses may be considered) DOCETAXEL 75mg/m2

infusion in 250ml sodium chloride 0.9% over 60 minutes Cycle Frequency: Every 21 days Number of cycles: Individualised but not usually more than 6 (subject to tolerance and response)

DOSE MODIFICATIONS Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Patients who have both elevations of transaminase (ALT and/or AST) > 1.5 x ULN and ALP > 2.5 x ULN: the SPC recommended dose is 75mg/m2. 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.


Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5


CONCURRENT MEDICATION Ensure pre-medication is given. This can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions

Docetaxel Upper GI CAG Chair Authorisation: Date:


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ANTIEMETIC POLICY Low emetic risk


Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. REFERENCES 1. Shepherd F et al. J Clin Oncol 2000; 18: 2095 2103. Fossella F et al. J Clin Oncol 2000; 18:

2354 2362 2. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic

impairment. 2009, The North London Cancer Network.

Docetaxel Upper GI CAG Chair Authorisation: Date:


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MITOMYCIN + FLUOROURACIL (MF) Indication: Second line therapy for gastric or oesophageal cancer after failure of platinum based chemotherapy

DRUG REGIMEN Day 1 MITOMYCIN 7mg/m2 IV bolus.

FLUOROURACIL 300mg/m2/24 hours continuous infusion for 7 days via an infusor Day 8 FLUOROURACIL 300mg/m2/24 hours continuous infusion for 7 days via an infusor Day 15 FLUOROURACIL 300mg/m2/24 hours continuous infusion for 7 days via an infusor Cycle Frequency: Mitomycin – repeat every 3 - 6 weeks according to blood count Fluorouracil – repeat day 21 for 6 cycles

DOSE MODIFICATIONS Symptoms including diarrhoea, mucositis and leucopenia, discuss with Registrar or Consultant. 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 The 5FU course should be delayed for a week or until completely recovered in the event of either low blood counts (neutrophils <1.5x109 or platelets <100x109) or any persistent mucositis or diarrhoea. Non-haematological toxicity (diarrhoea, stomatitis) CTC Grade 0-1 2 3 4 Haematological toxicity: 0-2 (P=or>50 & N=or>1.0) 100% 80% 50% No further treatment (NFT) Platelets (P), 3 (P=25-49 or N=0.5-0.9) 80% 70% 50% NFT Neutrophils (N) 4 (P<25 or N<0.5) 50% 50% 50% NFT Mitomycin: GFR >10ml/min give 100% dose GFR <10ml/min give 75% dose

MF Upper GI CAG Chair Authorisation: Date:


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GFR assessed using 51Cr-EDTA result or calculated creatinine clearance at the Consultant’s discretion. 2) Non-urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION

ANTI-EMETIC POLICY Low emetogenic risk

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. 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.

MF Upper GI CAG Chair Authorisation: Date:


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PACLITAXEL 7 day and CARBOPLATIN 7 day with RT Indication: Oesophageal cancer chemo radiotherapy

DRUG REGIMEN Days 1, 8, 15, 22 and 29 PRE-MEDICATION 30 minutes prior to infusion: DEXAMETHASONE 8mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 50mg/m2 in 250ml sodium chloride 0.9% infusion over 1 hour (cap BSA 2.0) CARBOPLATIN AUC 2 in 500ml glucose 5% infusion over 30 minutes Dose (mg) = (GFR + 25) x AUC

*EDTA Ideally GFR is measured using 51Cr-EDTA

Cycle Frequency: One cycle

DOSE MODIFICATIONS

Previous neutropenic sepsis, discuss with Consultant or Registrar 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 reducing dose of paclitaxel Delay 1 week if day 1 neutrophil count < 1.5x109/L and / or platelet count is < 100x109/L. Myelosuppression is reasonably common consider dose reduction from 80 to 60 mg/m2 In the absence of Gilbert's syndrome: Bilirubin >51micromol/L stop treatment Carboplatin: If GFR = or < 20ml/min contraindicated

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INVESTIGATIONS 1) Blood results required before chemotherapy administration:

Liver function tests (LFTs).

GFR assessed using 51Cr-EDTA result or calculated creatinine clearance the Consultant’s discretion.

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.

2) Non-urgent blood tests- Tests relating to disease response/progression

CONCURRENT MEDICATION Anaphylaxis treatment should be prescribed if the patient has had an anaphylactic episode previously. DEXAMETHASONE 20mg IV bolus CHLORPHENAMINE 10mg IV bolus RANITIDINE 50mg IV bolus 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 5HT3 antagonist may be required if there is inadequate control).

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS 2% risk of severe hypersensitivity. Reactions range from mild hypotension (light-headedness) 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

Paclitaxel carboplatin 7 day + RT



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CAPECITABINE (5 day) with RT Indication: Locally advanced pancreatic cancer

DRUG REGIMEN CAPECITABINE 830mg/m2 twice daily (1660mg/m2/day) for 5 days per week Tablets available as strengths of 150 mg and 500 mg. Cycle Frequency: for duration of radiotherapy (i.e. 28 days up to 30 days)

DOSE MODIFICATIONS Capecitabine Consider giving 75% dose of capecitabine for patients >70 years depending on performance status Check CrCl prior to every cycle CrCl (ml/min) > 50 give 100% dose CrCl (ml/min 30 -50 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 for detailed guidance on dose modifications 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. Users of these guidelines should also refer to the more detailed guidance contained within the Summary of Product Characteristics (SPC) which can be viewed at www.medicines.org.uk. 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.

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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 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75% - 3rd appearance Interrupt until resolved to grade 0-1 50% - 4th appearance Discontinue treatment permanently Not applicable * Grade 3 - 1st appearance Interrupt until resolved to grade 0-1 75% - 2nd appearance Interrupt until resolved to grade 0-1 50% - 3rd appearance Discontinue treatment permanently Not applicable * Grade 4 - 1st appearance Discontinue permanently OR if 50% physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1 - 2nd appearance Discontinue permanently Not applicable

INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss

Hb x g/dL ≥10 < 10


Serum creatinine - GFR should be calculated or measured using EDTA

CONCURRENT MEDICATION 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.

ANTIEMETIC POLICY Low emetogenic risk




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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 Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease or those who develop chest pain during treatment with capecitabine. REFERENCES 1. SCALOP study




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GEMCITABINE Indication: Adjuvant and advanced pancreatic cancer NICE guidance – www.nice.org.uk Gemcitabine may be considered as a treatment option for patients with advanced or metastatic adenocarcinoma of the pancreas and a Karnofsky performance score of 50 or more, where first line chemotherapy is to be used

DRUG REGIMEN Day 1 GEMCITABINE 1000mg/m2

in 250ml sodium chloride 0.9% infusion over 30 minutes Day 8 GEMCITABINE 1000mg/m2


in 250ml sodium chloride 0.9% infusion over 30 minutes Cycle Frequency: Every 28 days for 6 cycles

DOSE MODIFICATIONS Gemcitabine: Do not give with concurrent radiotherapy. CrCl <30ml/min consider dose reduction (Clinical decision) If bilirubin >27micromol/L initiate treatment with dose of 800mg/m2. Neutrophils > 1.0 x 109/L and platelets > 100 x 109/L give 100% dose Neutrophils =<1.0 x 109/L or platelets =<100 x 109/L Delay 1 week and consider reducing future day 8 or 15 doses to 75%. It is possible to give gemcitabine on low neutrophil/platelet counts but at a reduced dose. However empirical dose reduction should be considered if for example a patient is likely to be repeatedly delayed. If dose reduction instigated empirically for delayed neutropenia for day 8 and 15 e.g. 75% dose prescribed then on day 8 and day 15: Neutrophils >0.5 x 109/L and platelets >50 x 109/L Go ahead at prescribed reduced dose e.g. 75% dose 750mg/m2 as long as patient otherwise well. Diarrhoea and/or mucositis Grade 2 toxicity – omit until toxicity resolved then restart at 100% dose Grade 3 toxicity – omit until toxicity resolved then restart at 75% dose Grade 4 toxicity – omit until toxicity resolved then restart at 50% dose

Gemcitabine Upper GI CAG Chair Authorisation: Date:


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2) Non-urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION ANTI-EMETIC POLICY Low emetogenic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Diarrhoea – see dose modifications treat with loperamide or codeine Mucositis – see dose modifications use routine mouth care

REFERENCES 1. Burris HA et al. J Clin Oncol 1997; 6: 2403-13 2. ESPAC-3 trial



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GEMCITABINE with radiotherapy Indication: Locally advanced non-metastatic pancreatic cancer unable to receive capecitabine NICE guidance – www.nice.org.uk Gemcitabine may be considered as a treatment option for patients with advanced or metastatic adenocarcinoma of the pancreas and a Karnofsky performance score of 50 or more, where first line chemotherapy is to be used

DRUG REGIMEN Days 1, 8, 15, 22, 29 and 36 GEMCITABINE 300mg/m2

in 250ml sodium chloride 0.9% infusion over 30 minutes

Day 1 to be prescribed to start on day 2 of radiotherapy (total planning target volume should be restricted to smaller than 800 CM3). Gemcitabine should be given prior to RT when pt is due both. Cycle Frequency: For 1 cycle (5.5 weeks) with radiotherapy

DOSE MODIFICATIONS Gemcitabine: CrCl <30ml/min consider dose reduction (Clinical decision) If bilirubin >27micromol/L initiate treatment with 80% dose Neutrophils > 1.0 x 109/L and platelets > 100 x 109/L give 100% dose Neutrophils =<1.0 x 109/L or platelets =<100 x 109/L Delay 1 week and consider reducing future day 8 or 15 doses to 75%. It is possible to give gemcitabine on low neutrophil/platelet counts but at a reduced dose. However empirical dose reduction should be considered if for example a patient is likely to be repeatedly delayed. If dose reduction instigated empirically for delayed neutropenia for day 8 and 15 e.g. 75% dose prescribed then on day 8 and day 15: Neutrophils >0.5 x 109/L and platelets >50 x 109/L Go ahead at prescribed reduced dose e.g. 75% dose as long as patient otherwise well.

Gemcitabine RT



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2) Non-urgent blood tests Tests relating to disease response/progression Liver function tests

CONCURRENT MEDICATION Mouth & Bowel support



REFERENCES 1. International archives of Medicine 2009 2:7-13 2. Huang et al IJROBP (2009) 73 (1): 159-165

Gemcitabine RT



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GEMCITABINE and CAPECITABINE Indications: Advanced pancreatic cancer Gemcitabine may be considered as a treatment option for patients with advanced or metastatic adenocarcinoma of the pancreas and a Karnofsky performance score of 50 or more, where first line chemotherapy is to be used. Adjuvant pancreatic cancer Capecitabine with gemcitabine combination therapy should be considered as adjuvant treatment in cases of pancreatic cancer, where either microscopic clearance (R0) or microscopic infiltration (R1) of the margins has been achieved following surgical resection. Treatment should commence within 12 weeks of surgery and continue for six months.

DRUG REGIMEN Day 1 GEMCITABINE 1000mg/m2

in 250ml sodium chloride 0.9% infusion over 30 minutes CAPECITABINE 830mg/m2

twice daily (1660mg/m2/day) for 21 days followed by a 7 day rest

Day 8 GEMCITABINE 1000mg/m2


in 250ml sodium chloride 0.9% infusion over 30 minutes Cycle Frequency: Every 28 days for 6 cycles NB capecitabine tablets are available in strengths of 150 mg and 500 mg.

DOSE MODIFICATIONS Gemcitabine: Do not give with concurrent radiotherapy. CrCl <30ml/min consider dose reduction (Clinical decision) If bilirubin >27micromol/L initiate treatment with dose of 800mg/m2. Neutrophils > 1.0 x 109/L and platelets > 100 x 109/L give 100% dose Neutrophils =<1.0 x 109/L or platelets =<100 x 109/L Delay 1 week and consider reducing future day 8 or 15 doses to 75%. It is possible to give gemcitabine on low neutrophil/platelet counts but at a reduced dose. However empirical dose reduction should be considered if for example a patient is likely to be repeatedly delayed. If dose reduction instigated empirically for delayed neutropenia for day 8 and 15 e.g. 75% dose prescribed then on day 8 and day 15: Neutrophils >0.5 x 109/L and platelets >50 x 109/L Go ahead at prescribed reduced dose e.g. 75% dose 750mg/m2 as long as patient otherwise well. Diarrhoea and/or mucositis Grade 2 toxicity – omit until toxicity resolved then restart at 100% dose Grade 3 toxicity – omit until toxicity resolved then restart at 75% dose Grade 4 toxicity – omit until toxicity resolved then restart at 50% dose

Gemcitabine and Capecitabine



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Capecitabine: Check CrCl prior to every cycle CrCl (ml/min) >50 give 100% dose CrCl (ml/min) 30 - 50 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 for detailed guidance on dose modifications 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. Users of these guidelines should refer to the more detailed guidance contained within the Summary of Product Characteristics (SPC) which can be viewed at www.medicines.org.uk. 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 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75% - 3rd appearance Interrupt until resolved to grade 0-1 50% - 4th appearance Discontinue treatment permanently Not applicable * Grade 3 - 1st appearance Interrupt until resolved to grade 0-1 75% - 2nd appearance Interrupt until resolved to grade 0-1 50% - 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 0-1 - 2nd appearance Discontinue permanently Not applicable




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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles – treat with pyridoxine 50mg tds Diarrhoea – see dose modifications treat with loperamide or codeine Mucositis – see dose modifications 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. Gemcap trial arm 2




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FLUOROURACIL continuous with radiotherapy

Indication: Pancreatic cancer

DRUG REGIMEN Day 1 FLUOROURACIL 225mg/m2/24 hours continuous infusion for 7 days

Cycle Frequency: repeat Fluorouracil day 8, 15, 22 and 29 and so it is given continuously for 5 weeks during radiotherapy

DOSE MODIFICATIONS Symptoms including diarrhoea, mucositis and leucopenia, discuss with Registrar or Consultant.

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

The 5FU course should be delayed for a week or until completely recovered in the event of either low blood counts (neutrophils <1.5x109 or platelets <100x109) or any persistent mucositis or diarrhoea. Non-haematological toxicity (diarrhoea, stomatitis) CTC Grade 0-1 2 3 4 Haematological toxicity: 0-2 (P=or>50 & N=or>1.0) 100% 80% 50% No further treatment NFT Platelets (P), 3 (P=25-49 or N=0.5-0.9) 80% 70% 50% NFT Neutrophils (N) 4 (P<25 or N<0.5) 50% 50% 50% NFT

INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration 2) Non-urgent blood tests Tests relating to disease response/progression



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. 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.

5FU pancreas



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FOLFIRINOX Indication: Advanced pancreatic cancer Adjuvant pancreatic cancer - Not NHSE commissioned regimen - Trust to fund locally, and not charge to NHSE

DRUG REGIMEN Day 1 ATROPINE 250mcg subcutaneously, premedication 30 minutes prior to treatment

IRINOTECAN 180mg/m2 in 250ml sodium chloride 0.9% IV infusion over 30 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/m2

in 250ml glucose 5% infusion over 2 hours FLUOROURACIL 400mg/m2

IV bolus FLUOROURACIL 2400mg/m2

continuous infusion over 46 hours via an infusor Cycle Frequency: Every 14 days for 12 cycles (review after 8 weeks)

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 This regimen would not normally be given to jaundiced patients. Symptoms including diarrhoea, mucositis and leucopenia, discuss with Registrar or Consultant. If neutrophils<1.5x109/L or platelets<100x109/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/m2

FOLFIRINOX Colorectal CAG Chair Authorisation: Date:


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Irinotecan: If Bilirubin 25 - 50micromol/L give 50% dose Bilirubin >51 clinical decision If patients suffer from severe diarrhoea, which required IV rehydration or neutropenic fever, consider reduction in subsequent cycles, discuss with SpR or Consultant.

INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Serum creatinine - GFR should be calculated or measured using EDTA


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 Highly 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 Drink large volumes of fluid containing electrolytes and an appropriate antidiarrhoeal therapy e.g. loperamide 4mg initially then 2mg every 2 hours, continuing for 12 hours after the last liquid stool (maximum of 48 hours in total). 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. Mucositis – use routine mouth care

FOLFIRINOX Colorectal CAG Chair Authorisation: Date:


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OXALIPLATIN and CAPECITABINE 21 day Indication: 2nd line advanced pancreatic cancer Unknown primary if appropriate Ensure funding is available prior to prescribing. DRUG REGIMEN Day 1 OXALIPLATIN 130mg/m2 in 500ml* glucose 5% infusion over 2 hours Flush with glucose 5% after infusion

CAPECITABINE 1000mg/m2 twice daily (2000mg/m2/day) po for 14 days followed by a 7 day rest

*doses 55mg to 200mg in 250ml sodium chloride 0.9% Cycle frequency: Every 21 days [1] for 8 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 Previous neutropenic sepsis, discuss with SpR or Consultant Symptoms including diarrhoea, mucositis and leucopenia, discuss with SpR or Consultant. Capecitabine: Check CrCl prior to every cycle CrCl (ml/min) > 50 give 100% CrCl (min/min) 30 - 50 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 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. Users of these guidelines should also refer to the more detailed guidance contained within the Summary of Product Characteristics (SPC) which can be viewed at www.medicines.org.uk. 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.

Oxaliplatin + capecitabine



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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 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75% - 3rd appearance Interrupt until resolved to grade 0-1 50% - 4th appearance Discontinue treatment permanently Not applicable * Grade 3 - 1st appearance Interrupt until resolved to grade 0-1 75% - 2nd appearance Interrupt until resolved to grade 0-1 50% - 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 0-1 - 2nd appearance Discontinue permanently Not applicable Oxaliplatin: If persistent sensory symptoms occur, withdraw treatment GFR >20ml/min give 100% dose and adjust according to toxicity GFR <20ml/min [4] 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 by 20%.

INVESTIGATIONS Routine Blood tests 1. Blood results required before chemotherapy administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥75 <75 Neutrophils x 109/L ≥1.5 <1.5 2. GFR assessed using 51Cr-EDTA result or calculated creatinine clearance the Consultant’s

discretion. 3. LFTs Non-urgent Blood tests Tests relating to disease response/progression.




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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 Moderately emetogenic day 1 Low emetogenic risk all other days


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 capecitabine. REFERENCES 1. Twelves C Oncology 2002; 16:23-26 2. Capecitabine SPC 03/2005. www.medicines.org.uk 3. Oxaliplatin SPC 09/2004 www.medicines.org.uk


Upper GICAG Chair Authorisation: Date:


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GEMCITABINE + PACLITAXEL albumin bound Indication: The treatment of untreated metastatic pancreatic cancer only if other combination chemotherapies are unsuitable and they would otherwise have gemcitabine monotherapy 2. Confirmed histological or cytological diagnosis of pancreatic adenocarcinoma 3. Patient must have metastatic disease (patients with locally advanced disease are ineligible) 4. Patient has not received any previous systemic chemotherapy for the pancreatic cancer unless given as a radiosensitiser in the adjuvant setting and completed at least 6 months previously 5. Nab-paclitaxel is to be used only in combination with gemcitabine 6. Nab-paclitaxel plus gemcitabine is to be used as 1st line treatment only 7. Patient has a performance status of 0 or 1 8. Patient is not considered to be a suitable candidate for oxaliplatin- and irinotecan-based combination chemotherapy and would otherwise receive gemcitabine monotherapy 9. No treatment breaks of more than 6 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or intercurrent comorbidities to improve)

DRUG REGIMEN Days 1, 8 and 15 PACLITAXEL ALBUMIN BOUND 125mg/m2 over 30 minutes GEMCITABINE 1000mg/m2


DOSE MODIFICATIONS Gemcitabine: Do not give with concurrent radiotherapy. CrCl <30ml/min consider dose reduction (Clinical decision) If bilirubin >27micromol/L initiate treatment with dose of 800mg/m2. Neutrophils > 1.0 x 109/L and platelets > 100 x 109/L give 100% dose Neutrophils =<1.0 x 109/L or platelets =<100 x 109/L Delay 1 week and consider reducing future day 8 or 15 doses to 75%. It is possible to give gemcitabine on low neutrophil/platelet counts but at a reduced dose. However empirical dose reduction should be considered if for example a patient is likely to be repeatedly delayed.



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If dose reduction instigated empirically for delayed neutropenia for day 8 and 15 e.g. 75% dose prescribed then on day 8 and day 15: Neutrophils >0.5 x 109/L and platelets >50 x 109/L Go ahead at prescribed reduced dose e.g. 75% dose 750mg/m2 as long as patient otherwise well. Diarrhoea and/or mucositis Grade 2 toxicity – omit until toxicity resolved then restart at 100% dose Grade 3 toxicity – omit until toxicity resolved then restart at 75% dose Grade 4 toxicity – omit until toxicity resolved then restart at 50% dose Paclitaxel albumin-bound Previous neutropenic sepsis, discuss with Consultant or Registrar If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration See SPC for Paclitaxel albumin bound (Abraxane) section 4.2 for details of dose modifications during treatment of pancreatic adenocarcinoma


2) Non-urgent blood tests Tests relating to disease response/progression 1.Blood results required before chemotherapy administration 2. Tests relating to disease progression/ response

CONCURRENT MEDICATION ANTI-EMETIC POLICY Moderate emetogenic risk


REFERENCES 1. SPC December 2014 2. CDF June 2014



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CAPECITABINE Indication: Patients with completely-resected cholangiocarcinoma (CCA) or gallbladder cancer (including liver and pancreatic resection, as appropriate), with adequate biliary drainage, no ongoing infection, adequate renal, haematological and liver function, and ECOG PS ≤2. To begin within 12 weeks of radical surgery Not NHSE commissioned regimen - Trust to fund locally, and not charge to NHSE

DRUG REGIMEN CAPECITABINE 1250mg/m2 twice daily days 1 to 14 Tablets available as strengths of 150 mg and 500 mg. Cycle Frequency: every 21 days for 8 cycles

DOSE MODIFICATIONS Capecitabine Consider giving 75% dose of capecitabine for patients >70 years depending on performance status Check CrCl prior to every cycle CrCl (ml/min) > 50 give 100% dose CrCl (ml/min 30 -50 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 for detailed guidance on dose modifications 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. Users of these guidelines should also refer to the more detailed guidance contained within the Summary of Product Characteristics (SPC) which can be viewed at www.medicines.org.uk. 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.

Capecitabine BILCAP



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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 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75% - 3rd appearance Interrupt until resolved to grade 0-1 50% - 4th appearance Discontinue treatment permanently Not applicable * Grade 3 - 1st appearance Interrupt until resolved to grade 0-1 75% - 2nd appearance Interrupt until resolved to grade 0-1 50% - 3rd appearance Discontinue treatment permanently Not applicable * Grade 4 - 1st appearance Discontinue permanently OR if 50% physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1 - 2nd appearance Discontinue permanently Not applicable

INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss

Hb x g/dL ≥10 < 10





Capecitabine BILCAP



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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 Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease or those who develop chest pain during treatment with capecitabine. REFERENCES BILCAP trial




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CISPLATIN + MODIFIED DE GRAMONT infusor Indication: Locally advanced or metastatic carcinoma of the gallbladder


CISPLATIN 80mg/m2

in 1000ml sodium chloride 0.9% infusion over 4 hours CALCIUM LEVOFOLINATE 175mg in 250ml glucose 5% over 2 hours FLUOROURACIL 400mg/m2

IV bolus Post hydration

FLUOROURACIL 2400mg/m2

continuous infusion over 46 hours via an infusor Day 15 CALCIUM LEVOFOLINATE 175mg in 250ml glucose 5% over 2 hours

FLUOROURACIL 400mg/m2

IV bolus FLUOROURACIL 2800mg/m2

continuous infusion over 46 hours via an infusor

Cycle Frequency: Every 28 days for 3 cycles NB*Calcium folinate (calcium leucovorin) is not the same as Calcium levofolinate. Calcium levofolinate is a single isomer of folinic acid and the dose is generally half that of Calcium folinate.

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Registrar or Consultant Symptoms including diarrhoea, mucositis and leucopenia, discuss with Registrar or Consultant.

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

If neutrophils<1.5x109/L or platelets<100x109/L delay 1 week, only treat when neutrophils and platelets are above these limits. If >1 delay or 1 delay >= 2 weeks reduce all the 5FU doses to 80% for future cycles. A further dose reduction may be made at the Clinician’s discretion.

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

Cisplatin Mod de Gram infusor



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INVESTIGATIONS 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 Ensure adequate pre and post hydration prescribed as per day case schedule at the end of TVCN protocols. 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

ANTI-EMETIC POLICY Highly emetogenic day 1 Low emetogenic risk days 2, 15 and 16

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, arrhythmias or angina pectoris or those who develop chest pain during treatment with fluorouracil.

Cisplatin Mod Gram infusor



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GEMCITABINE (1000) and CISPLATIN (25) Indication: Advanced cholangiocarcinoma gallbladder and ampullary cancer Unknown primary if appropriate

DRUG REGIMEN Day 1 CISPLATIN 25mg/m2 IV in 500ml sodium chloride 0.9% IV over 1 hour Sodium chloride 0.9% 500ml over 30 minutes

GEMCITABINE 1000mg/m2

in 250ml sodium chloride 0.9% infusion over 30 minutes Day 8 CISPLATIN 25mg/m2 IV in 500ml sodium chloride 0.9% IV over 1 hour Sodium chloride 0.9% 500ml over 30 minutes

GEMCITABINE 1000mg/m2


DOSE MODIFICATIONS Gemcitabine: Do not give with concurrent radiotherapy. CrCl <30ml/min consider dose reduction (Clinical decision) If bilirubin >27micromol/L initiate treatment with dose of 800mg/m2. Neutrophils >1.5x109/L and platelets >100x109/L give 100% dose Neutrophils 0.5-1.5x109/L or platelets 50-100x109/L give 75% dose or delay based on clinical assessment Neutrophils <0.5x109/L or platelets <50x109/L delay treatment (Day 1) or omit treatment (Day 8) and give 75% dose for subsequent cycles once count has recovered Diarrhoea and/or mucositis Grade 2 toxicity – omit until toxicity resolved then restart at 100% dose Grade 3 toxicity – omit until toxicity resolved then restart at 75% dose Grade 4 toxicity – omit until toxicity resolved then restart at 50% dose 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

Gemcitabine and Cisplatin



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INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration If Neutrophils x 109/L = 0.5-1 and or Platelets x 109/L = 50-99 give 75% dose gemcitabine and full dose cisplatin If Neutrophils x 109/L <0.5 and or Platelets x 109/L <50 delay both drugs Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) Liver function tests 2) Non-urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per day case schedule at the end of the TVCN protocols. 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.

ANTIEMETIC POLICY High emetogenic risk day 1 and 8

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Diarrhoea - see dose modifications Mucositis - see dose modifications Nephrotoxicity - ensure adequate pre and post hydration is prescribed. Ototoxicity - assess patient for tinnitus or hearing abnormalities. REFERENCES 1. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London Cancer Network 2. J.W Valle et al; 2009 ASCO meeting Abstract 4503; J Clin Oncol 27:15s 2009(suppl;abstr 4503) 3. J.W Valle et al; ABC-02 trial; NEJM 8.4.10: Vol 362:1273-81

Gemcitabine and Cisplatin



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LENVATINIB (Hepatocellular) Indication: The first line systemic therapy of Child-Pugh A locally advanced or metastatic hepatocellular carcinoma where the following criteria are met: 2. One of the following applies to the patient, either: - option 1 in which the patient has a confirmed histological diagnosis of hepatocellular carcinoma (HCC) or - option 2 in which a biopsy is deemed to be very high risk or technically not feasible in the patient and the criteria below are also all met:a. the decision not to biopsy has been made and documented by a specialist HCC multi-disciplinary team meetingb. the tumour meets the non-invasive diagnostic criteria of HCC*c. data is submitted as part of the ongoing 'Systemic Therapy Audit, previously known as the Sorafenib Audit 2’.It is expected that option 2 will only apply in exceptional circumstances and it should be noted that audit of non-biopsy rates will be reviewed regularly.*EASL-EORTC Clinical Practice Guidelines: Management, Journal of Hepatology 2012 vol 56 p908-943. Non-invasive criteria can only be applied to cirrhotic patients and are based on imaging techniques obtained by 4-phase multidetector CT scan or dynamic contrast-enhanced MRI. Diagnosis should be based on the identification of the typical hallmark of HCC (hypervascular in the arterial phase with washout in the portal venous or delayed phases). While one imaging technique is required for nodules beyond 1cm in diameter, a more conservative approach with 2 techniques is recommended in suboptimal settings. 3. The patient has either metastatic disease or locally advanced disease that is ineligible for or failed surgical or loco-regional therapies 4. The patient has either:- not received any previous systemic therapy for hepatocellular carcinoma (option 1) or- had to discontinue sorafenib within 3 months of starting sorafenib and solely because of toxicity (ie there was sorafenib toxicity which could not be managed by dose delay or dose modification) and there has been no disease progression whilst on sorafenib (option 2). 5. The patient has Child-Pugh liver function class A 6. The patient has an ECOG PS of 0 or 1.Lenvatinib is not commissioned in patients of ECOG PS of 2 or more 7. Lenvatinib is to be used as monotherapy. 8. The prescribing clinician is aware of the differing starting doses of lenvatinib according to the patient body weight being above or below 60Kg 9. A formal medical review as to whether treatment with lenvatinib should continue or not will be scheduled to occur at least by the end of the first 8 weeks of treatment 10. Lenvatinib is to be continued until loss of clinical benefit or unacceptable toxicity or patient choice to stop treatment. 11. No treatment breaks of more than 6 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or intercurrent comorbidities to improve). 12. Lenvatinib will be otherwise used as set out in its Summary of Product Characteristics. Blueteq registration required for patients prior to prescribing.

Lenvatinib Upper GI CAG Chair Authorisation: Date:


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DRUG REGIMEN Day 1 Lenvatinib 8mg orally daily under 60kg Lenvatinib 12mg orally daily 60kg or over

Cycle Frequency: Continuous

DOSE MODIFICATIONS Lenvatinib: Renal impairment No adjustment of starting dose is required on the basis of renal function in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended starting dose is 14 mg taken once daily. Further dose adjustments may be necessary based on individual tolerability. Patients with end-stage renal disease were not studied, therefore the use of lenvatinib in these patients is not recommended Hepatic impairment No adjustment of starting dose is required on the basis of hepatic function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose is 14 mg taken once daily. Further dose adjustments may be necessary on the basis of individual tolerability. See Lenvatinib (Lenvima) SPC for specific adverse reaction related dose modifications. http://www.medicines.org.uk/emc/medicine/30412

INVESTIGATIONS Routine Blood test 1) Blood results required before drug administration

Give Discuss

Hb x g/dL 10 < 10

Plt x 109/L 100 < 100 Neutrophils x 109/L 1.5 < 1.5

Creatinine Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression


ANTIEMETIC POLICY None required



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ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Hypertension Cardiac dysfunction Hepatotoxicity Haemorrhage

REFERENCES Lenvima SPC October 2016 CDF list



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REGORAFENIB Indication: Regorafenib is recommended as an option for treating advanced unresectable hepatocellular carcinoma in adults who have had sorafenib, if they have Child–Pugh grade A liver impairment and an Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 Ensure Trust has signed up to compassionate use scheme. Supply FOC stock until 13/4/19

DRUG REGIMEN Days 1 to 21 REGORAFENIB 160mg orally ONCE daily Cycle Frequency: Every 28 days

DOSE MODIFICATIONS Renal impairment No dose adjustment is required in patients with mild or moderate renal impairment. No clinical data are available in patients with severe renal impairment (eGFR <30 mL/min/1.73m2). Hepatic impairment Regorafenib is eliminated mainly via the hepatic route. No dose adjustment is required in patients with mild hepatic impairment. Since only limited data are available for patients with moderate hepatic impairment (Child Pugh B), no dose recommendation can be provided. Close monitoring of overall safety is recommended in these patients. Regorafenib is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as regorafenib has not been studied in this population Observed elevations of ALT and/or AST: ≤5 x ULN Continue treatment and monitor liver function weekly until transaminases

return to <3 times ULN (Grade 1) or baseline. >5 - ≤20 x ULN ULN Interrupt regorafenib treatment. Monitor transaminases weekly until

return to <3 times ULN or baseline. Restart: If the potential benefit outweighs the risk of hepatotoxicity, re-start regorafenib treatment, reduce dose by 40 mg (one tablet), and monitor liver function weekly for at least 4 weeks.

>20 x ULN Discontinue treatment with regorafenib permanently. >3 x ULN and bilirubin >2 x ULN

Discontinue treatment with regorafenib permanently. Monitor liver function weekly until resolution or return to baseline.

Exception: patients with Gilbert's syndrome who develop elevated transaminases should be managed as above recommendations for the respective observed elevation of ALT and/or AST. Dose modification levels: Dose level 0 (standard dose) 160 mg po od Dose level -1 120 mg po od Dose level -2 80 mg po od

Regorafenib Upper GI CAG Chair Authorisation: Date:


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Give Discuss

Hb x g/dL 10 < 10


Blood tests should initially be performed 4 weekly Liver function tests (LFT). It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of treatment with regorafenib and monitor closely (at least every two weeks) during the first 2 months of treatment. Thereafter, periodic monitoring should be continued at least monthly and as clinically indicated

2) Non urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy.


ANTIEMETIC POLICY Low emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Monitor blood pressure RERERENCES 1) Regorafenib SPC

Regorafenib Upper GI CAG Chair Authorisation: Date:


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Sorafenib (Hepatocellular carcinoma) Indication: The first line treatment of Child-Pugh A locally advanced or metastatic hepatocellular carcinoma where all of the following criteria are met: 2. Confirmed histological diagnosis of hepatocellular carcinoma 3. Patient must have either metastatic disease or locally advanced disease that is ineligible for or failed surgical or locoregional therapies 4. Patient has not received any previous systemic therapy for hepatocellular carcinoma9. No treatment breaks of more than 6 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or intercurrent comorbidities to improve) 5. Patient must have Child-Pugh liver function class A 6. Patient has a performance status of 0-2 7. Sorafenib is to be used as a single agent 8. Sorafenib is to be continued until disease progression or unacceptable toxicity or patient choice to stop treatment 9. No treatment breaks of more than 6 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or intercurrent comorbidities to improve) 10. Sorafenib to be otherwise used as set out in its Summary of Product Characteristics

DRUG REGIMEN Day 1 Sorafenib 400mg orally twice daily Cycle Frequency: Continuous

DOSE MODIFICATIONS Sorafenib: Renal impairment No dose adjustment is required in patients with mild, moderate or severe renal impairment. No data is available in patients requiring dialysis. Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised Hepatic impairment No dose adjustment is required in mild or moderate hepatic impairment. No data available for severe hepatic impairment

Sorafenib Upper GI CAG Chair Authorisation: Date:


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Give Discuss

Hb x g/dL 10 < 10


Blood tests should initially be performed 4 weekly, but later in the treatment course can be done less often in stable patients. Creatinine Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Take one hour before or two hours after meals

ANTIEMETIC POLICY None required

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Skin - Palmar / plantar syndrome Neutropenia Mouth pain / irritation / sensitivity may occur Haemorrhage – an increased risk of bleeding may occur. Hypertension – An increased incidence of arterial hypertension. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was amenable to management with standard antihypertensive therapy. Blood pressure should be monitored regularly and treated. Gastrointestinal – gastrointestinal perforation have occurred rarely. RERERENCES 1. SPC September 2010

Sorafenib Upper GI CAG Chair Authorisation: Date:


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Pre-hydration and post-hydration regimens

Ensure adequate diuresis is obtained prior to administration and maintained during and after administration. 1. Inpatient

Pre 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours Give cisplatin in 1000ml volume over 4 hours Post 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours

NB 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 6 hours if oral intake is inadequate

2. Day case Pre 1L sodium chloride 0.9% + 20 mmol KCl + 8mmol MgSO4 infusion over 2 hours 200ml mannitol 10% infusion over 30 minutes Give cisplatin in 1000ml volume over 2 hours Post 1L sodium chloride 0.9% + 20 mmol KCl + 8mmol MgSO4 infusion over 2 hours

NB Furosemide 40mg may be added if required

Hydration Upper GI CAG Chair Authorisation: Date


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