Cost-Effectiveness of Adjuvant Chemotherapy in the Treatment of Early-Stage Colon Cancer

Review

Cost-Effectiveness of Adjuvant Chemotherapy in the Treatment of Early-Stage Colon Cancer Amy Soni, Edward Chu Abstract Several adjuvant chemotherapy regimens exist for the treatment of stage III colon cancer. In conjunction with the clinical data from randomized trials, cost-effectiveness studies might help to inform the selection of the optimal treatment regimen. In this review, the outcomes from randomized clinical trials and the elements and process of a cost-effectiveness analysis in this setting are discussed. In addition, the data from several published costeffectiveness analysis studies in the adjuvant setting are reviewed. In general, capecitabine-based regimens have been found to be less costly and more effective than 5efluorouracil-based regimens. The combination of oxaliplatin leads to a modestly improved effectiveness and at an acceptable incremental cost. Future studies using data obtained outside the setting of a clinical trial might help to further guide selection of the most cost-effective regimen. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Capecitabine, Cost-effectiveness analysis, 5-Fluorouracil, Oxaliplatin, Pharmacoeconomics, Stage III colon cancer

Introduction The adjuvant treatment of stage III colon cancer was transformed with the results of randomized phase III studies published in 2004 and 2005, investigating the addition of oxaliplatin to a fluoropyrimidine backbone: FOLFOX (infusional 5-fluorouracil/ LV plus oxaliplatin) and XELOX (capecitabine plus oxaliplatin).1,2 Regimens containing oral capecitabine or intravenous (I.V.) 5-fluorouracil (5-FU) and regimens with or without oxaliplatin are all acceptable treatment options, and the decision on the particular regimen is dependent on patient preferences as they relate to oral versus I.V. chemotherapy and the type of side effects that are considered acceptable.3 Cost-effectiveness analysis (CEA) studies might provide additional information and guidance to individual health care providers who treat the disease and to various health care institutions, including academic cancer centers, hospital-based community practices, office-based practices, and third-party insurers. Data from published clinical trials are the primary source for making treatment decisions, and cost-effectiveness studies provide further supporting data.

Division of Hematology-Oncology, Department of Medicine and Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA Submitted: Jan 27, 2015; Revised: Apr 10, 2015; Accepted: May 15, 2015 Address for correspondence: Amy Soni, MD, Division of Hematology-Oncology, University of Pittsburgh Cancer Institute, UPMC Cancer Pavillion, Fourth Floor, Room 463, 5150 Centre Ave, Pittsburgh, PA 15232 Fax: 412-648-6579; e-mail contact: [email protected]

1533-0028/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2015.05.002

Evolution of Adjuvant Chemotherapy for Early-Stage Colon Cancer Fluorouracil-based chemotherapy has been the standard treatment for stage III colon cancer after surgery since the 1960s.4-9 Adjuvant 5-FU with leucovorin (LV) for 6 months was eventually established as the standard approach, with 3 possible schedules of administration, each with similar efficacy but different toxicity profiles (Table 1).1,2,4,10-15 The Mayo Clinic regimen consists of 5-FU with low-dose LV,10 the Roswell Park regimen consists of 5-FU with high-dose LV,4,11,12 and the de Gramont regimen consists of infusional 5-FU with LV.13,14 It has been well established that the Mayo Clinic regimen is associated with significantly more neutropenia and stomatitis (24.1% and 18.1% Grade
3 toxicities, respectively),8 and the Roswell Park regimen is associated with a greater incidence of diarrhea (30.4% Grade 3/4 toxicity).8 Of the 3 different fluoropyrimidine-based I.V. regimens, the de Gramont infusional regimen appears to be associated with the most manageable safety profile. The FOLFOX regimen was associated with superior diseasefree (DFS) and overall survival (OS) as has now been well established from the Multicenter International Study of Oxaliplatin/ 5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC)1 and National Surgical Adjuvant Breast and Bowel Project (NSABP) C-0712 studies (Table 1). In the pivotal MOSAIC study conducted in Europe, André et al compared infusional 5-FU/LV for 2 days with FOLFOX4 (the same infusional 5-FU/LV schedule with oxaliplatin), with each regimen being administered every 2 weeks for 12 cycles. Three-year DFS rates for

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Cost Effectiveness in Adjuvant Colon Cancer Table 1 Major Colon Cancer Adjuvant Therapy Regimens Used in the United States Name of Trial or Regimen

Studied Chemotherapeutic Regimen

Cycle Duration

Number of Cycles

Reference

LV 20 mg/m2 with 5-FU 425 mg/m2 I.V. bolus on days 1-5

1 Month

6

O’Connell et al10

5-FU/LV Mayo Clinic

2

2

Roswell Park

LV 500 mg/m over 2 hours with 5-FU 500 mg/m I.V. bolus on days 1, 8, 15, 22, 29, 36

8 Weeks

3

Petrelli et al,4,11 Kuebler et al12

de Gramont

LV 200 mg/m2 over 2 hours with 5-FU 400 mg/m2 bolus I.V., then 5-FU 600 mg/m2: 22-hour infusion for 2 days

2 Weeks

12

de Gramont et al13; André et al14

MOSAIC (FOLFOX4)

Infusional 5-FU with LV per de Gramont (see above) with oxaliplatin 85 mg/m2 I.V. over 2 hours on day 1

2 Weeks

12

André et al1

NSABP C-07 (FLOX)

High-dose LV with 5-FU per Roswell Park (see above) with oxaliplatin 85 mg/m2 I.V. over 2 hours on days 1, 3, 5

8 Weeks

3

Kuebler et al12

Capecitabine 1250 mg/m2 p.o. b.i.d. for 2 weeks

3 Weeks

8

Twelves et al2

Capecitabine 1000 mg/m2 p.o. b.i.d. for 2 weeks with oxaliplatin 130 mg/m2 I.V. over 2 hours on day 1

3 Weeks

8

Haller et al15

5-FU/LV With Oxaliplatin

Capecitabine X-ACT Capecitabine With Oxaliplatin XELOXA

Abbreviations: b.i.d. ¼ twice daily; FLOX ¼ 5-FU with leucovorin and oxaliplatin; FOLFOX ¼ infusional 5-fluorouracil/LV plus oxaliplatin; 5-FU ¼ 5-fluorouracil; I.V. ¼ intravenous; LV ¼ leucovorin; MOSAIC ¼ Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer; NSABP ¼ National Surgical Adjuvant Breast and Bowel Project; p.o. ¼ by mouth; X-ACT ¼ Xeloda in Adjuvant Colon Cancer Therapy; XELOXA ¼ XELOX in Adjuvant Colon Cancer Treatment.

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stage III disease were 72.2% in the group that received FOLFOX4 versus 65.3% with 5-FU/LV alone.1 Updated results have documented a 6-year OS rate of 72.9% with FOLFOX4 and 68.7% with infusional 5-FU/LV (P ¼ .023).16 In the United States, in the NSABP C-07 study 5-FU in a weekly bolus regimen for 3 cycles of 6 weekly doses with high-dose LV (Roswell Park regimen) were compared with the FLOX (the same 5-FU/LV regimen with oxaliplatin) every 2 weeks. Three-year DFS for all patients (stage II and III) in this study was 76.1% for the FLOX-containing arm versus 71.8% in the 5-FU/LV arm.12 Subsequent 5-year OS rates for stage III patients were 76.5% with FLOX and 73.8% with 5-FU/LV, and this difference was of borderline significance (P ¼ .052).17 Taken together, the 2 randomized clinical studies have shown that the combination of oxaliplatin with 5-FU/LV-based regimens confers significant clinical benefit in terms of OS.16,17 However, it should be noted that the absolute increase in OS is still somewhat modest, ranging from a 2.7% to a 4.2% improvement. The use of the oral prodrug capecitabine is an appealing option for adjuvant chemotherapy. The X-ACT (Xeloda in Adjuvant Colon Cancer Therapy) study randomized patients with stage III colon cancer to adjuvant treatment with either 5-FU/LV for 5 days every month using the Mayo Clinic regimen or to oral capecitabine only.2 The primary end point was noninferiority of capecitabine in terms of 3-year DFS, and secondary end points were OS and relapse-free survival (RFS). Capecitabine was found to be noninferior to 5-FU/LV but not superior (DFS rates of 64.2% and 60.6%, respectively; P ¼ .12). RFS, which incorporates death from colon cancer or from treatment but not any cause, was superior for capecitabine compared with 5-FU.2 Of note, RFS, not a prespecified primary end point, has been used in some cost-effectiveness studies that compared capecitabine with 5-FU. With longer follow-up of patients treated in X-ACT, OS was noninferior but not statistically superior for capecitabine compared with 5-FU (P ¼ .06); 5-year OS

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rates were 71.4% versus 68.4%, respectively (although superiority was demonstrated in multivariate analyses).18 This study showed that capecitabine is certainly an acceptable alternative to I.V. 5-FU, because it confers similar clinical efficacy. Capecitabine was subsequently combined with oxaliplatin (XELOX) in the XELOXA (XELOX in Adjuvant Colon Cancer Treatment) trial (Table 1). This randomized phase III trial compared XELOX with 5-FU/LV (Mayo Clinic or Roswell Park regimens) monotherapy, and the treatment in each arm was for 6 months in the adjuvant stage III setting.15 XELOX was found to be superior to the I.V. 5-FU/LV regimens, and the 3-year DFS rates were 70.9% versus 66.5%, respectively. Longer-term data published in abstract form suggest a benefit for XELOX in terms of OS at 7 years.19 To date, no study has been conducted in the adjuvant setting that directly compared XELOX and FOLFOX; the XELOXA trial was designed before the reporting establishment of capecitabine or FOLFOX as alternatives to 5-FU/LV. Extrapolating from the metastatic setting,20 where XELOX was found to be noninferior to FOLFOX (median OS of 19 vs. 18.9 months, respectively), clinicians often consider XELOX or FOLFOX to have similar efficacy in the adjuvant setting. However, because of the goal of cure in the adjuvant setting, there are potential concerns regarding patient adherence and compliance with capecitabine. As such, FOLFOX is presently favored over XELOX by clinicians, especially in the United States, for patients able to tolerate either regimen. There are other oral fluoropyrimidines presently being used in the treatment of stage III colon cancer patients in Japan and other Asian countries. The first oral agent to have received approval was tegafur-uracil (UFT), which is comprised of tegafur, an oral 5-FU prodrug, and uracil, an inhibitor of dihydropyrimidine dehydrogenase, in a 1:4 molar ratio. In randomized phase III studies in Japan and the United States, UFT/LV was found to be noninferior to 5-

Amy Soni, Edward Chu FU/LV with respect to DFS and OS.21,22 S-1 is an oral prodrug made up of tegafur, gimeracil (an inhibitor of dihydropyrimidine dehydrogenase), and oteracil (an inhibitor of orotate phosphoribosyltransferase). Recent studies have shown that S-1 is noninferior to UFT in terms of DFS, and is associated with a reduced incidence of hand-foot syndrome.23 In the metastatic setting, UFT/LV with oxaliplatin or S-1 with oxaliplatin24 have been shown to be reasonably well-tolerated and efficacious. However, neither UFT nor S-1 are presently available in the United States for adjuvant therapy.

Cost-Effectiveness Analyses There are at present several chemotherapy regimens that may be used in the United States for the adjuvant treatment of stage III colon cancer: capecitabine, 5-FU/LV, FOLFOX, and XELOX. The clinical decision as to which regimen to use might be based on several patient characteristics, including age, performance status, comorbidities, history of neuropathy, ability to comply with an oral regimen, patient preference for an oral regimen, and acceptability of having a central line. Cost is another important factor for individual clinicians and health care institutions to consider in the present era of ever-increasing costs and limited resources, and data from clinical trials can guide the calculation and use of cost information.25 The basic component of CEA is the incremental cost effectiveness ratio (ICER). In a comparison of 2 potential adjuvant chemotherapy regimens, the ICER is defined as the difference in costs for the regimens divided by the difference in benefit. Calculation of costs is discussed in the next section. Benefits are typically defined according to survival, specifically, quality-adjusted life years (QALYs) gained. The ICER value (cost per QALY) that is acceptable varies significantly by country. In the United States, a value of $100,000 per QALY is often used as a threshold, but there are many interventions that cost more than this.26,27 If a particular strategy is more effective and less costly, it is termed “dominant.” Five-year OS is the traditionally accepted value for survival in the adjuvant setting. However, in a previous study by Sargent, data from large randomized trials of adjuvant 5eFU-based colorectal cancer treatments were combined, and 3-year DFS was shown to be a strong predictor of 5-year OS.28 Eighty percent of disease recurrences were found to occur within the first 3 years after enrollment and median time from recurrent disease to death was 12 months, which supports the use of 3-year DFS as an appropriate surrogate for OS. However, the 18 randomized clinical trials included in this analysis were conducted over a period of 22 years, from 1977 to 1999,28 and the considerable advances made in adjuvant chemotherapy since 1999 could significantly affect those results. Several of the major clinical trials have, at least initially, reported 3-year DFS as the primary outcome.1,2 CEA studies based on these trials then use 3-year DFS to extrapolate 5-year OS. The life-years gained are calculated and ultimately adjusted for quality of life. Further extrapolation can then be done in some studies to calculate benefits for the remaining lifetime horizon and not just for 5 years. Another important factor to consider in CEA studies is perspective. The broadest perspective is societal, and this includes costs of health care resources, non-health care resources, caregiver time, and patient time. Another commonly used perspective is that of the

payer or health care system. Previous CEA studies have typically been conducted from either the societal or, more frequently, the health care system/payer perspective. The main difference between these 2 perspectives is the inclusion of patient time and caregiver time with the societal perspective.

Elements of Cost Analyses Cost is an essential component of CEA studies. Cost calculations can vary greatly among countries and even among providers within a single institution, because of differences in the price for a given element and differences in utilization. For this reason, reconstructing similar CEA studies in different countries can be meaningful even if methodology is quite similar. The key components of cost calculations include costs of the chemotherapy itself (drug, administration costs), cost of adverse effects, patient costs (missed work and travel), surveillance costs after treatment, and costs of treating relapsed disease, and these specific elements are shown in Table 2. There are several components to consider when determining the cost of chemotherapy. The actual drug cost can be calculated by multiplying the cost of the medication on a per milligram basis, by the dose used (in mg/m2), and then by a particular body surface area (BSA), for the duration of treatment. For example, if 5-FU was administered using the Roswell Park schedule and it costs $0.05 per milligram, this would be multiplied by a dose of 500 mg/m2, then by a BSA of 2 to get a weekly cost, and this cost is then multiplied by 18 weekly doses to arrive at a cost of $900 for 6 months. Costs of administering the medications are also important to consider in this setting, particularly because the oral drug capecitabine typically requires fewer health system resources compared with I.V. medications. Administration costs can include salaries of pharmacists, pharmacy technicians, and nurses. In some countries, when continuous infusion 5-FU is used for 2 days, chemotherapy is actually administered on an inpatient basis and for this reason, hospitalization costs need to be taken in to account.29,30 With respect to infusional 5-FU chemotherapy, central line placement is generally required, and there are significant costs associated with line placement and potential costs of complications (infection, thrombosis, pump malfunction).31 Costs for associated laboratory tests, office visits, and prophylactic medications such as antiemetics must also be factored in to the overall costs associated with a given treatment regimen. The various regimens used for adjuvant therapy for colon cancer have unique side effect profiles, which are associated with distinct frequencies and costs. The costs of emergency department visits, hospitalizations, and key high-cost drugs (for example, hematopoietic growth factors) are often important drivers in this setting. Extra office visits (in addition to the standard number during treatment) and potential ambulance costs might also contribute. Immediate side effects that occur during treatment, such as diarrhea, hand-foot syndrome, and cytopenias, lead to higher costs compared with longterm effects such as the neuropathy associated with oxaliplatin. Neuropathy is particularly difficult to quantitate because differing rates are reported by patients versus providers and rates often greatly decrease with time after treatment.32 Regardless, the relative contribution of chronic complications are typically greatly outweighed by costs of acute complications.

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Cost Effectiveness in Adjuvant Colon Cancer Table 2 Elements of a Cost Analysis for the Adjuvant Treatment of Colon Cancer Cost Element

Notes

Chemotherapy Drug Cost

Based on dose (typically in mg/m2), average BSA in study, duration of treatment

Administration

Salaries of pharmacists, pharmacy technicians, nurses

Central line

Placement, care, and complications

Laboratory testing

Before each cycle

Health care provider visits

Before each cycle

Prophylactic medications

Antiemetics and any other medications needed for hypersensitivity reactions, etc

Adverse Effects Acute: additional medical care visits

Emergency department use and hospitalization

Acute: additional medications

Hematopoietic growth factors, I.V. antiemetics

Chronic

Medications to treat neuropathy

Patient Costs Time away from work Travel time

Consider hourly wage and total time away To and from visits for medical care, consider distance from clinic

Surveillancea Colonoscopy

At years 1 and 4 after treatment, every 5 years thereafter

Carcinoembryonic antigen levels

Every 3-6 months for 5 years

Healthcare provider visits

History and physical every 3-6 months for 5 years

CT scan

Yearly for 5 years

Disease Relapse Chemotherapy/biological agents Adverse effects

Similar to above under Chemotherapy. Treatment duration is indefinite as long as there is efficacy and tolerability Similar to above under Adverse Effects, cumulative effects of therapy important to consider

Patient costs Follow-up studies

Similar to above under Patient Costs CT scans, laboratory testing, health care provider visits for indefinite duration

Abbreviations: BSA ¼ body surface area; CT ¼ computed tomography; I.V. ¼ intravenous. a Based on current National Comprehensive Cancer Network guidelines.

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Patient time away from work and travel time for treatment are also important factors to consider but more difficult to precisely quantitate. Most patients are diagnosed with colon cancer at an older age, and they might not be working at the time of diagnosis. For patients who are working, they can have widely variable hourly wages. Attempts have been made to evaluate travel costs in some studies by calculating the distance from each patient’s residence to the clinic, but such information is often not possible nor practical to obtain.29,30 Treatment with oral capecitabine would have less associated office visits, thereby resulting in lower patient-specific costs. However, the overall patient-specific costs are modest compared with the other costs described.29,30 Surveillance costs after the completion of chemotherapy are often not reported in adjuvant colon cancer CEA studies, yet the costs are not insignificant. Regimens with higher OS rates are associated with greater long-term costs simply because there are more patients alive to receive follow-up surveillance. Oxaliplatin-containing regimens will, therefore, be generally associated with higher surveillance costs. As per the National Comprehensive Cancer Network guidelines,3 screening colonoscopies are usually recommended at years 1 and 4 after completion of treatment and every 5 years thereafter, carcinoembryonic antigen levels every 3 to 6 months for 5 years, history and physicals every 3 to 6 months for 5 years, and computed tomography (CT) scans yearly for 5 years. Using cost data from

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the Center for Medicare Services, the cost for such surveillance testing over 5 years was calculated to be approximately $14,000; depending on the treatment venue, this cost can actually surpass that of chemotherapy and complications. This surveillance recommendation is not without controversy. In one recent study it was suggested that more intensive surveillance does not necessarily lead to improved clinical outcomes.33 Patients with resected colon cancer in the study were assigned to have either: minimal follow-up (1 CT scan at 12-18 months if desired, and colonoscopy), carcinoembryonic antigen follow-up, CT follow-up, or the combination of carcinoembryonic antigen and CT follow-up. The minimal follow-up group had a lower rate of curative intent surgery after recurrence compared with the other 3 groups. However, the CT scan with carcinoembryonic antigen group was not found to be better than either the carcinoembryonic antigen alone or CT alone groups. Survival was examined as a secondary end point, and no significant differences were observed between the minimal and more intensive follow-up groups. Surveillance practices can certainly differ according to institution and provider, and results of this study suggest that less intensive surveillance might be adequate, with the potential to considerably reduce costs. The costs associated with recurrent disease could also be meaningful to study in a CEA analysis. One argument against examining

such costs is that relapse treatment regimens and outcomes are often not available from the randomized controlled trials on which many adjuvant colorectal cancer CEA studies are based. The treatment at relapse could be similar regardless of the adjuvant chemotherapeutic option examined. However, the costs of using targeted agents such as bevacizumab and cetuximab for treatment of relapsed disease that is metastatic might be significant. Differing rates of relapse for regimens could then translate in to much greater financial costs.

Attard et al43 Cost-effectiveness Lifetime Canada 5-FU (dG)/Capecitabine

Quality of Life and Patient Preferences

Abbreviations: dG ¼ de Gramont; 5-FU ¼ 5-fluorouracil; ICER ¼ incremental cost effectiveness ratio; MC ¼ Mayo Clinic; QALY ¼ quality-adjusted life-year; XELOX ¼ capecitabine plus oxaliplatin.

Chu et al42 United States 5-FU (Any)/Capecitabine

Cost (minimization)

Payers: National Health Service, societal insurance funds, and patients Insurance providers (medical and pharmacy claim data) Payer (Cancer Care Ontario New Drug Funding Program) Cost minimization

Median >1 year (since randomization) Treatment period XELOX/FOLFOX

Greece

Cost-effectiveness Cost consequence Lifetime 3 Years United States France

Payer (Medicare) Payer (French Sickness Funds)

Aballéa et al40 Douillard et al30

Reference

Jansman et al29 Cassidy et al38 Eggington et al39

Favored Strategy

Capecitabine (cost saving, V934) Capecitabine dominant 1. Capecitabine dominant 2. FOLFOX (ICER of £2970 per QALY) FOLFOX (ICER of $22,800 per QALY) Capecitabine (for MC: cost-saving V6937.71 and for dG: cost-saving V3569.02) XELOX (cost-saving from all perspectives; V4955, V3623, and V104 saved respectively) Capecitabine (cost-saving: $786 per treatment episode per month when adjusted for patient population differences) FOLFOX (CAN$24,104 per QALY) Not specified Payers: National Health Service and societal Payer (National Health Service)

Perspective

Cost-benefit Cost-effectiveness Cost-effectiveness Treatment period Lifetime Lifetime Netherlands United Kingdom United Kingdom

5-FU (MC)/Capecitabine 5-FU (MC)/Capecitabine 1. 5-FU (MC)/Capecitabine 2. 5-FU (dG)/FOLFOX4 5-FU (dG)/FOLFOX4 5-FU (MC or dG)/Capecitabine

Type of Cost Analysis Time Horizon Country Chemotherapy Regimens Compared

Table 3 Cost Studies for Adjuvant Colon Cancer Chemotherapy

Maniadakis et al41

Amy Soni, Edward Chu

Benefits in CEA studies are typically measured in terms of quality of life-years gained; the absolute number of life-years gained is multiplied by a healthy utility score. Utility scores range from 0 to 1, with 1 being perfect health and 0 death. Different parts of a patient’s treatment course have different utility scores. For example, a patient actively receiving 5-FU might have significant diarrhea with an associated quality of life that will be different from a patient who, 3 years after treatment remains disease-free. Utility scores might be obtained by directly surveying patients who have had colorectal cancer treatment.34 Alternatively, healthy volunteers can be asked a series of questions to determine societal values for these disease states.35,36 To date, patient preferences have not been directly accounted for in CEA studies, but they might ultimately be valuable to consider by health care institutions in making decisions about the best adjuvant regimen. One critical element of patient preference to consider is the use of I.V. infusional chemotherapy compared with oral chemotherapy. When asked before receiving treatment in the metastatic colorectal cancer setting, patients generally prefer oral capecitabine to I.V. 5-FU (78% preferred oral, 18% were undecided, and 4% preferred I.V. therapy).37 However, when asked after the completion of treatment, the preference for oral therapy was less strong (64% vs. 36% overall). In fact, for patients who received I.V. 5-FU on an outpatient basis according to the infusional de Gramont regimen (and not those who received inpatient 5-FU), patient preference was evenly split (50%/50%) for I.V. versus oral therapy.37

Cost Studies in the Adjuvant Setting Several studies have examined cost and cost-effectiveness for adjuvant therapy (Table 3).29,30,38-43 Many of these studies were based on data from the major phase III randomized trials,1,2,12 that used information from the trials on clinical outcomes, adverse effects, and resource utilization. Costs are typically calculated from the perspective of the individual country performing the analysis. To date, these types of cost studies have been completed in the United Kingdom, United States, Netherlands, France, Greece, and Canada (Table 3). It should be noted, however, that most of these cost studies were conducted before the publication of long-term follow-up data from the clinical trials (ie, the publications containing data on 5-year OS).16-18 To address the initial lack of availability of 5-year OS data, one such cost study used RFS from the X-ACT study (1.3 months greater for capecitabine)2 for clinical efficacy analysis. Several other studies used extrapolative models using the data from

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Cost Effectiveness in Adjuvant Colon Cancer

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the initial publications on DFS and preliminary OS to estimate long-term survival.38-40,43 For cost studies that compared FOLFOX with 5-FU alone, FOLFOX was found to be associated with improved survival but at a higher cost, with ICERs (converted to 2014 US dollars) ranging from $4070 per QALY to $22,800 per QALY.39,40,43 These ICERs are less than the cost per QALY thresholds used in the United States and Europe. The US study by Aballéa et al in 2007 used data from the MOSAIC trial to model extended DFS and management of lifetime costs were calculated from trial data with estimations of costs for treatment of recurrent disease. Overall mean lifetime costs were found to be $39,000 with 5-FU/LV versus $56,300 for FOLFOX, resulting in an ICER of $22,800 per QALY.40 The United Kingdom study by Eggington et al39 and the Canadian study by Attard et al43 were also performed over the lifetime horizon and yielded even lower ICERs. In CEA studies that compared capecitabine with 5-FU, capecitabine was often found to improve survival and to be less costly, and was therefore dominant.38,39 However, the survival improvement with capecitabine assumed in each of these analyses is not without controversy. Only in multivariate analyses did the long-term followup of X-ACT data show a statistically significant improvement in OS.18 In terms of actual drug cost, capecitabine is more expensive than 5-FU, but drug administration costs and costs of treating adverse effects ultimately drive up 5-FU costs, according to some of these studies.29,30,38,42 For example, Cassidy et al in the United Kingdom found that higher 5-FU/LV administration costs resulted in 57% cost savings with capecitabine. Oral capecitabine also required fewer medications and hospitalizations to manage adverse side effects, resulting in a cost savings of £3653 during the treatment course.38 There is one cost study that compared XELOX with FOLFOX in the adjuvant setting,41 but unfortunately, no randomized phase III trial data have been published on the pharmacoeconomics of these 2 regimens. In the short clinical follow-up time available for this study with a median of 1 year, there was no difference in survival for the 2 regimens. Costs were then compared for the 2 regimens, and XELOX was found to cost less, primarily because of a reduction in hospital day care visits,41 and thus overall drug administration costs, as seen in other studies of capecitabine. XELOX has been compared with FOLFOX in several analyses performed in the metastatic setting (next section). It is important to note that drug administration costs might vary significantly by country, and this is particularly relevant in comparisons of the costs of infusional 5-FU. In several European countries, 5-FU is administered in the inpatient setting or in dayhospital care wards. The use of the hospital setting to administer 5-FU chemotherapy results in a significant increase in drug administration costs. In contrast, however, in the United States, patients typically receive infusional 5-FU in the outpatient setting. There are 2 US studies that have been done in the adjuvant chemotherapy setting,40,42 but neither has specifically investigated infusional 5-FU and capecitabine. The time horizon used, typically either patient lifetime after diagnosis or treatment period, has made a difference in the results from some studies. In the Canadian 5-FU versus FOLFOX cost effectiveness study, the ICER for FOLFOX was CAN$24,104 per

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QALY over the lifetime horizon. Limiting the analysis to 4 years resulted in an ICER of CAN$200,000 per QALY.43 This marked difference might be the result of high upfront costs of treatment and modest direct improvements in survival in the short-term. However, lifetime benefits have been modeled and could be subject to error.

CEA Studies in the Metastatic Disease Setting Because of the relatively limited available data regarding XELOX in the adjuvant setting, CEA studies from the metastatic setting might be informative. The oral administration of capecitabine as opposed to administration in-hospital for 5-FU, is a major driver for metastatic disease analyses. Cost and medical resource utilization studies that compared capecitabine monotherapy with 5-FU in the metastatic setting44-46 have shown potential cost savings with capecitabine, similar to the adjuvant setting. In a cost study of XELOX versus FOLFOX4 in Hong Kong it was found that XELOX costs less from the payer and societal perspectives.47 Similar to the adjuvant studies, the primary driver for the differences in cost was that of hospital stay for infusional 5-FU (1 day at $180 for XELOX and $848 for 3 days for FOLFOX). Another XELOX versus FOLFOX cost study in the metastatic setting was performed in the United States, and the results of this study have been presented in abstract form. In this study, Garrison et al found that drug acquisition costs were higher for XELOX but administration costs were higher for FOLFOX, with the total direct medical cost being similar for the 2 regimens ($44,500 and $45,800, respectively).48 In the French setting, Perrocheau and colleagues performed a cost minimization study, and they also observed overall lower costs with XELOX. This cost reduction with XELOX was driven again by hospitalization costs incurred by FOLFOX infusion and also “disease management” costs with FOLFOX.49 A Japanese cost effectiveness study found XELOX to be dominant to FOLFOX4 in the metastatic setting.50 Cost savings was up to V3000 with XELOX, and this was because of a combination of increased costs of the chemotherapy itself, antiemetics, and outpatient chemotherapy fees with FOLFOX. The effectiveness was measured in quality-adjusted progression-free survival days (not QALYs), and a modest benefit of 10.5 such days were gained with XELOX when adverse events and patient preferences were included in utility score calculations. Thus, in this study, the dominance of XELOX appears to be based on a modest effectiveness improvement and multifactorial cost savings.

Discussion With the changing landscape in health care, we are presently in an era in which cost-saving measures are of critical importance. Cost effectiveness analyses on alternative (and each potentially acceptable) treatment regimens might help to identify regimens that are highly efficacious and cost-effective, so that more patients can receive highvalue care. Because of the high prevalence of colon cancer in the United States and throughout the world and the potential for curing stage III disease, identification of a cost-effective regimen is of significant importance. In fact, CEAs are now being used in some countries to determine which regimens are approved for use in cancer patients. Several of

Amy Soni, Edward Chu the analyses reviewed here were conducted to guide national decisions about approval of the adjuvant colon cancer chemotherapy. For example, the CEA by Cassidy et al was written for use by the United Kingdom’s National Institute for Clinical Excellence.38 In the United States, CEAs are used by national agencies less formally at this time, but nonetheless, will increasingly become important in prioritizing treatments, because of ever-increasing health care costs. Although some CEA studies in the adjuvant colon cancer setting have used data from retrospective or “real world” sources,41,42,51 most are based on data from phase III randomized clinical trials.38-40,43 The accuracy and completeness of these trials make them an ideal source for CEA calculations.25 One potential disadvantage of using trial data is that the estimates of OS and DFS might be overly optimistic. Patients enrolled in clinical trials tend to be younger and to have a better performance status compared with the general population of patients diagnosed with colon cancer.39 In particular, patients older than the age of 65 years, and especially those older than age 75 years, are significantly less likely to enroll in clinical trials compared with younger patients.52 Furthermore, compliance with oral capecitabine might be suboptimal in the real world setting, although at least from a patient self-reported cohort analysis, compliance was found to be high at 91%.53 Additionally, cost data might vary from country to country, based on differing reimbursement schedules and practice patterns, especially as it relates to site of drug administration. This cost variation makes comparison of the published analyses somewhat challenging. For example, in many European countries, 5-FU is administered in the inpatient setting, which would certainly drive up drug administration costs. The costs of certain medications and the typical management of complications might also vary from country to country. Despite these differences, certain trends in CEA have been observed. First, capecitabine monotherapy has been found to be dominant (less costly and possibly more effective) compared with I.V. 5-FU in the adjuvant and metastatic disease settings.29,30,39,42,44-46 The cost savings have been primarily driven by the need to administer 5-FU on an inpatient basis, but capecitabine was also associated with decreased costs of adverse side effect management. Similarly, XELOX is at least cost-saving compared with FOLFOX, with any improved clinical efficacy being modest.41,47,50 The cost savings with XELOX are again driven by the need for inpatient 5-FU administration in most analyses,41,47-49 and because of more globally increased costs in others.50 Therefore, at least in settings in which I.V. 5-FU is administered in the inpatient setting, capecitabine-based regimens appear to be more cost-effective and might thus be preferred by payers over 5-FU based regimens. Second, the combination of oxaliplatin with either 5-FU or capecitabine has been found to be more expensive but with an ICER that is generally acceptable (ie, less than $50,000 per QALY). ICERs for the combination of oxaliplatin with I.V. 5-FU range from $4070 per QALY to $22,800 per QALY.39,40,43 For patients who are able to tolerate more aggressive chemotherapy, the addition of oxaliplatin to a fluoropyrimidine appears to be a cost-effective and worthwhile treatment strategy. Because of the ongoing controversies in adjuvant therapy and the longer duration of practical experience with using adjuvant

chemotherapy regimens, additional cost effectiveness studies will be important in the future. The clinical efficacy of 3 versus 6 months of adjuvant chemotherapy is currently being evaluated, and potential pharmacoeconomic benefits of a short course of 3-month adjuvant therapy will be interesting to consider, when clinical efficacy data become available.54 The use of adjuvant chemotherapy for stage II disease continues to be a subject of ongoing debate,55,56 and the cost-effectiveness of treating stage II disease, with and without high-risk features, might aid clinical decision-making.51 On September 16, 2013, the US Food and Drug Administration approved a generic version of capecitabine, which is presently being marketed by Teva Pharmaceuticals. Although presently not available, updated CEAs using lower cost, generic capecitabine might be quite informative in future years. In addition, studies based on efficacy and toxicity information from real world data might be informative, because of the differences in patients treated in trials versus the real world setting and also the fact that sufficient time has passed to evaluate OS in the real world setting. Using real world data will be particularly relevant for comparisons of single-agent oral capecitabine and infusional 5-FU or oxaliplatin-based chemotherapy (FOLFOX vs. XELOX), because assessment of outpatient 5-FU administration and toxicity management in a less fit population could affect the results of CEAs.

Conclusion Published CEA studies regarding the adjuvant treatment of stage III colon cancer have suggested that capecitabine is less costly and potentially more effective than 5-FU and that the combination of oxaliplatin with a fluorouracil derivative has an acceptable ICER. Future analyses regarding the use of 3 months of chemotherapy instead of 6, the treatment of stage II disease, and the use of real world data might better inform payers and health care providers who make decisions on the optimal adjuvant chemotherapy regimen for early-stage colon cancer.

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