Comparative net cost impact of the utilization of panitumumab versus cetuximab for the treatment of patients with metastatic colorectal cancer in Canada

Abstract

Objective:

Clinical practice guidelines support the use of the epidermal growth factor receptor (EGFR) inhibitors panitumumab and cetuximab for the treatment of metastatic colorectal cancer (mCRC) after failure of other chemotherapy regimens, based on significant clinical benefits in patients with wild-type KRAS. The purpose of the analysis was to compare provincial hospital costs when using panitumumab vs cetuximab with or without irinotecan in this patient population using a Net Impact Analysis (NIA) approach.

Methods:

The NIA determined the total per patient cost of the reimbursed regimens of panitumumab vs cetuximab in British Columbia, Alberta, Manitoba, Ontario, and Québec. Utilization of healthcare resources related to EGFR inhibitor infusions, follow-up monitoring, and treatment of adverse events (AEs) were also included. Healthcare resource use including drugs, medical supplies, laboratory testing, oncology infusion time, and healthcare professionals’ time was obtained through expert consultation and the use was then multiplied by the province-specific cost of each resource. Numerous sensitivity analyses were conducted.

Results:

Based on the dosing regimens in place in each province, the total annual per patient cost of panitumumab ranged from $22,203–$32,600, while the total annual per patient cost of cetuximab treatment varied from $30,321–$40,908. Treatment with panitumumab resulted in lower costs in all cost categories including drug acquisition, infusion preparation/administration, patient monitoring, and AE management. Per patient savings with panitumumab ranged from a low of $3815 in British Columbia to a high of $10,603 in Ontario. In sensitivity analyses, panitumumab remained cost saving in all scenarios where the savings ranged from $150–$16,006 per patient.

Conclusions:

Treating chemorefractory mCRC patients with panitumumab rather than cetuximab reduced healthcare resource costs. Provincial healthcare savings achieved with the use of panitumumab could potentially be re-allocated to other cancer treatments, although further study would be needed to validate this assumption.

Keywords::

• Panitumumab
• Cetuximab
• mCRC
• Net cost impact
• Economic analysis
• Reimbursement

Introduction

Panitumumab and cetuximab are monoclonal antibodies that specifically target the epidermal growth factor receptor (EGFR). Both are indicated for the treatment of patients with EGFR-expressing metastatic colorectal carcinoma (mCRC) with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens1^,2. The recommended dose of panitumumab is 6 mg/kg, given once every 2 weeks as monotherapy. The recommended dose of cetuximab is 400 mg/m² initially, followed by a weekly dose of 250 mg/m².

A phase III, randomized, controlled, multi-center trial of patients with mCRC that had progressed following treatment with fluoropyrimidine, irinotecan, and oxaliplatin demonstrated that panitumumab plus best supportive care (BSC) improved progression-free survival (PFS) compared with BSC alone (p < 0.0001)3. After 2 years of follow-up, no difference was observed in overall survival (OS) and this finding was likely confounded by the study design whereby patients in the BSC arm with disease progression were permitted to cross over and receive panitumumab. A subsequent analysis done by Amado et al.4 using the data from the pivotal trial by Van Cutsem et al. showed that the treatment effect of panitumumab on PFS in the wild-type (WT) KRAS group was significantly greater (p < 0.0001) than in the mutant group.

Cetuximab was similarly assessed in a trial comparing cetuximab to BSC in patients with mCRC who had been previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin, or had contraindications to treatment with these drugs5. In contrast with the panitumumab study, the cetuximab trial did not allow for patient crossover following disease progression. The study demonstrated an improvement in PFS and OS. As with the panitumumab trial, a retrospective biomarker analysis of the cetuximab study demonstrated that the WT KRAS status was required for cetuximab efficacy6. An earlier study of cetuximab examined the relative efficacy of cetuximab monotherapy vs cetuximab plus irinotecan in mCRC patients refractory to irinotecan7. In this study, the response rate was significantly higher with combination therapy compared with monotherapy (p = 0.007). The impact of the KRAS biomarker was unknown at the time of this analysis, so efficacy results from this study assessed by KRAS status remain unknown.

The two monoclonal antibodies have been compared directly in a randomized, multi-center, open-label, phase III study called ASPECCT8. The study enrolled adult patients with WT KRAS mCRC, ECOG performance status of 0–2, prior irinotecan, oxaliplatin and fluorouracil-based treatment for mCRC, and no prior anti-EGFR treatment. Patients were randomized to panitumumab 6 mg/kg every 2 weeks (n = 499) or cetuximab 400 mg/m² followed by 250 mg/m² weekly (n = 500) until disease progression, intolerability, consent withdrawal, or death. Cross-over between treatments was not permitted. The primary end-point of the study was OS. The authors concluded that non-inferiority of OS was met, whereby median overall survival was 10.4 months (95% CI = 9.4–11.6) with panitumumab and 10.0 months (9.3–11.0) with cetuximab (HR 0.97; 95% CI = 0.84–1.11). The incidences of grade 3–4 skin toxicity, grade 3–4 infusion reactions, and grade 3–4 hypomagnesaemia for panitumumab vs cetuximab were 13%/10%, 0.5%/2%, and 7%/3%, respectively. The observed safety profiles between the two treatment arms were consistent with previously reported studies for both agents.

Differences in EGFR inhibitor drug acquisition cost between cetuximab and panitumumab were identified in the respective national oncology drug reviews previously conducted. However, it is not clear whether additional healthcare costs beyond drug acquisition were considered in the review. Because panitumumab is dosed once every 2 weeks and cetuximab is administered weekly, panitumumab may further reduce the cost of EGFR inhibitor in mCRC relative to cetuximab, due to differences in other healthcare resource consumption (e.g., nursing time, infusion supplies), thereby resulting in further savings to the overall provincial healthcare budget. The purpose of this analysis was to compare the total hospital costs of using panitumumab vs cetuximab in several provinces of Canada in the approved patient population using a net impact analysis (NIA) approach.

Patients and methods

A net cost impact model was constructed to capture all hospital costs related to the use of panitumumab or cetuximab in each province. The number of chemotherapy cycles included was based on either the allowable duration of treatment of mCRC according to reimbursement funding or according to expert opinion, in the absence of reimbursement, in each province. The duration of treatment ranged from 14–20 weeks. The costs included: the drug acquisition costs; costs related to preparation and administration of the medications; patient follow-up monitoring costs; and costs related to the treatment of adverse events (AEs). The provinces included in the analysis were British Columbia, Alberta, Manitoba, Ontario, and Québec.

The analysis was conducted from the perspective of the provincial hospital or cancer care budgets. Physician fees were not included because they are covered by the provincial health ministries rather than the hospitals or cancer care centres. Similarly, costs to determine patients’ KRAS status (i.e., WT or mutant) were not included because these costs are generally borne by the manufacturers of the EGFR inhibitor, occur prior to the decision regarding which EGFR inhibitor to use, and are the same, irrespective of which EGFR inhibitor will be used in the KRAS WT patients.

The time horizon for the analysis (14–20 weeks) was based on the standards of care in each province regarding the median number of infusions of each EGFR inhibitor that would be recommended. According to the pivotal studies, the duration of treatment required to derive a benefit in PFS was 7 biweekly cycles with panitumumab monotherapy3, and 16 weekly cycles with cetuximab monotherapy5. However, the clinical practices and EGFR inhibitor reimbursement in place in each province vary as follows: British Columbia recommends 10 infusions of panitumumab or cetuximab plus irinotecan where both regimens are infused every 2 weeks; Alberta recommends seven infusions of panitumumab biweekly or 14 infusions of cetuximab weekly; Manitoba recommends 10 biweekly and 20 weekly infusions of panitumumab or cetuximab, respectively; Ontario recommends nine biweekly infusions of panitumumab or 18 weekly infusions of cetuximab plus nine biweekly infusions of irinotecan; clinicians in Québec recommend seven infusions of panitumumab biweekly or 16 infusions of cetuximab weekly. The dosing regimens selected for the analysis were based on the funding protocols in place in each province that are aligned with the dosing schedule approved in the respective product monographs1^,2 (except in British Columbia where cetuximab is dosed biweekly rather than weekly).

Table 1 outlines the calculations used to derive the total average dose of panitumumab or cetuximab required per infusion. Briefly, the recommended dose according to each product monograph1^,2 was multiplied by a commonly assumed body weight (70 kg) or body surface area (1.73 m²). The total dose required per infusion was then divided by the number of milligrams per vial of the available formats for each EGFR inhibitor. The cost of the EGFR inhibitor treatment per cycle was then multiplied by the respective number of cycles of each treatment funded in each province.

Table 1. Calculated average EGFRi dose and number of vial requirements in each province.

	British Columbia	Alberta	Manitoba	Ontario	Québec
Panitumumab
Dose requirement	6 mg/kg × 70 kg^a= 420 mg over 60 min every 2 weeks 5 mL vial of 20 mg/mL = 100 mg per vial 5 vials required per infusion
No. of infusions	10	7	10	9	7
Cetuximab
Dose requirement	500 mg/m^2× 1.73 ^a m^2= 865 mg every 2 weeks, given over 120 min in cycle 1 and over 60 min thereafter 4 vials × 200 mg/100 mL plus 1 vial × 100 mg/50 mL	Initial dose: 400 mg/m^2× 1.73^a m^2= 692 mg over 120 min in week 1 3 vials × 200 mg/100 mL plus 1 vial × 100 mg/50 mL, or 7 vials × 100 mg/50 mL Subsequent weekly dose: 250 mg/m^2× 1.73 m^2= 433 mg over 60 min weekly 2 vials × 200 mg/100 mL plus 1 vial × 100 mg/50 mL, or 5 vials of 100 mg vials
No. of infusions	10	14	20	18	16
Pre-medication with cetuximab	Dexamethasone 8 mg oral plus 50 mg of diphenhydramine oral 45 min prior to cetuximab infusion	50 mg of diphenhydramine IV 45 min prior to cetuximab infusion
Irinotecan	180 mg/m^2 given over 90 min every 2 weeks for 10 infusions	Not reimbursed for combination	Not reimbursed for combination	180 mg/m^2 given over 90 min every 2 weeks for 9 infusions	Not reimbursed for combination
Pre-medication with irinotecan	None	None	None	Anzemet 100 mg IV, Decadron 10 mg IV, Atropine 0.4 mg/ml and Decadron 4 mg PO	None

^aThe average patient with mCRC was assumed to weigh 70 kg or have 1.73 m² of body surface area.

The average utilization of all healthcare resources was obtained through consultation with a minimum of one pharmacist or one physician in each province. The number of healthcare practitioners interviewed in each province was three in British Columbia and Alberta, two in Québec, and one from Manitoba and Ontario. Nursing time was collected by one author (MP) through consultation with nurses in Québec who administer IV infusions, and these Québec estimates were further validated by physicians or pharmacists in the other provinces. Detailed interviews were conducted to obtain the personnel time, medical supplies, and infusion time9 required for treating mCRC patients with EGFR inhibitor and pre-medication (Table 2) and patient follow-up and monitoring resources (Table 3).

Table 2. Resources involved in the preparation and administration of the medications.

	British Columbia	Alberta	Manitoba	Ontario	Québec
Panitumumab
Drug preparation	Pharmacist time: • 30 min per script for patient file review and dose calculation of panitumumab  Assistant tech time: • 20 min per script for drug preparation	Pharmacist time: • 15 min per first script • 10 min for subsequent scripts  Assistant tech time: • 15 min per script for drug preparation	Pharmacist time: • 15 min per first script • 10 min for subsequent scripts  Assistant tech time: • 15 min per script for drug preparation	Pharmacist time: • 15 min per first script • 10 min for subsequent scripts • 15 min per script for drug preparation	Pharmacist time: • 15 min per first script • 10 min for subsequent scripts  Assistant tech time: • 15 min per script for drug preparation
Drug administration	Nursing time: • 30 min/infusion for IV line set up, injection access and removal, plus 15 min/infusion for supervision during infusion	Nursing time: • 30 min/infusion for IV line set up, injection access and removal, plus 15 min/infusion for supervision during infusion	Nursing time: • 30 min/infusion for IV line set up, injection access and removal, plus 15 min/infusion for supervision during infusion	Nursing time: • 30 min/infusion for IV line set up, injection access and removal, plus 15 min/infusion for supervision during infusion	Nursing time: • 30 min/infusion for IV line set up, injection access and removal, plus 15 min/infusion for supervision during infusion
	Medical supplies: 10 of each: • Needles (18G) and syringes (10 mL) • Second line IV infusion system • NaCl 0.9% solution (100 ml) • Filters 0.22 micron • Needles (22 G) and syringes (30 mL) • Paclitaxel infusion set	7 of each: • Needles and syringes • Second line IV infusion system • NaCl 0.9% solution (100 ml) • Filters	10 of each: • Needles and syringes • Second line IV infusion system • NaCl 0.9% solution (100 ml) • Filters	9 of each: • Needles and syringes • Second line IV infusion system • NaCl 0,9% solution (100 ml) • Dextrose 5% (250 ml)	7 of each: • Needles and syringes • Second line IV infusion system • NaCl 0.9% solution (100 ml) • Filters
	Infusion chair time:^a • 30 min/infusion for IV line set up, injection access and removal plus 60 min for drug infusion	Infusion chair time:^a • 30 min/infusion for IV line set up, injection access and removal plus 60 min for drug infusion	Infusion chair time:^a • 30 min/infusion for IV line set up, injection access and removal plus 60 min for drug infusion	Infusion chair time:^a • 30 min/infusion for IV line set up, injection access and removal plus 60 min for drug infusion	Infusion chair time:^a • 30 min/infusion for IV line set up, injection access and removal plus 60 min for drug infusion
Cetuximab
Drug preparation	Pharmacist time: • 30 min per script for patient file review and dose calculation of cetuximab and pre-medication Assistant technician time: • 30 min per script for drug preparation Nursing time: • 5 min review pre-medication script	Pharmacist time: • 20 min per first script • 10 min for subsequent scripts Assistant technician time: • 15 min per script for drug preparation Nursing time: • 5 min review premedication script	Pharmacist time: • 20 min per first script • 10 min for subsequent scripts Assistant technician time: • 15 min per script for drug preparation Nursing time: • 5 min review pre-medication script	Pharmacist time: • 20 min per first script for patient file review and dose calculation • 10 min for subsequent • 17 min for cetuximab and pre-medication preparation • 10 min for the first irinotecan script for patient file review and dose calculation • 4 min for subsequent scripts request • 17 min per script for irinotecan and pre-medication preparation	Pharmacist time: • 20 min per first script • 10 min for subsequent scripts Assistant technician time: • 17 min per script for drug preparation
Drug administration	Nursing time:  Per infusion: • 30 min for IV line set-up, injection access and removal • 30 min for supervision during the first drug infusion • 15 min during subsequent infusions	Per infusion: • 30 min for IV line set-up, injection access and removal • 30 min for supervision during the first drug infusion • 15 min during subsequent infusions • 10 min for pre-medication	Per infusion: • 30 min for IV line set-up, injection access and removal • 30 min for supervision during the first drug infusion • 15 min during subsequent infusions • 10 min for pre-medication	Per infusion: • 30 min for IV line set-up, injection access and removal • 30 min for supervision during the first drug infusion • 15 min during subsequent infusions • 10 min for pre-medication • 10 min for dextrose IV line set-up • 20 min for supervision during irinotecan • 10 min Anzemet administration • 1 min Decadron • 1 min atropine	Per infusion: • 30 min for IV line set-up, injection access and removal • 30 min for supervision during the first drug infusion • 15 min during subsequent infusions • 10 min for pre-medication
	Medical supplies: 50 of each: • Syringes, 60 mL • Chemo pins • Tip caps (non-luer lock) 10 of each: • Needles 18Gx1" • Syringes 10 mL • Second line IV infusion system • filters 0.22 micron • NaCl 0.9%, 50 mL • Viaflex bag, 250 mL • Paclitaxel set • Universal spike	28 of each: • Needles and syringes • Second line IV infusion system 14 of each: • Filters • Mini-bag NaCl • Viaflex bag, 500 mL	40 of each: • Needles and syringes • Second line IV infusion system • Filters 20 of each: • Mini-bag NaCl • Viaflex bag 500 mL	18 of each: • Primary IV line for NaCl • NaCl 0.9%, 250 mL 9 of each: • Primary IV lines for dextrose • Dextrose 5%, 250 mL Cetuximab plus pre-medication 36 of each: • Second IV lines for cetuximab and pre-medication • Needles, syringes • Filters, 22 micron 18 of each: • Viaflex bag 500 mL • mini-bags reg. NaCl 50 ml Irinotecan and its pre-medication 36 of each: • Syringes for irinotecan, Anzemet, Decadron, atropine 18 of each: • Second IV lines for irinotecan and Anzemet • Needles for irinotecan and Anzemet • Multi-ad luer caps 9 of each: • Filters for irinotecan • Needles 21G for irinotecan bag preparation • Dextrose 5%, 500 mL • NaCL 0.9%, 50 mL for Anzemet	32 of each: • Needles and syringes • Second line IV infusion system • Filters 16 of each: • Mini-bag NaCl • Viaflex bag, 500 mL
	Infusion chair time:^a Per infusion: • 30 min for IV line set-up, injection access and removal • 120 min for first infusion • 60 min for subsequent infusions • 45 min pre-medication infusion plus waiting time post-infusion • 90 min for Irinotecan	Per infusion: • 30 min for IV line set-up, injection access and removal • 120 min for first drug infusion • 60 min for subsequent infusions • 60 min pre-medication infusion plus waiting time post-infusion	Per infusion: • 30 min for IV line set-up, injection access and removal • 120 min for first drug infusion • 60 min for subsequent infusions • 60 min pre-medication infusion plus waiting time post-infusion	Per infusion: • 40 min for IV line set-up, injection access and removal and dextrose line set-up • 120 min for first drug infusion • 60 min for subsequent infusions • 60 min pre-medication infusion plus waiting time post-infusion • Irinotecan: 90 min • Antiemetic: 12 min	Per infusion: • 30 min for IV line set-up, injection access and removal • 120 min for first drug infusion • 60 min for subsequent infusions • 60 min pre-medication infusion plus waiting time post-infusion

^aInfusion chair time refers to overhead cost (maintenance, security, energy, hospital administration) for a chemotherapy department based on hemato-oncology department statistic data from an average size hospital in Québec9.

G, gauge; IV, intravenous; min, minute(s); NaCl, sodium chloride (saline).

Table 3. Patient follow-up and safety monitoring resources.

	British Columbia	Alberta	Manitoba	Ontario	Québec
Panitumumab
Personnel time per infusion	Nursing:  • 30 min for first education • 10 min for subsequent consultations • 8 min for blood withdrawal	Nursing: • 30 min for first education • 10 min for subsequent consultations Laboratory assistant: • 8 min for blood withdrawal		Nursing: • 30 min for first education • 10 min for subsequent consultations Phlebotomist: • 8 min for blood withdrawal	Pharmacist: • 30 min for first education • 10 min for subsequent consultations Nursing: • 8 min for blood withdrawal
Laboratory tests	At baseline: CBC, liver function • At each cycle and monthly for 2 months after last infusion: • Ca, Mg At each oncology visit: • Carcinoembryonic antigen (CEA) Every 8 weeks: • CT scan	Prior to each cycle: • CBC, Ca, Mg At each oncology visit: • Liver function and CEA Every 8 weeks: • CT scan		Prior to each cycle: • CBC, Ca, Mg At each oncology visit: • Liver function and CEA Every 8 weeks: • CT scan	Prior to each cycle: • CBC, Ca, Mg At each oncology visit: • Liver function and CEA Every 8 weeks: • CT scan
Cetuximab
Personnel time per infusion	Nursing: • 30 min for first education • 10 min for subsequent consultations • 15 min for monitoring patient after the end of each infusion • 8 min for blood withdrawal	Nursing: • 30 min for first education • 10 min for subsequent consultations • 15 min for monitoring patient after the end of each infusion Lab assistant: • 8 min for blood withdrawal		Nursing: • 30 min for first education • 10 min for subsequent consultations • 15 min for monitoring patient after the end of each infusion Phlebotomist: • 8 min for blood withdrawal	Pharmacist: • 30 min for first education • 10 min for subsequent consultations Nursing: • 15 min for monitoring patient after the end of each infusion Phlebotomist: • 8 min for blood withdrawal
Laboratory tests^a	At baseline: CBC, liver function • Prior to each cycle and monthly for 2 months after last infusion: • Ca, Mg At each oncology visit: • CEA Every 8 weeks: • CT scan	Prior to each cycle: • CBC, Ca, Mg At each oncology visit: • Liver function, CEA Every 8 weeks: • CT scan		Prior to each cycle: • CBC, Ca, Mg At each oncology visit: • Liver function, CEA Every 8 weeks: • CT scan	Prior to each cycle: • CBC, Ca, Mg At each oncology visit: • Liver function, CEA Every 8 weeks: • CT scan
Infusion chair time^b	Patients remain in chair for 60 min after each infusion of cetuximab	Patients remain in chair for 60 min after each infusion of cetuximab		Patients remain in chair for 60 min after each infusion of cetuximab	Patients remain in chair for 60 min after each infusion of cetuximab

^aDoes not include tests to monitor safety of irinotecan.

^bInfusion chair time refers to overhead cost (maintenance, security, energy, hospital administration) for a chemotherapy department based on hemato-oncology department statistic data from an average size hospital in Québec9.

Ca, calcium; CBC, complete blood count; CEA, carcinoembryonic antigen; CT, computed tomography; Mg, magnesium; min, minute(s).

Personnel time, medication, and medical supplies costs required for the management of adverse events (AEs) due to EGFR inhibitor treatment were also obtained through consultation with pharmacists, physicians, and nurses (Table 4). Only the most frequently observed AEs (e.g., infusion reactions, grade 1 or 2 and grade 3 or 4 rash, and grade 3 or 4 hypomagnesemia) thought to be due to EGFR inhibitor treatment were included in the analysis. Incidence rates for each AE were obtained from the respective product monographs for panitumumab and cetuximab, and it was assumed that the AEs would occur in actual practice with the same incidence as reported in the product monographs. To be conservative, the treatment for severe (i.e., grade 3 or 4) infusion reactions was not included. Although the cost of severe infusion reactions is likely high (it has been estimated to be US$13,174 per episode10), the cost varies widely across patients, and reported incidences are rare and similar between the treatments (i.e., less than 1% with panitumumab1 and 2% with cetuximab5). For hypomagnesemia, because there is little data available reporting on the treatment duration with grade 3 or 4 cases, it was assumed that hypomagnesemia would occur 3 weeks after the first infusion of panitumumab or cetuximab treatment and patients would be treated with magnesium sulphate until the end of therapy3^,11.

Table 4. Resources utilized in managing adverse events related to EGFRi treatment.

	British Columbia	Alberta	Manitoba	Ontario	Québec
Treatments to manage adverse events
Infusion reaction (all grades) Incidences: Panitumumab, 3% Cetuximab, 21%	• Solumedrol IV 100 mg • Ranitidine 50 mg IV • 30 min nursing time	• Diphenhydramine 50 mg IV • 30 min nursing time	• Diphenhydramine 50 mg IV • 30 min for nursing time	• Diphenhydramine 50 mg IV • 30 min nursing time	• Diphenhydramine 50 mg IV • 60 min nursing time
Rash grade 1–2 Incidences: Panitumumab, 75%^a Cetuximab, 82%^b	• Hydrocortisone cream 1% • Clindamycin cream 2% • Minocycline 100 mg bid for 4 weeks	• Hydrocortisone cream 1% • Minocycline 100 mg bid for 8 weeks	• Hydrocortisone cream 1% • Minocycline 100 mg bid for 4 weeks • Clindamycin cream 2%	• Hydrocortisone cream 1% • Minocycline 100 mg bid for 4 weeks • Clindamycin lotion 1%	• Hydrocortisone cream 1% • Minocycline 100 mg bid for 4 weeks
Rash grade 3 Incidences: Panitumumab, 14%^a Cetuximab, 8%^b	• Hydrocortisone cream 1% • Clindamycin cream 2% • Minocycline 100 mg bid for 4 weeks	• Hydrocortisone cream 1% • Minocycline 100 mg bid for 8 weeks • Methylprednisolone 4 mg per day for 21 days	• Hydrocortisone cream 1% • Minocycline 100 mg bid for 4 weeks • Clindamycin cream 2%	• Hydrocortisone cream 1% • Minocycline 100 mg bid for 4 weeks • Clindamycin lotion 1% • Triamcinolone acetonide 0.1%	• Hydrocortisone cream 1% • Minocycline 100 mg bid for 4 weeks • Methylprednisolone 4 mg/day for 21 days
Hypomagnesemia grade 3–4^c Incidences: Panitumumab, 3% Cetuximab, 5.8%	• 2 g of Mg sulphate IV over 30 min every cycle At each infusion: • Chair time^d: 30 min • Nurse time: 7.5 min • Medical supplies: NaCl 0.9% 500 mL, needles, syringes, and second line IV infusion system	• 4 g of Mg sulphate IV over 3 h every week At each infusion: • Chair time^d: 180 min • Nurse time: 60 min • Medical supplies: NaCl 0.9% 500 mL, needles, syringes, and second line IV infusion system	• 5 g of Mg sulphate IV over 3 h every cycle At each infusion: • Chair time^d: 180 min • Nurse time: 60 min • Medical supplies: NaCl 0.9% 500 mL, needles, syringes, and second line IV infusion system	• 5 g of Mg sulphate IV over 3 h every cycle At each infusion: • Chair time^d: 180 min • Pharmacist time: 13 min • Nurse time: 60 min • Medical supplies: NaCl 0.9% 500 mL, needles, syringes, and second line IV infusion system	• 5 g Mg sulphate IV over 3 h every infusion At each infusion: • Chair time^d: 180 min • Pharmacist time: 5 min • Assistant technician time: 8 min • Nurse time: 60 min • Medical supplies: NaCl 0.9% 500 mL, needles, syringes, and second line IV infusion system

^aRash with panitumumab included all skin and subcutaneous tissue disorders.

^bRash with cetuximab included only acne, rash, maculopapular rash, pustular rash, dry skin, and exfoliative dermatitis.

^cThere were no data available for treatment duration or occurrence of grade 3/4 hypomagnesaemia; the analysis assumed that hypomagnesaemia occurs 3 weeks after the first infusion of EGFRi and patients would be treated with magnesium sulphate until the end of therapy. The total cost includes professional time, infusion chair time, and medical supplies.

^dInfusion chair time refers to overhead cost (maintenance, security, energy, hospital administration) for a chemotherapy department based on hemato-oncology department statistic data from an average size hospital in Québec9.

bid, twice daily; CBC, complete blood count; d, day; IV, intravenous; Mg, magnesium; min, minute(s); NaCl, sodium chloride (saline).

Unit costs for all healthcare resources identified in Tables 1–4 were obtained from a variety of sources. The resources used and their respective unit costs in each province are shown in Table 5.

Table 5. Canadian provincial health resource unit costs.

Resource	Unit costs					Source
	BC	AB	MB	ON	QC
EGFRi and pre-medication drug costs
Panitumumab, 100 mg vial	$600.00					Amgen Canada
Cetuximab, 100 or 200 mg vial	$335.00 (100 mg) $670.00 (200 mg)					Bristol-Myers Squibb Canada
Pre-medication						Oncology department of each institution
With panitumumab	$0	$0	$0	$0	$0
With cetuximab	n/a	$57	$81	n/a	$59
With cetuximab + irinotecan	$23	n/a	n/a	$148	n/a
Irinotecan, per mg	$0.50	n/a	n/a	$0.50	n/a	Oncology department of each institution
Personnel hourly wage						Provincial health services collective agreements^a,b,c,d,e
Pharmacist	$51.95	$52.90	$53.95	$48.94	$44.79
Assistant pharmacy technician	$33.88	$32.81	$20.63	n/a	$18.15
Nursing	$43.56	$43.30	$49.90	$42.44	$39.36
Assistant laboratory technician	n/a	n/a	$22.48	n/a	n/a
Phlebotomist	n/a	n/a	n/a	$25.37	n/a
Medical supplies						Provincial hospital buying groups or cancer agency/board^f,g,h,i,j
With panitumumab	$256	$108	$98	$171	$51
With cetuximab	n/a	$369	$242	n/a	$271
With cetuximab + irinotecan	$511	n/a	n/a	$808	n/a
Infusion chair time^k per minute	$0.71					Hemato-oncology department statistical data from the Québec Ministry of Health9
Laboratory tests						Provincial Ministries of Health
Complete blood count	$10.88	$17.11	$11.95	$8.27	$1.30
Ca and Mg tests	$8.34	$32.87	$23.15	$5.18	$1.50
Liver function tests	$11.64	$88.52	$62.95	$28.47	$5.60
Carcinoembryonic antigen	$10.39	$54.78	$23.85	$25.00	$3.80
CT scan	$157.75	$480.97	$103.95	$250.00	$94.70

^aProvincial Agreement - Health Science professionals bargaining association and Health Employers Association of British Columbia.

^bAlberta Health Services Employees’ Collective Agreement, March 31, 2011.

^cCollective Agreement - Manitoba Association of Health Care Professionals and Winnipeg Regional Health Authority, March 31, 2010 and Collective Agreement - Winnipeg Regional Health Authority and Health Sciences Centre Nurses, March 31, 2010.

^dOntario Public Service Employees Union (OPSEU), March 1, 2012.

^eComité patronale de négociations de la santé et des services sociaux (CPNSSS) without social benefits.

^fBritish Columbia Cancer Agency.

^gAlberta Cross Cancer Institute.

^hCancer Care Manitoba.

ⁱBuyer’s group of Sunnybrook Hospital.

^jService d’approvisionnement de la Montérégie.

^kInfusion chair time refers to the overhead cost for a chemotherapy treatment and does not include nursing time.

Ca, calcium; CT, computed tomography; Mg, magnesium; n/a, not applicable.

Sensitivity analyses were performed to test the impact of changing assumptions on the study outcome. The sensitivity analyses were: (1) the use of pre-medication and irinotecan with cetuximab was removed (including the associated pharmacist and nursing time and infusion supplies); (2) lower (1.5 m²) and higher (1.9 m²) average body surface area was assumed; (3) lower (65 kg) and higher (80 kg) average body weights were assumed; (4) only EGFRi (plus irinotecan) drug costs were considered (i.e., all drug preparation, drug administration, safety monitoring, and AE treatment costs were excluded); and (5) adverse event rates reported in the ASPECCT study were incorporated rather than the rates reported in the respective product monographs.

Results

The total costs related to drug acquisition, medication preparation and administration, patient monitoring and follow-up, and treatment of AEs were substantially higher for cetuximab (with or without irinotecan) than for panitumumab in all provinces. Total costs for each cost category in provinces where cetuximab is used with or without irinotecan are shown in Figure 1. The total annual per patient costs of panitumumab ranged from $22,203–$32,600, while the total annual per patient costs of cetuximab and cetuximab plus irinotecan treatment varied from $30,321–$40,908 and $36,081–$39,910, respectively (Tables 6 and 7). Per patient savings with panitumumab ranged from a low of $3815 in British Columbia to a high of $10,603 in Ontario.

Figure 1. Total per patient costs of managing mCRC with panitumumab vs cetuximab in Canadian provinces.

Table 6. Total per patient costs of managing mCRC with panitumumab vs cetuximab.

	Alberta		Manitoba		Québec
	Panitumumab (7 infusions)	Cetuximab (14 infusions)	Panitumumab (10 infusions)	Cetuximab (20 infusions)	Panitumumab (7 infusions)	Cetuximab (16 infusions)
EGFRi	$21,000	$24,120	$30,000	$34,170	$21,000	$27,470
Pre-medication	n/a	$57	n/a	$81	n/a	$59
Drug preparation & administration
Professional time	$351	$864	$520	$1177	$294	$796
Medical supplies	$108	$369	$98	$242	$51	$271
Infusion chair time	$447	$1534	$639	$2173	$447	$1747
Sub-total	$906	$2767	$1257	$3592	$792	$2814
Monitoring
Professional time	$88	$313	$130	$492	$91	$346
Laboratory tests	$1885	$2235	$1097	$1448	$247	$272
Infusion chair time	$0	$596	$0	$852	$0	$682
Sub-total	$1973	$3145	$1227	$2792	$338	$1300
Adverse events management
Infusion reactions	$1	$5	$1	$6	$1	$9
Rash grade 1 or 2	$92	$102	$73	$80	$32	$35
Rash grade 3	$18	$11	$14	$8	$14	$8
Hypomagnesemia grade 3 and 4	$27	$116	$29	$179	$27	$134
Sub-total	$138	$233	$116	$273	$73	$185
Total cost	$24,017	$30,321	$32,600	$40,908	$22,203	$31,828
Incremental cost of Cetuximab	$6304 (26% higher)		$8308 (25% higher)		$9625 (43% higher)

EGFRi, epidermal growth factor receptor inhibitor; mCRC, metastatic colorectal cancer.

Table 7. Total per patient costs of managing mCRC with panitumumab vs cetuximab plus irinotecan.

	British Columbia		Ontario
	Panitumumab (10 infusions)	Cetuximab plus Irinotecan (10 infusions)	Panitumumab (9 infusions)	Cetuximab (18 infusions) plus Irinotecan (9 infusions)
EGFRi	$30,000	$30,150	$27,000	$30,820
Irinotecan	n/a	$1700	n/a	$1530
Pre-medication	n/a	$23	n/a	$148
Drug preparation & administration
Professional time	$699	$803	$474	$1542
Medical supplies	$256	$511	$171	$808
Infusion chair time	$639	$1640	$575	$2675
Sub-total	$1594	$2954	$1220	$5025
Monitoring
Professional time	$93	$202	$108	$393
Laboratory tests	$469	$469	$888	$1009
Infusion chair time	$0	$426	$0	$767
Sub-total	$562	$1097	$997	$2170
Adverse events management
Infusion reactions	$1	$6	$1	$5
Rash grade 1 or 2	$54	$59	$43	$47
Rash grade 3	$10	$6	$7	$4
Hypomagnesemia grade 3 and 4	$45	$86	$39	$161
Sub-total	$110	$157	$90	$217
Total cost	$32,266	$36,081	$29,307	$39,910
Incremental cost of Cetuximab plus Irinotecan	$3815 (12% higher)		$10,603 (36% higher)

EGFRi, epidermal growth factor receptor inhibitor; mCRC, metastatic colorectal cancer.

In all provinces, the costs for EGFR inhibitor and pre-medication, professional time, medical supplies, infusion time, laboratory tests, and AE management are all lower with panitumumab than with cetuximab or cetuximab plus irinotecan.

The sensitivity analyses shown in Tables 8 and 9 indicate that the analysis was robust and the results did not change when pre-medication costs or the costs related to drug preparation, drug administration, safety monitoring, and AE treatment were removed, or when assumptions regarding patients’ average body surface area and body weight were changed.

Table 8. Sensitivity analyses – Alberta, Manitoba, and Québec.

	Alberta		Manitoba		Québec
	Panitumumab (7 infusions)	Cetuximab (14 infusions)	Panitumumab (10 infusions)	Cetuximab (20 infusions)	Panitumumab (7 infusions)	Cetuximab (16 infusions)
Cost of pre-medication was removed	$24,017	$29,375	$32,600	$39,673	$22,203	$30,821
All costs other than the cost of EGFRi were removed	$21,000	$24,120	$30,000	$34,170	$21,000	$27,470
Average patient body surface area of 1.5 m^2	$24,017	$25,631	$32,600	$34,208	$22,203	$26,468
Average patient body surface area of 1.9 m^2	$24,017	$30,656	$32,600	$41,243	$22,203	$32,163
Average patient body weight of 65 kg	$19,817	$30,321	$26,600	$40,908	$18,003	$31,828
Average patient body weight of 80 kg	$24,017	$30,321	$32,600	$40,908	$22,203	$31,828
Incorporation of ASPECCT adverse event rates	$24,003	$30,216	$32,600	$40,782	$22,217	$31,742
Range of incremental costs of Cetuximab plus Irinotecan	$1614–$10,504		$1608–$14,308		$4265–$13,825

EGFRi, epidermal growth factor receptor inhibitor; mCRC, metastatic colorectal cancer; ASPECCT, Study of panitumumab vs cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer8.

Table 9. Sensitivity analyses – British Columbia and Ontario.

	British Columbia		Ontario
	Panitumumab (10 infusions)	Cetuximab plus Irinotecan (10 infusions)	Panitumumab (9 infusions)	Cetuximab (18 infusions) plus Irinotecan (9 infusions)
Cost of pre-medication was removed	$32,266	$35,703	$29,307	$38,739
All costs other than the cost of EGFRi plus irinotecan were removed	$30,000	$31,850	$27,000	$32,350
All costs other than the cost of EGFRi were removed	$30,000	$30,150	$27,000	$30,820
Average patient body surface area of 1.5 m^2	$32,266	$32,531	$29,307	$33,700
Average patient body surface area of 1.9 m^2	$32,266	$39,431	$29,307	$40,245
Average patient body weight of 65 kg	$26,266	$36,081	$23,907	$39,910
Average patient body weight of 80 kg	$32,266	$36,081	$29,307	$39,910
Incorporation of ASPECCT adverse event rates	$32,297	$36,010	$29,337	$39,809
Range of incremental costs of Cetuximab plus Irinotecan	$150–$9815		$4393–$16,003

EGFRi, epidermal growth factor receptor inhibitor; mCRC, metastatic colorectal cancer; ASPECCT, Study of panitumumab vs cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer8.

Discussion

Total costs for the management of KRAS wild-type mCRC with EGFR inhibitor in patients who are chemorefractory were substantially higher with cetuximab monotherapy or cetuximab plus irinotecan than with panitumumab in all provinces studied. Per patient savings in each province were substantial and resulted in consistently lower costs for drug acquisition, medication preparation and administration, patient monitoring, and treatment of AEs with panitumumab compared with cetuximab. In sensitivity analyses where the use of pre-medication with cetuximab was removed, lower and higher average body weights and body surface areas were assumed, adverse event rates reported in the ASPECCT study were incorporated, and only the cost of EGFRi (plus irinotecan) was included, panitumumab remained cost saving in all scenarios in all provinces. The range of cost savings in each province were: $1614–$10,504 in Alberta, $1608–$14,308 in Manitoba, $4265–$13,825 in Québec, $150–$9815 in British Columbia, and $4393–$16,006 in Ontario.

The current study finding of a lower drug acquisition cost of EGFR inhibitor treatment with panitumumab was predicted based on the requirement for weekly dosing with cetuximab v every other week with panitumumab and where the cost per panitumumab dose is less than double the cost of each cetuximab infusion. Often, a lower drug acquisition cost poses a trade off against higher administration or monitoring costs. With panitumumab, this is not the case, even in British Columbia, where both EGFRi are dosed biweekly. Despite the equivalent dosing frequency, panitumumab was still cost saving in British Columbia, although the difference in cost between the EGFRi was smaller than in the provinces where cetuximab is still dosed weekly as per the approved labelling2. As practice shifts in the other provinces to biweekly dosing of cetuximab, it is expected that the cost savings with panitumumab will be reduced but not entirely lost.

Although the finding of cost savings with panitumumab was consistent across the provinces, it should be pointed out that the total costs associated with the administration of both treatments varied significantly from one province to another. For example, the total patient costs for panitumumab in Québec were ∼30% less than in British Columbia and Manitoba.

Similarly, the cost of administration of cetuximab was 25% lower in Alberta than in the neighboring province of Manitoba. This result is not surprising in that each province runs its own Health Ministry with different cost structures and different standards of practice in terms of the delivery of healthcare. Even within a single province, the costs can vary across hospitals because each hospital establishes their own standards of care and manages their own budgets. In the case of the delivery of panitumumab and cetuximab, the primary reason for the difference in costs between the provinces lies in the number of infusions for each drug (as shown in Table 1), where, in British Columbia and Manitoba, the total number of panitumumab infusions is 10, compared to only seven infusions in QC; similarly, the cost difference between Manitoba and Alberta for cetuximab is driven by the preference for 20 cetuximab infusions in Manitoba compared with 14 in Alberta.

To our knowledge, there have been no similar studies conducted in Canada. However, the results of the present study were similar to findings of a cost-minimization analysis conducted from the National Health Service perspective in Greece12, where the use of panitumumab was associated with cost savings of 12.4% to 17.7%. Song et al.13 conducted a systematic review of the relative rates of infusion reactions associated with different treatments for mCRC along with the associated clinical and economic impact of the infusion reactions. They reported that all grade and grade 3–4 infusion reactions associated with cetuximab ranged from 7.6–33% and 0–22%, respectively. In contrast, rates of all grade and grade 3–4 infusion reactions associated with panitumumab ranged from 0–4% and 0–1%, respectively. The authors noted that the rates of IR for panitumumab appeared relatively consistent with rates observed in its clinical trials (as reported in the panitumumab product monograph), but that the rates seen with cetuximab varied widely across studies and acknowledged that many of the trials were small13. In their analysis of the cost of treatment in patients without and with infusion reactions, infusion reactions increased mean costs by $9308 where an emergency visit or hospitalization was required and by $1725 if treatment could be managed on an outpatient basis. The authors also concluded that infusion reactions can lead to treatment delays.

In a study conducted in the UK, Hoyle et al.14 compared the clinical effectiveness and cost-effectiveness of panitumumab monotherapy and cetuximab (mono- or combination chemotherapy) and bevacizumab in combination with non-oxaliplatin chemotherapy for patients with KRAS WT metastatic colorectal cancer after first-line chemotherapy. The clinical analysis was based on a systematic review of the literature. For the economic comparison, a decision-analytic model was developed. In the economic evaluation, the base-case incremental cost-effectiveness ratio (ICER) for KRAS WT patients compared with best supportive care was £98,000 per quality-adjusted life-year (QALY) for cetuximab, £88,000 per QALY for cetuximab plus irinotecan, and £150,000 per QALY for panitumumab. The authors of the paper concluded: ‘Although cetuximab and panitumumab appear to be clinically beneficial for KRAS WT patients compared with best supportive care, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK’(http://www.journalslibrary.nihr.ac.uk/hta/volume-17/issue-14#abstract). While the UK and Canada have similar HTA processes and criteria, not to mention a similarity in healthcare systems, the decisions reached to reimburse products do not always coincide. It should be noted that, while the purpose of the study by Hoyle et al.14 was to determine if the EGFRi are cost-effective and should be funded, the purpose of our study was to determine how the actual practice cost of the two EGFRi compare now that both are widely reimbursed in the third line setting.

Strengths of the current analysis include the fact that the costs were based on medication doses and treatment practices in use in Canada in several provinces. While an analysis conducted in one province may not always be generalizable to practice in another jurisdiction, the results of the comparison of panitumumab vs cetuximab in mCRC was consistent across the five provinces examined, despite differences in clinical practice and reimbursement guidelines. For this reason, the results are also expected to extend to the provinces not studied. In addition, the study also examined the cost differences between the two EGFRi according to shifting practice where cetuximab is now often dosed every 2 weeks rather than weekly (as is the case in British Columbia where cetuximab is used every other week in combination with irinotecan).

The study was somewhat limited in that the comparison between treatments was made based on health resource use and costs only and did not include a comparison of the treatments based on their relative efficacy or quality-of-life benefits. However, the ASPECCT study8 found that panitumumab and cetuximab similarly extended OS and resulted in similar rates of grade 3–4 adverse events. Therefore, with similar efficacy and safety/tolerability profiles, a comparison based on the costs of administering the products and following patient safety post-treatment is justified from the perspective of public drug plan decision-makers in Canada. In addition, because panitumumab and cetuximab are both reimbursed in the provinces studied in this NIA without qualification of how the treatments may differ in clinical effect or in whom a specific EGFR inhibitor should be used, the NIA comparison was felt to be relevant for physicians making decisions about which treatment to use.

A second limitation of the study stems from the fact that the health resource utilization information was collected according to expert opinion and was not validated through other methods such as chart review or prospective observation through a time-and-motion study. Third, payers and physicians in Canada may also be interested in a net impact analysis conducted from a societal perspective where patients’ and caregivers’ indirect costs related to lost time from work or other activities and/or out-of-pocket costs would be considered. However, because the resources utilized to deliver the EGFR inhibitors and monitor patients after their infusions differed so widely between the treatments, it was believed that the additional cost impact of patients’ out of pocket expenses and lost time from work or usual activities would not change the results in any meaningful way.

The findings of the study are important for hospitals in Canada because they show that considerable savings can be achieved across different budget items if an institution were to choose one EGFR inhibitor over another given the similar clinical outcomes. The analysis shows that, while the drug acquisition cost differences may be relatively minimal, the more intensive resource utilization in terms of personnel, medical supplies, laboratory tests, and infusion time make panitumumab a less costly option. Future research examining the real world clinical and economic outcomes associated with panitumumab and cetuximab may be of interest.

Conclusions

In conclusion, the study showed that the total health resource utilization costs related to the management of KRAS wild-type mCRC with EGFR inhibitor in patients for whom previous treatments have failed were higher with cetuximab monotherapy or cetuximab plus irinotecan than with panitumumab in the five Canadian provinces studied. While the findings of a lower drug acquisition cost of panitumumab could be predicted, the lower costs related to drug preparation and administration, patient safety monitoring, and management of AEs may not have been predicted. Given the consistency of the findings across the provinces, the results should be generalizable to other jurisdictions of Canada.

Transparency

Declaration of funding

Medical writing support was funded by Amgen Canada.

Declaration of financial/other relationships

MP has conducted net impact analysis research for Amgen Canada Inc. LS has been a consultant for and participated in advisory boards for Amgen and made oral presentations sponsored by Amgen. PK, HL have participated on Amgen advisory boards.

Acknowledgments

The authors would like to thank Dr Hagen Kennecke, British Columbia Cancer Agency for his assistance with the methodology of the study, and Dr Sharlene Gill, British Columbia Cancer Agency for her consultation and data access concerning practice in British Columbia. The authors also wish to thank Ms Lindy Forte for medical writing assistance.