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Health-Related Quality of Life of Patients with HPV-Related Cancers in Indonesia

  • Didik Setiawan
    Correspondence
    Address correspondence to: Didik Setiawan, Unit of PharmacoEpidemiology & PharmacoEconomics (PE2), Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, Building 3214, Groningen 9713AV, The Netherlands.
    Affiliations
    Unit of PharmacoEpidemiology & PharmacoEconomics (PE2), Department of Pharmacy, University of Groningen, Groningen, The Netherlands

    Faculty of Pharmacy, Universitas Muhammadiyah Purwokerto, Purwokerto, Indonesia
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  • Arrum Dusafitri
    Affiliations
    Faculty of Pharmacy, Universitas Muhammadiyah Purwokerto, Purwokerto, Indonesia
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  • Githa Fungie Galistiani
    Affiliations
    Faculty of Pharmacy, Universitas Muhammadiyah Purwokerto, Purwokerto, Indonesia
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  • Antoinette D.I. van Asselt
    Affiliations
    Unit of PharmacoEpidemiology & PharmacoEconomics (PE2), Department of Pharmacy, University of Groningen, Groningen, The Netherlands

    Health Technology Assessment Unit, Department of Epidemiology, University Medical Centre Groningen, Groningen, The Netherlands
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  • Maarten J. Postma
    Affiliations
    Unit of PharmacoEpidemiology & PharmacoEconomics (PE2), Department of Pharmacy, University of Groningen, Groningen, The Netherlands

    Institute of Science in Healthy Aging & healthcaRE (SHARE), University Medical Center Groningen, Groningen, The Netherlands
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Open ArchivePublished:September 03, 2017DOI:https://doi.org/10.1016/j.vhri.2017.07.010

      Abstract

      Background

      Human papillomavirus (HPV)-related cancers are a serious concern in developing countries. Valid estimates of a country-specific health-related quality of life (HRQOL) for patients with HPV-related cancers provide a substantial tool in determining the burden of the disease.

      Objectives

      To investigate the HRQOL of patients with HPV-related cancers in Indonesia.

      Methods

      The HRQOL of patients with HPV-related cancers (cervical, uterine, nasopharyngeal, head and neck, and anogenital cancer) was assessed using the EuroQol five-dimensional questionnaire (EQ-5D). Validity and reliability were assessed by means of construct validity and test-retest reliability methods, respectively. Subsequently, the EQ-5D utility index was calculated using the Thailand value set.

      Results

      The EQ-5D came out as a valid and reliable questionnaire for measuring the HRQOL of patients with HPV-related cancers in Indonesia. From a total of 520 patients diagnosed with HPV-related cancers, 404 patients were excluded because of not fulfilling the inclusion criteria, and so 116 patients finally participated in the study. The mean age of the patients was 47.5 ± 12.03 years. Most of the patients were women (56.0%) and married (97.4%), and less than half of them had finished high school (32.7%). Moreover, the proportions of nasopharyngeal, cervical, head and neck, anogenital, and uterine cancers in the study population were 29.3%, 24.6%, 22.4%, 14.2%, and 9.5%, respectively. The average HRQOL of the patients with HPV-related cancers was 0.69 ± 0.10, with the highest and lowest estimates applying to uterine cancer (0.84 ± 0.29) and head and neck cancer (0.58 ± 0.33), respectively.

      Conclusions

      The HRQOL of patients with HPV-related cancers was found to be reduced to a certain extent in our study for Indonesia.

      Keywords

      Introduction

      Human papillomavirus (HPV) infections are a well-established cause of not only cervical cancer [
      • Woodman C.B.J.
      • Collins S.I.
      • Young L.S.
      The natural history of cervical HPV infection: unresolved issues.
      ,
      • Clifford G.M.
      • Smith J.S.
      • Plummer M.
      • et al.
      Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis.
      ,
      • Schellekens M.C.
      • Dijkman A.
      • Aziz M.F.
      • et al.
      Prevalence of single and multiple HPV types in cervical carcinomas in Jakarta, Indonesia.
      ,
      • Burd E.M.
      Human papillomavirus and cervical cancer.
      ] but also other cancers, including head and neck, anogenital (anus, vulva, vagina, and penis), uterine, and nasopharyngeal cancers [
      • zur Hausen H.
      Papillomaviruses in anogenital cancer as a model to understand the role of viruses in human cancers.
      ,
      • Préaud E.
      • Largeron N.
      Economic burden of non-cervical cancers attributable to human papillomavirus: a European scoping review.
      ]. In addition, the global burden of HPV-related cancers is increasing, and developing countries, including Indonesia, bear a high proportion of this burden [
      • Ferlay J.
      • Soerjomataram I.
      • Ervik M.
      • et al.
      ]. For example, data reported by the Ministry of Health in Indonesia showed that HPV-related cancers, especially cervical and nasopharyngeal cancers, were among the 10 cancers with the highest incidence and mortality rate in Indonesia [

      Bruni L, Barrionuevo-Rosas L, Albero G, et al., Human Papillomavirus and Related Diseases Report. Afghanistan: HPV Cent.; 2014;iii.

      ].
      Various health technologies such as chemotherapy [
      • Li Y.
      • Pan K.
      • Liu L.Z.
      • et al.
      Sequential cytokine-induced killer cell immunotherapy enhances the efficacy of the gemcitabine plus cisplatin chemotherapy regimen for metastatic nasopharyngeal carcinoma.
      ,
      • Basu P.
      • Jenson A.B.
      • Majhi T.
      • et al.
      Phase 2 randomized controlled trial of radiation therapy plus concurrent interferon-alpha and retinoic acid versus cisplatin for stage III cervical carcinoma. Int.
      ], prevention strategies [
      • Lu B.
      • Kumar A.
      • Castellsagué X.
      • Giuliano A.R.
      Efficacy and safety of prophylactic vaccines against cervical HPV infection and diseases among women: a systematic review and meta-analysis.
      ,
      • Shah K.V.
      Asia Pacific: cervical cancer screening and human papillomavirus vaccination policy and delivery.
      ,
      • Moore M.A.
      • Tajima K.
      Cervical cancer in the Asian Pacific—epidemiology, screening and treatment.
      ,
      • Sharma M.
      • Ortendahl J.
      • van der Ham E.
      • et al.
      Cost-effectiveness of human papillomavirus vaccination and cervical cancer screening in Thailand.
      ], new hormonal therapies [
      • Cahir C.
      • Guinan E.
      • Dombrowski S.U.
      • et al.
      Identifying the determinants of adjuvant hormonal therapy medication taking behaviour in women with stages I-III breast cancer: a systematic review and meta-analysis.
      ,
      • Bae J.
      • Kim E.H.
      Hormonal replacement therapy and the risk of lung cancer in women: an adaptive meta-analysis of cohort studies.
      ], and clinical practice guidelines [
      • Ripamonti C.I.
      • Bandieri E.
      • Roila F.
      Management of cancer pain: ESMO clinical practice guidelines.
      ] are constantly developed and changed to combat cancer. The implementation of these health technologies has resulted in a wide range of improvements in outcome measures, with success being influenced by cancer type, study site, outcome measure, or even the cancer treatment and prevention itself [
      • Byrd J.K.
      • Wilhoit C.S.T.
      • Fordham M.T.
      • Reeves T.D.
      Predicting HPV status in head and neck cancer.
      ,
      • Hasegawa M.
      • Maeda H.
      • Deng Z.
      • et al.
      Prediction of concurrent chemoradiotherapy outcome in advanced oropharyngeal cancer.
      ]. Nevertheless, various, and sometimes life-threatening, side effects from the treatments could possibly occur, and the health technologies as well as their side effects occasionally influence not only the health status of the patients but also their social and emotional well-being.
      Within this broad variety of issues, the need for comparability of outcomes has been recognized and the term “health-related quality of life” (HRQOL) for this purpose is widely accepted [
      • Maxwell J.H.
      • Mehta V.
      • Wang H.
      • et al.
      Quality of life in head and neck cancer patients: impact of HPV and primary treatment modality.
      ,
      • Oates J.
      • Davies S.
      • Roydhouse J.K.
      • et al.
      The effect of cancer stage and treatment modality on quality of life in oropharyngeal cancer.
      ]. HRQOL generally captures the complete health state of an individual because it includes several important health parameters from, for example, the physical, psychological, and social health dimensions [
      • Group T.W.
      Development of the World Health Organization WHOQOL-BREF quality of life assessment. The WHOQOL Group.
      ]. Any reduction in the value of HRQOL reflects a reduction in the health of the individual. Therefore, HRQOL is able to convey important information for assessing the overall burden of a disease and the effectiveness of interventions as well.
      With regard to cancer disease, HRQOL measurement tools may be classified as generic, general cancer, cancer-site–specific, and cancer-problem–specific. General cancer, cancer-site–specific, and cancer-problem–specific HRQOL measurement tools generally provide more detailed information in a single cancer-type or cancer-related problem, whereas an ultimate advantage of generic HRQOL measurement tools is that because they can be implemented over a wide range of conditions and interventions, they enable comparison of outcomes across diseases [
      • Patrick D.L.
      • Devo R.A.
      Generic and disease specific measures in assessing health status and quality of life.
      ,
      • Krabbe P.P.F.M.
      • Peerenboom L.
      • Langenhoff B.B.S.
      • Ruers T.J.M.T.
      Responsiveness of the generic EQ-5D summary measure compared to the disease-specific EORTC QLQ C-30.
      ]. One example of a generic questionnaire is the EuroQol five-dimensional questionnaire (EQ-5D), which was developed by the EuroQol group and is widely used across the world [
      • Pickard A.S.
      • Wilke C.T.
      • Lin H.W.
      • Lloyd A.
      Health utilities using the EQ-5D in studies of cancer.
      ,
      • Oemar M.
      • Janssen B.
      ,
      • Lang H.-C.
      • Chuang L.
      • Shun S.-C.
      • et al.
      Validation of EQ-5D in patients with cervical cancer in Taiwan.
      ]. Further advantages of the EQ-5D are that it has only five questions and it is easy to administer and complete. The EQ-5D is of two types: the three-level EQ-5D (EQ-5D-3L) and the more recently developed version with five levels (EQ-5D-5L). Several studies support both the validity and the sensitivity of the EQ-5D in patients with cancer [
      • Krabbe P.P.F.M.
      • Peerenboom L.
      • Langenhoff B.B.S.
      • Ruers T.J.M.T.
      Responsiveness of the generic EQ-5D summary measure compared to the disease-specific EORTC QLQ C-30.
      ,
      • Tripathy S.
      • Hansda U.
      • Seth N.
      • et al.
      Validation of the EuroQol five-dimensions—three-level quality of life instrument in a classical Indian language (Odia) and its use to assess quality of life and health status of cancer patients in Eastern India.
      ]. Nevertheless, some studies suggest that the EQ-5D-5L has less ceiling effects and better discriminative abilities with potentially more power to detect differences between groups as compared with the EQ-5D-3L [
      • Pickard A.S.
      • De Leon M.C.
      • Kohlmann T.
      • et al.
      Psychometric comparison of the standard EQ-5D to a 5 level version in cancer patients.
      ,
      • Janssen M.F.
      • Pickard A.S.
      • Golicki D.
      • et al.
      Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study.
      ].
      Indonesia-specific HRQOL of HPV-related cancers provides initial information in decision-making processes because it will assist subsequent processes such as cost-utility analyses. Subsequently, this will allow for comparing outcomes of interventions for HPV-related cancers with the outcomes of other interventions, within as well as outside the area of HPV-related cancers. The purpose of this study was to investigate the HRQOL of patients with HPV-related cancers in Indonesia using the EQ-5D-5L.

      Methods

      A descriptive cross-sectional study was conducted, directed at the HRQOL of patients with HPV-related cancers in Indonesia. The study was divided into two main activities, consisting of pilot testing and the main study. Notably, this study was approved by the ethics committee of the Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia.

       Pilot Study

      Initially, a pilot study was conducted to evaluate the validity and reliability of the EQ-5D for patients with HPV-related cancers in the specific Indonesian setting. A convenience sample of 30 patients with HPV-related cancers was recruited from Dadi Keluarga Public Hospital, Purwokerto, Indonesia. On the recruitment day (day 0), patients filled out both the EQ-5D-5L and the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ-C30), a cancer-specific questionnaire. On day 14, patients filled out the EQ-5D-5L a second time.
      As mentioned, the EQ-5D is a generic quality-of-life instrument developed by the EuroQol group and contains five questions and a visual analogue scale (VAS). The questions comprise five different dimensions, that is, mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. We adopted the updated version of the EQ-5D containing five levels of severity on each dimension because it was considered to be more sensitive and reliable compared with the previous three-level version (EQ-5D-3L). In addition, the VAS records a patient’s self-rated health perception, graded between 0 (worst) and 100 (best).
      The EORTC QLQ-C30 is a disease-specific questionnaire developed mainly to assess the quality of life of patients with cancer. It consists of three different scales: functional (15 questions), symptoms (13 questions), and global quality of life (2 questions). The EORTC QLQ-C30 was chosen as the comparator in the validation process because the Indonesian version has been validated [
      • Perwitasari D.A.
      • Atthobari J.
      • Dwiprahasto I.
      • et al.
      Translation and validation of EORTC QLQ-C30 into Indonesian version for cancer patients in Indonesia.
      ] and some questions, particularly on global health status, physical function, role function, emotional function, and pain, have been identified as significant predictors of the EQ-5D outcomes according to several mapping studies [
      • Kim S.H.
      • Jo M.
      • Kim H.
      • Ahn J.
      Mapping EORTC QLQ-C30 onto EQ-5D for the assessment of cancer patients.
      ,
      • Brennan D.S.
      • Spencer A.J.
      Mapping oral health related quality of life to generic health state values.
      ,
      • McKenzie L.
      • van der Pol M.
      Mapping the EORTC QLQ C-30 onto the EQ-5D instrument: the potential to estimate QALYs without generic preference data.
      ,
      • Proskorovsky I.
      • Lewis P.
      • Williams C.D.
      • et al.
      Mapping EORTC QLQ-C30 and QLQ-MY20 to EQ-5D in patients with multiple myeloma.
      ]. Therefore, construct validity testing, that is, assessing whether the EQ-5D can be interpreted as a meaningful measure of quality of life, was performed by measuring the correlation between each mapped question of the EQ-5D and the EORTC QLQ-C30 because they have the same construct (convergent validity method) [
      • Onwuegbuzie A.J.
      • Witcher A.E.
      • Collins K.M.T.
      • et al.
      Students’ perceptions of characteristics of effective college teachers: a validity study of a teaching evaluation form using a mixed-methods analysis.
      ]. Each of the EORTC QLQ-C30 subscales was considered to be correlated with an EQ-5D dimension when the statistically significantly Pearson correlation coefficient indicated so [
      • Kim S.H.
      • Jo M.
      • Kim H.
      • Ahn J.
      Mapping EORTC QLQ-C30 onto EQ-5D for the assessment of cancer patients.
      ,
      • McKenzie L.
      • van der Pol M.
      Mapping the EORTC QLQ C-30 onto the EQ-5D instrument: the potential to estimate QALYs without generic preference data.
      ,
      • Proskorovsky I.
      • Lewis P.
      • Williams C.D.
      • et al.
      Mapping EORTC QLQ-C30 and QLQ-MY20 to EQ-5D in patients with multiple myeloma.
      ]. Furthermore, the value of the Pearson correlation coefficient represents the magnitude and the direction of the correlation [
      • Kirkwood B.R.
      • Sterne J.A.C.
      ].
      To ensure the reliability of the EQ-5D, the two measurements (day 0 and day 14) were compared within patients to assess test-retest reliability [
      • Neill J.
      ]. This method was chosen because in patients with cancer, significant changes in quality of life rarely occur within a 14-day interval and although a clear recommendation to avoid recall bias is scarcely available and often debatable, this 14-day interval is considered sufficient to avoid recall bias [
      • Streiner D.L.
      • Norman G.R.
      • Cairney J.
      ]. Test-retest reliability represents measurement stability, using intraclass coefficients (ICCs) [
      • Lundy J.J.
      • Coons S.J.
      Test-retest reliability of an interactive voice response version of the EQ-5D in a sample of cancer survivors.
      ,
      • Duarte P.S.
      • Ciconelli R.M.
      • Sesso R.
      Cultural adaptation and validation of the “Kidney Disease and Quality of Life-Short Form (KDQOL-SF 1.3)” in Brazil.
      ]. ICC values were interpreted as follows: weak agreement if the ICC is lower than 0.40, good agreement if the ICC lies between 0.40 and 0.75, and excellent agreement if the ICC is 0.75 or higher [
      • Duarte P.S.
      • Ciconelli R.M.
      • Sesso R.
      Cultural adaptation and validation of the “Kidney Disease and Quality of Life-Short Form (KDQOL-SF 1.3)” in Brazil.
      ]. In addition, the Cronbach α was calculated to assess internal consistency, that is, to determine whether the EQ-5D questions together measure the same construct of the HRQOL of patients with HPV-related cancers. Internal consistency was considered to be good if the Cronbach α was higher than or equal to 0.80 [
      • Neill J.
      ].

       Main Study

      All registered patients from 2010 to 2015 in Margono Public Hospital, Purwokerto, Indonesia, were screened for their eligibility. Inclusion criteria were as follows: patients were older than 18 years, were diagnosed with any HPV-related cancer (cervical, uterine, nasopharyngeal, head and neck, or anogenital cancer), and had received any care in the hospital. Patients with chronic disease comorbidity were excluded. A clinical convenient sample was implemented for all patients who were eligible and received and signed informed consent before both the EQ-5D and the EORTC QLQ-C30 were filled out while the patient’s sociodemographic and clinical information, such as age, sex, education level, and diagnosis of cancer, were collected from medical records. These two separate data sets were matched according to the medical record number for each patient.
      Each dimension of the EQ-5D-5L is presented as a dichotomous outcome: no problem (answer level 1) or problems (answer levels 2–5). Furthermore, a major outcome provided by the EQ-5D is an index-based value (utility index) allowing the calculation of quality-adjusted life-years [

      EuroQol. EQ-5D-5L value-sets. Available from: http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-5d-5l-value-sets.html. [Accessed February 3, 2016]

      ]. This utility index, ranging from lower than 0 (worse than death) to 1 (perfect health), is generated by transforming patients’ responses to the five questions, using a country-specific value set. Because an Indonesia-specific value set is not available yet, the utility index was calculated using the Thailand value set and subsequently presented by cancer type [
      • Tongsiri S.
      • Cairns J.
      Estimating population-based values for EQ-5D health states in Thailand.
      ].
      Statistical analysis was performed to identify the differences of both the EQ-5D utility index and the EQ-5D VAS score on the basis of the study characteristics and cancer groups. Because the results of the Shapiro-Wilk normality test showed that both parameters were not normally distributed (P value of 0.000 for both parameters), a nonparametric test was implemented. The Mann-Whitney U test was used for the variables sex and marital status, whereas the Kruskal-Wallis H test was used for education level and cancer groups.

      Results

       Pilot Study

      The age of the patients in the pilot study ranged from 22 to 68 years with a mean of 51.5 ± 11.5 years (data not shown). Most of the patients were women (56.7%) and diagnosed with head and neck cancer (70.0%), followed by cervical cancer at 13.4% and nasopharyngeal cancer at 10.0% (data not shown). According to the ICCs generated from test-retest reliability, each subscale in the Indonesian version of the EQ-5D had an excellent agreement (≥0.75). The EQ-5D VAS scores had a good agreement with the ICC of 0.73. In addition, the EQ-5D had a good internal consistency because the value of Cronbach α was higher than 0.80 (Table 1).
      Table 1Reliability test of the EQ-5D for patients with HPV-related cancer
      DimensionICCCronbach α
      Mobility0.970.84
      Self-care0.95
      Usual activities0.79
      Pain/discomfort0.84
      Anxiety/depression0.82
      EQ-5D VAS0.73
      EQ-5D, EuroQol five-dimensional questionnaire; HPV, human papillomavirus; ICC, intraclass correlation coefficient; VAS, visual analogue scale.
      There were significant relationships between almost all the dimensions of the Indonesian version of the EQ-5D with mapped subscales of the EORTC QLQ-C30 including physical function, role function, fatigue, and pain. Only the mobility dimension of the EQ-5D seemed uncorrelated with the social function subscale of the EORTC QLQ-C30. Meanwhile, only the global health status subscale of the EORTC QLQ-C30 correlated with the EQ-5D anxiety/depression dimension, whereas only the cognitive function subscale correlated with the pain/discomfort dimension. The EQ-5D VAS was apparently correlated with all the EORTC QLQ-C30 subscales except cognitive function (Table 2). Strong correlations were generated by some of the EQ-5D dimensions and the EORTC QLQ-C30 subscales, such as between self-care and physical function, usual activities and physical function, and pain/discomfort and pain, with correlation coefficients of −0.870, −0.855, and 0.842, respectively.
      Table 2Convergent validity reflected with Pearson correlation coefficients
      EORTC QLQ-C30EQ-5D
      MobilitySelf-careUsual activitiesPain/discomfortAnxiety/depressionEQ-5D VAS
      Global health status−0.198−0.08−0.081−0.288−0.482
      Significantly correlated at the P < 0.01 level.
      0.489
      Significantly correlated at the P < 0.01 level.
      Physical function−0.777
      Significantly correlated at the P < 0.01 level.
      −0.870
      Significantly correlated at the P < 0.01 level.
      −0.855
      Significantly correlated at the P < 0.01 level.
      −0.502
      Significantly correlated at the P < 0.01 level.
      −0.616
      Significantly correlated at the P < 0.01 level.
      0.691
      Significantly correlated at the P < 0.01 level.
      Role function−0.675
      Significantly correlated at the P < 0.01 level.
      −0.534
      Significantly correlated at the P < 0.01 level.
      −0.719
      Significantly correlated at the P < 0.01 level.
      −0.613
      Significantly correlated at the P < 0.01 level.
      −0.481
      Significantly correlated at the P < 0.01 level.
      0.618
      Significantly correlated at the P < 0.01 level.
      Emotional function−0.535
      Significantly correlated at the P < 0.01 level.
      −0.456
      Significantly correlated at the P < 0.05 level.
      −0.327−0.337−0.592
      Significantly correlated at the P < 0.01 level.
      0.426
      Significantly correlated at the P < 0.05 level.
      Cognitive function0.1140.059−0.025−0.490
      Significantly correlated at the P < 0.01 level.
      0.06−0.023
      Social function−0.304−0.406
      Significantly correlated at the P < 0.05 level.
      −0.364
      Significantly correlated at the P < 0.05 level.
      −0.498
      Significantly correlated at the P < 0.01 level.
      −0.433
      Significantly correlated at the P < 0.05 level.
      0.363
      Significantly correlated at the P < 0.05 level.
      Fatigue0.498
      Significantly correlated at the P < 0.01 level.
      0.430
      Significantly correlated at the P < 0.05 level.
      0.400
      Significantly correlated at the P < 0.05 level.
      0.520
      Significantly correlated at the P < 0.01 level.
      0.519
      Significantly correlated at the P < 0.01 level.
      −0.527
      Significantly correlated at the P < 0.01 level.
      Pain0.536
      Significantly correlated at the P < 0.01 level.
      0.503
      Significantly correlated at the P < 0.01 level.
      0.625
      Significantly correlated at the P < 0.01 level.
      0.842
      Significantly correlated at the P < 0.01 level.
      0.538
      Significantly correlated at the P < 0.01 level.
      −0.663
      Significantly correlated at the P < 0.01 level.
      EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30; EQ-5D, EuroQol five-dimensional questionnaire; VAS, visual analogue scale.
      low asterisk Significantly correlated at the P < 0.01 level.
      Significantly correlated at the P < 0.05 level.

       Main Study

      From the hospital database, a total of 520 patients were identified for this study of whom 374 were eligible for inclusion and subsequently, if possible, were visited at their home. Finally, 116 patients were included in the study (Fig. 1).
      Fig. 1
      Fig. 1Flow chart of the HPV-related cancer patients studied.
      The mean age of the patients was 47.5 ± 12.03 years (range 18–75 years). Most of the patients were women (56.0%) and married (97.4%), and less than half of them had finished high school (32.7%). Moreover, the proportions of nasopharyngeal, cervical, head and neck, anogenital, and uterine cancers in the study population were 29.3%, 24.6%, 22.4%, 14.2%, and 9.5%, respectively (Table 3).
      Table 3Characteristics of the study population (N = 116)
      CharacteristicnPercentEQ-5D indexP valueEQ-5D VASP value
      Age (y)
       Mean ± SD47.53 ± 12.03
       Range18–75
      Sex
       Male5144.00.66 (0.34)0.89175.86 (16.79)0.398
       Female6556.00.67 (0.36)76.12 (22.83)
      Education level
       No schooling43.40.87 (0.16)83.75 (11.09)
       Elementary school7463.80.61 (0.38)0.039*73.08 (22.75)0.404
       High school3126.70.81 (0.18)81.58 (14.43)
       Undergraduate76.00.59 (0.52)77.86 (14.10)
      Marital status
       Married11397.40.67 (0.35)0.63776.08 (20.39)0.713
       Not married32.60.72 (0.48)73.33 (20.82)
      EQ-5D, EuroQol five-dimensional questionnaire; VAS, visual analogue scale.
      *Significantly different at the p.
      The statistical analysis showed that utility index was not statistically significantly different with respect to most of the patients’ characteristics at baseline, except for education level (P = 0.039). Nevertheless, because the analysis was performed using nonparametric methods, the specific differences in each group could not be identified. Furthermore, the EQ-5D VAS score was not statistically significantly different with respect to patients’ characteristics.
      On the basis of information collected using the Indonesian version of the EQ-5D-5L (Table 4), the highest reduction on the mobility dimension was seen in cervical cancer (46.42%). With regard to the self-care dimension, only a few patients with HPV-related cancers (<20%) encountered problems. Meanwhile, almost half (41.38%) of the patients reported difficulties on the usual activity dimension. Problems on the pain/discomfort dimension were heterogeneous. Patients with nasopharyngeal cancer reported a high proportion of pain/discomfort issues (67.65%), whereas none of the patients with uterine cancer reported pain/discomfort. In addition, a high proportion of patients with nasopharyngeal cancer (55.88%), cervical cancer (53.85), and anogenital cancer (53.57%) experienced anxiety/depression problems.
      Table 4Frequency of reported problems, EQ-5D index, and VAS by cancer type
      DimensionLevelNasopharyngeal cancer (n = 34)Cervical cancer (n = 28)Head and neck cancer (n = 26)Anogenital cancer (n = 17)Uterine cancer (n = 11)HPV-related cancer (n = 116)
      Mobility (%)No problems26 (76.47)15 (53.57)21 (80.77)10 (58.82)9 (81.82)81 (69.83)
      Problems
      Covering four different levels of problems (levels 2–5).
      8 (23.53)13 (46.43)5 (19.23)7 (41.18)2 (18.18)35 (30.17)
      Self-care (%)No problems31 (91.18)25 (89.29)24 (92.31)14 (82.35)9 (81.82)103 (88.79)
      Problems
      Covering four different levels of problems (levels 2–5).
      3 (8.82)3 (10.71)2 (7.69)3 (17.65)2 (18.18)13 (11.21)
      Usual activity (%)No problems15 (44.12)14 (50.00)21 (80.77)9 (52.94)9 (81.82)68 (58.62)
      Problems
      Covering four different levels of problems (levels 2–5).
      19 (55.88)14 (50.00)5 (19.23)8 (47.06)2 (18.18)48 (41.38)
      Pain/discomfort (%)No problems11 (32.35)13 (46.43)14 (53.85)8 (47.06)11 (100.00)57 (49.14)
      Problems
      Covering four different levels of problems (levels 2–5).
      23 (67.65)15 (53.57)12 (46.15)9 (52.94)0 (0.00)59 (50.86)
      Anxiety/depression (%)No problems15 (44.12)13 (46.43)12 (46.15)10 (58.82)10 (90.91)60 (51.72)
      Problems
      Covering four different levels of problems (levels 2–5).
      19 (55.88)15 (53.57)14 (53.85)7 (41.18)1 (9.09)56 (48.28)
      EQ-5D VAS, mean ± SD75.47 ± 16.9974.82 ± 25.3676.03 ± 15.5972.05 ± 25.5588.54 ± 14.6077.38 ± 6.42
      EQ-5D index, mean ± SD0.75 ± 0.300.61 ± 0.390.58 ± 0.330.68 ± 0.350.84 ± 0.290.69 ± 0.10
      EQ-5D, EuroQol five-dimensional questionnaire; HPV, human papillomavirus; VAS, visual analogue scale.
      low asterisk Covering four different levels of problems (levels 2–5).
      The overall value of the EQ-5D VAS for all included patients with HPV-related cancers was relatively high (77.38 ± 6.42), ranging from 72.05 ± 25.55 to 88.54 ± 14.60 for anogenital cancer and uterine cancer, respectively. The utility index was also moderately high (0.69 ± 0.10) for the overall patient population included. The highest value for the EQ-5D utility index was found in uterine cancer (0.84 ± 0.29), followed by nasopharyngeal cancer (0.75 ± 0.30), anogenital cancer (0.68 ± 0.35), cervical cancer (0.61 ± 0.39), and head and neck cancer (0.58 ± 0.33). Finally, the Kruskal-Wallis H test showed that both utility index and VAS were not statistically significantly different because the P values were 0.059 and 0.144, respectively.

      Discussion

      Our study shows that there are various reductions in the HRQOL of patients with HPV-related cancers in Margono Public Hospital, Purwokerto, Indonesia. Although the reference utility index for the healthy population in Indonesia is not available yet, two studies showed that the utility index in a healthy population in Sri Lanka and South Australia was 0.85 (95% confidence interval 0.84–0.87) and 0.91 (95% confidence interval 0.90–0.91), respectively. These findings are apparently congruent with a study from Australia that suggested that the HRQOL of patients with HPV-related cancers ranged from 0.57 to 0.79 [
      • Conway E.L.
      • Farmer K.C.
      • Lynch W.J.
      • et al.
      Quality of life valuations of HPV-associated cancer health states by the general population.
      ]. In particular, our finding on head and neck cancer is similar to findings in studies from Italy (0.69 ± 0.30) and Australia (0.58 ± 0.50), but these findings were considerably lower than the finding in a study from Canada (0.83 ± 0.14) [
      • Conway E.L.
      • Farmer K.C.
      • Lynch W.J.
      • et al.
      Quality of life valuations of HPV-associated cancer health states by the general population.
      ,
      • Marcellusi A.
      • Capone A.
      • Favato G.
      • et al.
      Health utilities lost and risk factors associated with HPV-induced diseases in men and women: the HPV Italian Collaborative Study Group.
      ,
      • Noel C.W.
      • Lee D.J.
      • Kong Q.
      • et al.
      Comparison of health state utility measures in patients with head and neck cancer.
      ]. Several studies in patients with cervical cancer reported similar utility indexes, such as an Italian study (0.58 ± 0.31), a US study (0.68), and a study in another region of Indonesia using the EQ-5D-3L and the Malaysian value set (0.76 ± 0.20) [
      • Marcellusi A.
      • Capone A.
      • Favato G.
      • et al.
      Health utilities lost and risk factors associated with HPV-induced diseases in men and women: the HPV Italian Collaborative Study Group.
      ,
      • Gold M.R.
      • Franks P.
      • Mccoy K.I.
      • Fryback D.G.
      Toward consistency in cost-utility analyses: using national measures to create condition-specific values.
      ,
      • Endarti D.
      • Riewpaiboon A.
      • Thavorncharoensap M.
      • et al.
      Evaluation of health-related quality of life among patients with cervical cancer in Indonesia.
      ]. Furthermore, the utility indexes for anogenital cancer and nasopharyngeal cancer from this study were slightly higher compared with what were found in Italy (0.50 ± 0.26) and Australia (0.58 ± 0.05), respectively [
      • Conway E.L.
      • Farmer K.C.
      • Lynch W.J.
      • et al.
      Quality of life valuations of HPV-associated cancer health states by the general population.
      ,
      • Marcellusi A.
      • Capone A.
      • Favato G.
      • et al.
      Health utilities lost and risk factors associated with HPV-induced diseases in men and women: the HPV Italian Collaborative Study Group.
      ]. The differences in utility indexes across studies might be caused by several issues including different perceptions of health across populations and countries as partly represented by the different value sets [
      • Galante J.
      • Augustovski F.
      • Colantonio L.
      • et al.
      Estimation and comparison of EQ-5D health states’ utility weights for pneumoccocal and human papillomavirus diseases in Argentina, Chile, and the United Kingdom.
      ], several characteristics including age and education [
      • Deshpande A.D.
      • Sefko J.A.
      • Jeffe D.B.
      • Schootman M.
      The association between chronic disease burden and quality of life among breast cancer survivors in Missouri.
      ], and also the use of different types of EQ-5D (notably, 5L and 3L) [
      • Janssen M.F.
      • Pickard A.S.
      • Golicki D.
      • et al.
      Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study.
      ,
      • Agborsangaya C.B.
      • Lahtinen M.
      • Cooke T.
      • Johnson J.A.
      Comparing the EQ-5D 3L and 5L: measurement properties and association with chronic conditions and multimorbidity in the general population.
      ].
      According to our study, the most commonly reported problems by all types of patients with HPV-related cancers were pain/discomfort followed by anxiety/depression. These findings were considerably strengthened by previously published studies in patients with cervical cancer [
      • Endarti D.
      • Riewpaiboon A.
      • Thavorncharoensap M.
      • et al.
      Evaluation of health-related quality of life among patients with cervical cancer in Indonesia.
      ] and gynecological cancer [
      • Perwitasari D.A.
      • Atthobari J.
      • Dwiprahasto I.
      • et al.
      Translation and validation of EORTC QLQ-C30 into Indonesian version for cancer patients in Indonesia.
      ] in Indonesia using the EQ-5D and the EORTC QLQ-C30, respectively. The finding of zero cases of pain/discomfort reported by patients with uterine cancer may have been caused by the small number of patients, or the fact that patients were fully adapted to their condition. Nevertheless, most studies on the HRQOL of patients with cancer explained that the pain/discomfort dimension had the highest proportion of problems reported in comparison with other dimensions in the EQ-5D [
      • Pickard A.S.
      • Wilke C.T.
      • Lin H.W.
      • Lloyd A.
      Health utilities using the EQ-5D in studies of cancer.
      ,
      • Lang H.-C.
      • Chuang L.
      • Shun S.-C.
      • et al.
      Validation of EQ-5D in patients with cervical cancer in Taiwan.
      ,
      • Lee J.-A.
      • Kim S.-Y.
      • Kim Y.
      • et al.
      Comparison of health-related quality of life between cancer survivors treated in designated cancer centers and the general public in Korea.
      ,
      • Gao F.
      • Ng G.Y.
      • Cheung Y.B.
      • et al.
      The Singaporean English and Chinese versions of the EQ-5D achieved measurement equivalence in cancer patients.
      ]. Although several recommendations on cancer-related pain management exist [
      • Ripamonti C.I.
      • Bandieri E.
      • Roila F.
      Management of cancer pain: ESMO clinical practice guidelines.
      ,
      • Swarm R.A.
      • Abernethy A.P.
      • Anghelescu D.L.
      • et al.
      National Comprehensive Cancer Network
      Adult cancer pain.
      ], cancer-related pain, commonly caused by both the cancer itself and the cancer treatment, is still an important issue [
      • van den Beuken-van Everdingen M.H.J.
      • de Rijke J.M.
      • Kessels A.G.
      • et al.
      Prevalence of pain in patients with cancer: a systematic review of the past 40 years.
      ,
      • Marcus D.A.
      Epidemiology of cancer pain.
      ].
      The EQ-5D was found to be a reliable and valid instrument for measuring the HRQOL of patients with HPV-related cancers in Indonesia, as evidenced by excellent agreement on test-retest reliability (ICC ≥ 0.75 for all dimensions) and strong correlations with most of the dimensions of the EORTC QLQ-C30. The EORTC QLQ-C30 was chosen as the comparator in the validation process because it has been mapped for each dimension in the EQ-5D for patients with cancer [
      • Proskorovsky I.
      • Lewis P.
      • Williams C.D.
      • et al.
      Mapping EORTC QLQ-C30 and QLQ-MY20 to EQ-5D in patients with multiple myeloma.
      ]. Furthermore, our methods and results were consistent with other EQ-5D validation reports in several diseases and countries including cervical cancer in Taiwan [
      • Lang H.-C.
      • Chuang L.
      • Shun S.-C.
      • et al.
      Validation of EQ-5D in patients with cervical cancer in Taiwan.
      ] and chronic diseases (cardiovascular disease, respiratory disease, depression, diabetes, liver disease, personality disorders, arthritis, and stroke) in a multicountry setting [
      • Janssen M.F.
      • Pickard A.S.
      • Golicki D.
      • et al.
      Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study.
      ].
      The EQ-5D was chosen because this questionnaire provides a single utility index and has several advantages, including its brevity and ease of administration, and the availability of previous mapping exercise results. Also, it is recommended by several guidelines [
      • Kim S.H.
      • Jo M.
      • Kim H.
      • Ahn J.
      Mapping EORTC QLQ-C30 onto EQ-5D for the assessment of cancer patients.
      ,
      • Proskorovsky I.
      • Lewis P.
      • Williams C.D.
      • et al.
      Mapping EORTC QLQ-C30 and QLQ-MY20 to EQ-5D in patients with multiple myeloma.
      ,

      EQ-5D [Internet]. [cited 2016 Apr 3]. Available from: http://www.euroqol.org/.

      ,
      National Institute for Health and Care Excellence
      ,
      The Scottish Intercollegiate Guidelines Network
      ]. The utility index produced by the EQ-5D provides a simpler comparison between interventions for different health problems than do other patient-specific or disease-specific questionnaires such as the Patient Generated Index or the Cancer Patient Experiences Questionnaire [
      • Camilleri-Brennan J.
      • Ruta D.A.
      • Steele R.J.C.
      Patient generated index: new instrument for measuring quality of life in patients with rectal cancer.
      ,
      • Iversen H.H.
      • Holmboe O.
      • Bjertnaes O.A.
      The Cancer Patient Experiences Questionnaire (CPEQ): reliability and construct validity following a national survey to assess hospital cancer care from the patient perspective.
      ]. Furthermore, the implementation of utility information for economic evaluation is generally acceptable, quite often even required, for health technology assessment processes in almost all regions in the world.
      Although the prevalence of chronic diseases in patients with cancer is substantial [
      • Ogle K.S.
      • Swanson G.M.
      • Woods N.
      • Azzouz F.
      Cancer and comorbidity: redefining chronic diseases.
      ], we excluded patients with chronic diseases because several studies showed that chronic diseases, such as stroke, chronic obstructive pulmonary disease, or chronic kidney disease, further significantly decrease the HRQOL of patients with cancer [
      • Deshpande A.D.
      • Sefko J.A.
      • Jeffe D.B.
      • Schootman M.
      The association between chronic disease burden and quality of life among breast cancer survivors in Missouri.
      ,
      • Wong G.
      • Howard K.
      • Chapman J.
      • et al.
      How do people with chronic kidney disease value cancer-related quality of life?.
      ,
      • Wang J.-W.
      • Gong X.-H.
      • Ding N.
      • et al.
      The influence of comorbid chronic diseases and physical activity on quality of life in lung cancer survivors.
      ,
      • Maric D.
      • Jovanovic D.
      • Nagorni-Obradovic L.
      • et al.
      Assessment of health-related quality of life in end-stage chronic obstructive pulmonary disease and non-small-cell lung cancer patients in Serbia.
      ]. A study from Serbia showed that patients with cancer with chronic disease complications showed a higher level of depressive symptoms [
      • Maric D.
      • Jovanovic D.
      • Nagorni-Obradovic L.
      • et al.
      Assessment of health-related quality of life in end-stage chronic obstructive pulmonary disease and non-small-cell lung cancer patients in Serbia.
      ]. There was also a substantial reduction in the physical and social functioning of patients with breast cancer with chronic disease complications [
      • Deshpande A.D.
      • Sefko J.A.
      • Jeffe D.B.
      • Schootman M.
      The association between chronic disease burden and quality of life among breast cancer survivors in Missouri.
      ]. Although an Indonesian-specific HRQOL estimate with respect to the influence of chronic disease complications in patients with cancer would be generally interesting, this would require a substantially larger sample size.
      One of the limitations of this study was that the cancer substages could not be presented because the medical records or hospital database did not provide sufficient information. Cancer stage information is valuable in cancer treatment because guidelines generally provide treatment recommendations on the basis of cancer stage. The lack of information about the substage of each cancer might be a reason why no cases of pain/discomfort got reported by patients with uterine cancer. It may indeed be that most patients were in the early stage of cancer. A possible explanation for the unavailability of data on cancer stage is that the documentation process in the hospitals concerned might not be standardized; there may even be a lack of standard operating procedures altogether in this area. An Indonesia-specific EQ-5D value set for the five-level version is not available yet. Therefore, we converted the descriptive information produced by the questionnaire into a health utility index by using the value set from Thailand [
      • Tongsiri S.
      • Cairns J.
      Estimating population-based values for EQ-5D health states in Thailand.
      ]. The Thailand-specific value set was chosen because Indonesia and Thailand have several similarities including social, cultural, and economic factors. Moreover, the adoption of another country’s value set is practically acceptable [
      • Brooks R.
      • Rabin R.
      • de Charro F.
      The Measurement and Valuation of Health Status Using EQ-5D: A European Perspective: Evidence from the EuroQol BIOMED Research Programme.
      ].
      Because the patient data were collected from a single public hospital in Central Java, the generalizability of the result could be considered questionable. Nevertheless, Margono Public Hospital can be considered as a representative of a public hospital that provides services for patients with cancer at the district and province level in the Indonesian region. According to the data from the Ministry of Health, every province has at least one hospital that has comparable characteristics with Margono Public Hospital. In addition, an analysis in terms of demographic information for respondent versus nonrespondent patients could increase the generalizability of the results. Therefore, further study should also collect the data from nonrespondent patients.
      The descriptive cross-sectional approach used in this study limits the amount of information provided. Further research adopting a comparative cohort study could be an interesting option for providing the complete picture, including the ratio of HPV-related cancers’ utility indexes compared with a healthy population in Indonesia. Nevertheless, this study provides a significant addition to the literature on HPV-related cancers’ utility values in Indonesia by implementing a valid and reliable questionnaire and coming up with findings mostly consistent with various other studies in the same field in other regions of the world.
      Further research into the HRQOL of patients with precancer, substages of cancer, or even HPV-related genital warts is worthwhile in completing the information on the full scale of consequences of HPV infections in Indonesia. In terms of the decision-making process, a cost-effectiveness analysis on HPV-related cancer prevention strategies using our findings will provide useful information for decision makers in Indonesia.

      Acknowledgments

      We acknowledge the assistance and support received from Fretty Setiawati, Mayang Setianing Hadi, Siti Robi’atul Adawiyah, and Sulastri for data collection in this research.
      Source of financial support: These findings are the result of work supported by the Directorate General of Higher Education Scholarship, Ministry of National Education, Indonesia. The authors’ work was independent of the funders, who had no role in the study design, analysis of data, writing of the manuscript, or decision to submit for publication. The views expressed in this article are those of the authors, and no official endorsement by the Ministry of National Education is intended or should be inferred.

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