cost considerations in the treatment of colorectal cancer

Pharmacoeconomics 2007; 25 (7): 537-562REVIEW ARTICLE 1170-7690/07/0007-0537/$44.95/0

© 2007 Adis Data Information BV. All rights reserved.

Cost Considerations in the Treatmentof Colorectal CancerFrank G.A. Jansman,1,2 Maarten J. Postma3 and Jacobus R.B.J. Brouwers1

1 Groningen University Institute for Drug Exploration (GUIDE), Department ofPharmacotherapy & Pharmaceutical Care, University of Groningen, Groningen,The Netherlands

2 Department of Clinical Pharmacy, Isala Klinieken, Zwolle, The Netherlands3 Groningen University Institute for Drug Exploration (GUIDE), Department of Social

Pharmacy & Pharmacoepidemiology, University of Groningen, Groningen, The Netherlands

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5371. Literature Search Strategy and Selection Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5392. Socioeconomic Costs of Treatment of Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540

2.1 US/Canada . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5402.2 Europe. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544

3. Chemo- and Immunotherapy-Related Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5453.1 Cost Comparisons of Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545

3.1.1 US/Canada . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5453.1.2 Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5453.1.3 Other Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556

3.2 Cost-Effectiveness Analysis of Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5563.2.1 US/Canada . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5563.2.2 Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5585. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560

Colorectal cancer is among the most common malignancies in developedAbstractcountries. Screening can reduce mortality significantly, although the most appro-priate method is still under debate. Observational studies have revealed thatlifestyle measures may also be beneficial for prevention of colorectal cancer.

Surgery is still the most effective treatment modality for colorectal cancer. Thesurvival benefits of chemotherapy are only modest. For nearly 5 decades,5-fluorouracil (5-FU) has been the main cytotoxic agent for treatment ofcolorectal cancer. In the last decade, the new cytotoxic agents raltitrexed, irinote-can and oxaliplatin have been introduced, next to the oral 5-FU analoguescapecitabine and tegafur in combination with uracil (UFT). Moreover, the immu-notherapeutics bevacizumab and cetuximab have become approved for treatmentof metastatic colorectal cancer.

The economic implications of colorectal cancer treatment are substantial. Thecosts of treatment are mainly attributable to the early and terminal stage of the

538 Jansman et al.

disease (i.e. surgery, hospitalisation, chemo- and immunotherapy and supportivecare). The introduction of new chemo- and immunotherapeutics has caused acontinuing increase of treatment expenditures. Therefore, comparative costs andcost effectiveness are important for assessing the value of new treatment regi-mens.

The available study results suggest that addition of irinotecan or oxaliplatin to5-FU/folinic acid dosage regimens is cost effective. Also, capecitabine is calculat-ed to be cost effective when compared with 5-FU/folinic acid. For UFT, nocomparative studies of cost effectiveness were found. Since raltitrexed and 5-FU/folinic acid have shown equal efficacy in terms of survival, cost-effectivenessanalysis is considered not to be applicable and cost-minimisation analysis may besufficient. At present, pharmacoeconomic analyses of combination treatment withthe immunotherapeutics bevacizumab or cetuximab are not available, except forrecent cost-effectiveness considerations by the UK National Institute for Healthand Clinical Excellence with negative recommendations for both agents in thetreatment of metastatic colorectal cancer.

Given the high treatment costs, substantial toxicity and relatively limitedefficacy of the fast changing chemo- and immunotherapeutic combinations forcolorectal cancer, examination of cost-effectiveness studies should be conductedon a routine basis along with determination of clinical benefits.

Colorectal cancer is the third most common ma- Although the outcome of colorectal cancer pa-lignant disease and the fourth most frequent cause of tients also depends on treatment, the most importantcancer-related death worldwide, with an estimated 1 prognostic indicator is the pathological stage at themillion new cases and 0.5 million deaths each time of presentation.[1,2] The tumour node metastasisyear.[1,2] In developed countries, it is the second (TNM) system of the International Union Againstmost common tumour with a lifetime incidence of Cancer[4] and the American Joint Committee on5%. The prognosis of colorectal cancer is poor, with Cancer[5] is the most commonly used system forabout half of all diagnosed patients dying as a result staging colorectal cancer. This TNM system servesof metastatic spread, mainly due to the delay be- as a basis for curative or palliative therapeutic deci-tween initial development of the disease and clinical sions.symptoms, diagnosis and treatment. Surgery remains the most important treatment

modality for colorectal cancer.[2] Several improve-Most cases of colorectal cancer can be attributedments, for example regarding surgery for rectal can-to sporadic factors (88–94%), while hereditary can-cer, fast-track surgery and laparoscopic surgery,cer syndromes account for 5–10% of cases, i.e.have been achieved in the last decade.mainly hereditary nonpolyposis colorectal cancer

For rectal cancer, radiotherapy and ra-and familial adenomatous polyposis.[1,2] Screeningdiochemotherapy are also considered in order tois effective in reducing mortality from colorectalreduce local recurrence and improve survival andcancer, although the ideal screening method is stillquality of life.[2] The value of radiotherapy in coloncontroversial. Risk, costs and effectiveness have tocancer patients has to be established, but cannot bebe taken into account when evaluating the differentrecommended at this time.options. Published data that address the socioeco-

nomic costs associated with screening, prevention For >40 years, 5-fluorouracil (5-FU), frequentlyand management of colorectal cancer have been combined with folinic acid,[6] has been the maindiscussed in a previous article.[3] cytotoxic drug for treatment. However, in the last

© 2007 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2007; 25 (7)

Economics of Colorectal Cancer Treatment 539

decade new cytotoxic agents have been introduced: extended the median survival to >20 months. How-ever, treatment with combinations of these agents israltitrexed, irinotecan, oxaliplatin and oral ana-still associated with substantial toxicity.logues of 5-FU, i.e. tegafur in combination with

uracil (UFT), and capecitabine.[1,2] In addition, nov- Chemotherapy is also used as adjuvant treatmentel biologically targeted agents, i.e. angiogenesis in- in patients after curative surgery, because of the highhibitors (e.g. bevacizumab), epidermal growth fac- risk of relapse. A pooled analysis of three studiestor receptor-inhibitors (e.g. cetuximab), farnesyl revealed that adjuvant treatment of TNM stage IIItransferase inhibitors, cell-cycle-interacting agents resected colon cancer with 5-FU and folinic acidand gene therapy have been or are being investigat- increased 3-year overall survival from 78% toed as potential monotherapy and combination strate- 83%.[20] The MOSAIC (Multicenter Internationalgies.[1,2] Of these, bevacizumab and cetuximab have Study for Oxaliplatin/5-Fluorouracil/Leucovorin in

the Adjuvant Treatment of Colon Cancer) studyshown efficacy in large clinical trials, and evidencerevealed that adding oxaliplatin to a regimen of 5-suggests potential synergism among these classes ofFU and folinic acid further improves the adjuvantcompounds or with conventional chemotherapy.[7-9]

treatment of colon cancer.[21] Recently (May 2006),However, the small advances of these novel treat-the UK National Institute for Health and Clinicalments in terms of response rate, time to progressionExcellence (NICE) recommended that capecitabineand/or survival, must be weighted against the highand oxaliplatin should be considered for the adju-acquisition costs.[10,11] In 2004, bevacizumab andvant treatment of stage III colon cancer after sur-cetuximab were approved by the US FDA and thegery, based on clinical and cost-effectivenessEuropean Medicines Agency for the treatment ofdata.[22]metastatic colorectal cancer.[12]

Along with the increasing chemotherapeuticAt present, mainly 5-FU combined with folinictreatment modalities, the financial burden of theacid, or capecitabine, with or without irinotecan and/treatment of colorectal cancer grows. In order toor oxaliplatin are chosen for treatment of colorectaldecide whether the potential clinical benefits of newcancer in clinical practice.[1,2] In some cases, immu-anticancer agents warrant the high acquisition costs,notherapy with cetuximab and/or bevacizumab isseveral pharmacoeconomic studies have been con-also used.ducted.[11] Economic considerations are of major

In recent years, the use of chemo- and immu-significance, especially for chemotherapy, because

notherapy is increasing because of the addition ofof high treatment costs, substantial toxicity and rela-

second- and even third-line treatment options fortively limited efficacy. In this article, the economic

metastatic colorectal cancer, when first- or second-implications of new treatments for colorectal cancer

line treatment fails. Also, adjuvant chemotherapy isare considered, based on the currently available

now employed for treatment of Dukes’ B or stage IIpharmacoeconomic data.

as well as Dukes’ C or stage III colon cancer.[13-15]

Finally, elderly patients with colorectal cancer are 1. Literature Search Strategy andnot to be excluded any longer from chemotherapy, Selection Criteriasince elderly patients benefit to the same extent asyounger patients from treatment with cytotoxic The databases MEDLINE and EMBASE wereagents.[16,17]

searched for publications in the 10 years from Au-Better systemic chemotherapy has considerably gust 1996 to August 2006, because costs that were

improved prognosis. The median duration of surviv- calculated cannot be compared properly betweenal among patients with metastatic colorectal cancer years for a longer period of time. The medicalincreased from 6 to 8 months without chemotherapy subject headings (MeSH) ‘colorectal neoplasms’,to 11–12 months with 5-FU.[1,2,18,19] The availability ‘drug therapy’ and ‘costs and cost analysis’ wereof irinotecan and oxaliplatin, next to 5-FU, further combined with the Boolean operator ‘and’, leading


540 Jansman et al.

to 111 records (MEDLINE). For EMBASE, thiscombination of terms yielded 66 records. Abstractsfrom proceedings (no records in PUBMED, none inEMBASE) and supplements (seven records inPUBMED, three in EMBASE) were excluded, asthese publications are generally not peer reviewed.Also, studies that focus only on costs of chemothera-py-induced toxicities (three records in PUBMED,two in EMBASE) or only on costs of screening forcolorectal cancer (15 records in PUBMED, two inEMBASE), were disregarded, as were studies thatwere indirectly related to the subject of the presentreview (56 records in PUBMED, 32 in EMBASE).As a result, 30 records were selected (figure1).[10,11,22-49]

In order to investigate overall costs associatedwith the treatment of colorectal cancer, thekeywords ‘colorectal cancer’, ‘treatment’ and‘costs’ were combined. This strategy led to 718(MEDLINE) and 165 (EMBASE) records, respec-tively. We screened these for relevant articles, ad-ding 23 records to the first selection (figure 1).[3,50-71]

Finally, the selection of records was comparedwith the reference list from Redaelli et al.,[3] anextensive key review article discussing costs associ-ated with the treatment of colorectal cancer, result-ing in three more articles (figure 1).[72-74]

2. Socioeconomic Costs of Treatment ofColorectal Cancer

In order to determine the total economic burdenof colorectal cancer, costs associated with screen-ing, surveillance and diagnosis of the disease, aswell as costs of hospitalisation, surgery, radiothera-py, anticancer agents, supportive care, physiciancharges, clinic visits, laboratory fees and medica-tions need to be considered.[3,50] The highest costs oftreatment are encountered during the early stage of

MeSH subjects:• colorectal neoplasms• drug therapy• costs and cost analysis

(combined with boolean operator 'and')

Keywords combined:• colorectal cancer• treatment• costs

Exclusion: abstractssupplementscosts of toxicitiescosts of screening

MEDLINE: EMBASE:25 records 7 records

Exclusion: Studies indirectly relatedto the subject

MEDLINE: EMBASE:56 records 32 records

Selection of (30 and 23) records compared with reference list from Redaelli

et al.: three additional records selected

Result:30 records selected

Total:56 records selected

Records screened: 23 additional records selected

MEDLINE:111 records

EMBASE:66 records

MEDLINE:718 records

EMBASE:165 records

Fig. 1. Literature search strategy and selection criteria. MeSH =medical subject heading.

the disease, i.e. surgery, surveillance and monitor-ing, and during the terminal stage, i.e. hospitalisa- 2.1 US/Canadation, chemo- and immunotherapy and supportivecare. In the US, the annual expenditures for colorectal

In table I, cost-of-illness data concerning treat- cancer have been estimated as between $US5.3 bil-ment of colorectal cancer are presented. lion (2000 prices) and $US6.5 billion (1994 values),


Econom

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Table I. Estimated socioeconomic costs of treatment of colorectal cancer

Country Study design Colon and/or Costs included Costs Number of patients Reference Referencerectal cancer year(s)

US Retrospective analysis CRC Direct and indirect costs $US5.3 billiona US nationwide 2000 3$US14–22 billiona Worldwide

US Retrospective claims Metastatic Direct and indirect costs $US97 031 more for 699 1998–2004 51data, case-control CRC CRC cases than foranalysis controls

US Retrospective, case- CRC Direct costs $US59 100 per case 210 (PPO) 1996–8 52control analysis from two $US58 600 per case 136 (HMO)health insurance plans:PPO and HMO

US Retrospective automated CRC Direct costs $US42 000 for colon 886 1987–91 53medical charts analysis cancer

$US51 000 for rectalcancer

US Retrospective Colon Direct hospital costs $US20 000 per hospital US nationwide 1991–4 54examination of hospital cancer admissiondischarge data

US Retrospective analysis of CRC Excess hospital costs of $US22 411 for carcinoma 34 670 males 1984–94 55SEER-Medicare care (including future in situ, 11y 36 849 femalesdatabase, case-control costs) compared with $US23 494 for carcinomaanalysis controls in situ, 25y

Projected to 11y and 25y $US29 365 for stage I,costs 11y

$US32 510 for stage I,25y$US28 114 for stage II,11y$US25 263 for stage II,25y$US27 397 for stage III,11y$US19 647 for stage III,25y$US3 006 for stage IV,11y$US 7837 for stage IV,25y

US Retrospective analysis of CRC Direct long-term excess $US33 700 for colon 73 714 1990–4 56SEER-Medicare costs compared with cancerdatabase, case-control controls $US36 500 for rectalanalysis cancer

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Table I. Contd

Country Study design Colon and/or Costs included Costs Number of patients Reference Referencerectal cancer year(s)

US Retrospective analysis of CRC Indirect costs, non- $US4 592 for 12mo of 75 470 1995–8 57SEER-Medicare medical patient time initial phasedatabase, case-control costs $US25 per mo foranalysis continuing phase;

$US2 788 for 12mo ofterminal phase

Canada Retrospective CRC Direct hospital costs $Can16 500 ($US14 700) 593 1990 58examination of for 3y of care afteradministrative patient diagnosisfiles

Switzerland Retrospective, 3-year CRC Hospital care resource €33 079 ($US42 100) for 83 3y follow-up 59follow-up using with surgery utilisation colon cancer for 3y of from diagnosiscomputerised care after diagnosis; in 1997–8administrative patient €40 230 ($US51 200) forrecords rectal cancer for 3y of

care after diagnosis

France Retrospective analysis CRC Direct costs €21 918 ($US27 900) for 142 1997–8 60using medical data from first year after diagnosisa cancer registry andeconomic data fromsocial security system

Italy Retrospective CRC Direct hospital costs $US15 800 for advanced 164 1987 61examination of Tuscan disease during 3y aftercancer registry diagnosis

$US4 750 for localiseddisease during 3y afterdiagnosis

Italy Prospective examination CRC Direct tumour-related £7 720 ($US14 700) for 56 1994–6 62of surgically treated with surgery peri-operative cost age <65y;patients referred to one £8 120 ($US15 400) forcentre age ≥65y

Belgium Retrospective Advanced Direct hospital costs $US21 700–27 300 2 × 20 patients per 1998 63examination of hospital CRC per treated patient country (two hospitals)charts

England $US16 000–16 100

France $US16 600–24 000

Germany $US21 400–27 300

Italy $US15 600–21 000

a Including costs of screening and diagnosis.

CRC = colorectal cancer; HMO = health maintenance organisation; PPO = preferred provider organisation; SEER = Surveillance, Epidemiology, and End Results.


including both direct and indirect costs. These costs the Healthcare Cost and Utilisation Project (USare second only to breast cancer at $US6.6 billion Agency for Health Care Policy and Research). Theper year (1994 prices), and exceed lung cancer at mean number of admissions was 237 754 per year,$US5.1 billion and prostate cancer at $US4.7 billion the mean length of stay was 11.1 days per admis-per year.[3,64] sion, the mean charge per admission was $US19 995

and the mean total hospital charges per year wereWorld expenditures for colorectal cancer could$US4.57 billion. Based on census projections be-be projected to be in the range of $US14–22 billiontween 1992 and 2050, the study estimated that theper year, assuming a cost ratio of 60 : 40 for the USannual number of colon cancer-related admissionsversus the rest of the world.[3]

would increase from 215 000 to 448 000 in peopleIn a recent study by Paramore et al.,[51] the cost ofaged ≥50 years.care for a patient with incident metastatic colorectal

cancer was examined based on analyses of retro- Etzioni et al.[55] assessed the impact of includingspective claims data from selected health plans in and excluding future costs to the costs of colorectalthe US. A case-control analysis was performed us- cancer treatment. Patients were drawn from the Sur-ing claims from the years 1998–2004. Total costs in veillance, Epidemiology, and End Results (SEER)-the follow-up period averaged $US97 031 more for Medicare database and a gender-matched controlmetastatic colorectal cancer cases than for controls. group from the general Medicare population. CostsThe main cost drivers were hospitalisations of care were projected over 11- and 25-year hori-($US37 369) and specialist visits ($US34 582), zons. The results were compared with those fromwhich included chemotherapy administration. These previous studies that did not include future costs forresults indicate that costs of colorectal cancer care added years of life. Outpatient drug costs and nurs-have increased dramatically in recent years, when ing home costs were not included in the Medicarecompared with the results of the following studies. database. Total respective 11- and 25-year estimated

excess costs for male patients were as follows:Kerrigan et al.[52] compared the cancer-related$US22 411 and $US23 494 for carcinoma in situ;medical costs and overall medical costs for working-$US29 365 and $US32 510 for stage I disease;aged people with colorectal cancer in two large$US28 114 and $US25 263 for stage II disease;health insurance plans in Washington State in the$US27 397 and $US19 647 for stage III disease; andUS, one a preferred provider organisation (PPO) and$US3006 and $US7837 for stage IV disease (yearthe other a group model health maintenance organi-1984–94 values). The authors concluded that addingsation (HMO). This study consisted of patients incosts of care in future years for colorectal cancerboth health plans, aged 20–64 years, diagnosed withpatients can reduce cost effectiveness of screening.colorectal cancer from 1996 to 1998. The cancer-Similarly, Brown et al.[56] used the SEER-Medicareattributable medical costs over 2 years werelinked database for obtaining data on payments for$US40 400 in the HMO and $US44 300 in the PPO,colorectal cancer patients for the years 1990–94 inwhile overall medical costs for the cancer casesorder to estimate long-term, cancer-related treat-were $US46 000 in the HMO and $US46 400 in thement costs. The average long-term cancer-relatedPPO.cost was calculated to be $US33 700 for colon can-Another HMO-based study by Fireman et al.[53]

cer and $US36 500 for rectal cancer. This represent-found that colorectal cancer-attributable costs fromed about half of the total long-term costs for Medi-1 month before diagnosis until death (or 15 years ofcare enrollees diagnosed with this disease.follow-up) were $US42 000 per patient for colon

and $US51 000 for rectal cancer (1987–91 values). Nonmedical time costs of colorectal cancer care,i.e. patient time associated with travel to, waitingSeifeldin and Hantsch[54] estimated the economicfor, and seeking medical care, were measured byburden of hospitalisations for colon cancer based onYabroff et al.,[57] using data from 1995 to 1998. Thehospital discharge data for the years 1991–4 from


544 Jansman et al.

net patient time costs averaged $US4592 over the 12 Moreover, a French study[60] investigated the costmonths of the initial phase of cancer care, $US2788 of the management of colorectal cancer using medi-over the 12 months of the terminal phase and $US25 cal data from a specialised cancer registry and eco-per month in the continuing phase of care, indicating nomic data from the national Social Security Sys-that patient time costs are an important component tem. The average cost for the first year of manage-of the costs of colorectal cancer care. ment of colorectal cancer after diagnosis was

assessed at €21 918 (approximately $US27 900)A Canadian study calculated that, in 1990 in the[year 1997/8 values].Nova Scotia region, an average of $Can16 500 (ap-

proximately $US14 700) was spent for the care of In an Italian study,[61] the costs of the time spentone colorectal cancer patient over a 3-year period.[58]

in hospital were calculated for 164 patients withIn summary, most recent North-American data colorectal cancer during the 3 years after the first

suggest lifetime costs for treatment and care of diagnosis in 1987. The parameters evaluated forcolorectal cancer are close to $US100 000. This each patient were the number of cytohistologicalreflects at least a doubling of the costs compared examinations, hospital admissions and days spent inwith studies performed during the 1990s, illustrating the hospital. The average number of admissions in 3that the newly introduced drugs may impact highly years was 1.93 and the mean number of days spenton the general treatment costs for colorectal cancer. in the hospital was 39.9. The total 3-year costs forHowever, some relevant differences between the patients with late-stage and metastatic disease werecosting studies should be noted. For example, we do $US15 800 versus $US4750 for patients with local-note that time horizons chosen to investigate the ised disease. Another Italian study[62] revealed thatcosts of colorectal cancer differ. In particular, not all costs of surgery for locoregional colorectal cancerstudies apply the lifetime perspective to costing and did not differ significantly between patients agedsome estimate those costs on an annual or 2-year <65 years and ≥65 years.basis only. Furthermore, some investigators did not

Finally, Neymark and Adriaenssen[63] collectedinclude predicted medical costs in life-years gained.data on resource utilisation and unit prices in orderSuch differences complicate the comparison be-to estimate and compare the direct hospital costs oftween the various costing studies.managing patients with advanced colorectal cancerin various countries. Data on the consumption of

2.2 Europe medical resources were obtained by a retrospectiveexamination of the hospital charts for 20 patients ineach of ten centres in five European countries. TotalA Swiss group investigated hospital healthcareresource utilisation regarded cost for hospital stays,utilisation, the use of various treatment modalitiesoutpatient visits, surgery, chemotherapy, radiothera-and costs of colorectal cancer cases undergoing sur-py, blood transfusions, diagnostic tests and othergery during the first 3-year period following diagno-examinations, and was reflected by a summary in-sis.[59] Three years are frequently chosen for follow-dex. This index showed that there were considerableup because the majority of patients survive at least 3differences in the amounts of resources used foryears and have a sufficient amount of complete costtreating these patients, between, as well as within,information.[65]

countries. The average imputed cost per patient va-Eighty-three patients at the University Hospitalried from approximately $US15 600 to $US27 300of Basel were included in the study[59] from 1997 to(year 1998 values).1998, of whom 58 had colon cancer and 25 had

rectal cancer. Mean costs incurred for rectal cancer In summary, cost analyses have been performedwere calculated to be €40 230 (approximately for many major European countries. As no very$US51 200) and for colon cancer €33 079 (approxi- recent study is available, the findings from Northmately $US42 100). America cannot be reproduced. However, it is not



unlikely that the same pattern exists for European 3.1 Cost Comparisons of Chemotherapy

countries. One relatively recent study[63] is available3.1.1 US/Canadathat presents a comprehensive generic approachSchrag[11] calculated the drug costs for a patientsimilarly applied to five European countries (Belgi-

with colorectal cancer who is 170cm tall, weighsum, England, France, Germany and Italy). Similar70kg and receives chemotherapy for 8 weeks, thearguments as specified for North American analysesduration required to determine response. The Mayo

complicate a valid comparison between the studies.Clinic dosage regimen with 5-FU and folinic acid

Additionally, for the European setting, differences costs only $US63, while the FOLFIRI regimen withbetween national healthcare systems are a further 5-FU, folinic acid and irinotecan costs $US9381, thecomplicating factor for comparison. FOLFOX regimen with 5-FU, folinic acid and ox-

aliplatin costs $US11 889, the FOLFOX regimencombined with bevacizumab costs $US21 033 and3. Chemo- andthe FOLFIRI regimen combined with cetuximabImmunotherapy-Related Costscosts $US30 675 (costs represent 95% of the aver-age wholesale price in May 2004).[11]

As 5-FU has been available since the 1950s, theIn a study by Maroun et al.,[23] the costs of 5-FU/

patent life has long since expired. Administration of folinic acid treatment, administered according to thethe drug requires nursing time, intravenous access Mayo regimen, were compared with treatment withand tubings, all adding to the overall costs, but the UFT (another oral 5-FU formulation) and folinicactual purchase price is low. In contrast, the whole- acid. A cost-minimisation analysis was conducted in

a subgroup of 154 Canadian patients from two largesale prices for the newer agents are much higher andtrials (n = 1396). The costs retrospectively consid-have a substantial impact on overall treatment costs.ered included those for hospital admissions, outpa-Moreover, the more complex administrationtient visits, laboratory studies, imaging modalities,

schedules require more hospital care and, therefore, other diagnostic procedures, physician resources,also affect treatment costs. Along with the large other health professionals, other procedures such asnumbers of patients with colorectal cancer, health- surgery and transfusion and concomitant medica-care providers are interested in whether these new tions. The costs of cytotoxic agents were not enteredagents also provide acceptable value for money in into the analysis. Treatment costs were estimated to

be $Can6139 (approximately $US5500) for 5-FU/terms of additional clinical benefits.folinic acid versus $Can4123 (approximatelySeveral studies have been published concerning$US3700) for UFT/folinic acid. The difference in

chemotherapy for colorectal cancer (table II) thatcosts was mainly due to fewer outpatient visits for

can be divided into cost comparisons and cost-effec- UFT/folinic acid treatment ($Can448 vs $Can2856;tiveness analyses of different treatment regimens. approximately $US400 vs $US2500).To date, no similar data are available for im-

3.1.2 Europemunotherapy. As a general comment to these stud-Pasetto et al.[24] compared the costs per treatmenties, we note that for most settings merely a cost

cycle of different dosage regimens of 5-FU, foliniccomparison is not sufficient as an analytical ap-acid, irinotecan and oxaliplatin. The costs of com-

proach. For example, for reimbursement issues, gen- mon regimens with irinotecan and 5-FU, with orerally a cost-effectiveness or cost-utility analysis in without folinic acid (i.e. FOLFIRI, AIO, IFL, NOR-oncology patients is required. Obviously, this limits DIC, IRIFAFU and chronomodulated regimens) va-the relevance and applicability for policy making of ried from €1115 to €2909 (approximatelythose comparisons listed in table II. $US1400 to $US3700) per treatment cycle (prices


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Table II. Studies involving chemotherapy-related costs for treatment of colorectal cancer

Country Study design Disease category Treatment Results Patients (n)(year of value)

Cost comparisons of chemotherapy

US[11] Drug costs for 8wks Metastatic CRC 5-FU/folinic acid $US63

of treatment (2004) (Mayo regimen)

5-FU/folinic acid/irinotecan (FOLFIRI) $US9381

5-FU/folinic acid/oxaliplatin (FOLFOX) $US11 889

FOLFIRI/bevacizumab $US21 399

FOLFOX/bevacizumab $US21 033

FOLFIRI/cetuximab $US30 675

Canada[23] Retrospective cost- Metastatic CRC UFT/folinic acid $Can4123 ($US3700) per treatment 154

minimisation analysis (hospital admissions, outpatient clinics,

based on two trials laboratories, diagnostic procedures, health

(1996) professionals, surgery, transfusions,

concomitant medication; study medication

not included)

5-FU/folinic acid $Can6139 ($US5 500)

(Mayo regimen)

Italy[24] Drug costs per Metastatic CRC FOLFIRI regimen (simplified regimen) €1229 ($US1600) (€1115 [$US1400])

treatment cycle (2003) 5-FU/folinic acid (AIO)/irinotecan €2329–2341 ($US3000)

5-FU/folinic acid (IFL)/irinotecan €1338 ($US1700)

5-FU/folinic acid (Nordic)/irinotecan €1184 ($US1500)

5-FU/folinic acid/irinotecan (IRIFAFU) €1216 ($US1600)

Chronomodulated regimen €2909 ($US3700)

France[25] Cost-minimisation Metastatic CRC FOLFOX simplified vs standard De €1997 ($US2500) savings (direct medical 87

analysis (1999–2004) Gramont regimen costs; per diem method)

FOLFOX simplified vs standard De €5982 ($US7600) savings (direct medical

Gramont regimen costs; DRG method)

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FOLFIRI simplified vs standard De €4773 ($US6100) savings (per diem

Gramont regimen method)

FOLFIRI simplified vs standard De €7274 ($US9300) savings (DRG method)

Gramont regimen

Belgium[26] Direct costs analysis Advanced CRC 5-FU/folinic acid + oxaliplatin, BeF107 176–131 340 ($US3400–4200) 186

(2000) standard vs chronomodulated [standard] vs BeF110 592–134 668

administration ($US3500–4300) [chronomodulated]

Italy[72] Direct costs analysis Advanced CRC 5-FU/folinic acid (Mayo regimen with L388 500 ($US250) per mo 78

(1999) 5-FU 375 mg/m2)

5-FU/folinic acid (Mayo regimen with L451 900 ($US300) per mo

5-FU 425 mg/m2)

5-FU/folinic acid (De Gramont L1286 900 ($US800) per mo

regimen)

5-FU high dose L884 800 ($US600) per mo

Irinotecan + raltitrexed L5 066 300 ($US3300) per mo

UK[27] Total treatment costs Metastatic CRC Capecitabine vs Mayo regimen £1461 ($US2800) cost saving (drug costs, 1219

by systematic analysis chemotherapy administration costs,

of resource-use data adverse event management costs

from published trials including hospital admissions, physician

and sponsor consultations and drug treatment)

submissions (2003)

UFT vs Mayo regimen £209 ($US400) cost saving

Capecitabine vs modified De Gramont £1353 ($US2600) cost saving

regimen

UFT vs modified De Gramont regimen £101 ($US200) cost saving

Capecitabine vs inpatient De Gramont £4123 ($US7800) cost saving

regimen

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UFT vs inpatient De Gramont regimen £2870 ($US5400) cost saving

UK[28] Cost-minimisation Metastatic CRC Capecitabine £2132 ($US4000) for a 12-wk treatment 1207

analysis based on trial course (costs for drug acquisition, drug

results from literature administration and treatment of adverse

(1999–2001) effects)

UFT/folinic acid £3385 ($US6400) for a 12-wk treatment 409

course

5-FU/folinic acid (Mayo regimen) £3593 ($US6800) for a 12-wk treatment 407

course

5-FU/folinic acid (standard De £6255 ($US11 900) for a 12-wk treatment 190

Gramont regimen) course

5-FU/folinic acid (modified De £3485 ($US6600) for a 12-wk treatment 190

Gramont regimen) course

The Cost-minimisation Early and metastatic Capecitabine vs 5-FU/folinic acid as €934 ($US1200) cost saving (costs for 32

Netherlands[29] analysis (2001–2) CRC adjuvant treatment outpatient visits, management of adverse

effects and travelling)

Capecitabine vs 5-FU/folinic acid as €1610 ($US2000) cost saving 33

palliative treatment

Different Rough estimation of Advanced CRC Capecitabine vs 5-FU/folinic acid €2300–5000 ($US2900–6400) cost saving 596

countries[66] costs per country depending on the country (treatment-

(2001) related costs and costs related to adverse

event management)

Italy[67] Retrospective cost- Advanced CRC Capecitabine vs 5-FU/ €823 ($US1000) cost saving over 6mo 596

minimisation analysis folinic acid (costs for hospital visits for drug

of clinical trial (2001) administration, and costs for treatment of

adverse events)

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Germany[30] Retrospective cost- Metastatic CRC Capecitabine vs 5-FU/folinic acid €310–410 ($US400–500) cost saving per 26

minimisation analysis (Mayo regimen) 12wk (direct medical costs for drug

(2002) administration)

Capecitabine vs 5-FU/folinic acid €7800–9100 ($US9900–11 600) cost

(AIO/Ardalan regimen) saving per 12wk

UK[31] Total societal costs Advanced CRC 5-FU/folinic acid (De Gramont £5051 ($US9600) over 12wk of treatment 68

analysis (1998–9) regimen) (costs for chemotherapy delivery, other

hospital costs, primary care costs and

patient-borne costs)

5-FU/folinic acid (Lokich regimen) £2576 ($US4900) over 12wk of treatment

Raltitrexed £2616 ($US5000) over 12wk of treatment

UK[32] Prospective indirect Advanced CRC with Raltitrexed £206 ($US400) travel plus time costs per 495

travel and time costs surgery treatment

analysis (1997)

5-FU/folinic acid £342 ($US650) travel plus time costs per

treatment

Norway[33] Direct costs analysis Metastatic CRC Raltitrexed €6800 ($US8700) per treatment (costs for 23

(2001) travelling, drugs, diagnostics,

hospitalisation, hospital hotel stay and

treatment-related complications)

5-FU/folinic acid (Nordic-FLv regimen) €6880 ($US8800) per treatment

Brazil[68] Cost-minimisation Early and metastatic UFT vs 5-FU as adjuvant treatment $Brz32 cost saving for six cycles of

analysis based on trial CRC treatment (costs during pre-chemotherapy,

results and modelling chemotherapy administration cycles 1–6,

(1996) chemotherapy follow-up and costs for

adverse event management)

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UFT vs 5-FU as palliative treatment $Brz335 cost saving for six cycles of

treatment

Argentina[68] Cost-minimisation Early and metastatic UFT vs 5-FU as adjuvant treatment $Arg782 cost saving for six cycles of

analysis based on trial CRC treatment

results and modelling

(1996)

UFT vs 5-FU as palliative treatment $Arg1188 cost saving for six cycles of

treatment

Israel[69] Prospective costs Advanced CRC Tegafur/folinic acid $US606 per month (drug acquisition costs, 61

analysis (1991–2) costs for home nurse care)

5-FU/folinic acid $US2203 per month (drug acquisition

costs, costs for clinical care)

Cost-effectiveness analysis of chemotherapy

US[34,75] Cost-effectiveness Metastatic CRC Oxaliplatin + 5-FU (FOLFOX regimen) $US29 523 incremental costs (costs for

analysis; projections vs irinotecan + 5-FU (IFL regimen) initial venous access, first- and second-line

based on trial results treatment, palliative care for advanced

(2004) disease, first-line toxic deaths and non-

fatal toxicities)

$US80 410 incremental cost-effectiveness

per life-year

$US111 890 per QALY

$US89 080 per progression-free year

US[35,76] Cost-utility analysis Metastatic CRC Irinotecan 3-wk regimen $US1362 incremental costs (costs for 291

based on phase III vs 1-wk regimen chemotherapy, treatment administration,

trial results (2001) tests, supportive medication and

hospitalisation)

$US78 627 per QALY

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UK[36] Systematic review of Advanced CRC Irinotecan vs 5-FU (De Gramont £58 400 ($US110 900) marginal costs per

cost effectiveness regimen) progression-free year (costs for line

(2000) insertion, chemotherapy, administration, in-

and outpatient days, adverse events,

hospital days, tests, clinician consultations

and primary care)

Oxaliplatin vs 5-FU (De Gramont £23 000 ($US43 700) marginal costs per

regimen) progression-free year

Irinotecan vs 5-FU (De Gramont £0 ($US0) marginal costs per life-year

regimen in second-line inpatient gained

treatment)

Irinotecan vs 5-FU (De Gramont £11 180 ($US21 200) marginal costs per

regimen in second-line outpatient life-year gained

treatment)

Irinotecan vs best Between £17 700 ($US33 600) and

supportive care £28 200 ($US53 500) marginal costs per

life-year gained

Raltitrexed No survival benefits

UK[73] Cost-effectiveness Advanced CRC Oxaliplatin + 5-FU/folinic acid vs £26 665 ($US50 600) incremental cost per 620

analysis based on 5-FU/folinic acid additional progression-free year (drug

results from two acquisition costs)

phase III trials (2000)

Irinotecan + 5-FU/folinic acid vs £30 171 ($US57 300) incremental cost per 387

5-FU/folinic acid additional progression-free year

UK[74] Cost-effectiveness Advanced CRC Oxaliplatin + 5-FU/folinic acid vs £25 600 ($US48 600) incremental cost per 417

analysis based on 5-FU/folinic acid additional progression-free year (drug

phase III trial results acquisition costs, costs of hospitalisation

(2000) and premedication costs)

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Austria[37] Cost-effectiveness Stage III colon cancer Oxaliplatin + 5-FU/folinic acid vs best $US12 485 discounted incremental cost- 47

analysis (2003) supportive care effectiveness ratio per life-year gained

(costs for follow-up, detection of

recurrence, chemotherapy, palliative care,

liver resection, second-line chemotherapy

and complications)

France[38] Cost-effectiveness Metastatic CRC Irinotecan vs infusional 5-FU second- $US9344 to $US10 137 per year of added 256

analysis based on line treatment survival (costs for chemotherapy, hospital

phase III trial results admissions for drug administration and for

(1999) complications and hospital outpatients

clinic visits)

UK[39] Cost-effectiveness Metastatic CRC Irinotecan + 5-FU/folinic acid vs 5-FU/ £14 794 ($US28 100) per life-year gained 385

analysis based on folinic acid first-line treatment (costs for drug acquisition, drug

phase III trial results administration, complications, further

(2001) chemotherapy and disease progression)

UK[40] Cost-effectiveness Metastatic CRC Irinotecan vs 5-FU (Lokich regimen £11 947 ($US22 700) per life-year gained 256

analysis based on second-line treatment) (costs for drug acquisition, drug

phase III trial results administration and complications)

(1996–8)

Irinotecan vs 5-FU/folinic acid (De £7700 ($US14 600) per life-year gained

Gramont regimen second-line

treatment)

Irinotecan vs 5-FU/folinic acid (AIO Irinotecan cost-saving and significant

regimen second-line treatment) survival gain over AIO regimen

UK[41] Cost-effectiveness Dukes’ C colon Capecitabine vs 5-FU/folinic acid £3653 ($US6900) cost-savings (costs for 1987

analysis based on cancer (Mayo regimen) drug acquisition, drug administration,

phase III trial results hospital use, adverse events and

(2004–5) ambulance trips)

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£1318 ($US2500) societal cost-saving and

9 quality-adjusted life-months gain (costs

of time and travel)

The Cost-effectiveness Advanced CRC Raltitrexed vs 5-FU/folinic acid $US3396 cost-effective ratio per patient 439

Netherlands[42] analysis based on (Mayo regimen) free of any severe adverse event (costs for

phase III trial results drug acquisition, drug administration,

(1995) diagnostics, hospitalisations, treatment of

adverse effects, hospital outpatient visits,

general practitioner visits and transport to

and from hospital)

$US154 611 per additional life-year

Norway[43] Cost-effectiveness Dukes’ B and C CRC 5-FU/levamisole + surgery £4800 ($US9100) to £16 800 ($US31 900) 95

analysis based on vs surgery alone per QALY (costs for hospital stay, surgery,

phase III trial results and chemotherapy and administrative and

(1995) travel costs)

Germany[44] Cost-effectiveness Stage II and III colon 5-FU/levamisole + folinic acid vs €33 008 ($US42 300) per disease-free 563

analysis based on cancer 5-FU/levamisole life-year (costs for drugs, hospital

phase III trial results admission for drug administration,

(2000) laboratory, physician, diagnostic

procedures, toxicity and travel)

€51 225 ($US65 200) per overall life-year

gained

France/US[45] Cost-effectiveness Non-resectable Floxuridine hepatic arterial infusion $US73 635 per life-year gained (Paris, 654

analysis based on colorectal liver vs 5-FU infusion or supportive care France) [costs for pump, procedure and

meta-analysis (1995) metastases hospitalisation, chemotherapy and follow-

up and toxic effects]

$US72 300 per life-year gained (Palo Alto,

USA)

Continued next page

554 Jansman et al.

according to the Italian Directory of Medicines andManufacturers, November 2003[77]). For combina-tions of oxaliplatin and 5-FU with or without folinicacid (i.e. FOLFOX, OXA-FU, OXAFUFA, OX-AFAFU and chronomodulated regimens), the costswere within the range of €1298–2374 (approxi-mately $US1700–3000) per cycle.

Direct costs related to two different De Gramontregimens with 5-FU/folinic acid (standard vs simpli-fied), given as first-line chemotherapy with ox-aliplatin (FOLFOX regimen) or irinotecan(FOLFIRI), were investigated from the FrenchHealth System perspective.[25] Overall costs (year1999–2004 values) were reduced in the simplifiedregimen, with patients treated by the FOLFOX sim-plified versus standard regimen saving €1997 and€5982 (approximately $US2500 to $US7600), re-spectively, according to the per diem and DRGcosting approaches of hospital stay. In patients treat-ed with the FOLFIRI regimen, cost savings of€4773 (approximately $US6100; per diem method)and €7274 (approximately $US9300; DRGmethod) were observed for the simplified vs stan-dard De Gramont regimen.

In a Belgian study,[26] overall costs of combina-tion chemotherapy with 5-FU, folinic acid and ox-aliplatin, given either as a flat or chronomodulatedinfusion for metastatic colorectal cancer, appearedto be equivalent. Cavallo et al.[72] compared thecosts of four different 5-FU-based chemotherapyregimens and the combination of irinotecan andraltitrexed in 78 patients with advanced colorectalcancer in a Northern Italian hospital. A wide differ-ence among monthly direct cost per patient wasfound from L388 500 (approximately $US250) forthe Mayo regimen to L5 066 300 (approximately$US3300) for the combination of irinotecan andraltitrexed.

A systematic review has been conducted to eval-uate the clinical and cost-effectiveness of oralcapecitabine and UFT with folinic acid, as com-pared with 5-FU/folinic acid regimens as first-linetreatments of metastatic colorectal cancer.[27] Thetotal costs of capecitabine and UFT/folinic acidtreatments were estimated at £2111 and £3375 (ap-


Tab

le I

I. C

ontd

Country

Study

design

Disease

categ

ory

Treatmen

tRes

ults

Patients

(n)

(year

of val

ue)

UK

[46]

Cos

t-ef

fectiveness

Unresec

table

Flo

xuridine

hepa

tic arteria

l inf

usion

£24

604

($US

4670

0) per

life

-yea

r ga

ined

134

anal

ysis

(19

95)

colore

ctal

liver

vs 5

-FU

/folinic

acid in

fusi

on(c

osts

for

drug adminis

tration,

hos

pita

l

metas

tases

admissi

on,

hospita

l out

patient

clinic

visits

,

nurse

visi

ts and

chem

othera

py and

other

drug

treatmen

ts f

or pal

liation an

d

com

plications

)

Flo

xuridine

hepa

tic arteria

l inf

usion

£26

157

($US

4970

0) per

life

-yea

r ga

ined

vs s

ympt

om c

ontr

ol

5-F

U/fo

linic

acid in

fusi

on£3

278

8 ($

US

4200

0) per

life

-yea

r ga

ined

vs s

ympt

om c

ontr

ol

5-F

U =

5-f

luor

oura

cil;

BeF

= Belgian

franc

; C

RC

= c

olorec

tal can

cer;

DR

G =

diagn

osis

-related

gro

ups;

L =

lira

; U

FT

= tegaf

ur/ura

cil;

$Arg

= Argen

tinian nu

evo

peso

; $B

rz =

Bra

zilian real.


proximately $US4000 and $US6400), respectively, Twelves et al.[66] collected data from a largephase III trial on hospital visits for drug administra-compared with total treatment costs with 5-FU/tion, as well as hospital admissions, drug costs andfolinic acid of £3579 (approximately $US6800;unscheduled physician’s consultations for the treat-Mayo regimen), £3684 (approximately $US7000;ment of adverse events. In this study, the reducedmodified De Gramont regimen) and £6155 (approx-costs for hospital drug administration visits forimately $US11 700; inpatient De Gramont regi-capecitabine were estimated to save €2300–5000men). Cost savings of capecitabine and UFT/folinic(approximately $US2900–6400) per patient for aacid over the Mayo regimen were estimated to beplanned treatment duration of 30 weeks when com-£1461 and £209 (approximately $US2800 andpared with 5-FU/folinic acid, depending on the$US400), respectively. Cost savings of capecitabinecountry involved (year 2001 values). The costs fromand UFT/folinic acid over the modified De Gramontthis phase III trial were also investigated by Giulianiregimen were £1353 and £101 (approximatelyet al.,[67] who applied Italian National Health Service

$US2600 and $US200), respectively, and over thecharges and market values. Subsequent calculations

inpatient De Gramont regimen £4123 and £2870 indicated that the use of capecitabine saved €823(approximately $US7800 and $US5400), respec- (approximately $US1000) per patient over atively (year 2003 values). 6-month period compared with 5-FU/folinic acid

(year 2001 values).A British group also compared the two new oralfluopyrimidine therapies against standard intrave- Furthermore, for German colorectal cancer pa-nous 5-FU regimens.[28] A cost-minimisation analy- tients, the treatment costs of capecitabine also ap-sis was conducted assuming that the treatments were peared to be beneficial compared with treatmentof equal efficacy. Treatment costs for a 12-week with 5-FU/folinic acid according to the Mayo andcourse of capecitabine (£2132, approximately the AIO/Ardalan regimens.[30] The potential savings$US4000) and UFT/folinic acid (£3385, approxi- of capecitabine therapy amounted to €310–410 (ap-mately $US6400) were lower than costs for the proximately $US400–500) versus Mayo and

€7800–9100 (approximately $US9900–11 600)intravenous Mayo regimen with 5-FU and folinicversus AIO/Ardalan per patient and quarter (12acid (£3593, approximately $US6800), and infu-weeks) in an office-based oncologist setting (yearsional 5-FU/folinic acid regimens according to De2002 values).Gramont (£6255, approximately $US11 900) and

modified De Gramont (£3485, approximately An English substudy compared three treatments$US6600) schedules over the same treatment period for 68 patients with advanced colorectal cancer, i.e.(year 1999–2001 values). Similarly, an analysis by De Gramont regimen with bolus and infusion 5-FUJansman et al.[29] showed that treatment of colorectal with folinic acid, protracted venous infusion ofcancer with oral capecitabine was cost saving in The 5-FU (Lokich regimen) and raltitrexed.[31] AlthoughNetherlands compared with 5-FU plus folinic acid treatments were fairly equivalent in overall survival

and response, the patients receiving the De Gramontadministered according to the Mayo regimen. Base-regimen generated significantly higher costs thanline savings were estimated at €1610 (approximate-the other patients, for chemotherapy administrationly $US2000) for palliative treatment and €934 (ap-and societal costs: £5051 versus £2576 (approxi-proximately $US1200) for adjuvant treatment, for amately $US9600 vs $US4900; Lokich regimen) andmedian treatment duration of 6 months. The cost£2616 (approximately $US5000; raltitrexed) [yearsavings (€380 [$US500] vs €3733 [$US4800])1998–9 values].were primarily related to the number of outpatient

visits for capecitabine versus the number of day-care Patients’ travel and time costs associated withtreatments for 5-FU/folinic acid, despite the higher treatment with raltitrexed and fluorouracil plusacquisition costs of capecitabine. folinic acid for advanced colorectal cancer were


556 Jansman et al.

analysed in another study from the UK.[32] Median $US2203 for intravenous 5-FU with folinic acid.total travel and time costs per patient were £206 Obviously, as a stand-alone result for 1 month of(approximately $US400) among patients randomis- treatment the implications of such a finding areed to raltitrexed (n = 129) and £342 (approximately difficult to decipher.$US650) for those in the 5-FU/folinic acid group(n = 141). 3.2 Cost-Effectiveness Analysis

of ChemotherapyIn a small Nordic study[33] in 23 patients withmetastatic colorectal cancer, raltitrexed treatmentcosts of €6800 (approximately $US8700) were 3.2.1 US/Canadafound not to be significantly different from treat- The results of a randomised study (N9471)ment costs of €6880 (approximately $US8800) with showed that oxaliplatin and infusional 5-FU5-FU plus folinic acid according to the Nordic-FLv (FOLFOX regimen) was superior to irinotecan andregimen (year 2001 values). The following health- bolus 5-FU (IFL regimen) as first-line therapy forcare-related costs were included: travelling, drug patients with metastatic colon carcinoma.[75] Usingand drug preparation, diagnostics, hospitalisation, simulated cohorts of patients starting FOLFOX orhospital hotel stay, outpatient visits and costs con- IFL, Hillner et al.[34] assessed that treatment withcerning treatment-related complications. FOLFOX versus IFL had an average incremental

NICE recently evaluated the cost effectiveness of cost of $US29 523, a survival benefit of 4.4 months,bevacizumab and cetuximab for the treatment of and an incremental cost-effectiveness of $US80 410metastatic colorectal cancer. Considering the avail- per life-year, $US111 890 per QALY andable evidence, bevacizumab in combination with 5- $US89 080 per progression-free year (year 2004FU plus folinic acid, with or without irinotecan, is values).not recommended for the first-line treatment, nor is In a randomised trial,[76] it was found that acetuximab in combination with irinotecan for the regimen of irinotecan every 3 weeks for patientssecond-line or subsequent treatment of metastatic with advanced colorectal cancer was associated withcolorectal cancer.[78] NICE appraisals have also a lower incidence of severe diarrhoea comparedbeen conducted for irinotecan, oxaliplatin, raltitrex- with weekly treatment, and both regimens had simi-ed, capecitabine and UFT.[79,80] lar efficacy. Therefore, Earle et al.[35] performed an

economic evaluation of these regimens using re-3.1.3 Other Countries source utilisation data for all 291 patients that wereAnother cost-minimisation analysis between included in the trial. The cost-utility ratio was

UFT/folinic acid and 5-FU in combination with $US78 627 per QALY for patients on the 3-weeklylevamisole or folinic acid was performed for Brazil regimen (year 2001 values).and Argentina, in the treatment of metastatic disease These two studies[34,35,75,76] indicate relativelyand as adjuvant treatment.[68] For Brazil, costs were high cost-effectiveness/cost-utility estimates, given$Brz335 (Brazilian reals) less per patient for the the US threshold at $US50 000 per QALY. Obvi-UFT-regimen when used for metastatic disease, but ously, in the presence of only two studies, we noteequivalent treatment costs were found in the adju- that only scarce information on cost effectiveness invant setting. For Argentina, in the treatment of meta- this area is available for the North American situa-static disease, the UFT-regimen provided $Arg1188 tion. For Europe, much more of this type of informa-(Argentinian nuevo peso) per patient in savings over tion is at hand.the 5-FU regimen and $Arg782 per patient in theadjuvant setting (year 1996 values). 3.2.2 Europe

In an Israelian study[69] in 61 patients with ad- A systematic review of the literature has beenvanced colorectal cancer, 1 month of treatment with conducted on the evidence of the clinical effective-oral tegafur with folinic acid cost $606 against ness and the cost effectiveness of irinotecan, ox-



aliplatin and raltitrexed in first- and second-line ratio of irinotecan over 5-FU ranged from $US9344treatment of advanced colorectal cancer.[36] The to $US10 317 per year of added survival, beingmarginal cost per progression-free year for oxalipla- similar to other cancer treatments (year 1999 val-tin compared with the De Gramont 5-FU regimen ues). Another UK study investigated the economicwas determined at £23 000 (approximately benefits of irinotecan in combination with 5-FU and$US43 700). The equivalent cost effectiveness folinic acid compared with 5-FU with folinic acidfor irinotecan was £58 400 (approximately alone as first-line treatment for metastatic colorectal$US110 900). For second-line treatment, the margi- cancer.[39] The incremental cost per life-year gainednal cost per life-year gained was zero when irinote- of £14 794 (approximately $US28 100) [year 2001can was compared with inpatient treatment with the values], supports the use of irinotecan with 5-FUDe Gramont regimen, £11 180 (approximately and folinic acid for treatment from the NHS per-$US21 200) when compared with outpatient De spective.Gramont treatment, and between £17 700 and Regarding second-line treatment of metastatic£28 200 (approximately $US33 600 and colorectal cancer, Iveson et al.[40] compared irinote-$US53 500) when compared with best supportive can with either 5-FU as single agent (Lokich regi-care (year 2000 values). Because there was no bene- men) or 5-FU in combination with folinic acid (Defit in either progression-free survival or survival Gramont or AIO regimen). The incremental costswhen treatment with raltitrexed was compared with per life-year gained (year 1996–8 values) with iri-5-FU, a cost-effectiveness analysis was considered notecan were £7700 (approximately $US14 600) innot to be appropriate. relation to the De Gramont regimen, and £11 947

Cost-effectiveness analyses for oxaliplatin, iri- (approximately $US22 700) in relation to thenotecan and 5-FU/folinic acid were also performed Lokich regimen. Regarding the AIO regimen, iri-from the UK NHS perspective.[73,74] Based on data notecan was more cost effective and also associatedfrom two large phase III trials, the incremental cost with a significant survival gain, i.e. irinotecan wasto achieve an additional progression-free year was dominant.£26 665 (approximately $US50 600) for oxaliplatin Recently, Cassidy et al.[41] used clinical data andplus 5-FU/folinic acid and £30 171 (approximately published sources to assess the cost effectiveness of$US57 300) for irinotecan plus 5-FU/folinic acid, adjuvant oral capecitabine versus intravenous 5-FU/respectively, compared with 5-FU/folinic acid folinic acid (Mayo regimen) in Dukes’ C colonalone.[73] A subsequent analysis revealed a corre- cancer. Capecitabine-associated adverse events re-sponding incremental cost of £25 600 (approximate- quired fewer medications and hospitalisations com-ly $US48 600) for oxaliplatin plus 5-FU/folinic acid pared with 5-FU/folinic acid-associated adverse(year 2000 values).[74]

events (cost savings £3653, approximatelyFor oxaliplatin in the treatment of stage III colon $US6900, year 2004/5 values). Societal costs, in-

cancer, Koperna and Semmler[37] calculated a cost- cluding patient travel and time costs, were reducedeffectiveness ratio of $US12 485 per life-year by >75% with capecitabine versus 5-FU/folinic acidgained when compared with best supportive care (cost savings £1318, approximately $US2500), with(year 2003 values). lifetime gain in quality-adjusted life-months of 9

months. With regard to the cost per life-year gained,A study measuring cost-effectiveness of second-capecitabine was dominant over 5-FU/folinic acid,line treatment with irinotecan (n = 127) versus infu-i.e. cost saving and more effective.sional 5-FU alone (n = 129) was reported by a

French group.[38] Although the acquisition costs of Groener et al.[42] balanced costs and effects ofirinotecan were significantly higher than for 5-FU, treatment with raltitrexed as an alternative to 5-FUthe additional cost of irinotecan was balanced by the plus folinic acid (Mayo regimen) in patients withadded months of survival. The cost-effectiveness advanced colorectal cancer. Based on data from a


558 Jansman et al.

study with 439 patients, cost-effectiveness ratios the UK threshold of £30 000 per life-year or QALYgained for these agents.[22] As shown in this review,resulted in $US3396 per additional patient free ofstudies also suggest oxaliplatin has favourable costany severe adverse event and $US154 611 per addi-effectiveness in other countries, and even suggesttional 1-year survival (year 1995 values).cost-saving potential for capecitabine.In a Norwegian study, the cost of one gained

A complication in comparing cost-effectivenessQALY for adjuvant treatment with 5-FU andstudies of chemotherapy refers to the comparatorlevamisole of Dukes’ B and C colorectal cancerchosen. In particular, with many treatments availa-versus surgery alone was assessed to be betweenble these days and shifting of therapies through lines£4800 (approximately $US9100) and £16 800 (ap-of treatment, many comparisons become availableproximately $US31 900) [year 1995 values].[43]

and relevant. In particular, with national differencesMoreover, a German study revealed that addingexisting in guidelines and treatment sequences,folinic acid to a 5-FU/levamisole regimen as adju-comparisons chosen for one specific country mayvant chemotherapy in patients with colon cancer isnot be relevant for other countries, obviously ham-associated with an incremental cost-effectivenesspering comparisons between studies and countries.ratio of €51 225 (approximately $US65 200) per

life-year gained (year 2000 values) versus 5-FU/4. Discussionlevamisole.[44]

Additional healthcare costs of hepatic arterial The total economic burden of colorectal cancer,infusion of 5-fluoro-2-deoxyuridine versus intrave- including screening, surveillance and diagnosis ofnous chemotherapy or symptom palliation (control) the disease, costs of hospitalisation, surgery, radio-in the treatment of nonresectable colorectal liver therapy, anticancer agents, supportive care, physi-metastases were assessed for two centres, one in cian charges, clinic visits, laboratory fees and medi-France (Paris) and the other in the US (Palo Alto), cations, is significant. World expenditures forbased on data from 654 patients from a meta-analy- colorectal cancer have been estimated in the rangesis.[45] The cost effectiveness with respect to survival of $US14–22 billion per year (year 2000 val-of the patients in the hepatic arterial infusion group ues).[3,64] In the last decade, chemo- and immu-compared with the patients in the control group was notherapy costs have increased dramatically and this$US73 635 per life-year in Paris and $US72 300 per is expected to continue in future years.life-year in Palo Alto (year 1995 values). In another The costs of treatment are mainly attributable tostudy, cost effectiveness of hepatic arterial infusion the early stage, i.e. surgery, surveillance and moni-for management of unresectable colorectal liver me- toring and the terminal stage of the disease, i.e.tastases was compared with systemic chemotherapy, hospitalisation, chemo- and immunotherapy andand with symptom control only.[46] Hepatic arterial supportive care. The results of several studies thatinfusion appeared to be the most cost-effective treat- have investigated the costs of colorectal cancer-ment with £24 604 (approximately $US46 700) per related treatment, are strongly dependent on thelife-year gained versus systemic chemotherapy, and country involved, the period of treatments included,with £26 157 (approximately $US49 700) per life- and the year(s) of cost calculations and tariffs used.year gained versus symptom control, but there was The additional cost of care for patients withno difference with regard to costs per QALY gained colorectal cancer compared with controls varied(year 1995 values). from approximately $US20 000 to $US50 000 in

most studies, to almost $US100 000 in a recentBased on the clinical and economic evidencestudy.[51]reviewed by NICE, they currently recommend that

capecitabine and oxaliplatin should be considered The introduction of new chemo- and im-for the adjuvant treatment of stage III colon cancer munotherapeutics in the last decade have signifi-after surgery, suggesting cost effectiveness below cantly increased the cost of treatment. The acquisi-



tion costs of 5-FU, as the cornerstone of treatment such new anticancer agents are either within hospitalfor almost 50 years, in combination with folinic acid budgets or that specific regulations for its financingare only $US63 (price in May 2004) for 8 weeks of apply. Furthermore, outpatient reimbursed alterna-treatment, while costs of new combinations with tives may be available on the market, and could beirinotecan, oxaliplatin, bevacizumab or cetuximab preferred based on outpatient administration. Thesecan exceed $US30 000 for 8 weeks of treatment.[11] outpatient drugs could also be relatively cost effec-Furthermore, the more complex administration tive compared with the inpatient alternatives. Oralschedules require more hospital care and generate capecitabine as an alternative for intravenous 5-FUhigher costs. serves as an example.[29]

Numerous cost comparisons and cost-effective- For costing, the availability of DRGs poses an-ness analyses have been performed concerning other important influencing factor. The use of DRGchemotherapy for colorectal cancer. However, a prices can avoid elaborate cost analyses. However,comparison of different dosage regimens for the in practice, DRG prices may vary depending on thetreatment of colorectal cancer is complicated by specific healthcare insurer and DRGs are only avail-several factors.[47,70] able for a limited number of diagnoses and treat-

ments, limiting its use in economic analyses. InFirst, the kind of direct and indirect costs that areaddition, future medical care costs can be includedincluded in a pharmacoeconomic evaluation have toor excluded when estimating attributable costs forbe considered carefully. Examples of direct costs arelife-saving interventions.[55,56]drug acquisition cost, cost for outpatient visits for

administration of anticancer agents, costs for health- Yet another factor to note is that dosage regimenscare use and medication to manage adverse effects used in clinical practice are continuously changing.and costs for travelling to and from the hospital. This phenomenon makes recent pharmacoeconomicIndirect costs, e.g. loss of productivity of the pa- data on dosage regimens become outdated in a shorttients, are harder to assess. For comparative pur- period of time. Newly introduced (often biological)poses, dosage regimens with equal efficacy are drugs may rapidly progress from last-line rescuemostly chosen. The main differences in costs usual- treatment to first-line preferred therapy. This canly refer to the incidence and severity of toxicity seriously hamper the quality of pharmacoeconomicsymptoms and the administration of the anticancer assessments in colorectal cancer. For example, withagents. respect to pharmacoeconomic guidelines, we forsee

limitations regarding the choice of the appropriateOne should also be on the alert for the duration ofcomparator and the adequate time horizon for analy-the treatment courses or the number of cycles ofsis. Also, traditional pharmacoeconomic methods,chemotherapy being investigated. For instance,such as trial-based analyses and Markov modellingsometimes patients who have received fewer thanmay not be applicable because of these rapidthree cycles of chemotherapy are excluded from thechanges in treatment practice.study, thereby missing patients with relatively high

treatment costs because of early major toxicity. To address these dynamics, bodies such as NICEAnother factor is the difference in healthcare and the Dutch Foundation for Health Care Insurance

system between countries, leading to discrepancies have developed specific requirements for the eco-in cost comparisons and actual utilisation. In partic- nomic analysis of such new oncological drugs, in-ular, the new anticancer agents are subject to vary- cluding the type of colorectal cancer drugs ad-ing regulations in different countries that may heavi- dressed in this article. In particular, fast-track as-ly impact on their use, market price and costs. Con- sessments should provide the tentative initialsequently, differences in cost impacts between evidence of cost effectiveness, to be confirmed incountries (or even between regions within countries) later years with observational evidence. This obser-result. For example, regulations may specify that vational research involves the development of new


560 Jansman et al.

analytical techniques, such as multivariate analyses, munotherapeutics bevacizumab or cetuximab arewhich have yet to be fully developed. not yet available except for recent cost-effectiveness

considerations by NICE.Still, some general conclusions can be derivedThe significant and increasing economic burdenfrom the present studies on cost comparisons of

of colorectal cancer treatment, and the use of contin-chemotherapy for colorectal cancer. Treatment ofuously changing chemo- and immunotherapeuticcolorectal cancer with capecitabine and UFT/foliniccombinations, have created concern about the asso-acid has been found to be economically beneficialciated costs. Therefore, examination of cost effec-versus 5-FU in combination with folinic acid intiveness of new treatment modalities for colorectalseveral studies.[23,27-30,41,66-69] In these studies, costscancer should be conducted more frequently, alongof treatment with the oral fluoropyrimidine ana-with determination of clinical benefits.logues were calculated against standard 5-FU/folin-

ic acid dosage regimens, i.e. Mayo regimen and DeAcknowledgementsGramont regimen. Moreover, costs of raltitrexed

treatment appeared not to be significantly differentNo sources of funding were used to assist in the prepara-

from 5-FU/folinic acid. tion of this review. The authors have no conflicts of interestWith regard to the new chemotherapeutic agents, that are directly relevant to the content of this review.

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Pharmacoeconomic evaluation of tegafur-uracil (UFT) vs E-mail: [email protected]


cost considerations in the treatment of colorectal cancer

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