Oxaliplatin, 5-Fluorouracil & Folinic Acid (OxMdG) plus Panitumumab

Transcription

1 Oxaliplatin, 5-Fluorouracil & Folinic Acid (OxMdG) plus Panitumumab Available for Routine Use in Not routinely commissioned, each case requires prior documented approval before offering & commencing therapy from the Cancer Drugs Fund. Indication Metastatic colorectal cancer, provided: 1st line indication Patients with wild-type RAS No previous treatment with Panitumumab or Cetuximab Treatment Intent Palliative Anti-Emetics Pre-chemotherapy 3 Post-chemotherapy C Plus dexamethasone (see notes below) Day 1 Panitumumab 6mg/kg Intravenous infusion in 100ml sodium chloride 0.9% over 60 minutes* (Doses >1000mg over 90 minutes) Followed by: Levofolinic Acid 175mg Intravenous infusion in 250ml Dextrose 5% or Folinic acid 350mg over 2 hours (protected from light) Concurrently with: Oxaliplatin 85mg/m 2 Intravenous infusion in 250ml dextrose 5% over 2 hours Followed by: 5-Fluorouracil 400mg/m 2 Intravenous bolus over 5 minutes 5-Fluorouracil 2400mg/m 2 Intravenous infusion in 120ml sodium chloride 0.9% in 5ml/hr infusor device over 48 hours via PICC or Hickman line * Final concentration should not exceed 10mg/ml Frequency & duration: every 14 days until disease progression PAGE 1 of 8

2 Notes: 1. FBC, U&Es (including corrected calcium & magnesium) & LFTs must be taken prior to Day 1 of each cycle and NCI toxicity scores performed on clinical assessment. 2. The dose of panitumumab is calculated using body weight at baseline. For patients who are obese (BMI >30 approx), consideration should be given to capping doses of panitumumab using the following scheme: Patients height (cm) < Cap weight (kg) at: Panitumumab administration should always be administered immediately prior to OxMdG. 4. The infusion line should be flushed with sodium chloride solution before and after Panitumumab administration to avoid mixing with other medicinal products or intravenous solutions 5. Panitumumab should be administered using a 0.2 or 0.22 micron in-line filter. 6. Oxaliplatin must NEVER come into contact with sodium chloride 0.9%. Ensure all lines are primed & flushed with dextrose 5% ONLY 7. Oxaliplatin administration should always precede that of 5-fluorouracil. 8. Emesis is insignificant with the MdG regimen, but dexamethasone is included because of its possible anti-cancer effect, as follows: Dexamethasone 8mg stat pre-chemotherapy Oral Dexamethasone 4 mg tds for 1day; 4 mg bd for 1 day; 4 mg od for 1 day then stop, post-chemotherapy. For patients at high risk of steroid side effects (e.g. diabetics) or for those who develop toxicity attributable to steroids (e.g. dyspepsia; dysphoria; etc), the oral steroid should be omitted and p.r.n. oral 5HT3 inhibitor given. 9. Toxicity & dose modifications for OxMdG Haematological Delay 1 week if neutrophils < 1.5 x 10 9 /l or Platelets < 75 x 10 9 /l. Only treat when neutrophils and platelets are above these limits. If > 1 delay, or 1 delay of > 2 weeks occurs, reduce doses of Oxaliplatin & 5FU (bolus & Infusion) by 20% for subsequent doses. PAGE 2 of 8

3 If a further delay(s) for myelotoxicity occurs despite a 20% dose reduction, further dose adjustments may be made, at the clinicians discretion (e.g. a further 20% dose reduction). Neurotoxicity Oxaliplatin commonly causes transient paraesthesia of hands, feet and sometimes throat, precipitated by cold and lasting up to a few days after each dose. This does not require treatment or dose reduction. With cumulative dosing, some patients develop more severe neurotoxicity, requiring omission of oxaliplatin. For example: - persistent paraesthesia occurring in warm as well as cold conditions with significant discomfort - numbness with loss of function (eg dropping objects) or pain If one or more of these occur and persist through the cycle until the next dose is due, consider omitting oxaliplatin from the regimen for the remainder of the course. If OxMdG has been well tolerated apart from neurosensory toxicity, consideration should be given to increasing the infusional 5-FU dose from 2400 to 2800 mg/m 2 over 46 hours. Bolus 5-FU and folinate remain the same.. Renal Function Oxaliplatin, like carboplatin, is not nephrotoxic but is renally cleared. The Cockroft-Gault formula should be used to estimate renal function Males = Females = 1.23 x (140-Age) x Weight (kg) Serum Creatinine (micromol/l) 1.04 x (140-Age) x Weight (kg) Serum Creatinine (micromol/l) For patients with body mass index (BMI) of 40 kg/m2 with stable serum creatinine values, the ideal body weight should be used to estimate the GFR i.e. Ideal Body Weight Female IBW (kg) = Height in cm Male IBW (kg) = Height in cm A Cockroft/Gault estimate of 50 ml/min is accepted as evidence of adequate renal function. Patients with a Cockcroft/Gault estimate of < 50 ml/min prior to randomisation should have formal GFR measurement with EDTA or 24 urinary creatinine, which must be within the normal range. The corrected EDTA clearance should be 50ml/min. PAGE 3 of 8

4 After the start of treatment, if the Cockroft/Gault estimate falls by >25% from baseline, to below 50 ml/min, the EDTA measurement should be rechecked. Check serum creatinine at each cycle. If this rises >25%, re-check EDTA clearance, and adjust oxaliplatin dose according to the table below GFR (ml/min) Oxaliplatin Dose 50 Full Full <30 Do not give Deteriorating organ function may be a sign of disease progression, so always discuss with the consultant oncologist. A CEA marker rise of > 20% from pre chemotherapy baseline will require a Consultant review. Stomatitis Good oral hygiene is recommended. If mouth ulcers occur despite this, reduce the 5FU doses (bolus and infusion) by 20% and continue at the lower dose for subsequent cycles unless further toxicity occurs. If further toxicity occurs, reduce 5FU (bolus and infusion) and oxaliplatin doses by a further 20%. Diarrhoea For diarrhoea occurring between cycles, treat symptomatically initially: loperamide 2-4 mg qds. and/or codeine phosphate mg qds. as required. If diarrhoea has not resolved by the time the next cycle is due, delay 1 week. If diarrhoea is a problem despite symptomatic treatment, or if more than one delay is required, reduce the oxaliplatin and 5FU (bolus and infusion) doses by 20% and continue at the lower dose for subsequent cycles unless further toxicity occurs. Hand-foot syndrome (HFS) Treat symptomatically. Pyridoxine 50 mg tds by mouth or topical corticosteroid may help. If HFS is still a problem, reduce the 5FU doses (bolus and infusion) by 20% for subsequent cycles. PAGE 4 of 8

5 DPD deficiency; cardiotoxicity With any 5FU regimen, the occasional patient is encountered (approx. 1-3%) who has markedly exaggerated toxicity due to reduced catabolism. If this occurs, await full recovery. Further treatment at much reduced 5FU dose (e.g. 50%) or with single agent oxaliplatin may be considered. Please discuss with one of the clinical coordinators. Rarely, 5FU may provoke angina attacks or even MI in patients with ischaemic heart disease. In this event, the risk of continuing adjuvant therapy is likely to outweigh its benefits, and discontinuation is recommended. Hypomagnesaemia management Patients should be evaluated and, if hypomagnesaemia is present, replacement should be managed as per local medical practice. A patient s serum magnesium level should be at or above 0.41 mmol/l throughout the study. It is important to assess and manage serum potassium and ionized calcium (corrected for albumin) in patients who have hypocalcaemia. Allergic reactions to oxaliplatin Approx. 0.5% patients develop acute hypersensitivity to oxaliplatin, usually after more than 6 cycles. During drug administration, the patient may develop rash, fever, swollen mouth or tongue, hypo- or hypertension and other signs/symptoms of hypersensitivity. This rarely develops to fullblown anaphylaxis, even with repeated treatment. If acute hypersensitivity occurs, discontinue the infusion and treat with IV corticosteroid and antihistamine. After full recovery, the patient may continue with the MdG for that cycle. At the consultant s discretion, the patient may be rechallenged with oxaliplatin at the next cycle. In this case, premedication is recommended as follows: - Dexamethasone 4mg p.o. 6 hourly starting 24 hours pre-treatment, + 8mg IV 30 minutes pre-dose. - Chlorphenamine 10mg + ranitidine 50mg IV 30 minutes pre-dose. - Continue dexamethasone, chlorphenamine and ranitidine for hours after treatment with oxaliplatin. 10. Panitumumab hypersensitivity reactions About 3% of patients treated with panitumumab have experienced infusionrelated reactions, including chills, dyspnoea, flushing, hypertension, hypotension, pyrexia, tachycardia and vomiting, with most infusion reactions being mild to moderate (NCI-CTC grade 2) in severity. Severe infusion PAGE 5 of 8

6 reactions (anaphylaxis, angioedema, bronchospasm, cardiorespiratory arrest and hypotension), occur in less than 1% of patients treated and, very rarely (<1 in 10,000), can be fatal. As of January 2012, three of over 75,000 patients with mcrc treated with panitumumab have died following hypersensitivity reactions. A fatal case of angioedema occurred 2 days after exposure, following a prior episode of angioedema that occurred 6 days after exposure. There have been two further post-marketing reports of hypersensitivity reactions with fatal outcomes during and immediately following an infusion of panitumumab. Both patients had previously experienced hypersensitivity reactions to cetuximab and oxaliplatin, respectively. Panitumumab is, therefore, contraindicated in patients with a history of severe or life threatening hypersensitivity reactions. Serious infusion-related reactions are unpredictable and can occur suddenly. Panitumumab should be permanently discontinued if a severe or life threatening reaction occurs. In patients experiencing a mild or moderate infusion-related reaction, the infusion rate should be reduced for the duration of that infusion. It is recommended to maintain this lower infusion rate in all subsequent infusions. Hypersensitivity reactions occurring more than 24 hours after infusion have also been reported. Patients should be warned of the possibility of a late onset reaction, made aware of possible symptoms and instructed to contact their physician if symptoms of a hypersensitivity reaction occur. PAGE 6 of 8

7 Panitumumab dermatological toxicity Dermatologic related reactions, a pharmacologic effect observed with epidermal growth factor receptor (EGFR) inhibitors, are experienced with nearly all patients (approximately 90%) treated with Panitumumab. Severe (NCI-CTC grade 3) skin reactions were reported in 34% and lifethreatening (NCI-CTC grade 4) skin reactions in < 1% of patients who received Panitumumab in combination with chemotherapy. I f a patient develops dermatologic reactions that are grade 3 (CTCAE v 4.0) or higher, or that are considered intolerable, the following dose modification is recommended: Occurrence of skin symptom(s): grade 3 1 Administration of Panitumumab Outcome Dose regulation Initial occurrence Withhold 1 or 2 doses Improved (< grade 3) Continuing infusion at 100% of original dose At the second occurrence Not recovered Withhold 1 or 2 doses Improved (< grade 3) Not recovered At the third occurrence Withhold 1 or 2 doses Improved (< grade 3) Not recovered At the fourth occurrence Discontinue Greater than or equal to grade 3 is defined as severe or life-threatening Discontinue Continuing infusion at 80% of original dose Discontinue Continuing infusion at 60% of original dose Discontinue Patients who have severe dermatologic reactions or soft tissue toxicity or who develop worsening reactions whilst receiving Panitumumab should be monitored for the development of inflammatory or infectious sequelae (including cellulitis and necrotising fasciitis), and appropriate treatment promptly initiated. Life threatening and fatal infectious complications including necrotising fasciitis and sepsis have been observed in patients treated with Panitumumab. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Panitumumab in the post-marketing setting. Withhold or discontinue Panitumumab in the event of dermatologic or soft tissue toxicity associated with severe or life threatening inflammatory or infectious complications. Treatment of dermatologic reactions should be based on severity and may include a moisturiser, sun screen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) applied to affected areas, and/or oral antibiotics. It is also recommended that patients experiencing rash/dermatological toxicities wear sunscreen and hats and limit sun exposure as sunlight can exacerbate any skin reactions that may occur. PAGE 7 of 8

8 Proactive skin treatment including skin moisturiser, sun screen (SPF > 15 UVA and UVB), topical steroid cream (not stronger than 1% hydrocortisone) and an oral antibiotic (e.g. doxycycline) may be useful in the management of dermatologic reactions. Patients may be advised to apply moisturiser and sunscreen to face, hands, feet, neck, back and chest every morning during treatment, and to apply the topical steroid to face, hands, feet, neck, back and chest every night during treatment Panitumumab non-dermatological toxicity In single-agent panitumumab studies, grade 1-2 diarrhoea, nausea, vomiting, abdominal pain and fatigue have been reported. In ongoing trials of combination chemotherapy + anti-egfr therapy, the addition of antibody increases the incidence of nausea, vomiting and diarrhoea. It is therefore possible that panitumumab may contribute to a range of toxicities when given in combination with OxMdG. Panitumumab delays If a chemotherapy cycle is delayed for chemotherapy-related reasons (e.g. neutropenia), panitumumab is also delayed, and given alongside the chemotherapy when next administered. References: 1. FOxTROT Trial protocol, version 6, 9 th July Panitumumab Summary of Product Characteristics Last Updated on emc 13-Apr-2015 (Accessed 24/4/15) PAGE 8 of 8