West of Scotland Cancer Network

Chemotherapy Protocol

Modified De Gramont with Oxaliplatin (OxMdg)

Adjuvant Colorectal Cancer (GIWOS-006)

The MOSAIC trial of oxaliplatin plus infusional 5FU/FA (given according to the De Gramont schedule)
vs. infusional 5 FU/FA1 improved disease free survival at 4 years 76.4 % vs. 68.8%2. On the basis on
this data the Scottish Medicines Consortium (SMC, No. 211/05) approved oxaliplatin in combination with
a standard 5-FU and folinic acid regimen for the adjuvant treatment of stage III colon cancer in October
2005. However the practical difficulties of the De Gramont regime mean that the Modified De Gramont
containing FOLFOX-6 regimen (although not approved) is a more practical solution to the large scale
administration of this therapy across the West of Scotland MCN for colorectal cancer (CRC).

Indication

1. Dukes C colon cancer patients

2. Dukes C rectal cancer patients
3. Some Dukes B patients with additional poor prognostic features such as T4 tumours,
4,5
perforated, obstructed and extra-mural vascular invasion those with < 12 nodes
examined and poorly differentiated tumours.

Case selection

CONSIDER ENTRY INTO CLINICAL TRIAL IF AVAILABLE/APPROPRIATE.

Inclusion

• Histologically proven stage Dukes « B » (certain patients as above) and « C » (stage III:
any T N1-2 M0) colon or rectal carcinoma.
• Patients must have undergone complete resection of the primary tumour without gross or
microscopic evidence of residual disease
• Patients should ideally start treatment within 8 weeks after surgery
• PS 0 - 2 (Karnofsky ≥ 60%)
• No biological major abnormalities: Absolute neutrophil count ≥ 1.5 x 109/l, Platelets ≥ 75 x
9
10 /l, creatinine clearance (CrCl) ≥ 30ml/min, bilirubin ≤ 3 times upper limit of normal
(ULN).
• CEA falling with the appropriate half life.
• Men and women who are fertile must use a medically acceptable contraceptive throughout
the treatment period and for 6 months following cessation of treatment with oxaliplatin.
• Written informed consent

Exclusion
• Pregnant or lactating females / woman of child bearing potential not using a contraceptive
method
• Clinically significant cardiac disease – uncontrolled congestive heart disease, unstable
angina or myocardial infarction within the last 6 months
• Peripheral neuropathy (NCI CTCAE Vesion 3 ≥ Grade I)
• Known or suspected dihydropyrimidine dehydrogenase (DPD) deficiency
• Known hypersensitivity to platinum based compounds
• Other intercurrent serious illness which in the opinion of the treating consultant would
render patient at risk of severe toxicity
• History of significant neurologic or psychiatric disorders
• Active Infection

Page 1 of 6
WoSCAN CP OxMDG Adj CR version 1.0 March 2007
Pre-treatment evaluation

1. Informed consent
2. Written and verbal information given to patient and carer/family member where appropriate.
3. Assessment of performance status
4. Height, weight and body surface area (BSA)
5. Referral letter from surgeon
6. Copy of histopathology reports
7. Copy of CT or MRI reports
8. Ideally discuss case at MDT and review pathology
9. Baseline FBC, U&Es, LFTs and CEA – calculate CrCl using Cockcroft – Gault equation
10. Medical history and examination

Regimen

Pre-medication: Dexamethasone 8mg + Granisetron 3mg Intravenously 30 minutes

prior to chemotherapy

Drug Dose Route Administration Infusion fluid Day to be given

Folinic Acid 350mg I.V Over 2 hours 250ml Glucose 5%* Day 1
Oxaliplatin 85mg/m2 I.V Over 2 hours 250ml Glucose 5%* Day 1
5fluorouracil 400mg/m2 I.V Over 10 minutes 100ml Sodium Day 1
Chloride 0.9%
5fluorouracil 2400mg/m2 I.V Over 46 hours 1000ml Sodium Day 1
Chloride 0.9% or
ambulatory infusion
device **
* folinic acid and oxaliplatin to be given concurrently; line to be flushed with
Glucose 5% before administration of 5fluorouracil.
** regimen given as day case treatment if patient has PICC/Hickman line in situ

Repeat every 14 days for 12 cycles

• Emetogenic Risk: Moderate – refer to local anti-emetic policy

Dose Banding Nomogram: calculate BSA to one decimal place (cap at 2.2 m2) and select dose from
table below:
B.S.A (m2) Standard doses (mg)

Oxaliplatin Infusion 5FU bolus 5FU infusion

85mg/m2 400mg/m2 2400mg/m2
1.4 120 550 3500
1.5 130 600 3600
1.6 130 650 4000
1.7 150 650 4000
1.8 150 750 4500
1.9 170 750 4500
2.0 170 800 4800
2.1 180 850 5200
2.2 180 850 5200

Page 2 of 6
WoSCAN CP OxMDG Adj CR version 1.0 March 2007
Adverse effects – for both Oxaliplatin and Fluorouracil

Very Common Common

Haematological: Haematological: febrile neutropenia
neutropenia, anaemia, thrombocytopenia, infection Autonomic Nervous system: flushing
Application site: Cardiovascular: chest pain, palpitations
injection site reaction, extravasation Central & peripheral nervous system:
General: dizziness, neuritis
fever, fatigue, allergic reactions including skin rash, Gastrointestinal:
conjunctivitis, rhinitis, asthenia, pain, weight increase. dyspepsia, gastroesophageal reflux, hiccup
Central & Peripheral Nervous system: peripheral General: increased lacriimation, dacryostenosis, v
sensory neuropathy, headache, sensory disturbance Metabolism& Nutrition: dehydration
Gastrointestinal: Musculoskeletal: arthralgia, skeletal pain
diarrhoea, nausea, vomiting, stomatitis/mucositis, Platelets, Bleeding & clotting:
abdominal pain, constipation, anorexia haemorrhage, haematuria, deep thrombophlebitis,
Musculoskeletal: back pain pulmonary embolism
Platelets, bleeding and clotting: epistaxis Psychiatric: depression, insomnia
Respiratory system: dysponea, coughing Respiratory:
Skin & Appendage: rhinitis upper respiratory tract infection
dermatitis, pigmentation, changes in nails, alopecia. Skin & Appendage:
Special Senses, other: taste perversion skin exfoliation (i.e hand foot syndrome),
Laboratory abnormalities: erythematous rash, rash, increased sweating, nail
increase in alkaline phosphatase, bilirubin, disorder.
transaminases, LDH; glycemia abnormalities, Urinary System:
hypokalaemia, natremia abnormalities. dysuria, abnormal micturition frequency
Vision: conjunctivitis, abnormal vision, photophobia

Oxaliplatin is associated with two types of neuropathy (see Dose modification table):

1. Laryngopharyngeal dysaesthesia - generally cold induced, short duration and self

limiting with no evidence of bronchospasm
although may cause shortness of breath.
- reassure patient, avoid cold drinks and
prolong oxaliplatin infusion time to 6 hours.

2. Mixed Sensory and Motor Neuropathy - transient at first between cycles becoming
permanent with cumulative dosing
- may be cold induced and usually reversible.

Uncommom

For more detailed information regarding Oxaliplatin and 5fluorouracil please refer to the full current
summary of product characteristics (SPC).

Extravasation Risk Category

Drug Group Category

Oxaliplatin 2 Exfoliant
5fluorouracil 4 Inflammatory Agent

In the event of an extravasation occurring refer to local extravasation policy

Contraindications

• A known history of hypersensitivity to any of the drugs

• In pregnancy and lactation
• Myelosuppression prior to starting first course, as evidenced by baseline
9 9
neutrophils < 2x10 /l and/or platelet count of <100x10 /l.
• Peripheral sensory neuropathy with functional impairment prior to first course.

Page 3 of 6
WoSCAN CP OxMDG Adj CR version 1.0 March 2007
Precautions

• Chest pain, tachycardia, breathlessness and ECG changes may occur with 5fluorouracil
therefore careful monitoring should be performed in those patients with a history of heart
disease or those who develop chest pain during treatment.

• In the case of unexplained respiratory symptoms such as non-productive cough,

dyspnoea, hypoxia or radiological infiltrates Oxaliplatin should be interrupted pending
investigations. If interstitial pulmonary fibrosis is confirmed, permanently discontinue
Oxaliplatin.

Drug Interactions

Drug Interaction Action

Coumarin-derivative Increased INR Monitor INR twice weekly
anticoagulants
Clozapine Increased risk of agranulocytosis Avoid concomitant use

• Various agents have been reported to biochemically modulate the antitumour efficacy or
toxicity of 5FU, common drugs include Methotrexate, Metronidazole, Leucovorin as well as
Allopurinol and Cimetidine which canm affect the availability of the active drug – obtain advice
from pharmacy.

Investigations prior to subsequent cycles

Day 1 - FBC, CEA, LFTs, U&Es

- Monitor weight
- Delay until neutrophils ≥1.5 and platelets ≥ 75
- Calculated Cr Cl must be > 30 mls/min

Dose modifications

Specific dose adjustments may apply to Oxaliplatin and Fluorouracil if the toxicity experienced is
considered to be due solely to one drug.

Haematological – as per SPC11 and MOSAIC trial3

Treatment should be delayed until Neutrophils ≥ 1.5 x 10 9/l and/or platelets ≥ 75 x 10 9/l

Result Value Action

Neutrophils
(non-febrile neutropenia) 1 – 1.5 x 10 9/l Delay treatment until ≥ 1.5

Delay treatment until ≥ 1.5 and reduce Oxaliplatin

< 1 x 10 9/l dose to 75mg/m2 , 5fluorouracil 300mg/m2 and
2000mg/m2
Platelets
9
50 – 75 x 10 /l Delay treatment until ≥ 75

Delay treatment until ≥ 75 and reduce Oxaliplatin

< 50 x 10 9/l dose to 75mg/m2 , 5fluorouracil 300mg/m2 and
2
2000mg/m

Dose Modifications for febrile neutropenia should be made at the discretion of

the responsible consultant.

Page 4 of 6
WoSCAN CP OxMDG Adj CR version 1.0 March 2007
Non-haematological Symptoms – as per SPC & MOSAIC trial3

• Diarrhoea - grade 3 / 4 reduce oxaliplatin to 75 mg/m2, bolus fluorouracil to

300mg/m2 and fluorouracil infusion to 2000 mg/m2 and treatment
should be delayed until these toxicities are ≤ CTC (version 3) grade 1

• Stomatitis - grade 3 / 4 reduce oxaliplatin to 75 mg/m2, bolus fluorouracil to

300mg/m2 and fluorouracil infusion to 2000 mg/m2 and treatment
should be delayed until these toxicities are ≤ CTC (version 3) grade1.

• Palmer planter erythrodysaesthesia ( Hand-Foot syndrome)

- grade 3 / 4 reduce fluorouracil bolus to 300 mg/m2 and infusion to
2000 mg/m2 ONLY.

• Neurological symptoms (Paraesthesia, dysaethesia) see table below:

TOXICITY GRADE 1-7 days › 7 days Persistent

Acute laryngopharyngeal N/A Increase infusion Not applicable Not applicable
dysaesthesia duration to 6
hours
Paraesthesia that does not 1 No change No change No change
interfere with function
Paraesthesia that does 2 No change No change 75 mg/m2
interfere with function but not
Active Daily Living (ADL)
Paraesthesia with pain or 3 No change 75mg/m2 Discontinue
functional impairment that permanently
does interfere with ADL
Persistent paraesthesia that is 4 Discontinue Discontinue Discontinue
disabling or life-threatening permanently permanently permanently

Renal

If creatinine clearance < 30ml/min discuss with responsible consultant

Hepatic

Limited information available

• No studies performed with Oxaliplatin in severe hepatic impairment

• SPC advises to use fluorouracil with caution in patients with hepatic impairment

Evaluation of response to treatment

• CEA to be assessed with every cycle of chemotherapy

• Review by consultant within 1 month of treatment cessation to ensure follow-up policy is

adhered to

Page 5 of 6
WoSCAN CP OxMDG Adj CR version 1.0 March 2007
References

1. Andre, T., et al., Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.
N Engl J Med, 2004. 350(23): p. 2343-51.

2. de Gramont, A. and e. al., Oxaliplatin/5-FU/LV in the adjuvant treatment of stage II and stage III
colon cancer: efficacy results with a median follow-up of 4 years. Proc Am Soc Clin Oncol
2005, 2005. 23: Abstract 3501.

3. Andre T et al;Multicenter international study of oxaliplatin/5fluorouracil/leucovorin in the adjuvant

treatment of colon cancer (MOSAIC) investigators. NEng J Med 2004 Jun 3; 350(23): 2343-51
4. Gray, R., QUASAR: a randomized study adjuvant chemotherapy (CT) vs observation
including 3238 colorectal patients. Proc Am Soc Clin Oncol 2004, 2004. 22: Abstr
3501.

5. Compton, C., et al., Prognostic factors in colorectal cancer. College of American Pathologist
Consensus Statement 1999. Archives Pathology Laboratory Medicine, 2000. 124: p. 979- 994.

6. Mamounas, E., et al., Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B
versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel
Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol, 1999. 17(5): p. 1349-55.

7. Berger, A.C., et al., Colon cancer survival is associated with decreasing ratio of metastatic to
examined lymph nodes. J Clin Oncol, 2005.23(34): p8706-12.

8. Cockcroft & Gault, Nephron 16: 31-41,1976

9. Cancer Therapy Evaluation Program, Common Terminolgy Criteria for Adverse Events, Version
3.0, DCTD, NCI,NIH, DHHS March 31, 2003 (http://ctep.cancer.gov), Publish date: December
12, 2003
10. Scottish medicines consortium: Adjuvant treatment of patients following surgery for
stage 3 Duke’s C stage colon cancer; July 2005.

11. National Institute for Clinical Execellence: Improving outcomes in colorectal cancers
manual update; May 2004. Available from http://www.nice.org.uk/pdf/GSGCCfullguidance.pdf

12. Summary of product Characteristics for Oxaliplatin August 2006 http://emc.medicines.org.uk/

13. Summary of product Characteristics for 5Fluorouracil September 2005 http://emc.medicines.org.uk/

Prepared By: Sarah Wilson, John Milne and Jeff White

Checked and Approved by: BOC colorectal site specific team
Approved by: RCAG Prescribing Advisory Subgroup March 2007
Review date: March 2009

Page 6 of 6
WoSCAN CP OxMDG Adj CR version 1.0 March 2007