Journal of Oncology Pharmacy Practice http://opp.sagepub.com/
Comparative cost-effectiveness of bevacizumab-irinotecan-fluorouracil versus irinotecan-fluorouracil in first-line metastatic colorectal cancer Oreto Ruiz-Millo, Asuncion Albert-Mari, Ana Sendra-Garcia and N Victor Jimenez-Torres J Oncol Pharm Pract 2014 20: 341 originally published online 31 October 2013 DOI: 10.1177/1078155213508437 The online version of this article can be found at: http://opp.sagepub.com/content/20/5/341
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Journal of
Oncology Pharmacy Practice
Original Article
Comparative cost-effectiveness of bevacizumab-irinotecan-fluorouracil versus irinotecan-fluorouracil in first-line metastatic colorectal cancer
J Oncol Pharm Practice 2014, Vol. 20(5) 341–350 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155213508437 opp.sagepub.com
Oreto Ruiz-Millo, Asuncion Albert-Mari, Ana Sendra-Garcia and N Victor Jimenez-Torres
Abstract Purpose: To evaluate the cost-effectiveness of the addition of bevacizumab to the irinotecan-fluorouracil (Douillard regimen-CPT-FUFA-) in first-line treatment of metastatic colorectal cancer in a single-institution population. Methods: Controlled, nonrandomized retrospective observational study. Treatment-naı¨ve metastatic colorectal cancer patients received CPT-FUFA (January 2000-December 2003; control group) and bevacizumab_CPT-FUFA (January 2007December 2010; study group). Variables related to: patient, clinical response (number of disease progression or death events, progression-free survival) and treatment (antineoplastic dose reduction, incremental cost/treated patient associated with the addition of bevacizumab). Statistical analysis: median progression-free survival (Kaplan-Meier method), and hazard ratio (Cox regression). Survival curves were compared (Mantel-Haenszel test). Results: In all, 69 patients were included: 32 (57.2 years –95%CI: 54.0–60.5–, 65.6% men) in CPT-FUFA group and 37 (68.1 years – 95%CI: 65.5–70.7–, 78.4% men) in bevacizumab_CPT-FUFA group. The disease progression or death events were 29 (90.6%) in CPT-FUFA group and 34 (91.9%) in bevacizumab_CPT-FUFA group. Median progression-free survival was 10.1 months (95%CI: 7.1–12.2) in CPT-FUFA and 11.0 months (95%CI: 7.6–12.6) in bevacizumab_CPT-FUFA (hazard ratio ¼ 1.22; 95%CI: 0.7–2.1). Dose reductions: irinotecan and fluorouracil 11% (range: 4–20) in 5/32 (15.6%) CPT-FUFA patients and 25% (range: 8–35) in 18/37 (48.6%) bevacizumab_CPT-FUFA patients; Bevacizumab 30% (range: 4–50) in 20/ 37 (54.1%) bevacizumab_CPT-FUFA patients. The incremental cost associated with the addition of bevacizumab was 12,696.5 (IC95%:10,860.8–14,532.1) euros/patient. Conclusion: The addition of bevacizumab to the irinotecan-fluorouracil regimen, does not improve progressionfree survival in our study population but increases costs per treated patient. These results potentially compromise the cost-effectiveness of the Bevacizumab_CPT-FUFA regimen.
Keywords Bevacizumab, first-line, cost-effectiveness, metastatic colorectal cancer
Introduction Colorectal cancer (CRC), the second or third most frequently diagnosed cancer, represents approximately 10% of all new cancer diagnosed annually.1–3 In Spain, mortality induced by CRC in 2010 was 14,883 patients (approximately 4%), with a higher incidence in patients older than 65 years.4 Nevertheless, in recent years, death rates have decreased due to early screening, accurate diagnosis and improved treatments.5,6 At diagnosis, 20% of patients with CRC present with metastatic disease,7,8 mainly in the liver and/or
lungs, due to venous drainage into the portal vein and the inferior cava vein, respectively. Choice of treatment for metastatic disease depends on previous treatments, metastasis number and location, performance status (PS) and patient comorbidities.9,10 Pharmacy Department, Doctor Peset University Hospital, Valencia, Spain Corresponding author: Oreto Ruiz-Millo, Pharmacy Department, Doctor Peset University Hospital, Gaspar Aguilar, 90, Valencia 46017, Spain. Email: [email protected]
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Journal of Oncology Pharmacy Practice 20(5) Table 1. Fluorouracil plus folinic acid and irinotecan in regimens to colorectal cancer. Regimen
Drug / dosage / administration days / period
CPT-FUFA (local acronym) Douillard et al.14
Irinotecan 180 mg/m2 IV day 1 Folinic acid 200 mg/m2 IV days 1,2 5-FU 400 mg/m2 IV bolus days 1,2 5-FU 600 mg/m2 IV 22-hour continuous infusion days 1,2 Period: every 2 weeks.
IFL Saltz et al.15
Irinotecan 125 mg/m2 IV days 1, 8, 15, 22 Folinic acid 20 mg/m2 IV days 1, 8, 15, 22 5-FU 500 mg/m2 IV bolus days 1, 8, 15, 22 Period: every 6 weeks
Modified IFL (mIFL) modified Saltz et al.15
Irinotecan 125 mg/m2 IV day 1, 8 Folinic acid 20 mg/m2 IV bolus days 1, 8 5-FU 500 mg/m2 IV bolus days 1, 8 Period: every 3 weeks
FOLFIRI Andre´ et al.16
Irinotecan 180 mg/m2 IV day 1 Folinic acid 400 mg/m2 IV day 1 5-FU 400 mg/m2 IV bolus day 1 5-FU 2400 mg/m2 IV 46-hour continuous infusion day 1 Period: every 2 weeks
Mayo Clinic Van Cutsem et al.17
Irinotecan 350 mg/m2 IV days 1, 43 Folinic acid 20 mg/m2 IV daily for 5 days (days 22–26) 5-FU 425 mg/m2 IV bolus daily for 5 days (days 22–26) Period: every 6 weeks
Irinotecan-AIO Ko¨hne et al.18
Irinotecan 80 mg/m2 IV days 1, 8, 15, 22, 29, 36 Folinic acid 500 mg/m2 days 1, 8, 15, 22, 29, 36 5-FU 2300/2000 mg/m2 IV 24-hour continuous infusion days 1, 8, 15, 22, 29, 36 Period: every 8 weeks
IV: intravenous; 5-FU: fluorouracil.
Currently, the standard first-line treatment for metastatic CRC (mCRC) is the combination of antineoplastics: fluoropyrimidines (fluorouracil or capecitabine), irinotecan or oxaliplatin and, since the appearance of new biological therapies, two classes of drugs: antivascular endothelial growth factor (VEGF) as bevacizumab, and anti-epidermal growth factor (EGF) as cetuximab and panitumumab.11–13 A major challenge nowadays is how best to integrate the use of these drugs. Before biological therapies were available, chemotherapy regimens most widely used were combinations of fluorouracil plus folinic acid with irinotecan at different doses and schedules in a variety of regimens: Douillard regimen – local acronym CPT-FUFA–,14 IFL,15 FOLFIRI,16 Mayo Clinic17 or irinotecanAIO.18 Table 1 summarizes these regimens. Several studies have analyzed the comparative effectiveness of these regimens. These show that all of them are effective, being considered equivalents in clinical practice, but with different safety profiles. CPTFUFA has the best tolerability profile with a lower
incidence of grade 3/4 neutropenia (28.8%) and diarrhea (44.4%).19 FOLFIRI’s efficacy was significantly improved when compared with mIFL: median progression-free survival (PFS), 7.6 months (FOLFIRI) versus 5.9 months (mIFL) (hazard ratio (HR) ¼ 1.51; 95%CI: 1.16 to 1.97).20 Scientific societies guidelines, based on more recent studies,21,22 establish that IFL regimen should not be considered the standard regimen any more due to its higher toxicity and its relative lower efficacy.23,24 First clinical trial available added bevacizumab to IFL, but due to an increase of severe toxicity recorded with the first patients treated at our institution, bevacizumab was added by interdisciplinary consensus to the regimen in use (Douillard-CPT_FUFA). Bevacizumab is a humanized monoclonal antibody that binds to VEGF, the key driver of vasculogenesis and angiogenesis, causing regression of tumour vascularisation and tumor neovascularization inhibition, thereby inhibiting tumour growth.25 Since the introduction of biological therapies, bevacizumab was approved in 2004 by the EMEA
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(European Medicines Regulatory Agency) and the U.S. FDA (US Medicines Regulatory Agency), and in 2005 by the AEMPS (Spanish Medicines Regulatory Agency) in combination with fluoropyrimidine and irinotecan-based chemotherapy for treatment of patients with metastatic carcinoma of the colon or rectum. The combination of bevacizumab with FOLFIRI or IFL regimens has shown increased efficacy in terms of median PFS compared to chemotherapy without bevacizumab, in clinical trials20,26–30 and cohorts observational studies.31,32 However, at present there is no available evidence to show improvement in response, when added to CPT-FUFA regimen in first-line treatment of mCRC. The toxicity profile depends on the chemotherapy regimen, but the overall incidence of adverse effects is generally increased by incorporating the antibody to the treatment regimen. Cost-effectiveness is an aspect to assess when selecting antineoplastic schemes, although it is usually considered as a secondary criterion in drug evaluations. However, given the actual situation of limited resources and high treatment costs, the parameter to consider should not be effectiveness, but cost-effectiveness.33,34 The aim of this study is to evaluate the cost-effectiveness of the addition of bevacizumab to the antineoplastic pharmacotherapeutic regimen with irinotecanfluorouracil (CPT-FUFA), for first-line treatment of patients with metastatic CRC in a single-institution population.
Methods
cycles of the chemotherapy regimens, (4) for patients receiving bevacizumab: absence of contraindications (bleeding, recent surgery, hypertension, cardiovascular history and/or thromboembolism). Exclusion criteria were patients with a non-CRC specialized prescribing oncologist, prior chemotherapy for mCRC and prior adjuvant or neo adjuvant chemotherapy for non-metastatic CRC.
Study design Patients were assigned to two groups. Control group (CG): CPT-FUFA regimen consisted on irinotecan 180 mg/m2 IV on day 1, levofolinic acid 100 mg/m2 IV on days 1 and 2, fluorouracil 400 mg/m2 IV bolus on days 1 and 2, fluorouracil 1200 mg/m2 IV 44-hour continuous infusion on day 1, repeated every 2 weeks for 30 cycles or until evidence of disease progression, unacceptable toxicity or withdrawal of chemotherapy patient consent. Study group (SG): bevacizumab-CPTFUFA regimen consisted on the aforementioned CPTFUFA regimen with bevacizumab 5 mg/kg IV on day 1. In both groups, patients were premedicated on day 1 prior to chemotherapy administration with prophylactic antiemetics (ondansetron/ dexamethasone) and anticholinergic (atropine) to prevent early diarrhea associated with irinotecan. Late diarrhea was controlled with loperamide protocol. All patients were followed until disease progression (DP), death, loss to follow-up or termination of study.
Variables and clinical end points
Study population
The following variables were recorded:
This is a controlled nonrandomized retrospective observational study on patients with mCRC in first-line treated with CPT-FUFA or Bevacizumab_CPT-FUFA regimens in a 600-bed general University Hospital. Periods of recruitment. Patients fall into two different recruitment periods. Initial period: patients who received CPT-FUFA regimen from 1 January 2000 through 31 December 2002 were included (follow-up period until 31 December 2003). Second period: patients in treatment with Bevacizumab_CPT-FUFA regimen from 1 January 2007 through 31 December 2009 (follow-up period until 31 December 2010). Recruitment period was 36 months and further follow-up period was at least 12 months for both groups. Patient selection criteria. Eligibility criteria were (1) treatment-naı¨ ve adult patients (18 years old), (2) diagnosis of histologically confirmed CRC with unresectable metastatic disease at presentation, (3) receiving 2
1. Patient: sex, age, weight, body surface area (BSA), body mass index (BMI). 2. Treatment: (a) total number of cycles received, (b) percentage of antineoplastic total dose reduction: irinotecan, fluorouracil and/or bevacizumab (difference between the cumulative base dose (planned dose), calculated using real BSA or weight considering the number of cycles received, and the actual cumulative prescribed dose for each patient), (c) reason for antineoplastic dose reduction documented in the information system, (d) relative dose intensity >85%, defined as the ratio of cumulative actual dose to planned dose intensity.35,36 3. Clinical: Eastern Cooperative Oncology Group (ECOG) performance status, primary tumor location, location and number of metastases, disease progression or death events (DP/D), progressionfree survival (PFS), defined as the time from treatment start to objective tumor progression or death from any cause,37,38 time to progression (TTP)
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defined as the time from inclusion until objective tumor progression,37 objective response. Tumor responses and progression were evaluated radiologically every 8–12 weeks, according to Response Evaluation Criteria in Solid Tumors RECIST,39 and were documented. 4. Cost: real direct drug costs per patient. Variable data were obtained from two information systems (the software Farmis_OncopharmTM and Orion-ClinicTM) and medical records. Percentage of patients with relative dose intensity >85%, mean PFS and TTP, and objective response rate (ORR) defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period (the sum of complete and partial responses, excluding stable disease)37 by treatment group were calculated. Bevacizumab addition–related incremental cost per patient treated was calculated as the difference between the average real treatment cost per patient in the bevacizumab-CPT_FUFA group and the CPT_FUFA group, considering: (i) equality between the pharmacotherapeutic regimens, with the exception of bevacizumab, (ii) direct healthcare costs (actual cost of doses prepared and administered to the patient, based on the cost per mg of drug), (iii) optimization of antineoplastics vials through the automated assisted management of partially used vials using an expert system.
Statistical analysis Categorical variables were reported as frequencies (%), continuous quantitative variables, as mean and 95% confidence interval (95%CI), and discrete quantitative variables, as median and range (R). Chi-square testing was used to compare categorical variables between treatment groups. Student’s t testing for independent samples was used to compare normal continuous quantitative variables. The Kaplan-Meier method was used to calculate median PFS and TTP. Survival data were censored at 31 December 2003 for the CPT-FUFA group and 31 December 2010 for the Bevacizumab_CPT-FUFA group, and at the end of the study period for patients without DP or death. For patients without documented DP, data were censored at the any cause death date in the absence of previously documented DP, the last tumor assessment with nonprogression status (patients with loss to follow-up) or the date of the start of a second-line treatment of metastatic CRC. Survival curves between both groups were compared by use of log-rank test. The hazard ratio (HR) and 95% confidence interval (CI) were obtained from a Cox proportional hazard model, adjusted for age.
Stepwise Cox multivariate analysis was performed in order to identify independent prognostic and predictive factors that are related to progression or death, including the following: sex, age, BMI, ECOG performance status, primary tumor location, number of metastases, regimen with bevacizumab. All statistical tests were two-sided, using a significance level of 5% (p < 0.05). Statistical analyses were performed using the SPSS package (SPSS version 15.0).
Results During study period, 69 patients were included, 32 mCRC patients in first-line treatment with CPTFUFA (CG) and 37, with Bevacizumab_CPT-FUFA (SG). Mean age was 57.2 years (95%CI: 54.0 to 60.5) for the CG and 68.1 years (95%CI: 65.5 to 70.7) for the SG (p < 0.01); 65.6% and 78.4% of patients were male, respectively. Colon as the primary tumor (75% versus 75.7%) and liver metastases (96.9% versus 91.9%) were the most frequent ones in both treatment groups. Table 2 shows patient-related and clinical variables for both treatment groups. Except for age, none of the variables shown in Table 2 had statistically significant differences (p > 0.05). The median number of cycles received were 12 (range: 2–24) in the CPT-FUFA group and 16 cycles (range: 2–30) in Bevacizumab_CPT-FUFA group, p ¼ .06. Antineoplastic total cumulative dose reduction (considering the total number of cycles administered) was 11% (range: 4–20) of irinotecan and fluorouracil in 5/ 32 (15.6%) patients with CPT-FUFA, and 25% (range: 8–35) of irinotecan and fluorouracil in 18/37 (48.7%) patients and 30% (range: 4–50) of bevacizumab in 20/ 37 (54.1%) with Bevacizumab_CPT-FUFA. Table 3 summarizes these data for each antineoplastic drug analyzed. In the CPT-FUFA group, 5/32 (15.6%) patients required dose individualization due to the adverse effects associated with chemotherapy (gastrointestinal (GI) (2/5), hematologic (3/5) and liver toxicity (1/5)); in the Bevacizumab_CPT-FUFA group, 20/37 (54.1%) patients required dose adjustments: 13/20 (65%, 35% of Bevacizumab_CPT-FUFA) patients with a 25% (range: 20–35%) dose reduction since the first cycle of chemotherapy because of advanced age, and 7/20 (35%, 19% of Bevacizumab_CPT-FUFA) patients due to adverse effects associated with chemotherapy: GI (2/7), hematologic (3/7) and not registered toxicity (2/7). Relative dose intensity >85% for irinotecan and fluorouracil was in 31/32 (96.9%) patients with CPT-FUFA and in 22/37 (59.5%) patients with
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Table 2. Biometric and clinical characteristics of mCRC patients in first-line treatment with CPT-FUFA or Bevacizumab_CPT-FUFA. Control group
Study group
CPT-FUFA (n ¼ 32)
Bevacizumab_CPT-FUFA (n ¼ 37)
Characteristics
No.
%
No.
%
Sex Male
21
65.6
29
78.4
Age (years) Mean (95%CI) Range 85% in 20/37 (54.1%) patients with Bevacizumab_CPT-FUFA. At the end of the study period, the events of DP/ D were 29 (90.6%) in the CPT-FUFA group and 34 (91.9%) in the Bevacizumab_CPT-FUFA group. The percentage of censored patients (including withdrawal without DP/ D and loss to follow-up) in the CPTFUFA group and the Bevacizumab_CPT-FUFA group were 9.4% and 8.1%, respectively (p ¼ 0.983). Clinical effectiveness was similar in patients who received CPT-FUFA or Bevacizumab_CPT-FUFA. The median PFS was 10.05 months (95%CI: 7.10–
12.22) in the CPT-FUFA group and 11.04 months (95%CI: 7.62–12.55) in the Bevacizumab_CPTFUFA group (HR adjusted by age ¼ 1.22; 95%CI: 0.69–2.15).The median TTP was 10.60 months (95%CI: 7.56–12.22) in the CPT-FUFA group and 11.73 months (95%CI: 7.75–13.08) in the Bevacizumab_CPT-FUFA group (HR adjusted by age ¼ 0.99; 95%CI: 0.53–1.85). The ORR was 31.3% (10/32 patients) with CPT-FUFA and 43.2% (16/37 patients) with Bevacizumab_CPT-FUFA, this difference was not statistically significant (p ¼ 0.175). Kaplan-Meier survival curves in both treatment groups for PFS and TTP are shown in Figures 1 and 2.
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Table 3. % Dose reduction of irinotecan, fluorouracil, and bevacizumab for mCRC patients in first-line treatment with CPT-FUFA or Bevacizumab_ CPT-FUFA. Control group
Experimental group
CPT-FUFA (n ¼ 32)
Bevacizumab_ CPT-FUFA (n ¼ 37)
Drug
Base CD (mg)
Actual CD (mg)
%DR
Base CD (mg)
Actual CD (mg)
% DR
Irinotecan No. (%) Median Range
5 (15.62) 1620 630–5476
1500 550–5250
11 4–20
18 (48.65) 5083 886–9990
3620 720–7580
25 8–35
Fluorouracil No. (%) Median Range
5 (15.62) 18,000 7000–60,840
16,540 6140–56,780
11 4–20
18 (48.65) 56480 9840–111000
41405 7920–84,810
25 8–35
— —
— —
20 (54.05) 5358 1050–11,100
3960 840–7960
30 4–50
Bevacizumab No. (%) — Median — Range —
CD: cumulative dose; %DR: % Dose reduction; No.: Number of patients.
Progression-free survival (probability)
1.0 Bevacizumab_CPT=FUFA CPT=FUFA
0.8
0.6
0.4
0.2
0.0 0
10
30 20 Time (months)
40
50
Figure 1. Kaplan-Meier estimates of PFS for mCRC patients in first-line treatment CPT-FUFA or Bevacizumab_ CPT-FUFA. (HR ¼ 1.22 [95%CI: 0.69–2.15]).
In multivariate analysis, none of the variables shown in Table 4 were independent neither prognostic nor predictive factors related to progression or death (p > 0.05). A conservative estimate of costs was performed, considering the cost associated with both treatment groups was similar with the exception of direct healthcare cost of drug treatment due to the addition of bevacizumab in the treatment of the Bevacizumab_CPT-FUFA group.
Since the effectiveness response variables are equivalent, the cost-effectiveness analysis has been simplified into a cost-minimization analysis. The difference between the mean direct cost of treatment in the Bevacizumab_CPT-FUFA group (14,474.3 euros; 95%CI: 12,296.7–16,651.9) and the CPT-FUFA group (1777.8 euros; 95%CI: 1435.9–2119.7) yielded a mean incremental cost of 12,696.5 (95%CI: 10,860.8– 14,532.1) euros/patient with mCRC patients in first-line treatment with bevacizumab_CPT-FUFA.
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Time to progression (probability)
1.0 Bevacizumab_CPT=FUFA CPT=FUFA
0.8
0.6
0.1
0.2
0.0 10
0
30 20 Time (months)
40
50
Figure 2. Kaplan-Meier estimates of TPP for mCRC patients in first-line treatment CPT-FUFA or Bevacizumab_ CPT-FUFA (HR ¼ 0.99 [95%CI: 0.53–1.85]).
Table 4. Multivariate analysis (Cox regression model) of independent prognostic and predictive factors related to progression or death in mCRC patients in first-line treatment with CPT-FUFA or Bevacizumab_ CPT-FUFA. Variables
HR
CI95%
Sex Age BMI (kg/m2) ECOG performance status Primary tumor location Metastases location Number of metastases Regimen with Bevacizumab
0.90 0.99 1.03 0.30 1.87 1.12 1.16 1.10
0.45–1.81 0.96–1.02 0.97–1.10 0.61–1.51 0.96–3.63 0.36–3.56 0.63–2.14 0.56–2.14
HR: Hazard ratio. CI95%: confidence interval at 95%.
Discussion The present study represents an approach to the costeffectiveness of bevacizumab added to the pharmacotherapeutic regimen CPT-FUFA in first-line treatment of mCRC. All collected biometric variables were similar for both groups, except for the average age, which was slightly higher in the Bevacizumab_CPT-FUFA group (p < .01). This difference is considered justified by the temporal difference between recruitment periods, the greatest life expectancy of patients and the increasing risk of CRC with age.4,5 Although this age difference
could be considered a factor limiting comparability, some authors have shown that PFS is similar between patients aged 65 years [fluorouracil/ leucovorin (FU/LV) or IFL (6.2 months (95%CI: 5.5–8.0) versus bevacizumab-bevacizumab-FU/LV or IFL (9.2 months (95%CI: 8.3–11.6)] and younger than 65 [5.8 months (95%CI: 5.5–7.1) versus 10.5 months (95%CI: 9.0–10.9)], for mCRC patients in first-line treatment, suggesting that decisions regarding use of bevacizumab-based mCRC therapy should not be contingent on age alone.40 The primary tumor location was mostly colonic (ratio 3 : 1) in both groups, which is consistent with similar previous published studies.20,26 Approximately 90% of patients had an event of disease progression or death during the study period (48 months). Regarding the total administered dose, we found a higher percentage of reduction of administered doses in the Bevacizumab_CPT-FUFA group. This dose reduction appears to be mainly associated with a higher incidence of adverse effects (19% vs. 15%), when bevacizumab is added to fluorouracil-irinotecan combination regimen, and with ‘‘a priori’’ dose reduction due to advanced age,36 as shown in other studies.26,27,30 So lower relative dose intensity was received by the Bevacizumab_CPT-FUFA group, being less than 85% in about 50% of patients treated. This value is the dose limit fixed by the clinical trials to consider an adequate regimen adherence, as cumulative doses less than 85% of planned dose may compromise treatment efficacy and long-term disease control and
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survival.35 This is the main limitation of the present study, as it could explain that there are no differences in response between both groups. In clinical practice, it is common to include different lines of active treatment available. The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer was overall survival, but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. Therefore, the response variables of choice are TTP or PFS, due to the fact that events occur quicker and more often than deaths37,38 and PFS can be considered an acceptable surrogate for OS in advanced colorectal cancer.41 A limitation to their use is that patient followup should be symmetrical in both treatment groups. The present study met usual clinical practice, therefore it fulfilled this condition. Patient follow-up was performed throughout the study period mainly by the same physician and with the same frequency (approximately every 5–6 cycles). The absence of statistically significant differences in median PFS for patients treated with Bevacizumab_ CPT-FUFA (11.04 months, 95%CI: 7.62–12.55) compared to those treated with CPT-FUFA (10.05 months, 95%CI: 7.10–12.22) (HR ¼ 1.22; 95%CI: 0.69–2.15) is consistent not only with the median PFS of 10.6 months (95%: not available-NA) achieved with bevacizumab_IFL in the pivotal clinical trial AVF2107g26 but also with the results achieved with bevacizumab_FOLFIRI in E2200,27 BICC-C20,28 and Sobrero et al.30 clinical trials, which reported 10.7 months (95%CI: NA), 11.2 months (95%CI: NA) and 11.1 months (95%CI: 10,3-12.1), respectively. Our results are also consistent with those found by Kopetz et al.29 with bevacizumab_FOLFIRI (12.8 months; 95%CI: 9.6–15.2) and they are higher than the 8.3 months (95%CI: NA) obtained by bevacizumab_mIFL.20,28 This confirms the greater efficacy of the administration of fluorouracil by infusion (FOLFIRI) than by bolus (IFL). It is also noteworthy that the results of the present study are similar to the median PFS of 10.8 months (95%CI: 9.7–11.7) and 11.6 months (95%CI: 10.8–12.5) achieved with bevacizumab_FOLFIRI in two uncontrolled cohort observational studies, BRiTE31 and BEAT,32 respectively. It is noteworthy that TTP obtained in the present study with CPT-FUFA (10.60 months, 95%CI: 7.56– 12.22) is well above the 6.7 months (95%CI: 0+ 13.8+)14 and the 7.9 months (95%CI: 5.5–8.9)19 previously published for CPT-FUFA. PFS (10.05 months, 95%CI: 7.10–12.22) is also above the 6.2 months (95%CI: NA) with IFL26 or the 7.6 months (95%CI: NA) with FOLFIRI.20 These divergences could be justified by differences in the
administration method of fluorouracil (bolus vs. infusion),26 the periodicity14 and the relative dose intensity received at the different regimes14 or by the inclusion of patients in second-line treatment26 or prior chemotherapy for non-metastatic CRC,20 which were excluded in the present study. In addition, the variability of follow-up and/or measurement of the response variables37 may also explain the discrepancies found. Despite the differences found on age between the CPT-FUFA group and the Bevacizumab_CPT-FUFA group, the multivariate analysis (Cox regression model) does not identify this or any other variable analyzed as a prognostic or predictive factor of disease progression or death. In the absence of differences in median PFS (95%CI: 0.69–2.15), TTP (95%CI: 0.53–1.85) and ORR (p ¼ 0.175) between both groups, both schemes analyzed can be assumed to present the same effectiveness as used in our setting, so pharmacoeconomic analysis to be applied is cost minimization. A conservative estimation of direct costs was performed, resulting in a mean drug incremental cost of 12,696.5 (95%CI: 10,860.8–14,532.1) euros/mCRC patient treated with bevacizumab_CPT-FUFA as first-line treatment. If indirect costs were included in the analysis, such as time employed by the different professionals involved in the pharmacotherapeutic process (longer preparation and administration time with Bevacizumab_CPT-FUFA) and management of toxicity, yet the incremental cost associated to the pharmacotherapeutic regimen containing bevacizumab would be higher. Since 2007, the British National Institute for Health and Clinical Excellence (NICE) does not recommend bevacizumab in combination with fluorouracil plus folinic acid, with or without irinotecan, for the first-line treatment of mCRC, considering that it only benefits a few patients and represents a high cost to the National Health Service (NHS),42 as the qualityadjusted life year cost (QALY) gained per patient for bevacizumab-IFL is 62,857,43 exceeding the established limit of 40,000 to consider a treatment as cost-effective. These data lead to the need for further research on adverse effects associated with both regimens in our study population (cycle of appearance, grading according to CTCAE v4 criteria, toxicity treatment) and to develop clinical studies to identify appropriate biomarkers for selecting candidate patients who gain the most benefit from the Bevacizumab_CPTFUFA regimen. Nevertheless, some authors have proposed the use of VEGF, plasminogen activator inhibitor (PAI-1), Von Willebrand factor (VWF) and fibrinogen as predictive factors at diagnosis,44
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as well as circulating endothelial cells and endothelial progenitors45,46 as predictive factors during treatment and follow-up of patients diagnosed of mCRC, but have not been incorporated into clinical practice. All this will promote the development of adequate criteria to achieve a wise use of dwindling resources.
Conclusion Despite the small study population and considering the limitation of the difference in the administered relative doses intensity, the addition of bevacizumab to the irinotecan-fluorouracil regimen (CPT-FUFA) does not improve PFS (11.04 months, 95%CI: 7.62–12.55; p ¼ .487) as used in our clinical setting but in addition represents an increase in costs of 12,696.5 (95%CI: 10,860.8-14,532.1) euros/patient treated in our study population. These results potentially compromise the cost-effectiveness of the Bevacizumab_CPT-FUFA regimen. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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35. Lyman GH. Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw 2009; 7: 99–108. 36. Wildiers H and Reiser M. Relative dose intensity of chemotherapy and its impact on outcomes in patients with early breast cancer or aggressive lymphoma. Crit Rev Oncol Hematol 2011; 77: 221–240. 37. Food and Drug Administration. Guidance for industry. Clinical trial endpoints for the approval of cancer drugs and biologics. Rockville: FDA. http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm071590.pdf (2007, accessed 18 August 2011). 38. European Medicines Agency. Methodological considerations for using progression-free survival (PFS) as primary endpoint in confirmatory trials for registration. Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man. London: EMA. http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2009/12/WC500017736.pdf (2007, accessed 18 August 2011). 39. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216. 40. Kabbinavar FF, Hurwitz HI, Yi J, et al. Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. J Clin Oncol 2009; 27: 199–205. 41. Buyse M, Burzykowski T, Carroll K, et al. Progression free survival is a surrogate for survival in advanced colorectal cancer. J Oncol 2007; 25: 5218–5224. 42. National Institute for Health and Clinical Excellence. Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. NICE technology appraisal guidance 118. London: NICE. http://www.nice.org.uk/ nicemedia/pdf/TA118Guidance.pdf (2009, accessed 24 May 2011). 43. Tappenden P, Jones R, Paisley S, et al. The cost-effectiveness of bevacizumab in the first-line treatment of metastatic colorectal cancer in England and Wales. Eur J Cancer 2007; 43: 2487–2494. 44. Gil-Bazo I, Paramo JA and Garcia-Foncillas J. [New prognostic and predictive factors in advanced colorectal cancer]. Med Clin (Barc) 2006; 126: 541–548. 45. Ronzoni M, Manzoni M, Mariucci S, et al. Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based firstline treatment in advanced colorectal cancer patients. Ann Oncol 2010; 21: 2382–2389. 46. Pohl M, Werner N, Munding J, Tannapfel A, et al. Biomarkers of anti-angiogenic therapy in metastatic colorectal cancer (mCRC): original data and review of the literature. Z Gastroenterol 2011; 49: 1398–1406.
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Comparative cost-effectiveness of bevacizumab-irinotecan-fluorouracil versus irinotecan-fluorouracil in first-line metastatic colorectal cancer Oreto Ruiz-Millo, Asuncion Albert-Mari, Ana Sendra-Garcia and N Victor Jimenez-Torres J Oncol Pharm Pract 2014 20: 341 originally published online 31 October 2013 DOI: 10.1177/1078155213508437 The online version of this article can be found at: http://opp.sagepub.com/content/20/5/341
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Journal of
Oncology Pharmacy Practice
Original Article
Comparative cost-effectiveness of bevacizumab-irinotecan-fluorouracil versus irinotecan-fluorouracil in first-line metastatic colorectal cancer
J Oncol Pharm Practice 2014, Vol. 20(5) 341–350 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155213508437 opp.sagepub.com
Oreto Ruiz-Millo, Asuncion Albert-Mari, Ana Sendra-Garcia and N Victor Jimenez-Torres
Abstract Purpose: To evaluate the cost-effectiveness of the addition of bevacizumab to the irinotecan-fluorouracil (Douillard regimen-CPT-FUFA-) in first-line treatment of metastatic colorectal cancer in a single-institution population. Methods: Controlled, nonrandomized retrospective observational study. Treatment-naı¨ve metastatic colorectal cancer patients received CPT-FUFA (January 2000-December 2003; control group) and bevacizumab_CPT-FUFA (January 2007December 2010; study group). Variables related to: patient, clinical response (number of disease progression or death events, progression-free survival) and treatment (antineoplastic dose reduction, incremental cost/treated patient associated with the addition of bevacizumab). Statistical analysis: median progression-free survival (Kaplan-Meier method), and hazard ratio (Cox regression). Survival curves were compared (Mantel-Haenszel test). Results: In all, 69 patients were included: 32 (57.2 years –95%CI: 54.0–60.5–, 65.6% men) in CPT-FUFA group and 37 (68.1 years – 95%CI: 65.5–70.7–, 78.4% men) in bevacizumab_CPT-FUFA group. The disease progression or death events were 29 (90.6%) in CPT-FUFA group and 34 (91.9%) in bevacizumab_CPT-FUFA group. Median progression-free survival was 10.1 months (95%CI: 7.1–12.2) in CPT-FUFA and 11.0 months (95%CI: 7.6–12.6) in bevacizumab_CPT-FUFA (hazard ratio ¼ 1.22; 95%CI: 0.7–2.1). Dose reductions: irinotecan and fluorouracil 11% (range: 4–20) in 5/32 (15.6%) CPT-FUFA patients and 25% (range: 8–35) in 18/37 (48.6%) bevacizumab_CPT-FUFA patients; Bevacizumab 30% (range: 4–50) in 20/ 37 (54.1%) bevacizumab_CPT-FUFA patients. The incremental cost associated with the addition of bevacizumab was 12,696.5 (IC95%:10,860.8–14,532.1) euros/patient. Conclusion: The addition of bevacizumab to the irinotecan-fluorouracil regimen, does not improve progressionfree survival in our study population but increases costs per treated patient. These results potentially compromise the cost-effectiveness of the Bevacizumab_CPT-FUFA regimen.
Keywords Bevacizumab, first-line, cost-effectiveness, metastatic colorectal cancer
Introduction Colorectal cancer (CRC), the second or third most frequently diagnosed cancer, represents approximately 10% of all new cancer diagnosed annually.1–3 In Spain, mortality induced by CRC in 2010 was 14,883 patients (approximately 4%), with a higher incidence in patients older than 65 years.4 Nevertheless, in recent years, death rates have decreased due to early screening, accurate diagnosis and improved treatments.5,6 At diagnosis, 20% of patients with CRC present with metastatic disease,7,8 mainly in the liver and/or
lungs, due to venous drainage into the portal vein and the inferior cava vein, respectively. Choice of treatment for metastatic disease depends on previous treatments, metastasis number and location, performance status (PS) and patient comorbidities.9,10 Pharmacy Department, Doctor Peset University Hospital, Valencia, Spain Corresponding author: Oreto Ruiz-Millo, Pharmacy Department, Doctor Peset University Hospital, Gaspar Aguilar, 90, Valencia 46017, Spain. Email: [email protected]
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Journal of Oncology Pharmacy Practice 20(5) Table 1. Fluorouracil plus folinic acid and irinotecan in regimens to colorectal cancer. Regimen
Drug / dosage / administration days / period
CPT-FUFA (local acronym) Douillard et al.14
Irinotecan 180 mg/m2 IV day 1 Folinic acid 200 mg/m2 IV days 1,2 5-FU 400 mg/m2 IV bolus days 1,2 5-FU 600 mg/m2 IV 22-hour continuous infusion days 1,2 Period: every 2 weeks.
IFL Saltz et al.15
Irinotecan 125 mg/m2 IV days 1, 8, 15, 22 Folinic acid 20 mg/m2 IV days 1, 8, 15, 22 5-FU 500 mg/m2 IV bolus days 1, 8, 15, 22 Period: every 6 weeks
Modified IFL (mIFL) modified Saltz et al.15
Irinotecan 125 mg/m2 IV day 1, 8 Folinic acid 20 mg/m2 IV bolus days 1, 8 5-FU 500 mg/m2 IV bolus days 1, 8 Period: every 3 weeks
FOLFIRI Andre´ et al.16
Irinotecan 180 mg/m2 IV day 1 Folinic acid 400 mg/m2 IV day 1 5-FU 400 mg/m2 IV bolus day 1 5-FU 2400 mg/m2 IV 46-hour continuous infusion day 1 Period: every 2 weeks
Mayo Clinic Van Cutsem et al.17
Irinotecan 350 mg/m2 IV days 1, 43 Folinic acid 20 mg/m2 IV daily for 5 days (days 22–26) 5-FU 425 mg/m2 IV bolus daily for 5 days (days 22–26) Period: every 6 weeks
Irinotecan-AIO Ko¨hne et al.18
Irinotecan 80 mg/m2 IV days 1, 8, 15, 22, 29, 36 Folinic acid 500 mg/m2 days 1, 8, 15, 22, 29, 36 5-FU 2300/2000 mg/m2 IV 24-hour continuous infusion days 1, 8, 15, 22, 29, 36 Period: every 8 weeks
IV: intravenous; 5-FU: fluorouracil.
Currently, the standard first-line treatment for metastatic CRC (mCRC) is the combination of antineoplastics: fluoropyrimidines (fluorouracil or capecitabine), irinotecan or oxaliplatin and, since the appearance of new biological therapies, two classes of drugs: antivascular endothelial growth factor (VEGF) as bevacizumab, and anti-epidermal growth factor (EGF) as cetuximab and panitumumab.11–13 A major challenge nowadays is how best to integrate the use of these drugs. Before biological therapies were available, chemotherapy regimens most widely used were combinations of fluorouracil plus folinic acid with irinotecan at different doses and schedules in a variety of regimens: Douillard regimen – local acronym CPT-FUFA–,14 IFL,15 FOLFIRI,16 Mayo Clinic17 or irinotecanAIO.18 Table 1 summarizes these regimens. Several studies have analyzed the comparative effectiveness of these regimens. These show that all of them are effective, being considered equivalents in clinical practice, but with different safety profiles. CPTFUFA has the best tolerability profile with a lower
incidence of grade 3/4 neutropenia (28.8%) and diarrhea (44.4%).19 FOLFIRI’s efficacy was significantly improved when compared with mIFL: median progression-free survival (PFS), 7.6 months (FOLFIRI) versus 5.9 months (mIFL) (hazard ratio (HR) ¼ 1.51; 95%CI: 1.16 to 1.97).20 Scientific societies guidelines, based on more recent studies,21,22 establish that IFL regimen should not be considered the standard regimen any more due to its higher toxicity and its relative lower efficacy.23,24 First clinical trial available added bevacizumab to IFL, but due to an increase of severe toxicity recorded with the first patients treated at our institution, bevacizumab was added by interdisciplinary consensus to the regimen in use (Douillard-CPT_FUFA). Bevacizumab is a humanized monoclonal antibody that binds to VEGF, the key driver of vasculogenesis and angiogenesis, causing regression of tumour vascularisation and tumor neovascularization inhibition, thereby inhibiting tumour growth.25 Since the introduction of biological therapies, bevacizumab was approved in 2004 by the EMEA
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(European Medicines Regulatory Agency) and the U.S. FDA (US Medicines Regulatory Agency), and in 2005 by the AEMPS (Spanish Medicines Regulatory Agency) in combination with fluoropyrimidine and irinotecan-based chemotherapy for treatment of patients with metastatic carcinoma of the colon or rectum. The combination of bevacizumab with FOLFIRI or IFL regimens has shown increased efficacy in terms of median PFS compared to chemotherapy without bevacizumab, in clinical trials20,26–30 and cohorts observational studies.31,32 However, at present there is no available evidence to show improvement in response, when added to CPT-FUFA regimen in first-line treatment of mCRC. The toxicity profile depends on the chemotherapy regimen, but the overall incidence of adverse effects is generally increased by incorporating the antibody to the treatment regimen. Cost-effectiveness is an aspect to assess when selecting antineoplastic schemes, although it is usually considered as a secondary criterion in drug evaluations. However, given the actual situation of limited resources and high treatment costs, the parameter to consider should not be effectiveness, but cost-effectiveness.33,34 The aim of this study is to evaluate the cost-effectiveness of the addition of bevacizumab to the antineoplastic pharmacotherapeutic regimen with irinotecanfluorouracil (CPT-FUFA), for first-line treatment of patients with metastatic CRC in a single-institution population.
Methods
cycles of the chemotherapy regimens, (4) for patients receiving bevacizumab: absence of contraindications (bleeding, recent surgery, hypertension, cardiovascular history and/or thromboembolism). Exclusion criteria were patients with a non-CRC specialized prescribing oncologist, prior chemotherapy for mCRC and prior adjuvant or neo adjuvant chemotherapy for non-metastatic CRC.
Study design Patients were assigned to two groups. Control group (CG): CPT-FUFA regimen consisted on irinotecan 180 mg/m2 IV on day 1, levofolinic acid 100 mg/m2 IV on days 1 and 2, fluorouracil 400 mg/m2 IV bolus on days 1 and 2, fluorouracil 1200 mg/m2 IV 44-hour continuous infusion on day 1, repeated every 2 weeks for 30 cycles or until evidence of disease progression, unacceptable toxicity or withdrawal of chemotherapy patient consent. Study group (SG): bevacizumab-CPTFUFA regimen consisted on the aforementioned CPTFUFA regimen with bevacizumab 5 mg/kg IV on day 1. In both groups, patients were premedicated on day 1 prior to chemotherapy administration with prophylactic antiemetics (ondansetron/ dexamethasone) and anticholinergic (atropine) to prevent early diarrhea associated with irinotecan. Late diarrhea was controlled with loperamide protocol. All patients were followed until disease progression (DP), death, loss to follow-up or termination of study.
Variables and clinical end points
Study population
The following variables were recorded:
This is a controlled nonrandomized retrospective observational study on patients with mCRC in first-line treated with CPT-FUFA or Bevacizumab_CPT-FUFA regimens in a 600-bed general University Hospital. Periods of recruitment. Patients fall into two different recruitment periods. Initial period: patients who received CPT-FUFA regimen from 1 January 2000 through 31 December 2002 were included (follow-up period until 31 December 2003). Second period: patients in treatment with Bevacizumab_CPT-FUFA regimen from 1 January 2007 through 31 December 2009 (follow-up period until 31 December 2010). Recruitment period was 36 months and further follow-up period was at least 12 months for both groups. Patient selection criteria. Eligibility criteria were (1) treatment-naı¨ ve adult patients (18 years old), (2) diagnosis of histologically confirmed CRC with unresectable metastatic disease at presentation, (3) receiving 2
1. Patient: sex, age, weight, body surface area (BSA), body mass index (BMI). 2. Treatment: (a) total number of cycles received, (b) percentage of antineoplastic total dose reduction: irinotecan, fluorouracil and/or bevacizumab (difference between the cumulative base dose (planned dose), calculated using real BSA or weight considering the number of cycles received, and the actual cumulative prescribed dose for each patient), (c) reason for antineoplastic dose reduction documented in the information system, (d) relative dose intensity >85%, defined as the ratio of cumulative actual dose to planned dose intensity.35,36 3. Clinical: Eastern Cooperative Oncology Group (ECOG) performance status, primary tumor location, location and number of metastases, disease progression or death events (DP/D), progressionfree survival (PFS), defined as the time from treatment start to objective tumor progression or death from any cause,37,38 time to progression (TTP)
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defined as the time from inclusion until objective tumor progression,37 objective response. Tumor responses and progression were evaluated radiologically every 8–12 weeks, according to Response Evaluation Criteria in Solid Tumors RECIST,39 and were documented. 4. Cost: real direct drug costs per patient. Variable data were obtained from two information systems (the software Farmis_OncopharmTM and Orion-ClinicTM) and medical records. Percentage of patients with relative dose intensity >85%, mean PFS and TTP, and objective response rate (ORR) defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period (the sum of complete and partial responses, excluding stable disease)37 by treatment group were calculated. Bevacizumab addition–related incremental cost per patient treated was calculated as the difference between the average real treatment cost per patient in the bevacizumab-CPT_FUFA group and the CPT_FUFA group, considering: (i) equality between the pharmacotherapeutic regimens, with the exception of bevacizumab, (ii) direct healthcare costs (actual cost of doses prepared and administered to the patient, based on the cost per mg of drug), (iii) optimization of antineoplastics vials through the automated assisted management of partially used vials using an expert system.
Statistical analysis Categorical variables were reported as frequencies (%), continuous quantitative variables, as mean and 95% confidence interval (95%CI), and discrete quantitative variables, as median and range (R). Chi-square testing was used to compare categorical variables between treatment groups. Student’s t testing for independent samples was used to compare normal continuous quantitative variables. The Kaplan-Meier method was used to calculate median PFS and TTP. Survival data were censored at 31 December 2003 for the CPT-FUFA group and 31 December 2010 for the Bevacizumab_CPT-FUFA group, and at the end of the study period for patients without DP or death. For patients without documented DP, data were censored at the any cause death date in the absence of previously documented DP, the last tumor assessment with nonprogression status (patients with loss to follow-up) or the date of the start of a second-line treatment of metastatic CRC. Survival curves between both groups were compared by use of log-rank test. The hazard ratio (HR) and 95% confidence interval (CI) were obtained from a Cox proportional hazard model, adjusted for age.
Stepwise Cox multivariate analysis was performed in order to identify independent prognostic and predictive factors that are related to progression or death, including the following: sex, age, BMI, ECOG performance status, primary tumor location, number of metastases, regimen with bevacizumab. All statistical tests were two-sided, using a significance level of 5% (p < 0.05). Statistical analyses were performed using the SPSS package (SPSS version 15.0).
Results During study period, 69 patients were included, 32 mCRC patients in first-line treatment with CPTFUFA (CG) and 37, with Bevacizumab_CPT-FUFA (SG). Mean age was 57.2 years (95%CI: 54.0 to 60.5) for the CG and 68.1 years (95%CI: 65.5 to 70.7) for the SG (p < 0.01); 65.6% and 78.4% of patients were male, respectively. Colon as the primary tumor (75% versus 75.7%) and liver metastases (96.9% versus 91.9%) were the most frequent ones in both treatment groups. Table 2 shows patient-related and clinical variables for both treatment groups. Except for age, none of the variables shown in Table 2 had statistically significant differences (p > 0.05). The median number of cycles received were 12 (range: 2–24) in the CPT-FUFA group and 16 cycles (range: 2–30) in Bevacizumab_CPT-FUFA group, p ¼ .06. Antineoplastic total cumulative dose reduction (considering the total number of cycles administered) was 11% (range: 4–20) of irinotecan and fluorouracil in 5/ 32 (15.6%) patients with CPT-FUFA, and 25% (range: 8–35) of irinotecan and fluorouracil in 18/37 (48.7%) patients and 30% (range: 4–50) of bevacizumab in 20/ 37 (54.1%) with Bevacizumab_CPT-FUFA. Table 3 summarizes these data for each antineoplastic drug analyzed. In the CPT-FUFA group, 5/32 (15.6%) patients required dose individualization due to the adverse effects associated with chemotherapy (gastrointestinal (GI) (2/5), hematologic (3/5) and liver toxicity (1/5)); in the Bevacizumab_CPT-FUFA group, 20/37 (54.1%) patients required dose adjustments: 13/20 (65%, 35% of Bevacizumab_CPT-FUFA) patients with a 25% (range: 20–35%) dose reduction since the first cycle of chemotherapy because of advanced age, and 7/20 (35%, 19% of Bevacizumab_CPT-FUFA) patients due to adverse effects associated with chemotherapy: GI (2/7), hematologic (3/7) and not registered toxicity (2/7). Relative dose intensity >85% for irinotecan and fluorouracil was in 31/32 (96.9%) patients with CPT-FUFA and in 22/37 (59.5%) patients with
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Table 2. Biometric and clinical characteristics of mCRC patients in first-line treatment with CPT-FUFA or Bevacizumab_CPT-FUFA. Control group
Study group
CPT-FUFA (n ¼ 32)
Bevacizumab_CPT-FUFA (n ¼ 37)
Characteristics
No.
%
No.
%
Sex Male
21
65.6
29
78.4
Age (years) Mean (95%CI) Range 85% in 20/37 (54.1%) patients with Bevacizumab_CPT-FUFA. At the end of the study period, the events of DP/ D were 29 (90.6%) in the CPT-FUFA group and 34 (91.9%) in the Bevacizumab_CPT-FUFA group. The percentage of censored patients (including withdrawal without DP/ D and loss to follow-up) in the CPTFUFA group and the Bevacizumab_CPT-FUFA group were 9.4% and 8.1%, respectively (p ¼ 0.983). Clinical effectiveness was similar in patients who received CPT-FUFA or Bevacizumab_CPT-FUFA. The median PFS was 10.05 months (95%CI: 7.10–
12.22) in the CPT-FUFA group and 11.04 months (95%CI: 7.62–12.55) in the Bevacizumab_CPTFUFA group (HR adjusted by age ¼ 1.22; 95%CI: 0.69–2.15).The median TTP was 10.60 months (95%CI: 7.56–12.22) in the CPT-FUFA group and 11.73 months (95%CI: 7.75–13.08) in the Bevacizumab_CPT-FUFA group (HR adjusted by age ¼ 0.99; 95%CI: 0.53–1.85). The ORR was 31.3% (10/32 patients) with CPT-FUFA and 43.2% (16/37 patients) with Bevacizumab_CPT-FUFA, this difference was not statistically significant (p ¼ 0.175). Kaplan-Meier survival curves in both treatment groups for PFS and TTP are shown in Figures 1 and 2.
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Table 3. % Dose reduction of irinotecan, fluorouracil, and bevacizumab for mCRC patients in first-line treatment with CPT-FUFA or Bevacizumab_ CPT-FUFA. Control group
Experimental group
CPT-FUFA (n ¼ 32)
Bevacizumab_ CPT-FUFA (n ¼ 37)
Drug
Base CD (mg)
Actual CD (mg)
%DR
Base CD (mg)
Actual CD (mg)
% DR
Irinotecan No. (%) Median Range
5 (15.62) 1620 630–5476
1500 550–5250
11 4–20
18 (48.65) 5083 886–9990
3620 720–7580
25 8–35
Fluorouracil No. (%) Median Range
5 (15.62) 18,000 7000–60,840
16,540 6140–56,780
11 4–20
18 (48.65) 56480 9840–111000
41405 7920–84,810
25 8–35
— —
— —
20 (54.05) 5358 1050–11,100
3960 840–7960
30 4–50
Bevacizumab No. (%) — Median — Range —
CD: cumulative dose; %DR: % Dose reduction; No.: Number of patients.
Progression-free survival (probability)
1.0 Bevacizumab_CPT=FUFA CPT=FUFA
0.8
0.6
0.4
0.2
0.0 0
10
30 20 Time (months)
40
50
Figure 1. Kaplan-Meier estimates of PFS for mCRC patients in first-line treatment CPT-FUFA or Bevacizumab_ CPT-FUFA. (HR ¼ 1.22 [95%CI: 0.69–2.15]).
In multivariate analysis, none of the variables shown in Table 4 were independent neither prognostic nor predictive factors related to progression or death (p > 0.05). A conservative estimate of costs was performed, considering the cost associated with both treatment groups was similar with the exception of direct healthcare cost of drug treatment due to the addition of bevacizumab in the treatment of the Bevacizumab_CPT-FUFA group.
Since the effectiveness response variables are equivalent, the cost-effectiveness analysis has been simplified into a cost-minimization analysis. The difference between the mean direct cost of treatment in the Bevacizumab_CPT-FUFA group (14,474.3 euros; 95%CI: 12,296.7–16,651.9) and the CPT-FUFA group (1777.8 euros; 95%CI: 1435.9–2119.7) yielded a mean incremental cost of 12,696.5 (95%CI: 10,860.8– 14,532.1) euros/patient with mCRC patients in first-line treatment with bevacizumab_CPT-FUFA.
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Time to progression (probability)
1.0 Bevacizumab_CPT=FUFA CPT=FUFA
0.8
0.6
0.1
0.2
0.0 10
0
30 20 Time (months)
40
50
Figure 2. Kaplan-Meier estimates of TPP for mCRC patients in first-line treatment CPT-FUFA or Bevacizumab_ CPT-FUFA (HR ¼ 0.99 [95%CI: 0.53–1.85]).
Table 4. Multivariate analysis (Cox regression model) of independent prognostic and predictive factors related to progression or death in mCRC patients in first-line treatment with CPT-FUFA or Bevacizumab_ CPT-FUFA. Variables
HR
CI95%
Sex Age BMI (kg/m2) ECOG performance status Primary tumor location Metastases location Number of metastases Regimen with Bevacizumab
0.90 0.99 1.03 0.30 1.87 1.12 1.16 1.10
0.45–1.81 0.96–1.02 0.97–1.10 0.61–1.51 0.96–3.63 0.36–3.56 0.63–2.14 0.56–2.14
HR: Hazard ratio. CI95%: confidence interval at 95%.
Discussion The present study represents an approach to the costeffectiveness of bevacizumab added to the pharmacotherapeutic regimen CPT-FUFA in first-line treatment of mCRC. All collected biometric variables were similar for both groups, except for the average age, which was slightly higher in the Bevacizumab_CPT-FUFA group (p < .01). This difference is considered justified by the temporal difference between recruitment periods, the greatest life expectancy of patients and the increasing risk of CRC with age.4,5 Although this age difference
could be considered a factor limiting comparability, some authors have shown that PFS is similar between patients aged 65 years [fluorouracil/ leucovorin (FU/LV) or IFL (6.2 months (95%CI: 5.5–8.0) versus bevacizumab-bevacizumab-FU/LV or IFL (9.2 months (95%CI: 8.3–11.6)] and younger than 65 [5.8 months (95%CI: 5.5–7.1) versus 10.5 months (95%CI: 9.0–10.9)], for mCRC patients in first-line treatment, suggesting that decisions regarding use of bevacizumab-based mCRC therapy should not be contingent on age alone.40 The primary tumor location was mostly colonic (ratio 3 : 1) in both groups, which is consistent with similar previous published studies.20,26 Approximately 90% of patients had an event of disease progression or death during the study period (48 months). Regarding the total administered dose, we found a higher percentage of reduction of administered doses in the Bevacizumab_CPT-FUFA group. This dose reduction appears to be mainly associated with a higher incidence of adverse effects (19% vs. 15%), when bevacizumab is added to fluorouracil-irinotecan combination regimen, and with ‘‘a priori’’ dose reduction due to advanced age,36 as shown in other studies.26,27,30 So lower relative dose intensity was received by the Bevacizumab_CPT-FUFA group, being less than 85% in about 50% of patients treated. This value is the dose limit fixed by the clinical trials to consider an adequate regimen adherence, as cumulative doses less than 85% of planned dose may compromise treatment efficacy and long-term disease control and
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survival.35 This is the main limitation of the present study, as it could explain that there are no differences in response between both groups. In clinical practice, it is common to include different lines of active treatment available. The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer was overall survival, but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. Therefore, the response variables of choice are TTP or PFS, due to the fact that events occur quicker and more often than deaths37,38 and PFS can be considered an acceptable surrogate for OS in advanced colorectal cancer.41 A limitation to their use is that patient followup should be symmetrical in both treatment groups. The present study met usual clinical practice, therefore it fulfilled this condition. Patient follow-up was performed throughout the study period mainly by the same physician and with the same frequency (approximately every 5–6 cycles). The absence of statistically significant differences in median PFS for patients treated with Bevacizumab_ CPT-FUFA (11.04 months, 95%CI: 7.62–12.55) compared to those treated with CPT-FUFA (10.05 months, 95%CI: 7.10–12.22) (HR ¼ 1.22; 95%CI: 0.69–2.15) is consistent not only with the median PFS of 10.6 months (95%: not available-NA) achieved with bevacizumab_IFL in the pivotal clinical trial AVF2107g26 but also with the results achieved with bevacizumab_FOLFIRI in E2200,27 BICC-C20,28 and Sobrero et al.30 clinical trials, which reported 10.7 months (95%CI: NA), 11.2 months (95%CI: NA) and 11.1 months (95%CI: 10,3-12.1), respectively. Our results are also consistent with those found by Kopetz et al.29 with bevacizumab_FOLFIRI (12.8 months; 95%CI: 9.6–15.2) and they are higher than the 8.3 months (95%CI: NA) obtained by bevacizumab_mIFL.20,28 This confirms the greater efficacy of the administration of fluorouracil by infusion (FOLFIRI) than by bolus (IFL). It is also noteworthy that the results of the present study are similar to the median PFS of 10.8 months (95%CI: 9.7–11.7) and 11.6 months (95%CI: 10.8–12.5) achieved with bevacizumab_FOLFIRI in two uncontrolled cohort observational studies, BRiTE31 and BEAT,32 respectively. It is noteworthy that TTP obtained in the present study with CPT-FUFA (10.60 months, 95%CI: 7.56– 12.22) is well above the 6.7 months (95%CI: 0+ 13.8+)14 and the 7.9 months (95%CI: 5.5–8.9)19 previously published for CPT-FUFA. PFS (10.05 months, 95%CI: 7.10–12.22) is also above the 6.2 months (95%CI: NA) with IFL26 or the 7.6 months (95%CI: NA) with FOLFIRI.20 These divergences could be justified by differences in the
administration method of fluorouracil (bolus vs. infusion),26 the periodicity14 and the relative dose intensity received at the different regimes14 or by the inclusion of patients in second-line treatment26 or prior chemotherapy for non-metastatic CRC,20 which were excluded in the present study. In addition, the variability of follow-up and/or measurement of the response variables37 may also explain the discrepancies found. Despite the differences found on age between the CPT-FUFA group and the Bevacizumab_CPT-FUFA group, the multivariate analysis (Cox regression model) does not identify this or any other variable analyzed as a prognostic or predictive factor of disease progression or death. In the absence of differences in median PFS (95%CI: 0.69–2.15), TTP (95%CI: 0.53–1.85) and ORR (p ¼ 0.175) between both groups, both schemes analyzed can be assumed to present the same effectiveness as used in our setting, so pharmacoeconomic analysis to be applied is cost minimization. A conservative estimation of direct costs was performed, resulting in a mean drug incremental cost of 12,696.5 (95%CI: 10,860.8–14,532.1) euros/mCRC patient treated with bevacizumab_CPT-FUFA as first-line treatment. If indirect costs were included in the analysis, such as time employed by the different professionals involved in the pharmacotherapeutic process (longer preparation and administration time with Bevacizumab_CPT-FUFA) and management of toxicity, yet the incremental cost associated to the pharmacotherapeutic regimen containing bevacizumab would be higher. Since 2007, the British National Institute for Health and Clinical Excellence (NICE) does not recommend bevacizumab in combination with fluorouracil plus folinic acid, with or without irinotecan, for the first-line treatment of mCRC, considering that it only benefits a few patients and represents a high cost to the National Health Service (NHS),42 as the qualityadjusted life year cost (QALY) gained per patient for bevacizumab-IFL is 62,857,43 exceeding the established limit of 40,000 to consider a treatment as cost-effective. These data lead to the need for further research on adverse effects associated with both regimens in our study population (cycle of appearance, grading according to CTCAE v4 criteria, toxicity treatment) and to develop clinical studies to identify appropriate biomarkers for selecting candidate patients who gain the most benefit from the Bevacizumab_CPTFUFA regimen. Nevertheless, some authors have proposed the use of VEGF, plasminogen activator inhibitor (PAI-1), Von Willebrand factor (VWF) and fibrinogen as predictive factors at diagnosis,44
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as well as circulating endothelial cells and endothelial progenitors45,46 as predictive factors during treatment and follow-up of patients diagnosed of mCRC, but have not been incorporated into clinical practice. All this will promote the development of adequate criteria to achieve a wise use of dwindling resources.
Conclusion Despite the small study population and considering the limitation of the difference in the administered relative doses intensity, the addition of bevacizumab to the irinotecan-fluorouracil regimen (CPT-FUFA) does not improve PFS (11.04 months, 95%CI: 7.62–12.55; p ¼ .487) as used in our clinical setting but in addition represents an increase in costs of 12,696.5 (95%CI: 10,860.8-14,532.1) euros/patient treated in our study population. These results potentially compromise the cost-effectiveness of the Bevacizumab_CPT-FUFA regimen. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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