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Colorectal Regimens APPROVED v6.01 NWLCN 11Jul14 no tracked changes.docColorectal Regimens APPROVED v6.01 NWLCN 11Jul14.doc Colorectal of 79

COLORECTAL REGIMENS Section by: Dr Pippa Riddle, Dr Riz Ahmad, Dr Suzy Cleator, Dr Harpreet Wasan, Dr Charles Lowdell. Version: Colorectal Regimens APPROVED v6.01 NWLCN 11th July 2014 Section last updated: 11th July 2014 Section last corrected 11th July 2014 Approved by GI Oncology Lead Clinician: Dr P Riddle Date

Review date: July 2016 I N D E X Page COLORECTAL CANCER: Chemotherapy alone (No radiotherapy) 5Fluorouracil Single Agent +/- Folinic Acid 1. MAYO 5FU 425/FA 20 5 day 3 5FU 370/FA 20 5 day 3 2. Degramont 5 3. Lokich/5FU-300 contin 7 Oral Fluoropyrimidine Single Agent 4. Capecitabine 2500. 14 day (DeGramont substitute) 9 Tegafur with uracil (Uftoral) – Discontinued by manufacturer March 2013 removed Irinotecan 5. IrMdG Irinotecan-Degramont (FOLFIRI) 11 6. Capiri Irinotecan-Capecitabine 1600 (CAPIRI) 14 7. Irinotecan Single Agent 17 Oxaliplatin 8. OxMdG Oxaliplatin-Degramont (FOLFOX) 19 9. Capox Oxaliplatin-Capecitabine 2000 23 Ox-Ralt Oxaliplatin-Raltitrexed (see page 34) Mitomycin 10. MitoC-5FU.Contin 26 11. MitoC-Capecitabine 2500 27 12. MitoC-MdG 30 Raltitrexed (Tomudex) 13. Raltitrexed Single Agent 32 14. Raltitrexed-Oxaliplatin (TOMOX) 34


Page Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibodies General advice on prophylaxis against EGFR skin reactions 35 Cetuximab (Erbitux) Funding of cetuximab 35 15. Cetuximab-OxMdG Cetux-Oxaliplatin-MdG NICE/ Cancer Drugs Fund 37 16. Cetuximab-reduced Capox Cetux-Oxali-Capecitabine 1700 NICE/Cancer Drugs Fund 40 17. Cetuximab-IrMdG Cetux-Irinotecan-MdG NICE/Cancer Drugs Fund 42 18. Cetuximab-Capiri Cetux-Irino-capecitabine 1600 NICE/Cancer Drugs Fund 44 19. Cetuximab Single Agent weekly Cancer Drugs Fund 46 20. Cetuximab Single Agent every 2 weeks Cancer Drugs Fund 47 Panitumumab (Vectibix) 21. Panitumumab-OxMdG Cancer Drugs Fund 47 Vascular Endothelial Growth Receptor (VEGF) Inhibitors Aflibercept 22. Aflibercept-IrMdG Aflibercept-Irinotecan-MdG Cancer Drugs Fund 49 Bevacizumab (Avastin) Funding of Bevacizumab 54 23. Bevacizumab-OxMdG Bev-Oxaliplatin-MdG Cancer Drugs Fund 54 24. Bevacizumab-Capox Bev-Oxaliplatin-Capecitabine 2000 Cancer Drugs Fund 59 25. Bevacizumab-IrMdG Bev-Irinotecan-MdG Cancer Drugs Fund 60 26. Bevacizumab-Capiri Bev-Irinotecan-Capecitabine 1600 Cancer Drugs Fund 61 27. Bevacizumab-Cape Bev-Capecitabine 2500 Cancer Drugs Fund 62 Embolisation (Additional Private Care) 28. SIR-spheres embolisation - OxMdG reduced dose Additional Private Care 63 COLORECTAL CANCER: Chemo radiation regimens Chemo-Radiation Dose Modifications 66 29. Bossett Regimen 5FU 350/FA 20 + RT 67 30. Capecitabine1650 + RT 68 ANAL CANCER ANAL CANCER Chemo-radiation Regimens 31. Mitomycin/5FU + RT, UKCCR Regimen local disease 70

ANAL CANCER Chemotherapy Alone 32. Cisplatin-5FU. CISP-60-5FU 4 day 72 33. Docetaxel 100 Single Agent (Additional Private Care) 73 WHO Performance status 75 Cockcroft Gault formula 75 Version Control Box 76


COLORECTAL REGIMENS Section by: Dr Pippa Riddle, Dr Riz Ahmad, Dr Suzy Cleator, Dr Harpreet Wasan, Dr Charles Lowdell. Version: Colorectal Regimens APPROVED v6.01 NWLCN 11Jul14 Section last updated: 11thJuly 2014 Last corrected: 11th July 2014 Approved by GI Oncology Lead Clinician: July 2014 Review date: July 2016 CHEMOTHERAPY ALONE (No radiotherapy)

5-Fluorouracil Single Agent Regimens +/- Folinic Acid Folinic acid refers to the mixed racemix D and L isomers. Calcium levofolinate refers to L folinic acid isomers only. MAYO Adaptations: 1. 5FU425/FA20 5day or 5FU 370/FA20 5day

Folinic Acid 20mg/m2 IV bolus Days 1 to 5 5 Fluorouracil dose determined by age see below

Dose under 70 years 425mg/m2 IV bolus Days 1 to 5

and ECOG 1 Dose over 70 years 370mg/m2 IV bolus Days 1 to 5

and/or ECOG 2 Interval between cycles: Repeat every 28 days Number of cycles: Colon cancer Neoadjuvant up to 6 cycles/6 months Adjuvant up to 6 cycles/6 months Metastatic/local recurrence 3-6 cycles/3-6 months Tests before starting course of chemo: FBC, U&Es, LFTs, tumour markers CEA,

CA19-9. Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Supportive drugs with each cycle: Low risk antiemetics as per NWLCN

guidelines or as per local policy Chlorhexidine mouthwash 10mls QDS Loperamide 2-4mg QDS PRN

Patient information: Chemotherapy treatment booklet (local information/Macmillan) Your chemotherapy record (Red book) Chemotherapy alert card

Macmillan drug specific information sheet(s) and information prescriptions as appropriate

Neutropenia DVD (NWLCN) Additional information:

Administration notes: Suck ice cubes or ice lollies 5 minutes before and for 30 minutes after injection (if tolerated) of 5FU may reduce the incidence of stomatitis.

Dose Modifications: See MAYO table page 4-5 References: J. Clin Oncol 1997 15:246-50. O’Connell et al Ann. Oncol 1998 9 (5):535-41. Borner MM


J. Clin Oncol 1989 7(10):1407-18 (425mg) J. Clin Oncol 1991;9:449-52 (ice chips)

Table: MAYO (Ref. QUASAR protocol UKCCCR 1998)

Radical treatment only: For combination of Haematological/non Haematological toxicity

Wait until FULL recovery ie. neutrophils 1.5 x109/L and platelets 100 x109/L and/or any persistent mucositis and diarrhoea have resolved.

If resolved within 2 weeks restart chemo using dose modifications below.

If FULL recovery takes more than 2 weeks discuss with consultant.

Haematological Toxicity

Non Haematological Toxicity On day of chemo or during previous cycle

(Diarrhoea or mucositis)

Neutrophils Platelets

x109/L x109/L

CTC Grade

0-1 2 3 4

≥ 1.5 And ≥100 Full dose Full dose Delay until recovery to toxicity ≤grade 2 then give 50% dose reduction

Do not give

≥1.0-1.5* And/or 50-99 Discuss with consultant as in some cases may go ahead with neutrophils 1.0 to 1.5 provided platelets ≥100

Delay until haematological recovery then give full dose

Delay until haematological recovery then give 20% dose reduction

Delay until full haematological and non-haematological recovery to toxicity grade ≤2 then give 50% dose reduction

Do not give

0.5-0.99 Or 25-49 Delay until full haematological recovery then give 20% dose reduction


Delay until full haematological and non-haematological recovery to toxicity ≤ grade 2 then give 50% dose reduction

Do not give

<0.5 Or <25 Delay until haematological recovery then give 50% dose reduction


Delay until full haematological and non-haematological recovery to toxicity ≤ grade 2 then give 50% dose reduction

Do not give

Do not dose reduce Folinic Acid


Side-Effect: MAYO Dose Modification (Source:Quasar/FOCUS trials)

Haematology See above

Renal function GFR ≤ 30mls/min Unclear guidance. Discuss with consultant

Hepatic function Unclear guidance. Discuss with consultant

Stomatitis Routine mouthcare with chlorhexidine. Ensure ice chips are being used during administration of 5FU. If still a problem reduce dose according to table above

Diarrhoea

Give loperamide 2-4mg oral QDS PRN (max 16mg/day) or codeine phosphate 30-60mg oral QDS PRN. If still a problem reduce dose according to table above

Hand-Foot Syndrome

Reduce dose according to table page 4 Phase III randomised controlled trials show no benefit for pyridoxine for prevention or treatment of 5FU induced hand foot syndrome. Pyridoxine is not recommended.

DPD Deficiency (Focus) 1-3% of patients have markedly exaggerated 5FU toxicity due to reduced 5FU catabolism. Discuss with consultant.

Cardiotoxicity (Focus) Uncommon. 5FU may provoke angina or MI in patients with ischaemic heart disease. Seek specialist opinion on upgraded anti-anginal medication and consider dose reduction or alternative non 5FU treatment.

Neurotoxicity (Focus) Uncommon – Cerebellar Consider alternative non 5FU treatment

2. DeGramont Regimen:

May 2005: Where possible DeGramont regimens should be standardised to the “Modified” version either via CVAD/Infusor or via peripheral line/litre infusion bags (unless dictated otherwise by clinical trials).

DeGramont – Modified

Folinic Acid 350mg IV over 2 hours Day 1 5 Fluorouracil 400mg/m2 IV bolus Day 1 5 Fluorouracil 2800mg/m2 IV over 46 hours Days 1 to 2

Interval between cycles: Repeat every 14 days

Number of cycles: Colon cancer: Neoadjuvant: Duration depends on response and future plans generally 3-4 cycles

Adjuvant: 12 cycles/6 months Metastatic Locally/advanced: 6-12 cycles/3-6 months Depends on response (tumour markers/CT

scans). Review as directed by markers/clinical assessment. Beyond 12 cycles at consultant’s directions only.

Tests before starting course of chemo: FBC, U&Es, LFTs, tumour markers CEA, CA19-9

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs


Supportive drugs with each cycle: Low risk antiemetics as per NWLCN guidelines or as per local policy

Chlorhexidine mouthwash 10mls QDS. Loperamide 2-4mg QDS PRN (max 16mg/24hrs)



Neutropenia DVD (NWLCN) Written information on mechanical pump (if via CVAD) Additional information: Administration notes: 5FU: If 5FU administered using an ambulatory infusion pump via a central venous

access device (CVAD) refer to relevant protocol for care of CVAD. Joint care with the community nursing services should be arranged in advance to support the patient and to assist with disconnecting the chemotherapy and flushing the CVAD. Written community nursing referral should be completed and the patient should be discharged with a home spillage kit, sharps container and a small supply of equipment to flush the line and dress the entry site of the CVAD.

Dose modifications: See DeGramont Modified table below References: J. Clin Oncol 1997;15:808-15 De Gramont et al J. Clin Oncol 1998;16:301-308 Meta Analysis Group in Cancer Annals Oncology 1998;9(Suppl 4):47 (modified) Table: DeGramont – Modified NB. Palliative patients will require greater dose reductions than stated below based on individual patient parameters. Discuss with consultant.

Side-Effect: MdG

Dose Modification (Source: Focus (CR08) Trial/2000)

Haematology (CR08)

Neutrophils Platelets x109/L x109/L

1.5 and 100 <1.5 or <100

Full dose Delay until recovery. Only treat when WBC/neutrophils and platelets are above these limits

If more than 1 delay, or one delay of 2 weeks occurs then restart with: 5FU: 20% dose reduction (bolus and infusion). Continue with this reduced dose unless further toxicity occurs. If further delays for myelotoxicity occur despite the 20% dose reduction, discuss with consultant



Stomatitis (Focus) If mouth ulcers occur despite routine chlorhexidine mouthwash: 5FU: 20% dose reduction (bolus and infusion). Continue with this reduced dose unless further toxicity occurs.


Side-Effect: MdG

Dose Modification (Source: Focus (CR08) Trial/2000)

Diarrhoea (Focus)

Between cycles – treat symptomatically loperamide 2-4mg QDS PRN and/or codeine phosphate 30-60mg QDS PRN Not resolved by next cycle: Delay 1 week/until recovered If diarrhoea still a problem

Despite symptomatic treatment

Or more than one delay is required Then dose reduce 5FU: 20% dose reduction (bolus and infusion). Continue with this reduced dose unless further toxicity occurs.

Hand-Foot Syndrome (Focus/Focus 2)

Grade 2

Dose reduce. 5FU: 20% dose reduction (bolus and infusion) for subsequent cycles. Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand foot syndrome. Pyridoxine is not recommended.

DPD Deficiency (Focus) 1-3% of patients have markedly exaggerated 5FU toxicity due to reduced 5FU catabolism. Discuss with consultant.

Cardiotoxicity (Focus)

Uncommon. 5FU may provoke angina or MI in patients with ischaemic heart disease. Seek specialist opinion on upgraded anti-anginal medication and consider dose reduction or alternative non 5FU treatment.

Neurotoxicity (Focus) Uncommon – Cerebellar Consider alternative non 5FU treatment

3. Lokich/5FU-300 Contin

5-Fluorouracil 300mg/m2/day IV continuous infusion for 12 weeks Continuous infusion for 12 weeks , 1 cycle = 3 weeks. Repeat tests every 21 days Interval between cycles: Continuous infusion for 12 to 24 weeks (4 to 8 cycles of 21 days) Number of cycles: Colon cancer Neoadjuvant: depends on response and future plans 12 weeks generally Adjuvant: 12-24 weeks Metastatic/locally advanced: 12-24 weeks/3-6 months

Duration depends on response (tumour markers/CT scans). Review as directed by markers/clinical assessment.

Beyond 24 weeks at consultant’s direction only. Tests before starting course of chemo: FBC, U&Es, LFTs, tumour markers

CEA,CA19-9. Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs



Chlorhexidine mouthwash 10mls QDS. Loperamide 2-4mg QDS PRN (max 16mg/ 24hrs)



Neutropenia DVD (NWLCN) Written information on mechanical pump (if via CVAD) Additional information: Administration notes: 5FU See page 6

Dose modifications: Table Lokich below References: J. Clin Oncol 1989;7:425-32. Lokich et al

NEJM 1994;331:502-7. O’Connell et al. Table: Lokich NB. Palliative patients will require greater dose reductions than stated below based on individual patient parameters. Discuss with consultant.

Side-effect: Lokich

Dose Modification (Source: CR06 Trial)

Haematology WBC <1.5 x 109/L OR Platelets <75 x 109/L

Interrupt infusion for 1 week (or until recovery Resume with 5FU: reduce dose by 50mg/m2/ day



Stomatitis (CR06)

Routine mouthcare with chlorhexidine. If still a problem: stop chemo until recovery then Restart with 5FU: Reduce by 50mg/m2/day

Diarrhoea (CR06) Give loperamide 2-4mg QDS or codeine phosphate 30-60mg QDS If still a problem: stop chemo until recovery then: Restart with 5FU: Reduce by 50mg/m2/day

Hand/Foot Syndrome

Grade 2

Stop chemo until recovery then: Restart with 5FU: Reduce by 50mg/m2/day. Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand foot syndrome. Pyridoxine is not recommended.

DPD Deficiency 1-3% of patients have markedly exaggerated 5FU toxicity due to reduced 5FU catabolism. Discuss with consultant.

Cardiotoxicity Uncommon. 5FU may provoke angina or MI in patients with ischaemic heart disease. Seek specialist opinion on upgraded anti-anginal medication and consider dose reduction or alternative non 5FU treatment.

Neurotoxicity Uncommon – Cerebellar


Side-effect: Lokich

Dose Modification (Source: CR06 Trial)

Consider alternative non 5FU treatment


Oral Fluoropyrimidine Single Agent Regimens

Capecitabine is not licensed as a substitute for 5Fluorouracil in all 5FU regimens/clinical circumstances. Capecitabine should only be substituted for infusional 5FU regimens where there is local New Drugs Panel approval. 4. Capecitabine 2500 (Degramont substitute)

Capecitabine 1250mg/m2 BD Oral Days 1 to 14 ie. 2500mg/m2/day after food with water If CrCl >50mls/min dose as per table page 10 If >70years reduced starting dose by 25%

Interval between cycles: Repeat every 21 days Number of cycles: Metastatic colorectal cancer 1st line only In line with NICE TA61: 4-8 cycles/3-6 months Depends on response (tumour markers and CT scans). Adjuvant following Duke’s C colon cancer: 8 cycles/6 months

Where there is local approval for capecitabine substitution for 5FU/Degramont Adjuvant following surgery of high risk Duke’s B 8 cycles/6 months ie. where there are additional adverse characteristics such as vascular invasion, bowel perforation, or adverse histological features.

Tests before starting course of chemo: FBC, U&Es, LFTs, Crcl (calculated). If <50mls/min do EDTA, tumour markers CEA, C19-9. ECG in patients with history of ischaemic heart disease or cardiac risk factors

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs, Crcl. Redo EDTA if rising creatinine




Neutropenia DVD (NWLCN) Capecitabine patient diary Patient must receive nurse capecitabine counselling; see below Additional information:

Unknown: effects on fertility. Administration notes: Patients must receive specific capecitabine counselling prior to treatment from a capecitabine trained nurse/pharmacist as per local policy. Patients must be given written and verbal information on capecitabine including how to take the tablets, when to stop (ie. In the event of toxicity and after 14 days), and whom to contact when side effects occur. Written information should be sent to the patient’s GP.


Capecitabine tablets should be taken with water 30 minutes after food and approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin and therefore patients on these drugs must have their blood levels monitored more regularly. Capecitabine is contraindicated with allopurinol.

Dose modifications: See Table below Reference: J. Clin Oncol 2001 19:2282-92. Hoff et al Table: Capecitabine – colorectal NB. Palliative patients will require greater dose reductions than below based on individual patient parameters. Discuss with consultant. Side-effects: Capecitabine

Dose Modifications (Focus 2/SPC)

Haematology Neutrophils Platelets x 109/L x 109/L

1.5 and 100 <1.5 or <100

If >1 delay or 1 delay 2 weeks

Further delays

Full dose. Only treat if neutrophils and platelets are above these levels. Delay 1 week or until recovery. Capecitabine: 20% dose reduction. Continue at this lower dose for subsequent cycles unless further toxicity occurs. If further delay(s) for myelotoxicity occur despite 20% dose reduction, discuss with consultant

Renal function (SPC)

Crcl 50mls/min 30-49mls/min

<30mls/min

Full dose Capecitabine 25% dose reduction. Do not give. Discuss with consultant. Consider 5FU.

Hepatic function Bilirubin Either AST or ALT ≤3 x ULN and ≤2.5 x ULN >3 x ULN or >2.5 x ULN

Full dose Capecitabine withhold and discuss with consultant

Diarrhoea Grade 1

Grade 2

Loperamide 2-4mg QDS PRN. Maximum 16mg/24 hours. As Grade 1 plus stop capecitabine until recovery then reduce dose according to SPC table page 11

Stomatitis (SPC)

Grade 1

Grade 2

Consider topical treatments eg. Difflam mouthwash or sucralfate 1g/5mls mouthwash QDS Stop capecitabine until recovery Reduce dose according to SPC table page 11. Mouthcare as grade 1

Hand-Foot Syndrome Grade 1

Grade 2

Stop capecitabine until recovery. Once recovered restart with full dose Stop capecitabine until recovery. Once recovered, reduce dose according to SPC table page 11 Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand foot syndrome. Pyridoxine is not recommended.

DPD Deficiency 1-3% of patients have markedly exaggerated capecitabine toxicity due to reduced capecitabine catabolism. Discuss


Side-effects: Capecitabine

Dose Modifications (Focus 2/SPC) with consultant.

Cardiotoxicity Uncommon. Capecitabine may provoke angina or MI in patients with ischaemic heart disease. Seek specialist opinion on upgraded anti-anginal medication and consider dose reduction or alternative non-capecitabine treatment.

Neurotoxicity Uncommon – Cerebellar Consider alternative non-capecitabine treatment

Capecitabine Non haematological toxicity (SPC) NCIC Grade

During course of treatment

Dose adjustment for next cycle

Grade 1

Continue treatment

Capecitabine full dose

Grade 2 1st appearance 2nd appearance 3rd appearance 4th appearance

Interrupt capecitabine until resolved to grade 0-1 Interrupt capecitabine until resolved to grade 0-1 Interrupt capecitabine until resolved to grade 0-1 Discontinue capecitabine permanently

All drugs full dose Capecitabine 25% dose reduction. Capecitabine 50% dose reduction. Stop treatment

Grade 3 1st appearance 2nd appearance 3rd appearance

Interrupt capecitabine until resolved to grade 0 to 1 Interrupt capecitabine until resolved to grade 0 to 1 Discontinue capecitabine treatment permanently

Capecitabine 25% dose reduction Capecitabine 50% dose reduction Do not give

Grade 4 1st appearance

Discontinue permanently. If consultant considers it is in best interest of patient to continue: interrupt capecitabine until resolved to grade 0 to 1

Under direction of consultant Capecitabine 50% dose reduction

Irinotecan Chemotherapy

5. MdG plus Irinotecan Atropine 250mcg SC Day 1 Irinotecan 180mg/m2 IV over 30-90mins Day 1

Folinic Acid 350mg IV over 2 hours Day 1 5-Fluorouracil 400mg/m2 IV bolus Day 1 5-Fluorouracil 2400mg/m2 IV over 46 hours Day 1 to 2 Interval between cycles: Repeat every 14 days Number of cycles: Colorectal cancer 1st line metastatic: 6-12 cycles/3-6 months Tests before starting course of chemo: FBC, U&Es, LFTs, tumour markers


CEA,CA19-9, Crcl (calculated). Performance status: PS 0 or 1: proceed PS 2: caution, PS3: Do not give Caution in patients with previous history of

diarrhoea or abdominal pelvic disease. Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Supportive drugs with each cycle: High risk antiemetics as per NWLCN

guidelines or as per local policy Chlorhexidine mouthwash 10mls QDS Atropine as above to prevent acute

cholinergic syndrome (diarrhoea, sweating, salivation, bradycardia). Loperamide if necessary see table below Ciprofloxacin if necessary see table below Patient information: Chemotherapy treatment booklet (local information/Macmillan) Your chemotherapy record (Red book) Chemotherapy alert card


Neutropenia DVD (NWLCN) Irinotecan patient information on diarrhoea Loperamide will be prescribed to be used when directed See table below for high doses with irinotecan Written information on mechanical pump (if via CVAD) Additional information:

Administration notes: Irinotecan: Give patient information on loperamide for diarrhoea. Patient must contact hospital if

diarrhoea continues for longer than 48 hours or if they are also experiencing vomiting and fever.

5FU: See MdG Colorectal page 6 Dose modifications: Table: DeGram-Irino below Reference: Lancet 2000 355:1014-7. Douillard JY et al Table: DeGram-Irino

Side-Effect: Ir-MdG

Dose Modification (Source: Focus Trial/SPC)

Haematological Neutrophils Platelets x109/L x109/L

1.5 and 100 <1.5 or <100 If neutropenia grade 4, febrile neutropenia, thrombocytopenia grade 4 or leucopenia grade 4 occurs (SPC

July 02) or if more than 1 delay or 1 delay greater than 2 weeks

Myelotoxicity more common than with degramont alone Full dose Delay 1 week and recheck FBC. Only give when neutrophils and platelets are above these limits. } Irinotecan: 20% dose reduction } 5FU (bolus and infusion): 20% dose reduction } } If further delays occur for myelotoxicity despite 20% } reduction, discuss with consultant


Side-Effect: Ir-MdG


Renal function Crcl ≤50mls/min

Unclear guidance. Discuss with consultant

Hepatic Function (SPC)

Bilirubin ALP <1.5 x ULN and ≤5.0 x ULN 1.5-3.0 x ULN or >5.0 x ULN >3 x ULN and Any

Irinotecan and metabolites cleared by biliary excretion. Delayed clearance in cholestasis. Full dose all drugs Irinotecan: 50% dose reduction 5-Fluorouracil: Full dose Irinotecan: Do not give 5-Fluorouracil: 50% dose reduction

Stomatitis (Focus)

Routine mouth care with chlorhexidine mouthwash. If mouth ulcers occur despite this, dose reduce 5FU: 20% dose reduction (bolus and infusion) for all subsequent cycles

Diarrhoea Immediate diarrhoea (within first 24 hours) Delayed diarrhoea occurring more than 24 hours after irinotecan and at any time before next cycle:

Initial treatment

Lasts >24 hours

Lasts >48 hours

Grade 3-4

Unresolved by next cycle

Incidence of immediate diarrhoea is low due to use of atropine premed. If acute diarrhoea/cholinergic syndrome occurs administer another dose of atropine 250mcg SC stat. Irinotecan induced delayed diarrhoea should be treated early with high dose loperamide, 4mg after first loose stool then 2mg every 2 hours until 12 hours after last loose stool (up to 24mg/day for a maximum of 48 hours because or risk of paralytic ileus). If diarrhoea lasts > 24 hours add Ciprofloxacin PO 500mg BD. If diarrhoea lasts > 48 hours or patient reports symptoms of dehydration, admit acutely for rehydration and further management. After an episode of severe diarrhoea (grade 3/4), delay until full recovery then resume at Irinotecan: 20% dose reduction 5FU (bolus & infusion) : 20% dose reduction. If diarrhoea from previous cycle (even if not severe) not resolved by next cycle due - delay 1 week.

Hand-Foot Syndrome

Grade 2

5FU: 20% dose reduction (bolus and infusion) Irinotecan: full dose. Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand foot syndrome. Pyridoxine is not recommended.


Side-Effect: Ir-MdG


DPD Deficiency (Focus) 1-3% of patients have markedly exaggerated 5FU toxicity due to reduced 5FU catabolism. Discuss with consultant

Cardiotoxicity (Focus) Uncommon. 5FU may provoke angina attack or MI in patients with ischaemic heart disease. Seek specialist opinion on upgraded anti-anginal medication and consider dose reduction or alternative non 5FU treatment.

Neurotoxicity (Focus) Uncommon – Cerebellar Consider alternative Non 5FU treatment

6. Irinotecan-Capecitabine (CAPIRI) Atropine 250mcg SC Day 1 Irinotecan 200mg/m2 IV over 30-90mins Day 1 Capecitabine 800mg/m2 Oral twice a day Day 1 to 14 Ie1600mg/m2/day with water after food Consider capecitabine 25% dose reduction in patients over 70years Interval between cycles: Repeat every 21 days Number of cycles: Colorectal cancer 1st line metastatic 4-8 cycles/3-6 months where there is local approval for capecitabine substitution of 5FU

Tests before starting course of chemo: FBC, U&Es, LFTs, tumour markers CEA, CA19-9, Crcl calculated, do EDTA if < 50mls/min. ECG in patients with history of ischaemic heart disease or cardiac risk factors

Performance status: PS 0 or 1: proceed PS 2: caution PS 3: do not give Caution in patients with previous history of

diarrhoea or abdominal pelvic disease. Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs, Crcl calculated. Do/redo

EDTA if rising creatinine Supportive drugs with each cycle: Day 1: High risk antiemetics as per

NWLCN guidelines or as per local policy Atropine to prevent acute cholinergic

reactions Loperamide if necessary see table below Ciprofloxacin if necessary see table below Patient information: Chemotherapy treatment booklet (local information/Macmillan) Your chemotherapy record (Red book) Chemotherapy alert card


Neutropenia DVD (NWLCN) Capecitabine patient diary

Patient must receive nurse capecitabine counselling Irinotecan information booklet on diarrhoea


Loperamide will be prescribed to be used when directed See table for high dose loperamide with irinotecan Additional information: Administration notes: Irinotecan:

Give patient information on loperamide to treat irinotecan induced diarrhoea. Patient must contact hospital if diarrhoea continues for longer than 48hours or if they are also experiencing vomiting and fever. Atropine should be administered subcutaneously as a pre medication to avoid acute cholinergic syndrome.

Capecitabine: Patients must receive specific capecitabine counselling prior to treatment from a capecitabine trained nurse/pharmacist as per local policy. Patients must be given written and verbal information on capecitabine including how to take the tablets, when to stop (ie. In the event of toxicity and after 14 days), and whom to contact when side effects occur. Written information should be sent to the patient’s GP. Capecitabine tablets should be taken with water 30 minutes after food and approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin and therefore patients on these drugs must have their blood levels monitored more regularly. Capecitabine is contraindicated with allopurinol.

Dose modifications: Reference: Table: Irinotecan-Capecitabine

Side effect: Capiri Dose modifications:

Haematology Neutrophils Platelets x109/L x109/L ≥1.5 and ≥100 <1.5 or <100 If more than 1 delay or 1 delay greater than 2 weeks, Neutropenia grade 4, Febrile neutropenia, or Leucopenia grade 4 (SPC 2002)

Full dose. Only treat if neutrophils and platelets are above these levels. Delay for 1 week or until recovery. Irinotecan: 20% dose reduction Capecitabine: 20% dose reduction If further delays occur for myelotoxicity despite 20% dose reduction discuss with consultant

Renal function (SPC) CrCl

≥50ml/min

30-49ml/min

<30mls/min

Full dose Irinotecan: Discuss with consultant Capecitabine: SPC recommends no dose adjustment of starting dose for 1600mg/m2/day, but recommends careful monitoring and prompt treatment interruption if patient develops a grade 2, 3 or 4 adverse event and dose adjustments as per SPC table on page 11 Do not give. Discuss with consultant



Hepatic function Bilirubin Either AST or ALT <1.5 x ULN and ≤2.5 x ULN <1.5 x ULN and 2.5-5.0 x ULN 1.5-3.0 x ULN and ≤2.5 x ULN 1.5-3.0 x ULN and 2.5-5.0 x ULN

1.5-3.0 x ULN or >5.0 x ULN

>3.0 x ULN and Any

Irinotecan Full dose Full dose Irinotecan 50% dose reduction Irinotecan 50% dose reduction Irinotecan 50% dose reduction Do not give

Capecitabine Full dose Withhold and discuss with consultant Full dose Withhold and discuss with consultant Withhold and discuss with consultant Withhold and discuss with consultant

Diarrhoea Capecitabine induced diarrhoea

Grade 1 ≥Grade 2

Irinotecan immediate onset diarrhoea within first 24 hours Irinotecan Induced Delayed Diarrhoea Occurring more than 24 hours after irinotecan and at

any time before next cycle Initial treatment

Lasts >24 hours

Lasts >48 hours

Grade 3-4


Loperamide 2-4mg QDS PRN (max 16mg/24hours). As grade 1 plus stop capecitabine until recovery then reduce dose according to SPC table on page 11. Incidence of immediate diarrhoea is low due to use of atropine premed. If acute diarrhoea/cholinergic syndrome occurs, administer another dose of atropine 250mcg SC stat. Irinotecan induced delayed diarrhoea should be treated early with high dose loperamide, 4mg after first loose stool then 2mg every 2 hours until 12 hours after last loose stool (up to 24mg/day for a maximum of 48 hours because of paralytic ileus). If diarrhoea lasts > 24 hours add Ciprofloxacin PO 500mg BD. If diarrhoea lasts > 48 hours or patient reports symptoms of dehydration, admit acutely for rehydration and further management. After an episode of severe diarrhoea (grade 3/4), delay until full recovery then resume at Irinotecan: 20% dose reduction 5FU (bolus & infusion) : 20% dose reduction. If diarrhoea from previous cycle (even if not severe) not resolved by next cycle due - delay 1 week.



Stomatitis (SPC)

Grade 1

≥Grade 2

Consider topical treatments eg. Difflam mouthwash or sucralfate 1g/5mls mouthwash QDS Stop capecitabine until recovery Reduce dose according to SPC table page 11 Irinotecan full dose. Mouthcare as grade 1


≥Grade 2

Stop capecitabine until recovery. Discuss with consultant if irinotecan should continue. Once recovered restart capecitabine next cycle with full dose. Stop chemotherapy until recovery. Once recovered reduce capecitabine dose according to table on page 11 Irinotecan full dose Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand foot syndrome. Pyridoxine is not recommended

DPD Deficiency

1-3% of patients have markedly exaggerated capecitabine toxicity due to reduced capecitabine catabolism. Discuss with consultant.

Cardiotoxicity

Uncommon. Capecitabine may provoke angina or MI in patients with ischaemic heart disease. Seek specialist opinion on upgraded anti-anginal medication and consider dose reduction or alternative non-capecitabine treatment.

Neurotoxicity

Uncommon – Cerebellar Consider alternative non-capecitabine treatment

7. Irinotecan Single Agent Atropine 250mcg SC Stat pre irinotecan Day 1

Irinotecan *350mg/m2 IV over 30-90mins Day 1 * Reduce dose to 300mg/m2 for patients > 70 years, or at any age if performance

status =2 Caution in patients with previous history of diarrhoea or abdominal-pelvic disease

Interval between cycles: Repeat every 21 days Number of cycles: Colorectal cancer 2nd line metastatic: 4-8 cycles/3-6 months Tests before starting course of chemo: FBC, U&Es, LFTs, tumour markers CEA,

CA19-9, Crcl (calculated). Performance status PS 0 or 1: proceed PS 2: Caution, PS3: Do not give

Tests to OK/Confirm each cycle of chemo : FBC, U&Es, LFTs, Crcl (calculated) Supportive drugs with each cycle: High risk antiemetics as per NWLCN

guidelines or as per local policy Atropine as above to prevent acute

cholinergic symptoms (diarrhoea, sweating, salivation, bradycardia).

Loperamide if necessary see table below Ciprofloxacin if necessary see table below




Neutropenia DVD (NWLCN) Irinotecan information booklet on diarrhoea Loperamide will be prescribed to be used when directed See table for high dose loperamide with irinotecan Additional information:

Administration notes: Give patient information on loperamide to treat irinotecan induced diarrhoea. Patient

must contact hospital if diarrhoea continues for longer than 48hours or if they are also experiencing vomiting and fever. Atropine should be administered subcutaneously as a pre medication to avoid acute cholinergic syndrome.

Dose modifications: See Table page 20 Reference: Lancet 1998;352:1413-18. Cunningham et al Lancet 1998;352:11407-1412 Rougier et al Table: Irinotecan alone

Side-effect: Irinotecan alone


Haematology Neutrophils Platelets x109/L x109/L

1.5 and 100 <1.5 or <100 If neutropenia grade 4, febrile neutropenia, thrombocytopenia grade 4 or leucopenia grade 4 occurs (SPC January

02) or if more than 1 delay or 1 delay greater than 2 weeks

Full dose all drugs Delay 1 week until recovery. Only treat above these levels Irinotecan: 20% dose reduction If further delays occur for myelotoxicity despite 20% dose reduction. Discuss with consultant

Renal function Crcl ≤50mls/min

Unclear guidance. Discuss with consultant


Bilirubin AST <1.5 x ULN and <5.0 x ULN 1.5-3.0 x ULN or >5.0 x ULN > 3.0 x ULN and Any

Irinotecan and metabolites cleared by biliary excretion. Delayed clearance in cholestasis. Full dose Irinotecan: 50% dose reduction Irinotecan: omit


Side-effect: Irinotecan alone


Diarrhoea Irinotecan Immediate Onset Diarrhoea within first 24 hours

Irinotecan Induced Delayed Diarrhoea occurring more than 24 hours after irinotecan and at

any time before next cycle: Initial treatment

If diarrhoea lasts >24 hours

Lasts >48 hours

Grade 3-4


Incidence of immediate diarrhoea low due to use of atropine premed. If acute diarrhoea/cholinergic syndrome occurs administer another dose of atropine 250mcg SC Stat. Irinotecan induced delayed diarrhoea should be treated early with high dose loperamide 4mg after first loose stool then 2mg every 2 hours until 12 hours after last loose stool (up to 24mg/day for a maximum 48 hours because of risk of paralytic ileus). Add Ciprofloxacin 500mg BD PO. If diarrhoea lasts > 48 hours or patient reports symptoms of dehydration, admit acutely for rehydration and further management. After an episode of severe diarrhoea (grade 3 / 4), delay until full recovery then resume at Irinotecan: 20% dose reduction 5FU : 20% dose reduction (bolus & infusion) If diarrhoea from previous cycle (even if not severe) not resolved by next cycle due – delay 1 week.

Oxaliplatin Chemotherapy

8. OxMdG DeGramont – Modified plus Oxaliplatin Folinic Acid 350mg IV over 2 hours Day 1 Oxaliplatin 85mg/m2 IV over 2 hours Day 1 5-Fluorouracil 400mg/m2 IV bolus Day 1 5-Fluorouracil 2400mg/m2 IV over 46 hours Day 1 to 2 Interval between cycles: Repeat every 14 days Number of cycles: Colorectal cancer Adjuvant Duke’s C if ineligible for trials: 12 cycles Metastatic 1st or 2nd line: 6-12 cycles/3-6 months Tests before starting course of chemo: FBC, U&Es, LFTs, tumour markers

CEA, CA19-9, Crcl (calculated). Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs, Crcl (calculated) Supportive drugs with each cycle: High risk antiemetics as per NWLCN

guidelines or as per local policy Chlorhexidine mouthwash 10mls QDS. Loperamide 2-4mg QDS, PRN (max 16mg/day)

Patient information: Chemotherapy treatment booklet (local information/Macmillan)


Your chemotherapy record (Red book) Chemotherapy alert card


Neutropenia DVD (NWLCN) Written information on mechanical pump (if via CVAD)

Additional information: Administration notes:

Oxaliplatin Oxaliplatin is incompatible with normal saline, therefore, the venous access device and administration sets should be flushed with 5% glucose. Folinic acid in 5% glucose is administered at the same time as the oxaliplatin. Patients should be advised to keep warm as exposure to cold post oxaliplatin infusion may aggravate symptoms of peripheral neuropathy and laryngopharyngeal dysthesia. In the event of laryngopharyngeal symptoms during an oxaliplatin infusion, reassure the patient that the symptoms are likely to resolve. This must not be confused with an allergic response which requires emergency intervention. The patient who suffers from laryngopharyngeal spasm may be re-challenged with oxaliplatin at a slower infusion rate of up to 6 hours. On occasions pain may be experienced in the infusion arm, if so, slow infusion rate to a maximum 6 hours. Consider CVAD if problematic. 5FU: See MdG Colorectal page 6 If 5FU administered using an ambulatory infusion pump via a central venous access device (CVAD), refer to relevant protocol for care of CVAD. Joint care with the community nursing services should be arranged in advance to support the patient and assist with disconnecting the chemotherapy and flushing the CVAD. Written community nursing referral should be completed and the patient should be discharged with a home spillage kit, sharps container and a small supply of equipment to flush the line and dress the entry site of the CVAD.

Dose modifications: Table: OxMdG page 22 Reference: J. Clin Onc 2000;18:2938-47. DeGramont et al Table: OxMdG Side-effect: OxMdG

Dose Modification (Source: Focus Trial/SPC/Coin Trial)

Haematology (Coin)

Neutrophils Platelets x109/L x109/L

1.5 and 75 <1.5 or <75

If more than 1 delay or 1 delay 2 weeks:

Further delays Neutrophils <1.0x109/L at any time (SPC)

Myelotoxicity more frequent (30%) with OxMdG than with MdG. Full dose all drugs Delay 1 week then recheck FBC. Only give if neutrophils and platelets above these limits. Lower limit for platelets is due to possible mild thrombocytopenia after a number of cycles of OxMdG. Wait for full recovery then: Oxaliplatin: Full dose 5FU: Omit bolus dose but give full dose infusion. Continue without bolus dose on subsequent cycles. If further delays for myelotoxicity occur despite omitting bolus 5FU discuss with consultant. Oxaliplatin: 25% dose reduction in addition to any 5FU reduction above


Side-effect: OxMdG


Renal Function (Coin) Crcl

30mls/min <30mls/min

Oxaliplatin – Not nephrotoxic but is renally cleared. Full dose all drugs Oxaliplatin Omit 5-FU: Discuss with consultant consider 25%

dose reduction (bolus and infusion)

Hepatic Function (Coin)

AST/ALT >5 x ULN Bilirubin > 3 x ULN (>51micromol/l)

NB. Significantly impaired hepatic function may be a sign of disease progression ie. review treatment. Oxaliplatin not principally cleared by liver but is evidence of delayed clearance in patients with marked hepatic dysfunction. Withhold 5FU until recovery Oxaliplatin: 50% dose reduction 5-Fluorouracil: 50% dose reduction (bolus and infusion)

Neurotoxicity Paraesthesia of hands and feet Dysaesthesia in throat (often precipitated by cold) Symptoms lasts few hours to a few days after oxaliplatin administration Acute laryngopharyngeal dysaesthesia during or within the hours following the oxaliplatin 2 hour infusion Symptoms last longer than 7 days and are troublesome If paraesthesia without functional impairment persists until the next cycle If paraesthesia with functional impairment persist until the next cycle Persistent peripheral sensory neuropathy

Oxaliplatin : peripheral sensory symptoms 5FU : uncommon and cerebellar. Consider other chemo regimen No treatment or dose reduction required. Administer next oxaliplatin over 6 hours (SPC). Reduce oxaliplatin dose from 85mg/m2 to 65mg/m2 (metastatic setting) or 75mg/m2 (adjuvant) (SPC). Reduce oxaliplatin from 85mg/m2 to 65mg/m2 (metastatic setting) or 75mg/m2 (adjuvant) (SPC)

Omit oxaliplatin, give DeGramont alone until fully resolved. Resumption of oxaliplatin may be considered once fully resolved. Check dose with consultant (SPC). Localised moderate paraesthesia or paraesthesia that may interfere with functional activities can persist for up to 3 years following treatment cessation in the adjuvant setting.

Stomatitis (Coin)

If mouth ulcers occur despite chlorhexidine mouthcare delay until recovery to grade 1 or less then 5FU: 20% dose reduction (bolus and infusion). If further toxicity occurs despite above reductions then: 5FU: 40% dose reduction (bolus and infusion) Oxaliplatin: 20% dose reduction


Side-effect: OxMdG


Diarrhoea Between cycles (Coin)

Not resolved by next cycle

Unresolved

If Grade 4 diarrhoea, neutrophils <1.0 and platelets <50 (SPC)

Between cycles - treat symptomatically loperamide 2-4mg QDS and/or codeine phosphate 30-60mg QDS as required Not resolved by next cycle: Delay 1 week/until resolved If problematic despite symptomatic treatment or more than 1 delay give 5FU: 20% dose reduction (bolus and infusion) Oxaliplatin : 20% dose reduction If further toxicity occurs despite above dose reduction; then 5FU: 20% dose reduction (bolus and infusion) Oxaliplatin: further 20% dose reduction Delay until recovered then reduce oxaliplatin from 85mg/m2 to 65mg/m2 (metastatic) or to 75mg/m2 (adjuvant) plus 5FU: 20% dose reduction bolus and infusion

Hand-Foot Syndrome

Grade 2

5FU: 20% dose reduction (bolus and infusion) Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand foot syndrome. Pyridoxine is not recommended

DPD Deficiency (FOCUS) 1-3% of patients have markedly exaggerated 5FU toxicity due to reduced 5FU Catabolism. Discuss with consultant

Cardiotoxicity (FOCUS) Uncommon. 5FU may provoke angina attack or MI in ischaemic heart disease. Seek specialist opinion on upgraded anti-anginal medication and consider dose reduction or alternative non 5FU treatment.

Allergic reactions to oxaliplatin Approximately 9.1% (SPC) incidence of acute hypersensitivity to oxaliplatin. During administration patient may develop rash, fever, swollen mouth/tongue hyper or hypotension etc. This rarely develops to full blown anaphylaxis even with repeated treatment

Grade 1 and 2 If acute hypersensitivity occurs:

Discontinue infusion

Treat with IV corticosteroids and antihistamine

After full recovery continue with 5FU/FA alone

Rechallenge at consultant’s discretion with: (COIN) Dexamethasone 4mg orally every 6 hours starting 24 hours pre chemo Dexamethasone 8mg IV 30 minutes pre chemo Chlorphenamine 10mg IV bolus dose 30 mins pre chemo Ranitidine 50mg IV bolus dose 30mins pre chemo Continue dexamethasone, chlorphenamine and ranitidine for 24-48 hours after oxaliplatin Grade 3 and 4 Treat for full anaphylaxis. DO NOT GIVE further oxaliplatin


9. Oxaliplatin-Capecitabine (CAPOX) Oxaliplatin 130mg/m2 IV over 2 hours Day 1 Capecitabine 1000mg/m2 Orally twice a day Day 1 to 14 ie 2000mg/m2/day after a meal with water Consider capecitabine 25% dose reduction in patients over 70years Interval between cycles: Repeat every 21 days Number of cycles: Adjuvant Dukes C: 8 cycles Where there is local approval for capecitabine substitution 5FU Tests before starting course of chemo: FBC, U&Es, LFTs, CrCl (calculated). If

<50mls/min do EDTA, tumour markers CEA, C19-9. ECG in patients with history of ischaemic heart disease or cardiac risk factors.

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs, CrCl. Redo EDTA if rising creatinine

Supportive drugs with each cycle: High risk antiemetics as per NWLCN guidelines or as per local policy



Neutropenia DVD (NWLCN) Capecitabine patient diary Patient must receive nurse capecitabine counselling;

Additional information: Administration notes: Oxaliplatin: See Colorectal page 21 Capecitabine:

Patients must receive specific capecitabine counselling prior to treatment from a capecitabine trained nurse/pharmacist as per local policy. Patients must be given written and verbal information on capecitabine including how to take the tablets, when to stop (ie. In the event of toxicity and after 14 days), and whom to contact when side effects occur. Written information should be sent to the patient’s GP. Capecitabine tablets should be taken with water 30 minutes after food and approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin and therefore patients on these drugs must have their blood levels monitored more regularly. Capecitabine is contraindicated with allopurinol.

References: J.Clin Onc 2008 26:5910-5917 Dose modifications: Table Oxaliplatin-Capecitabine

Side effect: Capox Dose modification:

Haematology (REAL 2)

Neutrophils Platelets x 109/L x 109/L

1.0 and 75 0.5-0.9 or 50-74

Oxaliplatin

Full dose

Delay oxaliplatin until recovery then restart with oxaliplatin 100mg/m2

Capecitabine

Full dose Stop capecitabine until recovery then full dose



< 0.5 or 25-49 Any and <25 Neutropenic fever OR Grade 3 infection/fever with neutropenia (ANC <1) at any time Grade 4 infection/fever with neutropenia (ANC <1) at any time If more than 1 delay or 1 delay >2 weeks

Delay oxaliplatin until recovery then restart with oxaliplatin 100mg/m2 Delay oxaliplatin until recovery then restart with oxaliplatin 100mg/m2 Reduce to oxaliplatin 100mg/m2 on subsequent cycles Reduce to oxaliplatin 100mg/m2 on subsequent cycles Maintain oxaliplatin dose reduction

Stop capecitabine until recovery then full dose Stop capecitabine until recovery then full dose

Full dose on subsequent cycles Full dose on subsequent cycles Capecitabine: 20% dose reduction. Continue this dose for subsequent cycles unless further toxicity occurs. If further delays occur despite 20% dose reduction discuss with consultant.

Hepatic function (SPC/Real 2)

Bilirubin Either AST or ALT ≤1.5 x ULN and ≤2.5 x ULN

1.5-3.0 x ULN and 2.5 x ULN >3.0 x ULN and >2.5 x ULN

Full dose Discuss with consultant Discuss with consultant

Full dose Full dose Stop capecitabine Discuss with consultant


≥50mls/min

30-49mls/min

<30mls/min

Oxaliplatin Full dose Full dose Do not give EOX

Capecitabine Full dose SPC recommends no dose adjustment of starting dose for 2000mg/m2/day, but recommends careful monitoring and prompt treatment interruption if patient develops a grade 2, 3 or 4 adverse event and dose adjustments as per SPC table on page 11 Do not give EOX



Cardiotoxicity (REAL 2)

Unexplained cardiac failure Any patient who develops unexplained cardiac failure while on treatment should undergo evaluation of cardiac function with a MUGA scan or echocardiogram. If left ventricular function is less than the lower limit of normal range then epirubicin should be omitted.

Stomatitis (SPC/REAL 2)

Grade 1

Grade 2

Recurrent Grade 3

Consider topical treatments eg. Difflam mouthwash or sucralfate mouthwash 1g/5mls QDS As Grade 1 and stop capecitabine until recovery, then restart with dose according to SPC table page 11 As Grade 2 but if Grade 3 / 4 stomatitis recurs despite appropriate capecitabine dose reduction then reduce oxaliplatin doses to 100mg/m2 in subsequent cycles

Diarrhoea (REAL 2/SPC)

Grade 1

Grade 2

Recurrent ≥Grade 3

Full dose all drugs Stop capecitabine, start codeine phosphate 30-60mg oral QDS or loperamide 2-4mg QDS prn (max 16mg in 24hours). If diarrhoea resolves within 2 days restart all drugs full dose. If diarrhoea persists, wait until recovery then restart Capecitabine: dose reduction as per SPC table page 11 As for Grade 2 but if grade 3 / 4 diarrhoea recurs despite appropriate capecitabine dose reduction then reduce oxaliplatin dose to 100mg/m2 in subsequent cycles

Hand-Foot Syndrome (SPC) Grade 1

Grade 2

Stop capecitabine until recovery. Once recovered – restart full dose all drugs Stop capecitabine until recovery. Once recovered, restart chemo with dose according to SPC table page 11 Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand foot syndrome. Pyridoxine is not recommended.

Neurotoxicity (REAL 2) Cold related dysaethesia

Lasting 1-7 days Lasting >7 days

Persistent between cycles

Full dose Full dose Oxaliplatin: withhold until recovery then restart

oxaliplatin at 100mg/m2 If recurs despite dose reduction, omit oxaliplatin in subsequent cycles. Discuss carboplatin substitution with consultant.


Mitomycin Regimens

10. Mitomycin-5FU Contin Mitomycin 7mg/m2

(max14mg) IV bolus Day 1 5-Fluorouracil 300mg/m2/day IV continuous infusion for 42 days

Interval between cycles: Repeat every 42 days Number of cycles: Colorectal metastatic relapse: Maximum 4 cycles (total

mitomycin dose 28mg/m2, max 56mg) Tests before starting course of chemo: FBC (including manual film haemolysis

screen), U&Es, LFTs, tumour markers CEA, CA19-9, Crcl (calculated).

Tests to OK/Confirm each cycle of chemo: FBC (including manual film haemolysis screen), U&Es, LFTs

Do not give mitomycin C unless

Creatinine within normal range

Bilirubin <30 micromol/L

WBC ≥3.0 x 109/L

Neutrophils ≥1.5 x 109/L

Platelets ≥100 x 109/L

No red blood cell fragmentation seen in blood film

Supportive drugs with each cycle: Low risk antiemetics as per NWLCN guidelines or as per local policy Chlorhexidine mouthwash 10mls QDS. Loperamide 2-4mg QDS PRN (max 16mg/day)



Neutropenia DVD (NWLCN) Written information on mechanical pump (if via CVAD) Additional information: Administration notes:

Mitomycin: Mitomycin is a vesicant, administer in line with the NWLCN administration policy. 5Fluorouracil: See MdG Colorectal page 6

Dose modifications: Table Mito-5FU Contin below Reference: Annals Oncology 1997;8:995-1001 Ross P et al Table: Mito-5FU Contin Side effect: Mito-5FU Contin

Dose Modification (FOCUS)


1.5 and 100 <1.5 or <100 If Grade 3-4 neutropenic fever occurs

Full dose Delay mitomycin 1 week (but continue 5FU) If still not recovered after 1 week, delay mitomycin further 5 weeks. Stop 5FU until recovery. Resume chemo with 5FU alone ie. omit any further mitomycin C.


Side effect: Mito-5FU Contin

Dose Modification (FOCUS)

Renal Function Creatinine >ULN

Do not give mitomycin

Hepatic Function Bilirubin >30micromol/L

Do not give mitomycin

Stomatitis Grade 1

Grade 2

Grade 3

Consider topical treatment eg. Difflam mouthwash or sucralfate 1g in 5ml mouthwash 10mls QDS If occurs despite above interrupt 5FU infusion until resolved. Then 5FU: Dose reduce by 50mg/m2/day Interrupt 5FU infusion until resolved. Then 5FU: Dose reduce by 100mg/m2/day

Diarrhoea Grade 1

Grade 2

Grade 3

Loperamide 2-4mg QDS PRN max 16mg/24 hours Or Codeine phosphate 30-60mg QDS PRN If occurs despite above, interrupt 5FU infusion until resolved then: 5FU: dose reduce by 50mg/m2/day Interrupt 5FU infusion until resolved then: 5FU: dose reduce by 100mg/m2/day

Hand Foot Syndrome

Grade 2

Stop 5FU until recovered then: 5FU: dose reduce by 50mg/m2/day Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand

foot syndrome. Pyridoxine is not recommended.

Haemolytic Uraemic Syndrome (HUS) Extremely rare with this dose of mitomycin. Usually fatal if it does occur

HUS suspected eg. red blood cell fragmentation

Do not give mitomycin unless

Serum creatinine within normal range


WBC 3.0 x 109/L

Neutrophils 1.5 x 109/L

Platelets 100 x 109/L

No red blood fragmentation seen in blood film If early HUS suspected: Stop mitomycin permanently Treat with prednisolone 40mg OD x 7 days

11. Mitomycin C-Capecitabine

Mitomycin 7mg/m2 (max 14mg) IV bolus Day 1 Capecitabine 1250mg/m2 Orally twice a day Days 1 to 14

ie. total 2500mg/m2/day with water after a meal and 22 to 35 If CrCl >50mls/min dose capecitabine as per table If >70years reduce capecitabine starting dose by 25%

Interval between cycles: Repeat every 42 days Number of cycles: Colorectal metastatic relapse where there is

local approval for capecitabine substitution of 5FU:


Maximum 4 cycles (total mitomycin dose 28mg/m2, max 56mg)

Tests before starting course of chemo: FBC (including manual film haemolysis screen), U&Es, LFTs, tumour markers, CEA, CA19-9, Crcl (calculated) if <50mls/min do EDTA. ECG in patients with history of ischaemic heart disease or cardiac risk factors.

Tests to OK/Confirm each cycle of chemo: FBC (including manual film haemolysis screen), U&Es, LFTs




WBC ≥3.0 x 109/L







Neutropenia DVD (NWLCN) Capecitabine patient diary Patient must receive nurse capecitabine counselling Additional information: Administration notes:

Mitomycin: Mitomycin is a vesicant and should be administered in line with the NWLCN administration policy.

Capecitabine: Patients must receive specific capecitabine counselling prior to treatment from a capecitabine trained nurse/pharmacist as per local policy. Patients must be given written and verbal information on capecitabine including how to take the tablets, when to stop (ie. In the event of toxicity and after 14 days), and whom to contact when side effects occur. Written information should be sent to the patient’s GP. Capecitabine tablets should be taken with water 30 minutes after food and approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin and therefore patients on these drugs must have their blood levels monitored more regularly. Capecitabine is contraindicated with allopurinol.

Reference: B.J.Cancer. 2005;93:510-514. Chong G et al. Dose modifications: table Mito-C-Cape page 29


Table: Mito-Capecitabine Side effect: Mito-Capecitabine

Dose Modification


1.5 and 100 <1.5 or <100 If Grade 3-4 neutropenic fever occurs

Full dose. Only treat if WBC, neutrophils and platelets are above these levels Delay all chemotherapy 1 week (or until recovery) If still not recovered after 1 week, delay mitomycin further 5 weeks. If > 1 delay or 1 delay ≥2 weeks give capecitabine 20% dose reduction on all future cycles. If further delays occur despite dose reduction discuss with consultant. Stop chemotherapy until recovery. Resume chemo with capecitabine alone ie. omit any further mitomycin C.

Renal (SPC)


<30mls/min

Full dose all drugs Omit mitomycin. Capecitabine 25% dose reduction. Do not give. Discuss with consultant

Hepatic

Bilirubin >30micromol/L Bilirubin Either AST or ALT

≤3 x ULN and 2.5 x ULN >3 x ULN or >2.5 x ULN

Do not give mitomycin Full dose capecitabine Do not give chemo. Discuss with consultant

Stomatitis Grade 1

≥Grade 2

Consider topical treatments eg. Difflam mouthwash or sucralfate mouthwash 1g/5ml QDS As grade 1 and stop capecitabine until recovery then reduce dose according to SPC table on page 11

Diarrhoea Grade 1

≥Grade 2

Loperamide 2-4mg QDS PRN (max 16mg/24 hours) Or codeine phosphate 30-60mg QDS PRN As grade 1 and stop capecitabine until recovery then reduce dose according to SPC table on page 11

Hand Foot Syndrome Grade 1

≥Grade 2

Stop capecitabine until recovery. Once recovered restart capecitabine with full dose. Stop capecitabine until recovery. Once recovered reduce capecitabine dose according to SPC table on page 10 Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand foot syndrome. Pyridoxine is not recommended.


Side effect: Mito-Capecitabine

Dose Modification

Haemolytic Uraemic Syndrome (HUS) Extremely rare with this dose of mitomycin. Usually fatal if it does occur

HUS suspected eg. red blood cell fragmentation




WBC ≥3.0 x 109/L

Neutrophils 1.5 x 109/L



DPD Deficiency

1-3% of patients have markedly exaggerated 5FU/capecitabine toxicity due to reduced 5FU/capecitabine catabolism. Discuss with consultant.

Cardiotoxicity

Uncommon. 5FU/capecitabine may provoke angina or MI in patients with ischaemic heart disease. Seek specialist opinion on upgraded anti-anginal medication and consider dose reduction or alternative non 5FU/capecitabine treatment.

12. Mitomycin-C-Modified DeGramont (Mito-MdG) Mitomycin-C 7mg/m2 (max 14mg) IV over 2 hours Day 1 Folinic acid 350mg IV over 2 hours Days 1, 15, and 28 Fluorouracil 400mg/m2 IV bolus Days 1, 15, and 28 Fluorouracil 2400mg/m2 IV over 46 hours Days 1, 15, and 28 Interval between cycles: Repeat every 42 days Number of cycles: Colorectal metastatic relapse where other

mitomycin regimens inappropriate Maximum 4 cycles (total mitomycin dose 28mg/m2 and Max 56mg)

Tests before starting course of chemo: FBC (including manual film haemolysis screen), U&Es, LFTs, tumour markers CEA, CA19-9, Crcl calculated. .

Tests to ok each cycle of chemo: FBC (including manual film haemolysis screen), U&Es, LFTs



Bilirubin <30micromol/L

WBC ≥3.0 x 109/L





Loperamide 2-4mg QDS prn (max 16mg/day)

Chlorhexidine mouthwash 10mls QDS Patient information: Chemotherapy treatment booklet (local information/Macmillan)


Your chemotherapy record (Red book) Chemotherapy alert card


Neutropenia DVD (NWLCN) Additional information: Mitomycin: Vesicant 5FU: See MdG page 6 Dose modifications: Reference:

Table: Mitomycin-C - Modified DeGramont

Side-effect MitoC-MdG Dose Modification

Haematology Neutrophils Platelets x109/L x109/L ≥1.5 and ≥100 <1.5 and/or <100

Full dose Only treat above these limits. Delay until recovered. If not recovered after 1 week discuss with consultant. If more than one delay or one delay ≥2 weeks, discuss with consultant

Renal Function Creatinine > ULN

Do not give mitomycin Discuss regimen with consultant

Hepatic Function Bilirubin >30micromol/L

Do not give mitomycin Discuss regimen with consultant

Stomatitis (Focus) If mouth ulcers occur despite routine chlorhexidine mouthwash 5FU: 20% dose reduction (bolus and infusion) Continue with this reduced dose unless further toxicity occurs

Diarrhoea (Focus) Between cycles

Not resolved by next cycle

If diarrhoea still a problem despite symptomatic treatment If more than 1 delay is required due to diarrhoea

Treat symptomatically: Loperamide 2-4mg QDS PRN and/or Codeine phosphate 30-60mg QDS PRN Delay 1 week/until recovered 5FU: 20% dose reduction (bolus and infusion). Continue with this dose unless further toxicity occurs. 5FU: 20% dose reduction (bolus and infusion). Continue with this dose unless further toxicity occurs.

Hand Foot Syndrome (Focus) ≥Grade 2

5FU: 20% dose reduction (bolus and infusion). Continue with this reduced dose unless further toxicity occurs. Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand/foot syndrome. Pyridoxine is not recommended


Raltitrexed Regimens

13. Raltitrexed-3 (single Agent) Raltitrexed 3mg/m2 IV over 15 minutes Day 1

Interval between cycles: Repeat every 21 days Note interval changes with renal impairment dose modifications

Number of cycles: Palliative chemotherapy for advanced colorectal cancer intolerant of 5Fluorouracil ie. develop angina or have poorly controlled angina or recent myocardial infarct. Under direction of Consultant. 4-8 cycles/3-6 months Tests before starting chemo: FBC, U&E, LFTs, Crcl calculated. Do

EDTA if <65mls/min Tests to OK/Confirm each cycle of chemo: FBC, U&E, LFTs, Crcl calculated, redo

EDTA if rising creatinine Supportive drugs with each cycle: Low risk antiemetics as per NWLCN

guidelines or as per local policy Chlorhexidine mouthwash 10mls QDS Loperamide 2-4mg QDS (max 16mg/day) PRN or codeine phosphate 30-60mg QDS PRN

Patient Information: Chemotherapy treatment booklet (local information/Macmillan) Your chemotherapy record (Red book) Chemotherapy alert card

Macmillan drug specific information sheet(s) and information prescriptions as appropriate Neutropenia DVD (NWLCN)

Additional information: Folinic acid, folic acid or vitamin preparations containing these products must NOT be given immediately prior to or during the raltitrexed administration as this may interfere with its action.

Reference: European J. Cancer. 1995;31: Cunningham et al

Side effect: Raltitrexed Dose modification:

Mucositis/diarrhoea See PAGE 34 for dose modifications. If severe mucositis associated with myelosuppression occurs patient should be vigorously supported with early hospitalisation for IV fluids, antiemetics, anti-diarrhoeals and antibiotics

Renal function (SPC) Crcl ≥65mls/min

55-64mls/min 25-54mls/min

< 25mls/min

Full dose 3mg/m2 every 21 days 2.25mg/m2 every 28 days (ie 25% reduction) 1.5mg/m2 every 28 days (ie 50% reduction) Do not give

Liver function Raised transaminases CR06 trial states “asymptomatic transient rises in liver transaminases are common, maximal in cycles 2 and 3, then tends to resolve with continued treatment”.

Discuss with consultant SPC states: No dose adjustment is recommended for patients with mild to moderate hepatic impairment. However given a proportion of the raltitrexed is excreted via the faecal route and that these patients form a poor prognosis group, patients with mild to moderate hepatic impairment need to be treated with caution. Raltitrexed has not been studied in patients with severe hepatic impairment, clinical jaundice or decompensated liver disease and its use in such patients is not recommended.


Table Raltitrexed (adapted from CR06) For combination haematological/non haematological toxicity

Wait until full recovery ie. neutrophils 2.0 x 109/L and platelets ≥100 x 109/L and/or any persistent mucositis and diarrhoea have resolved

If resolved within 2 weeks restart using dose modifications below

If FULL recovery takes more than 2 weeks discuss with consultant.

Haematological Toxicity

Neutrophils Platelets

x109/L x109/L

Non haematological toxicity

on day of chemo and during previous cycle (eg. diarrhoea or mucositis)

CTC Grade

0-1 2 3 4

≥ 2.0 And ≥100 Full dose Raltitrexed 25% dose reduction

Delay until non-haematological toxicity recovery to ≤grade 2 then give Raltitrexed 50% dose reduction

Do not give

≥1.0-1.9* And 50-99 * Discuss with consultant as in some cases may go ahead with neutrophils 1.0-1.9 provided platelets ≥100

Delay until haematological recovery then give full dose

Delay until haematological recovery then give raltitrexed 25% dose reduction

Delay until full haematological and non-haematological recovery to toxicity ≤grade 2 then give raltitrexed 50% dose reduction

Do not give

0.5-0.99 Or 25-49 Delay until haematological recovery then give raltitrexed 25% dose reduction


Delay until full haematological and non-haematological recovery to toxicity ≤grade 2 then give raltitrexed 50% dose reduction

Do not give

<0.5 Or <25 Delay until haematological recovery then give raltitrexed 50% dose reduction


Do not give Do not give


14. Raltitrexed/Oxaliplatin (TOMOX)

For additional Private Care unless local NDP approved/PCT agreement to fund Raltitrexed 3mg/m2 IV over 15 minutes Day 1 Oxaliplatin* 130mg/m2 IV over 2 hours Day 1 *Some papers used oxaliplatin 100mg/m2

Interval between cycles: Repeat every 21 days Number of cycles: Subject to local approval in combination for patients

Intolerant of 5Fluorouracil ie. develop angina or have poorly controlled angina or recent myocardial infarct. Under direction of Consultant. 4-8 cycles/3-6 months

Tests before starting chemo: FBC, U&E, LFTs, Crcl calculated. Do EDTA if <65mls/min, tumour markers CEA, CA19-9

Tests to OK/Confirm each cycle of chemo: FBC, U&E, LFTs, Crcl calculated, redo EDTA if rising creatinine


Chlorhexidine mouthwash 10mls QDS Loperamide 2-4mg QDS (max 16mg/day) PRN or codeine phosphate 30-60mg QDS PRN



Additional information: Oxaliplatin see page 21 Raltitrexed see page 33

Dose modifications: Oxaliplatin see page 25 Raltitrexed see page 33

Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibodies

EGFR Related Skin Reactions General advice: Sun: Advise patient to avoid sun and use sun-block Dry skin: Use oil for washing instead of soap

Avoid hot water for baths/shower Emollient creams help Topical corticosteroid creams NOT recommended Fissures may occur in dry skin and topical dressings eg. hydrocolloid dressings as advised by dermatologist are helpful

Pruritis: Consider oral antihistamines Nail toxicity: Seek Dermatological advice

Daily salt baths and local antiseptic/astringent ointments have been found to be helpful.


Anti-inflammatory drugs may help to ease the pain

Cetuximab (Erbitux) Cetuximab is licensed for the treatment of patients with epidermal growth factor receptor (EGFR) expressing KRAS wild type metastatic colorectal cancer:

In combination with chemotherapy

As a single agent in patients who have failed oxaliplatin and irinotecan based therapy and who are intolerant of irinotecan.

Kras testing is available from:

Molecular Diagnostics, Wales Gene Park, 2nd Floor Neuadd Merionnydd East Park, Cardiff, CF14 4YS Contact: [email protected]

Request form must be completed including patient consent. Funding for cetuximab on the NHS is available for EGFR expressing KRAS wild type metastatic colorectal carcinoma as follows:

Indication Regimen Funding Source

1st line metastatic colorectal cancer for 16 weeks in line with NICE (TA176) only when all of the following are met:

The primary colorectal tumour has been resected or is potentially operable

The metastatic disease is confined to the liver and is unresectable

The patient is fit enough to undergo surgery to resect the primary tumour and to undergo liver surgery if the metastases become resectable after treatment with cetuximab

The manufacturer rebates 16% of the amount of cetuximab used on a per patient basis

Cetux/5FU/Oxaliplatin (FOLFOX, OxMdG)

Cetux/Irinotecan/5FU (FOLFIRI, IrMdG)

NICE

1st line metastatic colorectal cancer which is not potentially operable ie. ineligible for NICE TA176 and have not received cetuximab or panitumumab previously. NB. CDF will not approve cetuximab with single agent fluoropyrimidine. However if excessive toxicity occurs with irinotecan/oxaliplatin, cetuximab plus fluoropyrimidine alone can continue until disease progression. No treatment breaks of longer than 4 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or in the case of intercurrent co-morbidities).

Cetux/Irinotecan/5FU (FOLFIRI, IrMdG) Cetux/Irinotecan/capecitabine (CAPIRI)

Cetux/Oxaliplatin/5FU (OxMdG, FOLFOX6, FOLFOX4)

Apply to Cancer Drug Fund

mailto:[email protected]



Continuation of cetuximab treatment in patients with metastatic colorectal cancer receiving cetuximab under NICE TA176 but have failed to become operable at 16 weeks but who have NOT progressed NB. CDF will not approve cetuximab with single agent fluoropyrimidine. However if excessive toxicity occurs with irinotecan/oxaliplatin, cetuximab plus fluoropyrimidine alone can continue until disease progression. No treatment breaks of longer than 4 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or in the case of intercurrent co-morbidities).


Cetux/Oxaliplatin/5FU (OxMdG, FOLFOX6, FOLFOX4)

Apply to Cancer Drug Fund

2nd/3rd line treatment of metastatic colorectal cancer in patients who are performance status 0 or 1 and have NOT received cetuximab or panitumumab previously. NB. CDF will not approve cetuximab with oxaliplatin or with single agent fluoropyrimidine. However if excessive toxicity occurs with irinotecan, cetuximab plus fluoropyrimidine alone can continue until disease progression. No treatment breaks of longer than 4 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or in the case of intercurrent co-morbidities).


Apply to Cancer Drugs Fund

2nd/3rd line treatment of metastatic colorectal cancer in patients who are performance status 0 or 1, received cetuximab under NICE TA176 responded and discontinued at 16 weeks for consideration of surgery (and therefore not treated to disease progression) NB. CDF will not approve cetuximab with oxaliplatin or with single agent fluoropyrimidine. However if excessive toxicity occurs with irinotecan, cetuximab plus fluoropyrimidine alone can continue until disease progression. No treatment breaks of longer than 4 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or in the case of intercurrent co-morbidities).





3rd or 4th line treatment of colorectal cancer in patients with performance status 0 or 1 who have NOT previously received cetuximab or panitumumab. No treatment breaks of longer than 4 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or in the case of intercurrent co-morbidities).

Single agent cetuximab Apply to Cancer Drugs Fund

3rd or 4th line treatment of metastatic colorectal cancer in patients who are performance status 0 or 1, received cetuximab under NICE TA176 , responded and discontinued at 16 weeks for consideration of surgery (and therefore not treated to disease progression) No treatment breaks of longer than 4 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or in the case of intercurrent co-morbidities).

Single agent cetuximab Apply to Cancer Drugs Fund

15. Cetuximab-Oxaliplatin-5Fluorouracil (Cetuximab-OxMdG)

Chlorphenamine 10mg IV bolus dose Day 1 Dexamethasone 8mg IV bolus dose Day 1 Cetuximab 500mg/m2 IV over 2 hours* Day 1 Minimum 1 hour later Folinic Acid 350mg IV over 2 hours Day 1 Oxaliplatin 85mg/m2 IV over 2 hours Day 1 5Fluorouracil 400mg/m2 IV bolus Day 1 5Fluorouracil 2400mg/m2 IV over 46 hours Day 1 * NB Do not exceed cetuximab infusion rate 10mg/min Interval between cycles: Repeat every 14 days Number of cycles: EGFR expressing KRAS wild type

metastatic colorectal cancer

In line with NICE TA176 for potentially operable liver metastases Max 16 weeks

Apply to Cancer Drugs Fund for 1st line not potentially operable disease (ineligible for NICE TA176) and no prior cetuximab or panitumumab

6 cycles/3 months then review. May continue up to 12 cycles/6 months after discussion with consultant. Single agent cetuximab maintenance not funded.

Apply to Cancer Drugs Fund for Continuation of NICE TA176 if at 16 weeks have failed to


become operable but have not progressed 6 cycles/3 months then review. May continue up to 12 cycles/6 months after discussion with consultant. Single agent cetuximab maintenance not funded.

DO NOT treat past progression Tests before starting course of chemo: FBC, U&Es, LFTs, Mg and Ca for 8 weeks after

last dose , CrCl (calculated), tumour markers, CEA, CA19-9.

Tests to OK/confirm each cycle of chemo: FBC, U&Es, Mg, Ca, LFTs Supportive drugs with each cycle: High risk antiemetics as per NWLCN guidelines

or as per local policy Chlorhexidine mouthwash 10mls QDS

Loperamide 2-4mg QDS PRN (Max 16mg/day) Chlorphenamine, dexamethasone, paracetamol and ranitidine as above to prevent cetuximab infusion related reactions



General advice on EGFR related skin reactions Written information on mechanical pump (if via CVAD) Additional information: Chemotherapy must be administered at least 1 hour after end of cetuximab infusion. Administration notes

Oxaliplatin: See OxMdG page 21 5Fluorouracil: See OxMdG page 21 Cetuximab: See cetuximab page 47 Dose modifications: OxMdG – see dose modifications page 22

Cetuximab – see dose modifications page 38 Table: Cetuximab

Side-effect: Cetuximab Dose modification (Coin/Crystal/SPC)

Allergic/Hypersensitivity Reaction Crystal

trial) CTC Grade Grade 1

Transient rash/drug fever <38oC

Grade 2 Urticaria, drug fever ≥ 38

oC and/or

asymptomatic bronchospasm

Grade 3 or Grade 4 Grade 3: Symptomatic bronchospasm,

Decrease cetuximab infusion rate by 50% and monitor closely for any worsening. The total infusion time for cetuximab should not exceed 240minutes. Stop cetuximab infusion contact doctor. Administer bronchodilators, oxygen etc as medically indicated. Once allergic/hypersensitivity reaction has resolved or decreased to grade 1 in severity, resume cetuximab infusion with 50% reduction in rate of infusion and monitor closely for any worsening. Stop cetuximab infusion immediately and disconnect infusion tubing from the patient.



requiring parenteral medication with or without urticaria, hypersensitivity-related oedema,

angio-oedema

Grade 4

Recurrent allergic/hypersensitivity reactions (Crystal)

Administer adrenaline/epinephrine, bronchodilators, antihistamines, glucocorticoids, intravenous fluids, vasopressor agents, oxygen as medically indicated. Grade 4 anaphylaxis DO NOT rechallenge with cetuximab If a patient has a second allergic/hypersensitivity reaction on the slower infusion rate, stop the cetuximab infusion and treat reaction but DO NOT rechallenge with cetuximab.

Skin Toxicity General Information (SPC) Skin reactions may develop in more than 80% of patients and mainly present as acne-like rash and/or less frequently as pruritus, dry skin, desquamation or nail disorders (eg. paronychia). Approximately 15% of skin reactions are severe including single cases of skin necrosis. The majority of skin reactions develop within the first 3 weeks of therapy. They generally resolve, without sequelae over time following cessation of treatment if the recommended adjustments in dose are followed. Skin lesions induced by cetuximab may predispose patients to suprainfections (eg. S Aureus) which may lead to subsequent complications eg. cellulitis, erysipelas or potentially with fatal outcome, staphylococcal scalded skin syndrome or sepsis. Nail Toxicity (COIN B) Nail toxicity occurs in 8% of patients with cetuximab characterised by paronychial inflammation with associated swelling of the lateral skin folds of toes and fingers, especially big toes and thumb which may be painful. This may persist for up to 12 weeks after cessation of cetuximab.

General Advice (COIN B) Sun Pruritis Dry skin (may contribute to pruritis) Nail toxicities

Advise patient to avoid sun and use sun-block Consider oral antihistamine Use oil for washing instead of soap Avoid hot water for baths/shower Emollient creams help Topical corticosteroid creams NOT recommended Fissures may occur in dry skin and topical dressings eg. hydrocolloid dressings as advised by dermatologist are helpful Seek Dermatological advice Daily salt baths and local antiseptic/astringent ointments have been found to be helpful. Anti-inflammatory drugs may help to ease the pain

Skin Toxicity (COIN B) NCI-CTC

Grade 1 acneform eruption

Full dose cetuximab. Consider topical antibiotics eg. metronidazole but caution as some users report increased irritation.



Grade 2 acneform eruption (Rash on up to 50% of body surface area)

Grade ≥ 3 acneform eruption (Rash on ≥50% of body surface area)

1st Appearance

2nd Appearance

3rd Appearance

4th Appearance (SPC)

Reactions do NOT resolve to grade 2

More than 2 consecutive infusions are withheld (Crystal).

Nail problems

Full dose cetuximab. Consider systemic antibiotics eg. second generation tetracyclines such as doxycycline 100mg oral daily and refer to dermatologist.

Start doxycycline 100mg oral once a day and refer to dermatologist. Interrupt cetuximab therapy until reaction has resolved to grade 2 or less then restart cetuximab without any change in dose ie. 250mg/m2 maintenance. If reaction does not resolve to ≤grade 2, discontinue cetuximab.

Interrupt cetuximab therapy until reaction has resolved to grade 2 or less then restart with reduced dose cetuximab: 200mg/m2 maintenance. If reaction does not resolve to ≤grade 2, discontinue cetuximab. Interrupt cetuximab therapy until reaction has resolved to grade 2 or less then restart with reduced dose cetuximab ie. 150mg/m2 maintenance. If reaction does not resolve to ≤grade 2, discontinue cetuximab. Discontinue cetuximab permanently Discontinue cetuximab permanently Discontinue cetuximab permanently Refer to dermatologist (see general advice page 41)

Electrolyte Disturbances (SPC)

Magnesium (up to 65% of patients)

<0.6mmol/L

Hypokalaemia

Hypocalcaemia

Correct electrolyte depletions as appropriate Progressively decreasing serum magnesium levels occur frequently and may lead to severe hypomagnesaemia which may last up to 8 weeks after the last dose. Hypomagnesaemia is reversible following discontinuation of cetuximab. Correct by intravenous supplementation if <0.6mmol/L. May develop as a consequence of diarrhoea May occur. In combination with platinum-based chemotherapy, the frequency of severe hypocalcaemia may be increased

Haematology Haemoglobin <90g/L Leucocytes <3.0 x 109/L Neutrophils <1.5 x 109/L

SPC states cetuximab has not been studied in patients with one or more of the parameters opposite. However, clinical trials (COIN, COIN B, Crystal) did not



Platelets <100 x 109/L always delay/interrupt cetuximab if haematological parameters were low and concomitant chemotherapy was delayed. Discuss continuing with consultant.

Renal Function Serum creatinine >1.5 x ULN

SPC states only patients with adequate renal function have been investigated to date. Discuss with consultant if serum creatinine > 1.5 x ULN

Hepatic Function Transaminases > 5 x ULN and/or Bilirubin > 1.5 x ULN

SPC states only patients with adequate hepatic function have been investigated to date. Discuss with consultant if parameters opposite occur.

16. Cetuximab-Capecitabine-Oxaliplatin (Cetux-Reduced dose CAPOX)

NB. Capecitabine reduced starting dose in CapeOx plus cetuximab due to increased toxicity of capecitabine-cetuximab combination

Cycle 1 Loading dose Cetuximab/Reduced Dose CapeOx Chlorphenamine 10mg IV bolus dose Day 1 Dexamethasone 8mg IV bolus dose Day 1 Cetuximab 400mg/m2 IV over 2 hours Once only on Day 1 of cycle 1 Minimum 1 hour later Oxaliplatin 130mg/m2 IV over 2 hours Day 1 Capecitabine 850mg/m2 Oral twice a day Day 1 to 14

ie. 1700mg/m2/day with water after food (28 doses starting evening of day 1)

Chlorphenamine 10mg IV bolus dose Day 8 and 15 Dexamethasone 8mg IV bolus dose Day 8 and 15 Cetuximab 250mg/m2 IV over 1 hour* Day 8 and 15 Cycle 2 onwards Cetuximab/Reduced dose CapeOx Chlorphenamine 10mg IV bolus dose Day 1, 8 and 15 Dexamethasone 8mg IV bolus dose Day 1, 8 and 15 Cetuximab 250mg/m2 IV over 1 hour Day 1, 8 and 15 Minimum 1 hour later Oxaliplatin 130mg/m2 IV over 2 hours Day 1 Capecitabine 850mg/m2 Oral twice a day Day 1 to 14

ie. 1700mg/m2/day with water after food (28 doses starting evening of day 1)

Cetuximab maintenance dose (week 2 onwards) infused over 1 hour if patient has tolerated loading dose week 1. NB Do not exceed infusion rate 10mg/min Interval between cycles: Repeat every 21 days

Cycle 1; Loading dose cetuximab 400mg/m2 plus reduced


dose CapeOx once only Day 1 Maintenance cetuximab 250mg/m2

Day 8 Maintenance cetuximab 250mg/m2

Day 15 Cycle 2 onwards

Cetuximab 250mg/m2 Day 1, 8 and 15

Reduced dose CapeOx Day 1 Number of cycles: EGFR expressing KRAS wild type



CDF will not fund CAPOX Plus Cetuximab Tests before starting course of chemo: FBC, U&Es, LFTs, Mg, Ca, tumour markers,

CEA, CA19-9, CrCl (calculated) if <50mls/min do EDTA. ECG in patients with history of ischaemic heart disease or cardiac risk factors

Tests to OK/confirm each cycle of chemo: FBC, U&Es, Mg, and Ca for 8 weeks after last dose, LFTs, CrCl (calculated). Redo EDTA if rising creatinine.

Supportive drugs with each cycle: Reduced Dose CapeOx Day 1: High risk antiemetics as per NWLCN guidelines or as per local policy Day 8, 15: No antiemetics Day 1,8 and 15: Chlorphenamine, dexamethasone, paracetamol and ranitidine as above to prevent cetuximab infusion related reactions



Capecitabine patient diary Patient must receive nurse capecitabine counselling General advice on EGFR related skin reactions Additional information:

Chemotherapy must be administered at least 1 hour after end of cetuximab infusion. Administration

Cetuximab: See colorectal page 47 CapeOx: See colorectal page 21 Dose modifications:

Cape-Ox dose modifications see colorectal page 25 Cetuximab dose modifications see colorectal page 38

Reference: BJC 2009 100:251-258. Adams RA et al 17. Cetuximab-Irinotecan-5Fluorouracil (Cetuximab-IrMdG)

Chlorphenamine 10mg IV bolus dose Day 1 Dexamethasone 8mg IV bolus dose Day 1 Cetuximab 500mg/m2 IV over 2 hours* Day 1


Minimum 1 hour later Atropine 250mcg SC Day 1 Irinotecan 180mg/m2 IV over 30-90mins Day 1 Folinic Acid 350mg IV over 2 hours Day 1 5Fluorouracil 400mg/m2 IV bolus Day 1 5Fluorouracil 2400mg/m2 IV over 46 hours Day 1 * NB. Do not exceed infusion rate 10mg/min. Interval between cycles: Repeat every 14 days Number of cycles: EGFR expressing KRAS wild type





Apply to Cancer Drugs Fund for Continuation of NICE TA176 if at 16 weeks have failed to become operable but have not progressed


Apply to Cancer Drugs Fund for 2nd/3rd line in patients who have not previously received cetuximab or panitumumab


Apply to Cancer Drugs Fund for 2nd/3rd line in patients who have received cetuximab under NICE TA176 not previously responded and discontinued at 16 weeks for consideration of surgery (and therefore not treated to disease progression)

6 cycles/3 months then review. May continue up to 12 cycles/6 months after discussion with consultant. Single agent cetuximab maintenance not funded

Do not give past progression Tests before starting course of chemo: FBC, U&Es, LFTs, Mg and Ca for 8 weeks

after last dose, tumour markers, CEA, CA19-9. Performance status: PS 0 or 1: Proceed PS 2: Caution PS 3: Do not give


(PS 2 or 3 not CDF funded) Caution in patients with previous history of diarrhoea or abdominal pelvic disease

Tests to OK/confirm each cycle of chemo: FBC, U&Es, Mg and Ca for 8 weeks after last dose, LFTs


Chlorhexidine mouthwash 10mls QDS Atropine as above to prevent acute cholinergic syndrome (diarrhoea, sweating, salivation, bradycardia.

Loperamide if necessary: see dose modification table. Ciprofloxacin if necessary: see dose modification table. Chlorphenamine, dexamethasone, paracetamol and ranitidine as above to prevent cetuximab infusion related reactions



General advice on EGFR related skin reactions Written information on mechanical pump (if via CVAD) Additional information: Chemotherapy must be administered at least one hour after end of cetuximab infusion

Administration notes: Cetuximab: See page 47

IrMdG: See page 14 Dose modifications: Cetuximab: See page 38

IrMdG: See page 14 18. Cetuximab-Irinotecan-Capecitabine (Cetux-Capiri)

Cycle 1 Loading dose Cetuximab/Capiri Chlorphenamine 10mg IV bolus dose Day 1 Dexamethasone 8mg IV bolus dose Day 1 Cetuximab 400mg/m2 IV over 2 hours Once only on Day 1 of cycle 1 Minimum 1 hour later Atropine 250mcg SC stat Day 1 Irinotecan 200mg/m2 IV over 30-90mins Day 1 Capecitabine 800mg/m2 Oral Twice a day Days 1 to 14 (1600mg/m

2/day)

Chlorphenamine 10mg IV bolus dose Day 8 and 15 Dexamethasone 8mg IV bolus dose Day 8 and 15 Cetuximab 250mg/m2 IV over 1 hour* Day 8 and 15 Cycle 2 onwards


Cetuximab/CAPIRI Chlorphenamine 10mg IV bolus dose Day 1, 8 and 15 Dexamethasone 8mg IV bolus dose Day 1, 8 and 15 Cetuximab 250mg/m2 IV over 1 hour Day 1, 8 and 15 Minimum 1 hour later Atropine 250mcg SC stat Day 1 Irinotecan 200mg/m2 IV over 30-90mins Day 1 Capecitabine 800mg/m2 Oral Twice a day Days 1 to 14 (1600mg/m

2/day)

Cetuximab maintenance dose (week 2 onwards) infused over 1 hour if patient has tolerated loading dose week 1. NB Do not exceed infusion rate 10mg/min Interval between cycles: Repeat every 21 days

Cycle 1; Loading dose cetuximab 400mg/m2 plus Capiri once only Day 1 Maintenance cetuximab 250mg/m2

Day 8 Maintenance cetuximab 250mg/m2

Day 15 Cycle 2 onwards

Cetuximab 250mg/m2 Day 1, 8 and 15

Capiri Day 1 Number of cycles: EGFR expressing KRAS wild type metastatic colorectal cancer




Apply to Cancer Drugs Fund for Continuation of NICE TA176 if at 16 weeks have failed to become operable but have not progressed


Apply to Cancer Drugs Fund for 2nd/3rd line in patients who have not previously received cetuximab or panitumumab


Apply to Cancer Drugs Fund for 2nd/3rd line in patients who are performance status 0 or 1, previously received cetuximab under NICE TA176 and responded and discontinued at 16 weeks for consideration of surgery (ie not treated to disease progression)


6 cycles/3 months then review. May continue up to 12 cycles/6 months after discussion with consultant. Single agent cetuximab maintenance not funded

Do not give past progression Tests before starting course of chemo: FBC, U&Es, LFTs, Mg, Ca, tumour markers,

CEA, CA19-9, CrCl (calculated) if <50mls/min do EDTA. ECG in patients with history of ischaemic heart disease or cardiac risk factors Performance status PS 0 or 1: proceed PS 2: Caution PS 3: do not give (PS2 or 3 not funded by CDF) Caution in patients with previous history of diarrhoea or abdominal pelvic disease

Tests to OK/confirm each cycle of chemo: FBC, U&Es, Mg, and Ca for 8 weeks after last dose, LFTs, CrCl (calculated). Redo EDTA if rising creatinine.

Supportive drugs with each cycle: Day 1: High risk antiemetics as per NWLCN guidelines or as per local policy Day 8, 15: No antiemetics Chlorphenamine, dexamethasone, paracetamol and ranitidine as above to prevent cetuximab infusion related reactions



Capecitabine patient diary Patient must receive nurse capecitabine counselling General advice on EGFR related skin reactions Additional information:

Chemotherapy must be administered at least 1 hour after end of cetuximab infusion. Administration notes:

Cetuximab: See colorectal page 47 Capiri : See colorectal page 16 Dose modifications:

Capiri dose modifications see colorectal page 17 Cetuximab dose modifications see colorectal page 38

Reference: 19. Cetuximab Monotherapy/Single Agent WEEKLY

Cycle 1 Loading dose Cetuximab Chlorphenamine 10mg IV bolus dose Day 1 Dexamethasone 8mg IV bolus dose Day 1


Cetuximab 400mg/m2 IV over 2 hours Once only day 1 Cycle 2 onwards Maintenance dose Cetuximab Chlorphenamine 10mg IV bolus dose Day 1 Dexamethasone 8mg IV bolus dose Day 1 Cetuximab 250mg/m2 IV over 1 hour* Day 1 * Over 1 hour if patient has tolerated loading dose NB. Infusion rate must NOT exceed 10mg/min Interval between cycles: Repeat every 7 days

Loading dose cetuximab 400mg/m2 ONCE only week one followed 7 days later by cetuximab 250mg/m2 repeated every 7 days thereafter. Number of cycles EGFR expressing KRAS wild type metastatic colorectal cancer

Apply to Cancer Drugs Fund for 3rd or 4th line in patients who have not previously received cetuximab or panitumumab and who are performance status 0 or 1 12 cycles/3 months then review

Do not continue past progression.

Apply to Cancer Drugs Fund for 3rd/4th line in patients who are performance status 0 or 1, previously received cetuximab under NICE TA176 and responded and discontinued at 16 weeks for consideration of surgery (ie not treated to disease progression

12 cycles/3 months then review. Do not continue past progression.

Tests before staring course of chemo: FBC, U&E, Mg, Ca, LFTs Tests to OK/confirm each cycle of chemo FBC, U&E, Mg and Ca for 8 weeks after the

last dose, LFTs. Supportive drugs with each cycle: Chlorphenamine, dexamethasone, paracetamol

and ranitidine to prevent infusion related reactions Patient information: Chemotherapy treatment booklet (local information/Macmillan) Your chemotherapy record (Red book) Chemotherapy alert card


Neutropenia DVD (NWLCN) General advice on EGFR related skin reactions

Additional information: Administration notes: (SPC) Cetuximab:

Close monitoring is required during and for at least 1 hour after the end of the infusion. Availability of resuscitation equipment must be ensured. Patients must receive premedication with antihistamine and corticosteroid prior to every cetuximab infusion. The first cetuximab infusion is infused over 2 hours. If well tolerated then subsequent infusions may be administered over 1 hour. If the patient experiences mild/moderate infusion related reactions consult the doctor as the infusion rate must be decreased. The maximum rate of infusion must not exceed 10mg/min.


If cetuximab is administered in combination with other chemotherapy, the chemotherapy must be administered at least 1 hour after the end of the cetuximab infusion.

Dose modifications: See table page 38 20. Cetuximab Monotherapy/Single Agent EVERY TWO WEEKS

Chlorphenamine 10mg IV bolus dose Day 1 Dexamethasone 8mg IV bolus dose Day 1 Cetuximab 500mg/m2 IV over 2 hours Day 1 NB. Infusion rate must NOT exceed 10mg/min Interval between cycles: Repeat every 14 days Number of cycles EGFR expressing KRAS wild type metastatic colorectal cancer

Apply to Cancer Drugs Fund for 3rd or 4th line in patients who have not previously received cetuximab and who are performance status 0 or 1;

12 cycles/3 months then review. Do not continue past progression.

Tests before staring course of chemo: FBC, U&E, Mg, Ca, LFTs Tests to OK/confirm each cycle of chemo FBC, U&E, Mg and Ca for 8 weeks after the

last dose, LFTs. Supportive drugs with each cycle: Chlorphenamine, dexamethasone, paracetamol

and ranitidine to prevent infusion related reactions Patient information: Chemotherapy treatment booklet (local information/Macmillan) Your chemotherapy record (Red book) Chemotherapy alert card


Neutropenia DVD (NWLCN) General advice on EGFR related skin reactions

Additional information: Administration notes: (SPC) Cetuximab: See page 47 Dose modifications: See table page 38

Panitumumab Funding for panitumumab single agent is not currently available on the NHS (June 2014). Panitumumab is licensed as monotherapy for the treatment of patients with EGFR expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-oxaliplatin and irinotecan containing chemotherapy regimens. The National Cancer Drugs Fund (June 2014) will fund Panitumumab plus FOLFOX6, FOLFOX4 or OxMdg as below


1st line treatment of metastatic colorectal cancer in patients with wild type RAS who have NOT received cetuximab or panitumumab previously. NB. CDF will only approve panitumumab as 1st line

Cetux/Oxaliplatin/5FU (OXMdG, FOLFOX6, FOLFOX4)




and will NOT approve panitumumab with other oxaliplatin based regimens, any irinotecan based regimens or with single agent fluoropyrimidine. However if excessive toxicity occurs with oxaliplatin, then cetuximab plus fluoropyrimidine alone can continue until disease progression. No treatment breaks of longer than 4 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle or in the case of intercurrent co-morbidities).

21. Panitumumab- Oxaliplatin-5Fluorouracil (Panitumumab-OxMdG)

Secure Cancer Drugs Fund Funding before starting treatment Panitumumab 6mg/kg IV over 1 hour* Day 1 Using low protein binding 0.2 or 0.22 micrometer

inline filter Folinic Acid 350mg IV over 2 hours Day 1 Oxaliplatin 85mg/m2 IV over 2 hours Day 1 5Fluorouracil 400mg/m2 IV bolus Day 1 5Fluorouracil 2400mg/m2 IV over 46 hours Day 1 *If the dose is tolerated without infusion related reaction, then subsequent infusion maybe infused over 30 minutes. However Panitumumab doses higher than 1000mg should be infused over 90 minutes (SPC) Interval between cycles: Repeat every 14 days Number of cycles: Apply to Cancer Drugs Fund for

1st line in patients who have not previously received cetuximab or panitumumab in line with table on page 49

12 cycles/3 months then review. May continue up to 24 cycles/6 months after discussion with consultant. The PRIME study continued until progression Single agent panitumumab maintenance not funded.

Do not continue past progression Tests before starting course of chemo: FBC, U&Es, Mg, Ca, LFTs, tumour markers

CEA, CA19-9. Tests to OK/confirm each cycle of chemo: FBC, U&Es, Mg and Ca for up to 8 weeks after completion of treatment, LFTs Supportive drugs with each cycle: None



Information on EGFR related skin reactions Additional information:


OxMdG can be administered immediately after the panitumumab (PRIME Trail protocol). Panitumumab doses must be diluted in sodium chloride 0.9%, maximum concentration 10mg/ml. Do not use any other fluid. Flush with normal saline before and after dose. Panitumumab must be administered as an intravenous infusion via an infusion pump, via a low protein binding 0.2 or 0.22 micron in line filter over approximately 60 minutes. Diluted solutions should be mixed by gentle inversion. DO NOT SHAKE. The final concentration should not exceed panitumumab 10mg/ml. Doses over 1000mg should be diluted to 150mls and infused over 90 minutes. Dose modifications: OxMdG see page 20

Panitumumab see below Table: Panitumumab

Side effect: Panitumumab Dose modification: (SPC)

Haematology White blood cells ≥ 3.0 x 109/L and/or Neutrophils ≥ 2.0 x 109/L and/or Platelets ≥ 100 x 109/L

Full dose Below these parameters discuss with consultant

Renal Function ≥ 60mls/min

<60mls/min

Full dose Panitumumab has not been studied in patients with renal impairment. Below 60mls/min discuss with consultant

Hepatic Function Panitumumab has not been studied in patients with hepatic impairment. Discuss with consultant.

Dermatological Reactions: NCI-CTC Grade 1 (if tolerable)

Grade 2 (if tolerable)

≥ Grade 3 Or Grade 1 / 2 if intolerable

If reaction does not recur

Reactions not resolved

If reaction recurs after dose reduction

If reaction is intolerable even with dose reduction

Full dose Full dose Withhold panitumumab until reaction has resolved to ≤ grade 2 then restart with panitumumab 50% dose reduction. If reactions do not recur with 50% dose reduction, then escalate the dose of panitumumab in 25% increments until the recommended dose is reached. If reactions do not resolve to ≤ grade 2 after withholding one or two doses of panitumumab, then panitumumab should be discontinued permanently. If reactions recur (after withholding treatment and restarting with 50% dose reduction) then panitumumab should be discontinued permanently. Panitumumab should be discontinued permanently

Pulmonary complications See SPC

Electrolyte Disturbances (Piccolo trial) Correct electrolyte disturbances as they occur. Hypomagnesaemia (and accompanying


Side effect: Panitumumab Dose modification: (SPC)

hypocalcaemia) may occur up to 8 weeks after completion of treatment. Serum magnesium <0.6mmol/L correct by intravenous supplementation.


Vascular Endothelial Growth Receptor (VEGF) Inhibitor

Aflibercept 22. Aflibercept-FOLFIRI (Aflibercept-Irinotecan-MdG) Secure Cancer Drugs Fund funding before commencing treatment Aflibercept 4mg/kg IV over 1 hour Day 1 Atropine 250micrograms Subcutaneously Day 1 Irinotecan 180mg/m2 IV over 90 minutes Day 1 Folinic acid 400mg/m2 IV over 2 hours Day 1 5Fluorouracil 400mg/m2 IV bolus Day 1 5Fluouracil 2400mg/m2 IV over 46 hours Day 1 Interval between cycles: Repeat every 14 days Number of cycles: Secure Cancer Drugs Fund funding for patients

who are performance status 0 to 2 with metastatic colorectal cancer who have progressed following 1st line treatment with oxaliplatin based chemo (+/- bevacizumab).

Continue until unacceptable toxicity or disease progression.

CDF only approve aflibercept in combination with irinotecan based chemotherapy and will not fund/approve as single agent maintenance therapy. No treatment breaks of more than 4 weeks beyond the expected cycle length are allowed (to allow any toxicity of current therapy to settle in case of intercurrent co-morbidities).

Tests before starting course of chemo: FBC, U&Es, LFTs, INR, blood pressure (BP must be controlled before starting aflibercept), urine dipstick for WBC, RBC and protein (morning spot urine), CrCl calculated, do EDTA if <60ml/min, tumour markers CEA, CA19-9.

Caution read SPC before prescribing Aflibercept Caution in patients with previous history of diarrhoea or

abdominal pelvic disease. Discontinue/Do not start aflibercept treatment in patients with

Severe haemorrhage

Gastrointestinal (GI) perforation

Fistula formation

Hypertension not adequately controlled with anti-hypertensive therapy or occurrence of hypersensitive crisis or hypertensive encephalopathy

Arterial thromboembolic events (ATE)

Grade 4 venous thromboembolic events (including pulmonary embolism)

Nephrotic syndrome or thrombotic microangiopathy (TMA)

Severe hypersensitivity reactions (including bronchospasm, dyspnoea, angioedema and anaphylaxis)

Compromised wound healing requiring medical intervention


Posterior reversible encephalopathy syndrome (PRES) or reversible posterior leukoencephalopathy syndrome (RPLS)

Do not use aflibercept for at least 4 weeks prior to elective surgery

Tests to OK/confirm each cycle of chemo: FBC, U&Es, LFTs, blood pressure, dipstick for proteinuria, monitor for signs of bleeding

or GI perforation, CrCl calculated. Do EDTA if rising serum creatinine.


Chlorhexidine mouthwash 10mls QDS Atropine as above to prevent acute cholinergic

syndrome. Loperamide if necessary. See table Ciprofloxacin if necessary. See table


Macmillan drug specific information sheets/information prescriptions as appropriate NWLCN Neutropenia DVD Irinotecan patient information on diarrhoea Loperamide will be prescribed to be used when directed Written information on mechanical pump (if via CVAD)

Additional information: Administration notes: Irinotecan and folinic acid to be administered at the same time.

Aflibercept should be administered via an infusion set containing a 0.2micron polyethersulfone filter. Irinotecan: Give patient information on loperamide for diarrhoea. Patient must contact hospital if diarrhoea continues for longer than 48 hours or if they are also experiencing vomiting and/or fever. 5FU – see MdG page 6 Hypersensitivity reactions: Mild to moderate hypersensitivity reactions to aflibercept (flushing, rash, urticarial, pruritis); stop infusion until reaction resolves. Treat with corticosteroids and antihistamines as clinically indicated. See SPC. Pre-treat with corticosteroids and/or antihistamines in subsequent cycles. Severe hypersensitivity reactions (bronchospasm, dyspnoea, angioedema, anaphylaxis): institute emergency treatment. Discontinue aflibercept. See SPC.

Dose modifications: See table on page 52 Reference; Lancashire & South Cumbria Cancer Network Aflibercept/FOLFIRI

chemotherapy protocol May 2013 version 1.0 (proteinuria & hypertension advice)

Zaltrap SPC Version dated 09/07/2013


Table: Aflibercept-IrMdG

Side-Effect: Aflibercept-IrMdG

Dose Modification (Source: Focus Trial/Campto SPC/Zaltrap

SPC) Haematological Neutrophils Platelets x109/L x109/L

1.5 and 100 <1.5 or <100 If neutropenia grade 4, febrile neutropenia, thrombocytopenia grade 4 or leucopenia grade 4 occurs (SPC

July 02) or if more than 1 delay or 1 delay greater than 2 weeks

Full dose. Only treat above these levels. Delay aflibercept and FOLFIRI for 1 week and recheck FBC. Only give when neutrophils and platelets are above these limits. } Irinotecan: 20% dose reduction } 5FU (bolus and infusion): 20% dose reduction } } If further delays occur for myelotoxicity despite 20% } reduction, discuss with consultant. Consider aflibercept dose reduction to 2mg/kg


CrCl ≤50mls/min

High molecular weight proteins are not cleared by the renal route, therefore, renal elimination of aflibercept is expected to be minimal. No formal studies have been done in patients with renal impairment. Clinical data suggest: Mild to moderate renal impairment: No change to starting dose Severe renal impairment: No Data: Caution. Unclear guidance for IrMdG/Aflibercept. Discuss with consultant.


Aflibercept Hepatic Function Irinotecan and metabolites cleared by biliary excretion. Delayed clearance in cholestasis Bilirubin ALP <1.5 x ULN and ≤5.0 x ULN 1.5-3.0 x ULN or >5.0 x ULN >3 x ULN and Any

No formal studies of aflibercept in patients with hepatic impairment. Clinical data suggests; Mild to moderate hepatic impairment: No change in aflibercept dose is required. Severe hepatic impairment: No data for aflibercept. Full dose all drugs Irinotecan: 50% dose reduction 5-Fluorouracil: Full dose Aflibercept: Discuss with consultant Irinotecan: Do not give 5-Fluorouracil: 50% dose reduction Aflibercept: Do not give




SPC) Hypertension (Ref; Sanofi unlicensed supply

of aflibercept guidance Nov 2012)

Grade ≤ 2 Grade 2 = Recurrent or persistent

(>24hrs) increase by 20mmHg (diastolic) or to >150/100mmHg

if previously within normal limits

Grade 3 Requiring more than one

drug or more intensive therapy than previously

Grade 4 Life threatening consequence

eg. hypertensive crisis

Initiate antihypertensive drug therapy and close monitoring of blood pressure for further adjustment as needed No dose modification and no delay Modify antihypertensive -as necessary Delay administration of FOLFIRI and aflibercept for a maximum of 2 weeks until recovery to blood pressure (BP) ≤ 140/90 or to systolic BP < 90 for patients with known history of isolated systolic hypertension:

If BP is controlled within 2 weeks delay; - First episode; re-administer FOLFIRI and

aflibercept at same dose - Second episode; re-administer FOLFIRI and

aflibercept with aflibercept reduced to 2mg/kg

- Third episode; discontinue aflibercept

If BP is still uncontrolled despite appropriate anti-hypertensive treatment and after 2 weeks delay;

Administer FOLFIRI and discontinue aflibercept for 1 cycle; the reintroduction of aflibercept at a reduced dose (2mg/Kg) will be considered at the time of administration of the subsequent cycles (in combination with FOLFIRI), only if the BP is controlled at the time of re-administration

In the case of recurrence of Grade 3 BP in presence of maximal/optimal antihypertensive therapy despite dose reduction of aflibercept or if BP still uncontrolled despite1 omission of aflibercept,

then the patient will be permanently discontinued from aflibercept. FOLFIRI may be continued if the consultant thinks the patient is benefiting form tit

Seek cardiologist opinion and permanently discontinue aflibercept




SPC)

Proteinuria Proteinuria should be monitored by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria before each aflibercept administration. Patients with a dipstick of ≥2+ for protein or a UPCR >1 should undergo a 24-hour urine collection. Discuss with consultant to determine if aflibercept administration can go ahead before result of 24hour collection known.

1st episode

≥2 grams/24 hours

1st recurrence

2nd recurrence

If proteinuria ≥2grams/24 hours suspend aflibercept treatment until proteinuria resolves to <2grams/24 hours. Resume aflibercept with full dose. Suspend aflibercept treatment until proteinuria <2grams/24 hours. Resume with aflibercept 2mg/kg. Discuss with consultant.

Stomatitis (Focus)

Routine mouth care with chlorhexidine mouthwash. If mouth ulcers occur despite this, dose reduce 5FU: 20% dose reduction (bolus and infusion) for all subsequent cycles. No change in aflibercept dose. If recurs despite 20% 5FU reduction discuss with consultant

Diarrhoea Immediate diarrhoea (within first 24 hours) Delayed diarrhoea occurring more than 24 hours after irinotecan and at any time before next cycle:

Initial treatment

Lasts >24 hours

Lasts >48 hours

Grade 3-4


Incidence of immediate diarrhoea is low due to use of atropine premed. If acute diarrhoea/cholinergic syndrome occurs administer another dose of atropine 250mcg SC stat. Irinotecan induced delayed diarrhoea should be treated early with high dose loperamide, 4mg after first loose stool then 2mg every 2 hours until 12 hours after last loose stool (up to 24mg/day for a maximum of 48 hours because or risk of paralytic ileus). If diarrhoea lasts > 24 hours add Ciprofloxacin PO 500mg BD. If diarrhoea lasts > 48 hours or patient reports symptoms of dehydration, admit acutely for rehydration and further management. After an episode of severe diarrhoea (grade 3/4), delay until full recovery then resume at Irinotecan: 20% dose reduction 5FU (bolus & infusion) : 20% dose reduction. Aflibercept: No dose reduction If diarrhoea from previous cycle (even if not severe) not




SPC) resolved by next cycle due; delay 1 week.

Hand-Foot Syndrome

Grade 2

5FU: 20% dose reduction (bolus and infusion) Irinotecan: full dose. Aflibercept: No dose reduction Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand foot syndrome. Pyridoxine is not recommended.

DPD Deficiency (Focus) 1-3% of patients have markedly exaggerated 5FU toxicity due to reduced 5FU catabolism. Discuss with consultant

Cardiotoxicity (Focus) Uncommon. 5FU may provoke angina attack or MI in patients with ischaemic heart disease. Seek specialist opinion on upgraded anti-angina medication and consider dose reduction or alternative non 5FU treatment.

Neurotoxicity (Focus) Uncommon – Cerebellar Consider alternative Non 5FU treatment

Bevacizumab (Avastin)

Bevacizumab is licensed in combination with fluoropyrimidine based chemotherapy for the treatment of patients with metastatic carcinoma of the colon or rectum. Funding for Bevacizumab is available from the Cancer Drugs Fund (September 2013) for indications in the table below. Secure funding from the Cancer Drugs Fund (CDF) before starting treatment NB. In all CDF indications; Bevacizumab is not CDF approved as single agent maintenance therapy on its own. No treatment breaks of more than 4 weeks beyond the expected cycle length are allowed (to allow toxicity of current therapy to settle or in the case of intercurrent morbidities).


1st line treatment of advanced colorectal cancer with a single agent fluoropyrimidine in patients who are PS 0 to 2, who are assessed unfit to receive oxaliplatin or irinotecan based combination chemotherapy and who have not received bevacizumab previously.

Bevacizumab plus single agent fluoropyrimidine; Bev-5FU Bev-Cape

CDF

1st line treatment of advanced colorectal cancer in combination with either oxaliplatin based chemo OR irinotecan based chemotherapy in patients with no prior bevacizumab treatment. If excessive toxicity with oxaliplatin or irinotecan occurs, bevacizumab can be continued with the fluoropyrimidine alone until disease progression.

Bev-OxMdG/BevFOLFOX Bev-Capox Bev-IrMdG/Bev-FOLFIRI Bev-CAPIRI

CDF



2nd or 3rd line treatment of advanced colorectal cancer in combination with oxaliplatin based chemotherapy in patients who have not previously received treatment with bevacizumab. If excessive toxicity from oxaliplatin develops, bevacizumab can be continued with a fluoropyrimidine alone until disease progression only.

Bev-FOLFOX Bev-OxMdG/BevFOLFOX Bev-CAPOX

CDF

23. Bevacizumab-Oxaliplatin-5Fluorouracil

Bevacizumab 5mg/kg IV over 90 mins* Day 1 Folinic acid 350mg IV over 2 hours Day 1 Oxaliplatin 85mg/m2 IV over 2 hours Day 1 5Fluorouracil 400mg/m2 IV bolus Day 1 5Fluorouracil 2400mg/m2 IV over 46 hours Day 1

*First infusion of bevacizumab should be infused over 90 minutes. If this first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes. Interval between cycles: Repeat every 14 days Number of cycles: Secure Cancer Drugs Fund funding

For 1st line treatment of metastatic colorectal cancer in patients who have not received prior bevacizumab .

6 cycles/3 months then review. Continue until progression

Secure Cancer Drugs Fund funding For 2nd or 3rd line treatment of colorectal cancer in patients who have not received prior bevacizumab

6 cycles/3 months then review. Continue until disease progression

Do not continue past progression If excessive toxicity with oxaliplatin CDF allows continuation of Bev-MdG alone until progression. CDF will NOT fund single agent bevacizumab maintenance. Single agent bevacizumab maintenance is NOT recommended or licenced or funded by CDF

Tests before starting course of chemo: FBC, U&Es, LFTs, tumour markers, CEA, CA19-9, CrCl (calculated), INR. Blood pressure, dipstick for proteinuria Do not administer bevacizumab within 28 days of surgery, see Colorectal page 37 See SPC for other cautions with bevacizumab eg. gastro intestinal perforations, wound healing, hypertension, proteinuria, thromboembolism, haemorrhage, CNS metastases, congestive heart failure.


Tests to OK/confirm each cycle of chemo: FBC, U&Es, LFTs, BP, dipstick proteinuria, Crcl calculated


Chlorhexidine mouthwash 10mls QDS Loperamide 2-4mg QDS PRN (Max 16mg/day)



Written information on mechanical pump (if via CVAD) Additional information: Administration notes: Bevacizumab: Bevacizumab should be administered diluted with normal saline.

Do NOT mix bevacizumab with any other fluids. Where other fluids follow bevacizumab infusion, flush first with normal saline then flush with the other fluid. Bevacizumab first infusion is administered over 90 minutes. If this first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated all subsequent infusions may be administered over 30 minutes. See dose modifications table for action if dose not tolerated. Oxaliplatin - see colorectal page 21 5Flourouracil – see colorectal page 21

Dose modifications/cautions: Bevacizumab dose reduction for adverse events is not recommended (SPC). If indicated, bevacizumab therapy should either be permanently discontinued or temporarily suspended until toxicity resolves. Chemotherapy alone may continue if bevacizumab toxicity/side effects dictate that bevacizumab should be withheld. OxMdG: Dose modifications see colorectal page 22

Reference: Table: Bevacizumab

Side effect: Bevacizumab Dose modification (SPC)

All toxicities graded according to CTCAE v3.0 guidelines

Thrombosis/Embolism Venous thromboembolic event Grade 3 (deep venous thrombosis or cardiac

thrombosis requiring anticoagulation) or incidentally discovered pulmonary embolus (first occurrence) Symptomatic Grade 4 venous thromboembolic event First occurrence. (Grade 4 = embolic event

including pulmonary embolism with life-threatening thrombus or death)

Hold bevacizumab for 2 weeks. Bevacizumab may be resumed after initiation of therapeutic-dose anticoagulant therapy as soon as all of the following criteria are met:

The patient must be on a stable dose of anticoagulant and, if on an oral coumarin-derivative, have an INR within the target range (usually between 2 and 3) prior to restarting bevacizumab.

Permanently discontinue bevacizumab



Arterial thromboembolic event – any grade

Permanently discontinue bevacizumab if patient develops any grade of arterial thromboembolic event.

Haemorrhage Grade 1 and 2 Grade 3 or 4 (first occurrence)

No schedule modifications Discontinue bevacizumab and institute appropriate treatment

Proteinuria First occurrence of proteinuria:

1+ (dipstick)

2+, 3+ and 4+ dipstick

Second and subsequent occurrence of ≥2+ proteinuria (dipstick)

2+ (dipstick)

3+ and 4+ (dipstick):

Administer bevacizumab as scheduled. NO additional evaluation is required. Administer bevacizumab as scheduled and collect 24-hour urine to determine the total protein within 3 days prior to the next scheduled dose. If

24-hour proteinuria ≤2g: Administer bevacizumab as scheduled

24-hour proteinuria >2g: Bevacizumab treatment should be withheld pending next 24 hour total protein.

If

Repeat 24 hour urine protein ≤2g: Administer bevacizumab as schedule. 24-hour

protein should be further monitored prior to each administration of bevacizumab until it has decreased to ≤1g/24 hour.

Repeat 24-hour urine protein > 2g: Bevacizumab dose should be withheld until 24-

hour protein has decreased to ≤2g. 24-hour protein should be further monitored prior to each administration of bevacizumab until it has decreased to ≤1g/24 hour.

Administer bevacizumab as scheduled. NO additional evaluation is required. Administer bevacizumab as scheduled and collect 24-hour urine to determine the total protein within 3 days prior to the next scheduled dose is required: If

24-hour proteinuria ≤2g: Administer bevacizumab as scheduled

24-hour proteinuria >2g: Bevacizumab treatment should be withheld pending next 24 hour total protein. If

repeat 24 hour urine protein ≤2g: Administer bevacizumab as schedule. 24-hour



Nephrotic Syndrome Grade 4

protein should be further monitored prior to each administration of bevacizumab until it has decreased to ≤1g/24 hour.

repeat 24-hour urine protein > 2g: Bevacizumab dose should be withheld until 24-

hour protein has decreased to ≤2g. 24-hour protein should be further monitored prior to each administration of bevacizumab until it has decreased to ≤1g/24 hour.

Discontinue bevacizumab treatment

Gastro-intestinal perforation Gastro-intestinal perforation or dehiscence

Discontinue bevacizumab permanently and institute appropriate treatment

Wound healing complications Prevention of wound healing complications Wound healing complications

Bevacizumab therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. Bevacizumab therapy should be withheld for at least 28 days before elective surgery. In patients who experience wound healing complications during bevacizumab treatment, bevacizumab should be withheld until the wound is fully healed.

Fistula or intra-abdominal abscess Fistula or intra-abdominal abscess

Patients who develop a fistula or intra-abdominal abscess should discontinue bevacizumab

Hypertension Patients should be monitored for development of, or worsening hypertension by frequent blood pressure measurement. BP measurement should be taken after the patient has been in a resting position for ≥5 minutes. Repeated measurement of BP for verification should be taken if the initial reading is ≥140mmHg systolic and/or ≥90mmHg diastolic blood pressure

Grade 1 Hypertension Asymptomatic, transient (<24hr) increase >20mmHg (diastolic) or to >150/100mmHg if previously within normal limits. Grade 2 Hypertension Recurrent or persistent (>24hrs) increase by 20mmHg (diastolic) or to >150/100mmHg if previously within normal limits Grade 3 Hypertension Requiring more than one anti-hypertensive or more intensive therapy than previously. Grade 4 Hypertension Life threatening consequence eg. hypertensive crisis

Continue with bevacizumab

Monotherapy of antihypertensive may be indicated. Withhold bevacizumab. Once BP controlled to <150/100mmHg patient may restart bevacizumab. Withhold bevacizumab for persistent or symptomatic hypertension, until BP controlled. If hypertension is not controlled with medication, permanently discontinue bevacizumab. Stop bevacizumab permanently.

Infusion-related or allergic reactions


Side effect: Bevacizumab Dose modification (SPC) Infusion related reactions eg. fever, chills, headaches, nausea. Allergic reactions eg. fever, rash, urticaria, bronchospasm

≤ Grade 2

Grade 3

Grade 4

If infusion related reactions occur with any infusion: Administer the next dose with premedication over the same time period (ie. do not reduce infusion time for next dose). If next dose with premedication is well tolerated, then the subsequent infusion time may be reduced by 30 minutes (+/- 10mins) provided premedication is still used ie. 90 minute infusion reduced to 60 minutes. If infusion related reactions occur with the reduced infusion time with premedication then all subsequent doses must be administered over the previous longer infusion time with premedication. eg. if infusion related reactions occur with a 60 minute infusion all subsequent doses should be administered over 90 minutes (+/- 15mins) with premedication. eg. if infusion related reactions occur with 30 minute infusion, all subsequent doses should be administered over 60 minutes (+/- 10mins) with premedication

Stop bevacizumab infusion. DO NOT restart on that day. Discuss with consultant to decide if bevacizumab should be permanently discontinued or reinstituted with premedication over 90 minutes (+/- 15mins). If the reaction occurred at the 90 minute rate, initially challenge at a slower rate and gradually increase to 90 minutes. When bevacizumab reinstituted, the patient should be monitored for a duration comparable to duration of previous reaction. If suspected anaphylactic reactions during bevacizumab infusion STOP bevacizumab infusion, institute usual medical response to reaction, consider application of tourniquet proximal to the injection site to slow systemic absorption of bevacizumab (do not obstruct arterial flow in the limb)

24. Bevacizumab-Oxaliplatin-Capecitabine (Bev-CAPOX) Bevacizumab 7.5mg/kg IV over 90 minutes* Day 1 Oxaliplatin 130mg/m2 IV over 2 hours Day 1 Capecitabine 1000mg/m2 Oral twice a day Day 1 to 14

Ie.2000mg/m2/day with water after food (28 doses) starting evening of Day 1


* First bevacizumab dose is administered over 90 minutes, if this first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated all subsequent infusions may be administered over 30 minutes. Interval between cycles: Repeat every 21 days Number of cycles: Secure Cancer Drugs Fund funding

For 1st line treatment of metastatic colorectal cancer in patients with no prior bevacizumab.

4 cycles/3 months then review. Continue until progression.

Secure Cancer Drugs Fund funding for 2nd or 3rd line treatment of colorectal cancer in patients with no prior

bevacizumab 4 cycles/3 months then review. Continue until progression.

Do not continue past progression If excessive toxicity with oxaliplatin CDF allows continuation of Bev-CAPE alone until progression. CDF will NOT fund single agent bevacizumab maintenance treatment. Bevacizumab single agent maintenance is not recommended or licensed or CDF funded.

Tests before course of chemo: FBC, U&Es, LFTs, tumour markers, CEA, CA19-9, Crcl calculated. EDTA if ≤50mls/min. BP, dipstick proteinuria. ECG in patients with history of ischaemic heart disease or cardiac risk factors

Tests to OK/confirm each cycle of chemo: FBC, U&Es, LFTs, Crcl calculated, BP, dipstick proteinuria.


Chlorhexidine mouthwash 10mls QDS Bevacizumab; none Patient information: Chemotherapy treatment booklet (local information/Macmillan) Your chemotherapy record (Red book) Chemotherapy alert card


Capecitabine patient diary Patient must receive nurse capecitabine counselling

Additional information: Administration: Bevacizumab: see page 49

Oxaliplatin: see page 21 Capecitabine: see page 9

Dose modification: Bevacizumab: see page 49 CapeOx: see page 25

25. Bevacizumab-Irinotecan-MdG (Bev-IrMdG/Bev-FOLFIRI)

Bevacizumab 5mg/kg IV over 90mins* Day 1 Atropine 250mcg SC stat Day 1


Irinotecan 180mg/m2 IV over 30-90mins Day 1 Folinic Acid 350mg IV over 2 hours Day 1 5Fluorouracil 400mg/m2 IV bolus Day 1 5Fluorouracil 2400mg/m2 IV over 46 hours Day 1 * First bevacizumab dose is administered over 90 minutes, if this first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated all subsequent infusions may be administered over 30 minutes. Interval between cycles: Repeat every 14 days Number of cycles: Secure Cancer Drugs Fund funding

For 1st line treatment of metastatic colorectal cancer in patients who have no previous bevacizumab.


If excessive irinotecan toxicity, CDF allows continuation of Bev-MdG alone until progression. CDF will NOT fund singe agent bevacizumab.

Do not continue past progression Bevacizumab single agent maintenance is NOT recommended or licensed or funded by CDF.

Tests before course of chemo: FBC, U&Es, LFTs, Crcl calculated. BP, dipstick proteinuria, tumour markers, CEA, CA19-9. .

Tests to OK/confirm each cycle of chemo: FBC, U&Es, LFTs, Crcl calculated, BP, dipstick proteinuria

Supportive drugs with each cycle: High risk antiemetics as per NWLCN guidelines or as per local policy Atropine as above to prevent acute cholinergic syndrome from irinotecan

Chlorhexidine mouthwash 10mls QDS Patient information: Chemotherapy treatment booklet (local information/Macmillan) Your chemotherapy record (Red book) Chemotherapy alert card

Macmillan drug specific information sheet(s) and information prescriptions as appropriate Neutropenia DVD (NWLCN) Written information on mechanical pump (if via CVAD) Irinotecan patient information on diarrhoea Loperamide will be prescribed to be used when directed

Additional information Administration: Bevacizumab: see page 49

Irinotecan/MdG: see page 14 Dose modification: Bevacizumab: see page 49

Irinotecan/MdG: see page 14

26. Bevacizumab-Cape-Irinotecan (Bev-Capiri) Bevacizumab 7.5mg/kg IV over 90mins* Day 1 Atropine 250mcg SC stat Day 1 Irinotecan 200mg/m2 IV over 30-90mins Day 1 Capecitabine 800mg/m2 Oral Twice a day Days 1 to 14 (1600mg/m

2/day)


Consider 25% capecitabine dose reduction in over 70 years. * First bevacizumab dose is administered over 90 minutes, if this first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated all subsequent infusions may be administered over 30 minutes. Interval between cycles: Repeat every 21 days Number of cycles: Secure Cancer Drugs Fund funding

For 1st line treatment of metastatic colorectal cancer in patients who have no prior bevacizumab.


Do not continue past progression If excessive irinotecan toxicity, CDF allows continuation of Bev-Cape alone until progression. CDF will NOT fund singe agent bevacizumab maintenance treatment. Bevacizumab single agent maintenance is NOT recommended or licensed or CDF funded.

Tests before course of chemo: FBC, U&Es, LFTs, Crcl calculated. BP, dipstick proteinuria, tumour markers, CEA, CA19-9. ECG in patients with history of ischaemic heart disease or cardiac risk factors.

Tests to OK/confirm each cycle of chemo: FBC, U&Es, LFTs, Crcl calculated, BP, dipstick proteinuria

Supportive drugs with each cycle: High risk antiemetics as per NWLCN guidelines or as per local policy Atropine as above to prevent acute cholinergic syndrome from irinotecan


Macmillan drug specific information sheet(s) and information prescriptions as appropriate Neutropenia DVD (NWLCN) Written information on mechanical pump (if via CVAD) Irinotecan patient information on diarrhoea, loperamide will be prescribed to be used when directed

Additional information Administration: Bevacizumab: see page 49

Irinotecan: see page 16 Capecitabine; see page 16

Dose modification: Bevacizumab: see page 49 Irinotecan: see page 17 Capecitabine; see page 17

27. Bevacizumab-Capecitabine (Bev-Cape) Bevacizumab 7.5mg/kg IV over 90 minutes* Day 1 Capecitabine *1250mg/m2 Oral twice a day Day 1 to 14


Ie.2500mg/m2/day with water after food (28 doses) starting evening of Day 1

Capecitabine starting dose; *If GFR ≥ 51ml/min <70 years full dose

≥ 70 years 1000mg/m2 twice a day GFR 30-50ml/min <70 years 1000mg/m2 twice a day ≥ 70 years 750mg/m2 twice a day

* First bevacizumab dose is administered over 90 minutes, if this first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated all subsequent infusions may be administered over 30 minutes. Interval between cycles: Repeat every 21 days Number of cycles: Secure Cancer Drugs Fund funding

For 1st line treatment of metastatic colorectal cancer in patients who are performance status 0 to 2 but who are unfit to receive oxaliplatin or irinotecan chemotherapy and have not previously received bevacizumab. Do not continue past progression CDF will not fund single agent bevacizumab maintenance treatment. Bevacizumab single agent maintenance is NOT recommended or licensed or CDF funded.

Tests before course of chemo: FBC, U&Es, LFTs, tumour markers, CEA, CA19-9, Crcl calculated. EDTA if ≤50mls/min. BP, dipstick proteinuria. ECG in patients with history of ischaemic heart disease or cardiac risk factors.

Tests to OK/confirm each cycle of chemo: FBC, U&Es, LFTs, Crcl calculated, BP, dipstick proteinuria.




Capecitabine patient diary Patient must receive nurse capecitabine counselling

Additional information: Administration: Bevacizumab: see Colorectal page 49

Capecitabine: see Colorectal page 9 Dose modification: Bevacizumab: see Colorectal page 49

Capecitabine: see Colorectal page 10


Radio-Embolisation SIR Spheres plus OxMdG Radioembolisation (RE) is a technique that has been developed to target multiple sites of disease within the liver as a form of bracytherapy. SIR-Spheres (Sirtex Medical Ltd, Sydney, Australia) contain the pure β-emitter, yttrium-90, labelled to resin microspheres with a mean diameter of approximately 32 μm. The physical half-life of yttrium-90 is 64.1 hours. In a single out-patient procedure involving trans-femoral catheterisation and fluoroscopic guidance, approximately 40 to 80 million microspheres are injected into the arterial supply of the liver. Hepatic metastases from colorectal cancer derive approximately 90% of their blood flow from the arterial vasculature rather than the portal venous system, and this characteristic ensures that the microspheres become lodged in the malignant microvasculature. Sine RE delivers high doses of ionising radiation to the tumour compartment whilst maintaining radiation exposure of the normal liver to a tolerable level, it can be regarded as a form of brachytherapy. It has also been termed selective internal radiotherapy (SIRT).

28. Radio Embolisation: Recruit to trials whenever possible

For additional Private Care unless local NDP approved/PCT agreement to fund SIR – Spheres microspheres plus OxMdG Summary: Cycle 1 Full dose OxMdG Cycle 2 Radio embolisation plus reduced dose OxMdG (bolus 5FU

removed Nov13)

Cycle 3 Reduced dose OxMdG (bolus 5FU removed Nov13)

Cycle 4 Reduced dose OxMdG (bolus 5FU removed Nov13)

Cycle 5 to 12 Full dose OxMdG Cycle 1 (Full dose OxMdG) Oxaliplatin 85mg/m2 IV over 2 hours Day 1 Folinic acid 350mg IV over 2 hours Day 1 5Fluorouracil 400mg/m2 IV bolus dose Day 1 5Fluorouracil 2400mg/m2 IV over 46hours Day 1 Cycle 2 only (Radio embolism plus reduced dose OxMdG) Oxaliplatin 60mg/m2 IV over 2 hours Day 1 Folinic acid 350mg IV over 2 hours Day 1 5Fluorouracil 2400mg/m2 IV over 46hours Day 1 Radio-embolism using SIR-spheres microspheres Day 3 (yttrium-90) Consult manufacturer’s users manual for dose Dose calculated based on BSA, % tumour involvement and “percentage lung shunting” Cycles 3 and 4 (Reduced dose OxMdG) Oxaliplatin 60mg/m2 IV over 2 hours Day 1 Folinic acid 350mg IV over 2 hours Day 1 5Fluorouracil 2400mg/m2 IV over 16hours Day 1 Cycle 5 to 12 As cycle 1 Interval between cycles: Repeat every 14 days as detailed above Number of cycles: For Additional Private Care only Only for loco-regional treatment of HCC confined to liver. Hepatocellular carcinoma with Childs Pugh A or possible good B 12 cycles (ie. one

radio-embolisation) Tests before starting course of chemo: FBC, U&Es, LFTs, Crcl (calculated). Do EDTA if

≤60mls/min.

Preliminary arteriogram of liver (within 32 days of RE) to determine


vascular anatomy of the liver (to provide “road map” of arterial supply of liver to plan delivery of SIR-spheres – see User manual

“Break through” macro-aggregated albumin (MAA) nuclear scan within 32 days of RE (to calculate percentage of SIR-spheres that will pass through the liver and lodge in lungs due to arteriovenous shunts. Dose must be adjusted to limit y99 damage to lung – see SIR-spheres User manual.

Contrast enhanced helical CT scan to calculate % tumour involvement (needed to calculate SIR-sphere dose see SIR-sphere users manual)

Tests to OK/confirm each cycle of chemo: FBC, U&Es, LFTs, Crcl (calculated). Supportive drugs with each cycle: High risk antiemetics as per NWLCN

guidelines or as per local policy NB. In cycle 2 continue 5HT3 antiemetics to cover day of RE as a minimum Chlorhexidine mouthwash 10mls QDS Loperamide 2-4mg QDS PRN (max 16mg/day) Proton pump inhibitor from day of diagnostic hepatic arteriogram for minimum 8 weeks. Fluids only 3 hours before RE Prophylactic antibiotics 1 hour before procedure according to local policy

Prophylactic narcotic analgesia for RE procedure. Minor opioids (dihydrocodeine) usually sufficient but major opioids (eg pethidine) may be required within first 24 hours of RE. Prophylactic antibiotics post procedure according to local policy.



Neutropenia DVD (NWLCN) SIR-Sphere patient information Additional information: OxMdG see page 22 Dose modification: Table: SIR-Spheres

Side-effect SIR-Spheres Dose Modification (FOXFIRE TRIAL)

Fever Most patients (up to 80%) develop a mild fever that lasts several days following RE administration but which does not require treatment

Abdominal Pain RE is followed by abdominal pain in approximately 50% of patients. This can vary from minor discomfort (grade 1) through to grade 3. In almost all cases it is self limiting (dissipating within 24 hours) but it may require narcotic analgesia (in about one third of patients). It is routinely managed by prophylactic pre-medication.


Side-effect SIR-Spheres Dose Modification (FOXFIRE TRIAL)

Lethargy Post RE treatment lethargy (approximately 40% of cases) may occur anywhere between 1 week and 8 weeks post treatment and can last up to 10 days.

Nausea Post RE treatment mild nausea (40-50% of cases) is most common in patients who have received multiple courses of chemo. Symptoms rarely last more than 24 hours and can be managed by prophylactic antiemetics medication.

Gastritis/Duodenitis/Ulceration Discuss with consultant. One of the most common potentially serious complications. Incidence rate of gastritis/duodenitis can be reduced by experience and meticulous attention to the administration procedure so as to ensure that there is minimal chance of SIR-spheres entering small arteries supplying the gut

Radiation Hepatitis Discuss with consultant. The other most common potentially serious complication. Radiation hepatitis is largely, but not totally, preventable by using correct SIR-sphere dose and making allowances for dose reduction where there is increased risk of causing radiation damage, such as in poor liver reserve or small volume tumour mass in liver – see SIR-Sphere user manual

Pancreatitis Discuss with consultant Rare complication is acute pancreatitis resulting from SIR-sphere refluxing back down hepatic artery and lodging in the pancreas and liver abscess from infection of necrotic tumour.

Haematological Discuss with consultant There is some evidence that there is a decrease in leukocyte (lymphocyte and neutrophils) levels following RE with a nadir 6-8 weeks after the RE procedure. The mechanism of leucopenia is unknown, although current clinical data (2009) suggest this adverse effect may have clinical sequelae when RE is used in combination with systemic radiosensitisers eg 5FU/Oxaliplatin.


COLORECTAL CANCER; Chemo Radiation Regimens

Dose modification: based on experience of 5FU regimens in anal/rectal cancer Table 1 – Radiotherapy modifications in case of haematological acute toxicity

Toxicity grade (CTC)

Neutrophils Platelets (x109/L) (x109/L)

Radiotherapy

0 - 2 1.0 and 50 Continue RT

3 0.5 – 0.9 and/or 10 – 49 Interrupt RT until neutrophils >1.0 and platelets >50

4 <0.5 and/or <10 Interrupt RT until neutrophils >1.0 and platelets >50

Table 2 – Chemotherapy dose modifications in case of combination of haematological and non-haematological toxicity (ACT II)

Wait until full recovery ie. neutrophils 1.0 and platelets 50

If within 2 weeks continue using dose modification below

If > 2 weeks discuss with consultant Haematological Parameters NB. Wait until full recovery before treatment

Non-haematological CTC grade (diarrhoea, stomatitis, mucositis)

0-1

2

3

4

Neutrophils x109/L 1.0 And/or

Platelets x109/L 50

Wait until full recovery then give full dose

Wait until full recovery then give full dose

Wait until full

recovery then give 50% dose reduction

No further treatment

Neutrophils x109/L 0.5-0.9 And/or Platelets x109/L 10-49

Wait until full recovery then give 25% dose

reduction


reduction

Wait until full



Neutrophils x109/L <0.5 And/or Platelets x109/L <10


reduction


reduction

Wait until full



Table 3 – Radiotherapy regimen modifications in case of diarrhoea (ACT II)

Toxicity Grade (CTC)

Diarrhoea (no colostomy)

Diarrhoea (colostomy)

Radiotherapy

CTC 0-2 None – increase of 4-6 stools/day or nocturnal stools

None – moderate increase in loose watery colostomy output compared with pre-treatment but not interfering with normal activity

Continue


Toxicity Grade (CTC)

Diarrhoea (no colostomy)

Diarrhoea (colostomy)

Radiotherapy

CTC 3 Increase of 7 stools/day or incontinence; or need for parenteral support for dehydration

Severe increase in loose watery colostomy output compared with pre-treatment, interfering with normal activity

Interrupt for 1-7 days. Radiotherapy may recommence if stools or stoma controlled on anti diarrhoeal medication. If stools not normalised, irradiation must be stopped indefinitely

CTC 4 Physiologic consequences requiring intensive care; or haemodynamic collapse

Physiological consequences requiring intensive care; or haemodynamic collapse

Interrupt for 1-2 weeks. Radiotherapy may only recommence if stools or stoma adequately controlled. If stools not normalised, irradiation must be stopped indefinitely

29. Bossett Regimen: 5FU350-FA20 + RT

Folinic acid 20mg/m2 IV bolus Days 1 to 5 and 29 to 33 5-Fluorouracil 350mg/m2 IV bolus/infusion Days 1 to 5 and 29 to 33 Interval between cycles: Repeat weeks 1 and 5 during a 5-6 week course of

radiotherapy. Number of cycles: Colorectal cancer: Neoadjuvant, adjuvant or local recurrence: Weeks 1 + 5 of of a 5-6 week course of RT Tests before starting course of chemo: FBC, U&Es, LFTs, tumour markers CEA, CA19-9, Crcl (calculated). Test to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Supportive drugs with each cycle: Moderate risk antiemetics (due to

radiotherapy) as per NWLCN guidelines or as per local policy

Chlorhexidine mouthwash 10mls QDS Loperamide 2-4mg QDS PRN



Neutropenia DVD (NWLCN) Additional information: Administration notes:

Sucking ice cubes or ice lollies 5 minutes before and for 30 minutes after injection (if tolerated) of 5FU may reduce the incidence of stomatitis.

Dose modifications: See 5FU-Chemo Radiation table Colorectal pages 54/55 If Grade 3 or 4 toxicity develops during days 1 to 5 chemo, consider omitting chemo during days 29 to 33


Reference: J Clin Oncol 2005 Bossett et al 30. Capecitabine 1650 + RT

Capecitabine 825mg/m2 Oral twice a day Days 1 to 5 Repeat day 7 ie. total 1650mg/m2/day See dose table page 62-64 Interval between cycles: Repeat day 7 ie. administer Monday to Friday each week during

5 weeks of radiotherapy. Repeat tests every 2 weeks. Ideally RT should be delivered within 2 hours of capecitabine.

Number of cycles: Colorectal cancer: Neoadjuvant, adjuvant, local recurrence: Monday to

Friday during 5-6 weeks of radiotherapy

Tests before starting course of chemo: FBC, U&Es, LFTs, tumour markers CEA, CA19-9, Crcl (calculated). Do EDTA if <50mls/min. ECG in patients with history of ischaemic heart disease or cardiac risk factors.

Tests to OK/Confirm each cycle of chemo: FBC and U&Es (weekly), LFTs (every 2-3 weeks), Crcl (calculated).

Supportive drugs with each cycle: Low risk antiemetics as per NWLCN guidelines or as per local policy Chlorhexidine mouthwash 10mls QDS



Neutropenia DVD (NWLCN) Capecitabine patient diary Patient must receive nurse capecitabine counselling

Additional information: Administration notes: Patients must receive specific capecitabine counselling prior to treatment from a capecitabine trained nurse/pharmacist as per local policy. Patients must be given written and verbal information on capecitabine including how to take the tablets, when to stop (ie. In the event of toxicity and after 14 days), and whom to contact when side effects occur. Written information should be sent to the patient’s GP. Capecitabine tablets should be taken with water 30 minutes after food and approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin and therefore patients on these drugs must have their blood levels monitored more regularly. Capecitabine is contraindicated with allopurinol.

Dose modifications: See Capecitabine table page 11 Reference: IJROBP 2005 Kim JC et al


Table: Capecitabine + RT Side-effects: Capecitabine +RT

Dose Modifications (Scope/SPC)

Haematology Neutrophils Platelets x 109/L x 109/L

1.5 and 100 <1.5 or <100

Full dose. Delay 1 week or until recovery. If >1 delay or 1 delay ≥2 weeks dose reduce Capecitabine: 20% dose reduction. Continue at this lower dose for subsequent cycles unless further toxicity occurs. If further delay(s) for myelotoxicity occur despite 20% dose reduction, discuss with consultant

Renal function (Scope)

Crcl 50mls/min 40-49mls/min 30-39mls/min

<30mls/min

Full dose Capecitabine 25% dose reduction. Capecitabine 50% dose reduction Do not give

Hepatic function Bilirubin Either AST or ALT ≤3 x ULN and ≤2.5 x ULN >3 x ULN or >2.5 x ULN

Full dose Capecitabine withhold until recovery then discuss with consultant

Diarrhoea Grade 1

Grade 2

Loperamide 2-4mg oral QDS PRN max 16mg/24hours As grade 1 plus stop capecitabine until recovery then reduce dose according to SPC table page 11

Stomatitis (SPC) Grade 1

Grade 2

Consider topical treatments eg Difflam mouthwash or sucralfate 1g/5ml mouthwash Stop capecitabine until recovery Consider topical treatments as grade 1 and reduce dose according to SPC table page 11


Grade 2

Stop capecitabine until recovery. Once recovered restart with full dose. Stop capecitabine until recovery. Once recovered, reduce dose according to SPC table page 11 Phase III randomised controlled trials show no benefit from pyridoxine for prevention or treatment of 5FU induced hand foot syndrome. Pyridoxine is not recommended.

DPD Deficiency 1-3% of patients have markedly exaggerated capecitabine toxicity due to reduced capecitabine catabolism. Discuss with consultant.

Cardiotoxicity Uncommon. Capecitabine may provoke angina or MI in patients with ischaemic heart disease. Seek specialist opinion on upgraded anti-angina medication and consider dose reduction or alternative non-capecitabine treatment.

Neurotoxicity Uncommon – Cerebellar Consider alternative non-capecitabine treatment


ANAL CANCER Chemo-Radiation Regimens

31. Mitomycin/5FU + RT UKCCR Regimen Local Disease Chemotherapy administered during weeks 1 and 5 of a 4-5 week course of radiotherapy.

Mitomycin C under 70yrs 12mg/m2 (max 20mg) IV bolus Day 1only Over 70yrs 10mg/m2 (max 20mg) IV bolus Day 1 only 5-Fluorouracil *1000mg/m2/ day IV 24 hour infusion** Days 1 to 4 and

Days 29 to 32 *(or 750mg/m2/day for 5 days) **outpatient regimen administer each 5FU over 24 hours via infusor

Interval between cycles: 1 cycle only weeks 1 and 5 of a 5 week course of RT Number of cycles: Anal cancer 1st line chemo during weeks 1 and 5 of a 5 week

course of RT: 1 cycle only Tests before starting course of chemo: FBC (including manual film for haemolysis

screen), U&Es, LFTs, tumour markers CEA, CA19-9, Crcl calculated. Do EDTA if <60mls/min.

Tests to OK/Confirm each cycle of chemo: FBC (including manual film for haemolysis screen), U&Es, LFTs, Crcl (calculated).




WBC 3.0 x 109/L





Chlorhexidine mouthwash 10mls QDS Consider prophylactic antibiotics during 6 weeks chemoradiation



Neutropenia DVD (NWLCN) Written information on mechanical (if via CVAD) Additional information: Administration notes:

Mitomycin is a vesicant and should be administered in accordance with the NWLCN administration policy. . If 5FU administered using an ambulatory infusion pump via a central venous access device (CVAD), refer to relevant protocol for care of CVAD. Joint care with the community nursing services should be arranged in advance to support the patient and to assist with disconnecting the chemotherapy and flushing the CVAD. Written community nursing referral should be completed and the patient should be


discharged with a home spillage kit, sharps container and a small supply of equipment to flush the line and dress the entry site of the CVAD.

Dose modifications: Table: Mito-5FU + RT below Reference: Int J Radiat Oncol Biol Phys 1991;21:1115-25. Cummings BJ UKCCR anal Cancer Trial. Lancet 1996;348:1049-54 Table: Mito-5FU+RT - UKCCR

Side-effect: Mito-5FU-RT

Dose Modification (Source: R Phillips/H Wasan/ Act ll

Trial) Haematology Neutrophils Platelets Hb x109/L x109/L g/L

1.5 and 100 and 100 <1.5 or <100 or <100 1.0-1.5 and 50-59 and ≥100 0.5-0.9 or 25-49 or any <0.5 or <25 or any

Full dose Delay 1 week until recovery. Discuss with consultant if >3 weeks, otherwise dose reduce as below Delay until recovery then full dose Delay until recovery then 5FU: 25% dose reduction Delay until recovery then 5FU: 50% dose reduction

Renal Function

Crcl 60ml/min 41-59 mls/min

40ml/min

Full Dose Mitomycin 30% dose reduction (8mg/m2) Consider alternative regimen

Diarrhoea or Stomatitis Grade 3 Grade 4

5FU: 25% dose reduction Omit 5FU

Haemolytic Uraemic Syndrome (HUS) Extremely rare with this dose of mitomycin. Usually fatal if it does occur HUS suspected Eg. red blood cell fragmentation




WBC 3.0 x 109/L





ANAL CANCER

Chemotherapy Alone Regimens

32. CISP60-5FU-4day CHEMO ALONE

Prehydrations Day 1 Cisplatin 60mg/m2 IV over 2 hours Day 1 Post hydrations Day 1 5-Fluorouracil 1000mg/m2/day Continuous infusion Day 1 to 4 Interval between cycles: Repeat every 21 days Number of cycles: Anal cancer; Relapsed/metastatic: 4-6 cycles Tests before starting course of chemo: FBC, U&Es, Mg, LFTs, Crcl calculated do

EDTA if <60mls/min. tumour markers CEA, CA19-9. .

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, Mg, LFTs, Crcl (calculated). Do EDTA if rising creatinine

Supportive drugs with each cycle: Very high risk antiemetics as per NWLCN guidelines or as per local policy

Chlorhexidine mouthwash 10mls QDS. Loperamide 2-4mg QDS PRN (max 16mg/day)



Neutropenia DVD (NWLCN) Written information on mechanical pump (if via CVAD) Additional information:

Administration notes: Cisplatin: Weigh patient before and after cisplatin infusion or monitor urine output. If weight gain >1.5kg or symptomatic of fluid retention; inform doctor, patient may require diuretics. Inpatients should be on a fluid-balance chart and weighed daily. Average urine output of at least 100ml/hr is expected during and for 6 hours after cisplatin infusion. Outpatients should be encouraged to drink 3 litres of fluid within the following 24 hours. If 5FU administered using an ambulatory infusion pump via a central venous access device (CVAD), refer to relevant protocol for care of CVAD. Joint care with the community nursing services should be arranged in advance to support the patient and to assist with disconnecting the chemotherapy and flushing the CVAD. Written community nursing referrals should be completed and the patient should be discharged with a home spillage kit, sharps container and a small supply of equipment to flush the line and dress the entry site of the CVAD.

Dose modifications: See 5FU-CISP-4 day table page 69 Reference: Eur J Cancer 1993;558, 29A (Suppl 6):S104


Table: 5FU-CISP 4 day

Side Effects: 5FU-CISP 4day

Dose Modification (Source ACT II Trial)


1.5 and 100 1.0-1.4 or 50-99 0.5-0.9 or 25-49 <0.5 OR < 25

Full dose Delay 1 week until recovery then full dose Delay until recovery then 5-Fluorouracil 25% dose reduction Delay until recovery then 5-Fluorouracil 50% dose reduction

Renal function (NCLN 2009)


<45mls/min

Full dose Cisplatin 25% dose reduction. 5FU: full dose 5FU: full dose Omit cisplatin, Consider carboplatin 5AUC

Stomatitis ≤ Grade 2 Grade 3 Grade 4

Full dose 5-Fluorouracil: 25% dose reduction 5-Fluorouracil: Omit

Diarrhoea ≤Grade 2 Grade 3 Grade 4

Full dose 5-Fluorouracil: 25% dose reduction 5-Fluorouracil: Omit

Hand-Foot syndrome Discuss with consultant

DPD Deficiency 1-3% of patients have markedly exaggerated 5FU toxicity due to reduced 5FU catabolism. Discuss with consultant.

Cardiotoxicity Uncommon. 5FU may provoke angina or MI in patients with ischaemic heart disease. Seek specialist opinion on upgraded anti-anginal medication and consider dose reduction or alternative non 5FU treatment.

Neurotoxicity Uncommon – Cerebellar Consider alternative non 5FU treatment

33. Docetaxel 100 Dexamethasone 8mg BD Oral Days 0 to 2 Docetaxel 100mg/m2 IV over 1 hour Day 1 Interval between cycles: Repeat every 21 days Number of cycles: Relapsed anal cancer – 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Supportive drugs with each cycle: High risk antiemetics as per NWLCN

guidelines or as per local policy Dexamethasone as above Patient information: Chemotherapy treatment booklet (local information/Macmillan) Your chemotherapy record (Red book) Chemotherapy alert card



Neutropenia DVD (NWLCN) Additional information:

Administration notes: Dexamethasone 8mg must be taken orally twice a day for 3 days (the day before, the day of and the day after docetaxel) to prevent fluid retention and hypersensitivity reactions; therefore, the patient must be discharged with enough dexamethasone to take before their next cycle. Ensure patient understands how to take their steroids at home. Diabetic patients will need to monitor blood sugar levels more regularly and inform their doctor if they are having problems with the control of their blood sugar levels. IV dexamethasone should not be given to replace oral doses. Acute hypersensitivity reactions can occur, observe closely especially during the first two cycles. Assess for any drug-induced neuropathy. Prior to treatment, discuss hair loss and liaise with wig fitter. Scalp cooling should be offered.

Dose modifications: See Docetaxel table below Table: Docetaxel

Side effect: Docetaxel Dose Modification

Haematology Neutrophils Platelets x 109/L x 109/L ≥1.5 and ≥100

Full dose. Do not give below these levels. Delay until recovery then discuss with consultant.

Renal Function Mild/Moderate

Severe

No dose reduction necessary in mild/moderate renal impairment Discuss with consultant

Hepatic Function (NLCN 2009)

Bilirubin ALT/AST ALT micromol/L

>1.5 x ULN and >2.5 x ULN >22 and/or >3.5 x ULN and >6 x ULN

Give docetaxel 75mg/m2

Do not give

Cutaneous Reactions Severe or cumulative cutaneous reactions (SPC)

Reduce dose from 100mg/m2 to 75mg/m2 or from 75mg/m2 to 60mg/m2 if already reduced. If patient continues to experience severe reactions, discontinue docetaxel

Neuropathy Severe peripheral neuropathy (SPC)

Reduce dose from 100mg/m2 to 75mg/m2 or from 75mg/m2 to 60mg/m2 if already reduced. If patient continues to experience severe reactions, discontinue docetaxel

Allergic Reactions (SPC) Mild

Severe

Rechallenge

If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require interruption of therapy. However, severe reactions such as severe hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. Patients who have developed severe reactions should not be rechallenged with docetaxel. Discuss with consultant. Extreme caution is required as cross reactivity occurs with taxanes.


WHO Performance Status

Clinical Performance

Status

0 Able to carry out all normal activity without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry out light work

2 Ambulatory and capable of all self-care but unable to carry out any work. Up and about more than 50% of waking hours

3 Capable only of limited self-care; confined to bed or chair more than 50% of waking hours

4 Completely disabled; cannot carry out any self-care; totally confined to bed or chair

Cockroft & Gault Formula The estimated GFR is given by: Males: 1.25 x (140 – age) x ideal body weight (kg)

Serum creatinine (mol/L) Females: 1.05 x (140 – age) x ideal body weight (kg)

Serum creatinine (mol/L) This formula usually under-estimates GFR by 10-30% compared with EDTA or measured 24-hour creatinine clearance, so is used as a screening test. A Cockcroft/Gault estimate of >50ml/min is accepted evidence of adequate renal function Patients with Cockroft/Gault estimate of <50ml/min should have formal GFR measurement with EDTA or 24hour urinary creatinine


COLORECTAL CANCER Section by: Dr Pippa Riddle, Dr Riz Ahmad, Dr Suzy Cleator, Dr Harpreet Wasan, Dr Charles Lowdell. Version Control Sheet

Version Date Author Status Comment

1.00 13.10.05 Susan Whear Draft

1.01 13.10.05 Susan Whear Replaced Previously approved version

2.00 09.07.07 Susan Whear Draft Not issued



3.02 Susan Whear Replaced Previously approved version

3.03 Susan Whear Replaced Previously approved version









6.00 12.11.13 Susan Whear Draft Version control box added. Capecitabine dose table removed because Aria will round doses. SIR-Spheres removed bolus 5FU dose in reduced oxaliplatin regimens in line with non-trial ARIA regimens. Mitomycin-5FU-RT, mitomycin capped at 20mg all ages in line with ARIA. Mitomycin-5FU-RT: Fluorouracil outpatient changed to infusor (not NSIL). Removed CTIS references. Added Aflibercept-IrMdG Updated CDF approval criteria. Removed Uftoral as discontinued product

6.00 13.12.13 Susan Whear Draft Proof read corrections

6.00 25.06.14 Susan Whear Draft Comments from Dr Pippa Riddle. Added aflibercept text on grade for proteinuria & hypertension Update panitumumab for NCDF status

6.00 07Jul14 Susan Whear Draft Additional text for aflibercept hypertension

6.00 08Jul14 Susan Whear Draft Correction of dates

6.00 11Jul14 Susan Whear Draft Amendment to aflibercept hypertension and proteinuria text

6.01 11Jul14 APPROVED Approved Dr Pippa Riddle Spell check

colorectal regimens v6.01 nwlcn - london ... · pdf filecolorectal regimens approved v6.01...

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