cost–effectiveness of ugt1a1 genotyping in second-line, high-dose, once every 3 weeks irinotecan...

RESEARCH ARTICLEFor reprint orders, please contact:[email protected]

Cost–effectiveness of UGT1A1 genotyping in second-line, high-dose, once every 3 weeks irinotecan monotherapy treatment of colorectal cancer
Marko Obradovic1, Ales Mrhar1,2 & Mitja Kos1,3†
†Author for correspondence1University of Ljubljana, Faculty of Pharmacy, Askerceva 7,1000 Ljubljana, SloveniaTel.: +386 1476 9686;Fax: +386 1425 8031;E-mail: [email protected]: [email protected]: [email protected]

part of

Keywords: colorectal cancer, cost–effectiveness, decision analysis, irinotecan, UGT1A1 genotyping

10.2217/14622416.9.5.539 © 2

Aim: The aim of the present study was to evaluate the cost–effectiveness of UGT1A1 genotyping in second-line, high-dose, once every 3 weeks irinotecan monotherapy treatment of colorectal cancer. Methods: Standard therapy was compared with alternative strategies based on UGT1A1 genotyping from the US healthcare payer perspective. Two alternative strategies (dose reduction and prophylactic use of G-CSF with prior genotyping) and standard therapy were evaluated in a decision analysis, whereas alternative regimens were considered in discussion. The effectiveness outcome was severe neutropenia occurrence and number of life-years gained. Results & Conclusion: Genotyping in combination with a subsequent reduction of initial irinotecan dose for UGT1A1 7/7 genotype patients was cost-saving for the population of African and Caucasian origin. By contrast, UGT1A1 genotyping was not cost effective for the population of Asian ancestry. Furthermore, the prophylactic use of G-CSFs in UGT1A1 7/7 genotype patients was not cost effective in any population group. Finally, the application of a 3-weekly high-dose treatment regimen with a 20% reduced dosage compared with the low-dose weekly irinotecan regimen in patients with UGT1A1 7/7 genotype was less expensive and is more convenient for the patient.

Irinotecan is a camptothecin analogue that actsas a topoisomerase I inhibitor with a strongchemotherapeutic activity [1]. Large randomized,clinical trials have established its position eitheras monotherapy or in combination with fluoro-uracil in the first- and second-line treatment ofmetastatic colorectal cancer [2–6].

In contrast to its well-established effective-ness, irinotecan can cause unpredictable, dose-limiting and life-threatening severe neutro-penia and diarrhea. In high-dose irinotecanregimens, severe neutropenia is a predominanttoxicity [7–9]. If it is present together with feverit requires immediate hospitalization, andresults in death in approximately 7% of suchpatients [10,11]. Furthermore, severe neutro-penia, particularly febrile neutropenia, canconsiderably contribute to the economicburden of cancer care [12].

Irinotecan is a prodrug that is converted inthe liver to the active metabolite SN-38, whichis also responsible for toxic effects [13,14].SN-38 is further metabolized through conju-gation into a pharmacologically inactiveSN-38 glucuronide (SN-38G) by the hepaticuridine diphosphate-glucuronosyltransferase1A1 (UGT1A1) enzyme [15,16]. Glucuronida-tion rate depends on the type of polymorphism

in the promoter region of the UGT1A1 gene,called the TATA box [13]. The wild-type geno-type is designated as UGT1A1 6/6, hetero-zygous as UGT1A1 6/7, and homozygous formutated genotype as UGT1A1 7/7, whichindicates the number of TA repeats in the twoalleles within the TATA box. Glucuronidationrate is decreased by 50 and 25% in individualswith the UGT1A1 7/7 and UGT1A1 6/7mutated genotype, respectively [13].

The frequency of the UGT1A1 7/7 genotypevaries in different population groups. Namely,the highest frequency is present in a populationof African ancestry (approximately 19%) [17–19],whereas in Caucasians this frequency is approxi-mately 11% [17,19–21], and in Asians is less than6% [17,20,21].

According to the published literature, at leastpart of the interpatient variability of irinotecantoxicity can be explained by the UGT1A1 poly-morphism in the promoter region [7–9,22–29].Patients who have UGT1A1 7/7 genotype havean increased risk of developing severe neutro-penia when receiving irinotecan. Although notall of the studies are consistent in their results,risk is evident at higher doses of irinotecan, as inthe case of the 300–350 mg/m2 every 3 weeksregimen [8,9,22,25]. Such a therapy is typical for

008 Future Medicine Ltd ISSN 1462-2416 Pharmacogenomics (2008) 9(5), 539–549 539

RESEARCH ARTICLE – Obradovic, Mrhar & Kos

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irinotecan used as monotherapy in the second-line treatment for patients who had progressedafter first-line oxaliplatin-based treatment [30,101].

A molecular assay is available to identify theat-risk subgroup and is recommended by theUS FDA as well as healthcare professionals tohelp guide irinotecan-treatment decisions [31,102].Subsequently, UGT1A1 7/7 genotype patientscan be given a reduced initial irinotecan dose,prophylactic G-CSFs or alternative treatmentregimens. However, the introduction of geno-typing into the standard clinical practice canresult in a substantial rise in healthcare costsdue to the relatively high prices of genetictests. Therefore, the aim of this study was toevaluate the cost–effectiveness of UGT1A1genotyping in second-line, high-dose, onceevery 3 weeks irinotecan monotherapy treatmentof colorectal cancer.

MethodsA decision analysis was used to simulate out-comes of a hypothetical cohort of metastaticcolorectal cancer patients who had newly startedsecond-line, high-dose, once every 3 weeks iri-notecan monotherapy treatment. The studytime frame began with the start of the second-line chemotherapy treatment and lasted untildeath, being a consequence of cancer progres-sion or another reason. The US healthcare payerperspective was used in the analysis.

A presentation of alternative options to stand-ard treatment for UGT1A1 7/7 genotypepatients is shown in Figure 1. In the ‘no UGT1A1genotyping’ treatment strategy, all patients aretreated in the same way regardless of UGT1A1genotype status, as it is unknown. In the case ofsevere neutropenia occurrence, chemotherapydose intensity is decreased.

The first alternative option to the ‘noUGT1A1 genotyping’ treatment strategy is toperform a UGT1A1 genotype test and apply areduced initial irinotecan dose to UGT1A1 7/7genotype patients who are at increased risk forsevere neutropenia occurrence. As a consequence,a decrease of severe neutropenia occurrence inthis group of patients is expected.

The second alternative option is to perform aUGT1A1 genotype test and apply a standardinitial irinotecan dose to the UGT1A1 7/7 geno-type patients, together with G-CSF. Theseagents reduce the occurrence of severe neutro-penia if given as a prophylactic treatment.Furthermore, they enable the maintenance ofhigher chemotherapy dose intensity [32].

Patients with other UGT1A1 genotypes obtainthe same treatment as in the ‘no UGT1A1 geno-typing’ strategy. Hence, they do not contribute tothe difference in the effectiveness between the‘UGT1A1 genotyping’ strategy and the ‘noUGT1A1 genotyping’ strategy. However, they docontribute to the cost of UGT1A1 genotype testingin the ‘UGT1A1 genotyping’ strategy.

The base-case model assumed no detrimentaleffect on survival if reduced irinotecan dosagewas used, either as reduced initial dose or as alowered dose after severe neutropenia occur-rence. However, as some studies found reducedsurvival when using low-intensity dosage regi-mens, the survival reduction of up to 30% wasexplored in the sensitivity analysis [33–37].

The effectiveness of alternative treatment strat-egies was evaluated in terms of severe neutropeniaprevention and the number of life-years gained.The incremental cost–effectiveness ratios (ICERs)were calculated separately for African, Asian andCaucasian population groups owing to differentfrequencies of the UGT1A1 7/7 genotype.

The ICER represents an additional cost for anadditional unit of effectiveness if an alternativetreatment intervention is implemented. It hasbeen commonly cited that an intervention ofICER below US$20,000–100,000 per quality-adjusted life-year gained or life-year gained is con-sidered cost effective in developed countries [38].In other words, this represents how much asociety is willing to pay for a gain in health unit.

In the manuscript, the same population grouplabeling was used as in studies exploring the fre-quency of the UGT1A1 7/7 polymorphism invarious populations [17–20]. These studies haveidentified individuals as of African, Asian orCaucasian origin. However, it has been reportedthat significant intraethnic variability inUGT1A1 7/7 genotype frequency can exist [39].Therefore, the minimum frequency of UGT1A17/7 genotype where genotyping could be costeffective was calculated.

A 50% incidence of severe neutropenia forUGT1A1 7/7 genotype patients was reported bytwo studies that used a 300–350 mg/m2 every3 weeks irinotecan chemotherapy regimen [22,25].Based on the relationship of UGT1A1 genotypeto active irinotecan metabolite exposure, a 20%reduction of initial irinotecan dose was proposedfor UGT1A1 7/7 genotype patients in second-line colorectal cancer treatment, and thereforewas used in this study [25]. Such a reduction isalso used in clinical practice if severe toxicityoccurs in first-line colorectal cancer treatment [3,5].

Pharmacogenomics (2008) 9(5) future science groupfuture science group

Cost–effectiveness of UGT1A1 genotyping in colorectal cancer treatment – RESEARCH ARTICLE

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Figure 1. Clinical pairinotecan monothe

Second-line coloreccancer treatment whigh-dose itinotecanmonotherapy

As a consequence, the incidence of severe toxic-ity in UGT1A1 7/7 homozygotes could at bestbe reduced to the incidence in patients withother UGT1A1 genotypes. However, a conserva-tive 30% reduction in the incidence of severeneutropenia was assumed. That means that if thebasic incidence of severe neutropenia inUGT1A1 7/7 genotype patients was 50%, the30%-reduced value was 35%.

The following direct medical costs, obtainedfrom the literature, were included in the analysis:cost of UGT1A1 genotyping, cost of second-linecancer treatment with irinotecan, cost of grade3/4 neutropenia treatment, and cost of prophy-lactic treatment with G-CSF. Costs were calcu-lated in 2006 US$ value using the annualizedinflation rate.

The cost of cancer treatment was obtainedfrom Earle et al. [40]. It included the cost ofchemotherapy, administration, monitoring, medi-cations, hospitalization, and other therapies andtests. However, only the difference in treatmentcost between the high-dose (3-weekly) and low-dose (weekly) irinotecan regimens was originallyreported in Earle et al. [40]. The absolute value ofthe total cost of treatment for the high-dose regi-men (this information was needed in the analysis)was obtained by personal communication withone of the authors. Patients who were given a20%-reduced initial irinotecan dose were assumedto have a 20%-reduced cost of chemotherapy.Other costs remained equal, as it was assumedthat treatment time did not change. The cost of

chemotherapy in the high-dose (3-weekly) iri-notecan regimen contributed 59% of the totaltreatment cost. This means that the total treat-ment cost was reduced by 12% when assuming a20%-reduced cost of chemotherapy. The 12%value was the base-case value in the model, andvaried from 6 to 18% in the probabilistic sensitiv-ity analysis. The same reduction in total treatmentcost was applied to patients who had neutropenia.This assumption was based on the fact thatneutropenia mostly occurs in the first two chemo-therapy cycles, and that the 20% reduction of iri-notecan dose is also used in clinical practice ifsevere toxicity occurs [3,5]. Likewise, the 12%value for the reduction of the total treatment costfor patients who had neutropenia varied from 6 to18% in the probabilistic sensitivity analysis.

In addition, the following estimations wereused in the analysis:

• The median survival of patients who dieowing to severe neutropenia was estimatedfrom the fact that the first occurrence of severeneutropenia mostly happens in the first twochemotherapy cycles [10,12].

• The cost of cancer treatment for patients whodie owing to severe neutropenia was estimatedto be a third of the chemotherapy plus admin-istration costs. This was based on the mediantreatment duration obtained by the Rouigeret al. study [4], and the fact that the first occur-rence of severe neutropenia mostly happens inthe first two chemotherapy cycles [10,12].

thways of alternative options of second-line colorectal cancer treatment with high-dose rapy with and without UGT1A1 genotyping.

Doseintensityreductiontal

ith

Less severe neutropeniaSurvival unchanged

Survival unchanged/survival reduced

Survival unchanged

Reduced initial irinotecandose for UGT1A1 7/7

Severeneutropenia

No or mildneutropenia

No UGT1A1genotyping

UGT1A1genotyping

Less severe neutropeniaSurvival unchanged/survival reduced

Standard initial irinotecandose with the use of G-CSFsin UGT1A1 7/7

No doseintensityreduction

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A probabilistic sensitivity analysis was run forboth alternative options to standard treatmentacross a wide range of parameter values. Valuesof all the variables in the model, including sensi-tivity range and data sources, are shown inTable 1. A triangular distribution was chosen inprobabilistic analysis for all variables, with thelower, most frequent and upper values definedby the basic value and range.

TreeAge Pro® (TreeAge Software Inc., MA,USA) software was used to perform the decisionanalysis [103].

ResultsReduction of initial irinotecan dose in UGT1A1 7/7 genotype patientsResults of a base-case model for a cohort of 100patients are presented in Table 2. Genotyping wasboth cost saving and more effective for the popu-lation of African and Caucasian ancestry.Namely, treatment of 100 patients with priorUGT1A1 genotyping resulted in 0.040 and0.023 life-years saved for patients of African andCaucasian origin, respectively. At the same time,US$46,704 and US$11,249 were saved for thesame cohort of patients of African and Caucasianorigin, respectively. On the other hand, theICER was US$6,818,203 per life-year gained forthe population of Asian origin.

The probability that genotyping was a cost-effective treatment in terms of life-years gainedwas nearly 100% for the African populationgroup, and 75% or more for the Caucasian popu-lation group, across wide range of willingness-to-pay thresholds. The probability that genotypingwas cost effective in the Asian population groupwas almost 0%. Results of the probabilistic sensi-tivity analysis are shown in Figures 2 & 3 for eacheffectiveness parameter: severe neutropeniaoccurrence and life-years gained.

In case a 10% reduced survival due to loweririnotecan dose intensity was taken into account,the survival was greater in the standard therapycompared with genotyping. As a consequence,the probability that genotyping was cost effectivedeclined with the rise of willingness to pay,which is shown in Figure 3.

G-CSF prophylaxis in UGT1A1 7/7 genotype patientsResults of a base-case model for a cohort of 100patients are presented in Table 2. G-CSF prophy-laxis in UGT1A1 7/7 genotype patients resultedin an ICER value above US$3 million per life-year gained for all the population groups. The

probability that G-CSF prophylaxis in UGT1A17/7 genotype patients was cost effective was lessthan 10% for all population groups, even whenwillingness to pay to avoid a severe neutropeniaevent was at its extreme values. Moreover, theprobability that this strategy was cost effectivewith regards to acceptable cost per life-yeargained was less than 2% in the African popula-tion group and even lower in the Caucasian andAsian population groups under all assumptionsof the sensitivity analysis.

DiscussionThis study is, to our knowledge, the firstcost–effectiveness study of UGT1A1 genotypingin the treatment of metastatic colorectal cancerpatients. In cases where UGT1A1 7/7 genotypepatients were given a 20% reduced initial iri-notecan dose, genotyping was a dominatingstrategy for African and Caucasian populationgroups. Moreover, even when considering verybroad ranges for parameter values, the probabil-ity that genotyping was cost effective wasapproximately 100 and 75% for patients ofAfrican and Caucasian origin, respectively. Onthe other hand, genotyping was not cost effec-tive for patients of Asian origin, with the proba-bility that genotyping was cost effective foralmost 0% of patients.

According to the base-case model, the mini-mum frequency of UGT1A1 7/7 genotype inone particular population group should be atleast 9% for genotyping to be cost effective,with a probability of more than 50% across thewhole range of cost–effectiveness thresholds(US$0–100,000 per life-year gained).

The possibility that the lowered irinotecan doseintensity reduces patient’s survival was evaluatedin a separate analysis. Namely, some studies haveshown that low-intensity chemotherapy regimenscan lead to a decreased survival in patients withvarious solid tumor types [33–37]. If the 10% sur-vival reduction due to reduced irinotecan doseintensity was taken into account, the probabilitythat genotyping was cost effective significantlydeclined for all population groups. However, nodetrimental effect on survival is to be expectedwhen an adequate dose reduction is administered.In theory, exposure to irinotecan’s active metabo-lite SN-38 is increased when the UGT1A1enzyme has a reduced activity, that is, in UGT1A17/7 genotype patients. Therefore, adequate dosereduction has no deleterious consequences, sinceit will equalize drug exposure to the same level asin wild-type (UGT1A1 6/6) patients. In our




Table 1. Probability

Parameters

UGT1A1 7/7 genotype

Prevalence of UGT1A1 7



Severe neutropenia

Probability of grade 3/4 standard chemotherapy

Reduction of grade 3/4 using reduced initial irin

Reduction of grade 3/4 prophylactic G-CSF

Probability of hospitaliza

Probability of death dur

Life expectancy

Median overall survival fsecond-line treatment (y

Median overall survival fneutropenia (years)

Mean number of treatm

Reduction of survival in irinotecan dose intensity

Costs (in 2006 US$ val

Cost of grade 3/4 neutr

Cost of cancer care for mchemotherapy – standar

Percentage of cost of careceived a 20% lower ir

Cost of cancer care for mtoxicity event

Cost of G-CSF prophyla

Cost of UGT1A1 genoty*Absolute values of costs w

analysis, a 20% initial irinotecan dose reductionwas assumed, as suggested by Innocenti et al. [25],based on the relationship of the UGT1A1 geno-type to active irinotecan metabolite exposure. Lastbut not least, clinicians who would utilize the dos-age reduction for UGT1A1 7/7 genotype patientscould increase subsequent doses if the patient tol-erated therapy and thus diminish the potentialsurvival reduction.

An alternative to the use of reduced initial iri-notecan dose in UGT1A1 7/7 genotype patientsis prophylactic use of G-CSFs. G-CSFs havebeen shown to effectively reduce the occurrenceof severe neutropenia and its complications [41].Furthermore, there is strong and consistent

evidence that G-CSF prophylaxis can be used tomaintain chemotherapy at the desired dose inten-sity [32]. From the patient’s perspective, the G-CSFstrategy improves quality of life with regards tosevere neutropenia avoidance, and at the sametime does not compromise survival. Therefore,G-CSFs would be preferred by patients comparedwith a reduction of the initial irinotecan dosestrategy. However, from the perspective of thehealthcare payer, the G-CSF strategy was not costeffective for any population group.

The third possible intervention for UGT1A17/7 genotype patients is the use of low- ratherthan high-dose irinotecan regimens. Namely,according to the guidelines published by the

parameters and costs used in the decision-analysis model.

Basic value

Range for sensitivity analysis

Ref.

frequency

/7 polymorphism in population of African origin 0.19 0.15–0.23 [17–19]

/7 polymorphism in population of Asian origin 0.02 0.00–0.06 [17,20,21,23]

/7 polymorphism in population of Caucasian origin 0.11 0.07–0.15 [17,19–21,52]

neutropenia in UGT1A1 7/7 genotype patients under 0.50 0.25–0.75 [22,25]

neutropenia occurrence in UGT1A1 7/7 genotype patients by otecan dose

0.3 0.0–0.6 [22,25]

neutropenia occurrence in genotype-dosing strategy by using 0.62 0.50–0.71 [41]

tion (febrile neutropenia) due to grade 3/4 neutropenia 0.25 0.10–0.40 [4–6,28,53]

ing hospitalization for febrile neutropenia 0.07 0.04–0.10 [10,11]

or metastatic colorectal patient treated with irinotecan as ears)

0.9 0.79–1.07 [4]

or metastatic colorectal patients who die owing to severe 0.1 0.0–0.2 [4,10,12]

ent cycles 5.6 5–6 [4]

UGT1A1 7/7 genotype patients when receiving reduced 0.0 0.0–0.3 [33,35,36]

ues)

openia episode 8592 4296–12,888 [54]

etastatic colorectal patient starting second-line irinotecan d dose*

33,137 16,569–49,706 [40]

ncer care reduction for metastatic colorectal cancer patient who inotecan dose

12% 6–18% [40]

etastatic colorectal cancer patient who died owing to severe 7609 3805–11,414 Estimated from [40]

ctic treatment per cycle 2473 1237–3710 [55–57]

ping 375 188–563 [8]

ere obtained by personal communication with one of the authors.



544

Table 2. Results of airinotecan dose or p

Alternative strategy

Reduced initial irinote

African origin

Asian origin

Caucasian origin

Prophylactic use of G-

African origin

Asian origin

Caucasian origin*Difference between ‘UGTA cohort of 100 patients wdose intensity on survival wICER: Incremental cost–effe

National Comprehensive Cancer Network, bothirinotecan as a monotherapy and as a folinicacid, fluorouracil and irinotecan (FOLFIRI) reg-imen can be used in second-line treatment ofpatients who were pretreated with oxaliplatinand/or bevacizumab [104]. In the case of irinote-can monotherapy, either a regimen with a300–350 mg/m2 dose every 3 weeks (high-doseregimen) or a regimen with a 125 mg/m2 doseevery week (low-dose regimen) are possible treat-ment options. However, high-dose irinotecanmonotherapy is mostly used in the USA, whilein Europe the low irinotecan dose intensity ismostly applied – either as a weekly irinotecanmonotherapy regimen (125 mg/m2) or as aFOLFIRI regimen (180 mg/m2 every 2 weeks).

The risk of hematologic toxicity for low-dose(<125 mg/m2) irinotecan regimens, in combina-tion with some other chemotherapeutic agents,was not significantly different between UGT1A17/7 and other genotype patients [7,27,42]. Further-more, Earle et al. found that the overall costs ofthe weekly regimen were lower than the cost ofthe 3-weekly regimen despite more frequent vis-its of patients to the hospital (US$31,587 andUS$33,137, respectively) [40]. Consequently,when the low dose is being considered for thesecond-line treatment of colorectal cancer, deci-sions concerning the best irinotecan dose for anindividual patient could be made based on thestandard clinical practice rather than the geno-type because it was not associated with theincreased risk of toxicity [43]. However, the3-weekly high-dose treatment regimen is stillconsidered to be appropriate by some physicians

and preferred by patients because of the conven-ience of less frequent administration [43]. Conse-quently, when genotyping is performed, theapplication of a 3-weekly high-dose treatmentregimen with a 20% reduced dosage comparedwith the low-dose weekly irinotecan regimen inpatients with UGT1A1 7/7 genotype was lessexpensive (US$29,161 vs US$31,587) and ismore convenient for the patient.

The safety of the FOLFIRI regimen inUGT1A1 7/7 genotype patients was evaluated in aprospective study that found an increased risk forsevere neutropenia in UGT1A1 7/7 genotypepatients in the first chemotherapy cycle [29]. Anincreased risk of irinotecan-induced severe toxicitywas also found in the studies performed by Mar-cuello et al. [26] and Rouits et al. [28]. However,both studies used several treatment regimens,FOLFIRI being one of them, and results werereported in an aggregate form for all treatment reg-imens. Nevertheless, evidence exists that irinotecandose adjustment for UGT1A1 7/7 genotypepatients would also need to be done for the FOLF-IRI regimen. Owing to the lack of cost studies forthe FOLFIRI regimen in the second-line treat-ment of colorectal cancer, a cost–effectivenessanalysis with this regimen has not been performed.

New targeted therapeutic drugs are being eval-uated to determine their role in the treatment ofcolorectal cancer [8,44]. At present, bevacizumab isused in first-line treatment together with eitheririnotecan or oxaliplatin. On the other hand,cetuximab and panitumumab have been approvedby the FDA for patients who are refractory tochemotherapy treatment, that is, in third-line

base-case model for UGT1A1 genotyping followed by either reduction of initial rophylactic use of G-CSF in UGT1A1 7/7 genotype patients.

Costs in US$* Outcomes* ICER

Severe NP cases avoided

Life-years gained

US$ per severe NP avoided

US$ per life-year gained

can dose

-46,704 2.850 0.040 STD STD

28,637 0.300 0.004 95,455 6818,203

-11,249 1.650 0.023 STD STD

CSF

289,126 5.89 0.082 49,088 3506,260

63,987 0.62 0.009 103,205 7371,770

183,178 3.41 0.048 53,718 3836,998

1A1 genotyping’ and ‘no UGT1A1 genotyping’.as considered. Results are presented for each population group separately. No detrimental effect of reduced irinotecan as assumed (i.e., due to reduced initial irinotecan dose or dose intensity reduction after severe neutropenia occurrence). ctiveness ratio; NP: Neutropenia; STD: Standard therapy dominated.




therapy [101]. Few cost–effectiveness studies existregarding these new agents in the therapy of color-ectal cancer, and they suggest that unrestrictedimplementation of new therapies is less likely tobe cost effective [45–48]. However, no such analysesexist for the US healthcare system, so thecost–effectiveness of administration of cetuximabto UGT1A1 7/7 genotype patients was not ana-lyzed. However, it is probably more reasonable toimplement irinotecan dose reduction for thesepatients in order not to deprive them of thepotential benefit, as cetuximab could still beapplied thereupon. Nevertheless, the forthcomingstudies with new and current targeted drugs willdetermine the new role of classical oncologydrugs, and hence the role of genotyping in thetreatment of colorectal cancer patients.

The question of the irinotecan dosage is alsorelevant for the patients with the UGT1A1 6/7genotype. It is thought that heterozygouspatients are at a higher risk for irinotecan toxicity

compared with homozygous UGT1A1 6/6 geno-type patients. However, no study has evaluatedthis risk unambiguously in such patients, andfurther research is needed. On the other hand,UGT1A1 genotype information could also beused to adjust initial irinotecan dose forUGT1A1 6/6 patients. Namely, it has beenreported that a large proportion of patients cantolerate much higher irinotecan dosages, up to500–700 mg/m2 [49,50]. Patients with theUGT1A1 6/6 genotype could therefore be givena higher irinotecan dosage. This assumption isdue to be investigated by other researchers [51].

ConclusionAccording to our study, UGT1A1 genotyping insecond-line, high-dose, once every 3 weeks iri-notecan monotherapy treatment of colorectal can-cer with a subsequent reduction of initialirinotecan dose for UGT1A1 7/7 genotypepatients was cost saving for populations of African

Figure 2. Probabilistic sensitivity analysis (10,000 simulations) for the reduction of initial irinotecan dose in UGT1A1 7/7 genotype patients of different origin.

The x-axis represents the willingness to pay for severe neutropenia case avoided, and the y-axis represents the probability that genotyping was cost effective over standard therapy. WTP: Willingness to pay.

WTP (US$ per severe neutropenia case avoided)

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and Caucasian origin. UGT1A1 genotyping wasnot cost effective for the Asian population group.Furthermore, the prophylactic use of G-CSF inUGT1A1 7/7 genotype patients was not costeffective in any population group. Finally, theapplication of a 3-weekly high-dose treatment reg-imen with a 20% reduced dosage compared withthe low-dose weekly irinotecan regimen inpatients with the UGT1A1 7/7 genotype was lessexpensive and is more convenient for the patient.

Future perspectiveThere is a need to conduct prospective control-led, clinical studies to establish evidence thattreatment guided by genetic polymorphismsoffers an improved net outcome versus empirictreatment. By reducing costly treatment failures

and serious adverse events, pharmacogenetictesting may help improve treatment, reduce theburden of rising prescription drug costs andlower the costs of drug development.

Financial & competing interests disclosureThe authors declare they have not received any specific finan-cial support for performing the present study, nor was anyfinancial support provided throughout the last 2 years by anypharmaceutical company involved in the treatment of color-ectal cancer, and any company involved in the production ofUGT1A1 test kits or any other cancer treatment-related test-ing kits. The authors have no other relevant affiliations orfinancial involvement with any organization or entity witha financial interest in or financial conflict with the subjectmatter or materials discussed in the manuscript apart fromthose disclosed.

Figure 3. Probabilistic sensitivity analysis (10,000 simulations) for the reduction of initial irinotecan dose in UGT1A1 7/7 genotype patients of different origin.

The x-axis represents the willingness to pay per life-year gained, and the y-axis represents the probability that genotyping was cost effective over standard therapy. Results are shown separately for each population group in case no detrimental effect on survival was assumed (solid lines) or when assuming a 10% survival reduction (dotted lines) due to the lower irinotecan dose intensity. WTP: Willingness to pay.

0 20,000 40,000 60,000 80,000 100,0000.0

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Executive summary

High-dose irinotecan

• In high-dose irinotecaimmediate hospitaliza

UGT1A1 7/7 genotype

• The frequency of the population of Africanless than 6%.

• Patients with the UGT

Genotyping as part of

• A molecular assay is aprofessionals to help

• UGT1A1 7/7 genotyptreatment regimens.

• The introduction of grelatively high prices o

Conclusion

• UGT1A1 genotyping populations of African

• UGT1A1 genotyping • The prophylactic use o• The application of a 3

irinotecan regimen in

No writing assistance was utilized in the production ofthis manuscript.

Ethical conduct of research The author states that they have obtained appropriate

institutional review board approval or have followed theprinciples outlined in the Declaration of Helsinki for allhuman or animal experimental investigations. In addition,for investigations involving human subjects, informedconsent has been obtained from the participants involved.

regimen adverse effect

n regimens, severe neutropenia is a predominant toxicity. If it is present together with fever it requires tion, and results in death in approximately 7% of such patients.

UGT1A1 7/7 genotype varies in different population groups. Namely, the highest frequency is present in a ancestry (approximately 19%), whereas in Caucasians this frequency is approximately 11%, and in Asians is

1A1 7/7 genotype have an increased risk for the occurrence of severe neutropenia.

the treatment strategy

vailable to identify the at-risk subgroup and is recommended by the US FDA as well as healthcare guide irinotecan-treatment decisions.e patients can be given a reduced initial irinotecan dose, prophylactic G-CSFs or alternative

enotyping into the standard clinical practice can result in a substantial rise of healthcare costs due to the f genetic tests.

and a subsequent reduction of initial irinotecan dose for UGT1A1 7/7 genotype patients is cost saving for and Caucasian origin.

is not cost effective for the Asian population group. f G-CSF in UGT1A1 7/7 genotype patients is not cost effective in any population group. -weekly high-dose treatment regimen with a 20% reduced dosage compared with the low-dose weekly patients with the UGT1A1 7/7 genotype was less expensive and is more convenient for the patient.

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