10.5826/dpc.1303a177
 
Introduction: Dysgeusia may occur during conventional or target-therapies and affect patients adherence-to-treatment. Therefore, it should be monitored to improve clinical outcome. To date, available questionnaires on dysgeusia relate to traditional antineoplastics and do not apply to target-therapies as the pathogenetic mechanism and clinical expression differ.
Objectives: To develop a patient-reported outcome measure (PROM) to screen for and monitor the occurrence and severity of dysgeusia in patients under Smoothened (SMO) inhibitors: the SMO-iD questionnaire.
Methods: Patients with locally advanced basal cell carcinomas referring dysgeusia under SMO inhibitors at the University Hospital of Naples Federico II, were enrolled between January-December 2020. The PROM was elaborated based on chemotherapy-induced dysgeusia (CiTas) scale (development phase) and then validated by measuring internal consistency and reliability (validation phase).
Results: Thirty-nine patients were enrolled and interviewed every 8 weeks. In the first phase, 160 CiTas questionnaires were collected, and the SMO-iD questionnaire was developed. In the second phase, 195 SMO-iD questionnaires were recorded, and reliability and validity assessed. Cronbach alpha was 0.89.
Conclusions: The SMO-iD questionnaire is a validated questionnaire that shows high face and content validity as well as high internal consistency and reliability. Hence, it may be introduced in daily clinical setting to monitor dysgeusia in patients under SMO-inhibitors.
text/xml
2160-9381
2887
en
Massimiliano Scalvenzi
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
basal cell carcinoma
Development of a Patient-Reported Outcome Measure (PROM) for Dysgeusia During Treatment With Smoothened (SMO) Inhibitors for Basal Cell Carcinomas: The SMO-iD Questionnaire
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-07-31
2022-10-02
2023-07-31
2023-08-24
e2023177
Dermatol Pract Concept
 
Introduction: Dysgeusia may occur during conventional or target-therapies and affect patients adherence-to-treatment. Therefore, it should be monitored to improve clinical outcome. To date, available questionnaires on dysgeusia relate to traditional antineoplastics and do not apply to target-therapies as the pathogenetic mechanism and clinical expression differ.
Objectives: To develop a patient-reported outcome measure (PROM) to screen for and monitor the occurrence and severity of dysgeusia in patients under Smoothened (SMO) inhibitors: the SMO-iD questionnaire.
Methods: Patients with locally advanced basal cell carcinomas referring dysgeusia under SMO inhibitors at the University Hospital of Naples Federico II, were enrolled between January-December 2020. The PROM was elaborated based on chemotherapy-induced dysgeusia (CiTas) scale (development phase) and then validated by measuring internal consistency and reliability (validation phase).
Results: Thirty-nine patients were enrolled and interviewed every 8 weeks. In the first phase, 160 CiTas questionnaires were collected, and the SMO-iD questionnaire was developed. In the second phase, 195 SMO-iD questionnaires were recorded, and reliability and validity assessed. Cronbach alpha was 0.89.
Conclusions: The SMO-iD questionnaire is a validated questionnaire that shows high face and content validity as well as high internal consistency and reliability. Hence, it may be introduced in daily clinical setting to monitor dysgeusia in patients under SMO-inhibitors.
Massimiliano Scalvenzi
2023/07/31
10.5826/dpc.1303a177
e2023177
Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
2160-9381
basal cell carcinoma
en
e2023177
Villani A, Costa C, Fabbrocini G, et al. Dose reduction during routine treatment of locally advanced basal cell carcinoma with the hedgehog inhibitor sonidegib to manage adverse effects: a retrospective case series. J Am Acad Dermatol. 2021;84(4):e211-e212. DOI: 10.1016/j.jaad.2020.12.006. PMID: 33301802. 14. Villani A, Megna M, Fabbrocini G, et al. Long-Term Efficacy of Vismodegib After its Withdrawal and Patients’ Health-Related Quality of Life Using the Dermatology Life Quality Index (DLQI). Dermatol Ther (Heidelb). 2019;9(4):719-724. DOI: 10.1007/s13555-019-00323-4. PMID: 31506916. PMCID: PMC6828856.9:719–724.
Development of a Patient-Reported Outcome Measure (PROM) for Dysgeusia During Treatment With Smoothened (SMO) Inhibitors for Basal Cell Carcinomas: The SMO-iD Questionnaire
https://dpcj.org/index.php/dpc/article/download/2887/2191
    Development of a Patient-Reported Outcome
   Measure (PROM) for Dysgeusia During Treatment
   With Smoothened (SMO) Inhibitors for Basal Cell
       Carcinomas: The SMO-iD Questionnaire
    Elisa Camela1, Alessia Villani1, Sonia Sofia Ocampo Garza2, Claudia Costa1, Gabriella
   Fabbrocini1, Matteo Megna1, Luca Potestio1, Angelo Ruggiero1, Massimiliano Scalvenzi1


1 Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
2 Universidad Autónoma de Nuevo León, University Hospital ̈ Dr. José Eleuterio González ̈, Dermatology Department, Monterrey,
  Nuevo León, México



Key words: patient-reported outcome measure, dysgeusia, sonic hedgehog inhibitors, PROM, basal cell carcinoma
Citation: Camela E, Villani A, Ocampo Garza SS, et al. Development of a Patient-Reported Outcome Measure (PROM) for Dysgeusia
During Treatment With Smoothened (SMO) Inhibitors for Basal Cell Carcinomas: The SMO-iD Questionnaire. Dermatol Pract Concept.
2023;13(3):e2023177. DOI: https://doi.org/10.5826/dpc.1303a177
Accepted: February 16, 2023; Published: July 2023
Copyright: ©2023 Camela et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Elisa Camela, Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples, Federico II,
Naples, Italy. Tel: +39 - 081 -7462457 Fax: +39 - 081 – 7462442 ORCID: 0000-0001-7201-9163 Email: elisacamela@gmail.com
Acknowledgement: The patients in this manuscript have given written informed consent to publication of their case details




  ABSTRACT             Introduction: Dysgeusia may occur during conventional or target-therapies and affect patients
                       adherence-to-treatment. Therefore, it should be monitored to improve clinical outcome. To date,
                       available questionnaires on dysgeusia relate to traditional antineoplastics and do not apply to
                       target-therapies as the pathogenetic mechanism and clinical expression differ.
                       Objectives: To develop a patient-reported outcome measure (PROM) to screen for and monitor the
                       occurrence and severity of dysgeusia in patients under Smoothened (SMO) inhibitors: the SMO-iD
                       questionnaire.
                       Methods: Patients with locally advanced basal cell carcinomas referring dysgeusia under SMO inhib-
                       itors at the University Hospital of Naples Federico II, were enrolled between January-December 2020.
                       The PROM was elaborated based on chemotherapy-induced dysgeusia (CiTas) scale (development
                       phase) and then validated by measuring internal consistency and reliability (validation phase).




Original Article | Dermatol Pract Concept. 2023;13(3):e2023177                                                                          1
                       Results: Thirty-nine patients were enrolled and interviewed every 8 weeks. In the first phase, 160
                       ­CiTas questionnaires were collected, and the SMO-iD questionnaire was developed. In the second
                        phase, 195 SMO-iD questionnaires were recorded, and reliability and validity assessed. Cronbach
                        alpha was 0.89.
                       Conclusions: The SMO-iD questionnaire is a validated questionnaire that shows high face and con-
                       tent validity as well as high internal consistency and reliability. Hence, it may be introduced in daily
                       clinical setting to monitor dysgeusia in patients under SMO-inhibitors.




Introduction                                                       contrast, exclusion criteria included any pre-existing gusta-
                                                                   tory and/or olfactory disturbs, gastrointestinal and/or men-
Dysgeusia is a prominently subjective gustatory disturb that       tal diseases that could interfere with the analysis. The study
may occur during chemotherapies and affect patients ad-            was drawn according to the ethical standards laid down in
herence to treatment and quality of life with severe implica-      the World Medical Association Declaration of Helsinki (June
tions on clinical outcome [1,2]. Therefore, physicians should      1964) and its later amendments and was approved by the lo-
thoroughly monitor the occurrence of any taste alteration in       cal Ethical Committee. The questionnaire creation was struc-
order to undertake strategies to address it and at the same        tured in two phases: development and validation.
time not compromise the therapeutic goal. To date, there are
several questionnaires that investigate dysgeusia and related      The Development Phase (January 2020- June 2020)
symptoms following traditional chemotherapies and radio-
                                                                   An extensive literature research concerning question-
therapy [2,3]; however, the advent of new target therapies
                                                                   naires on dysgeusia was performed. Above all, the
has led to the occurrence of selective side effects, including
                                                                   Chemotherapy-induced Taste alterations (CiTas) scale devel-
taste impairment, that are different under both the qualita-
                                                                   oped by Kano and Kanda in 2013 was selected and employed
tive and quantitative aspects and brought out the need of
                                                                   as theorical model from which developing the questionnaire
new reporting tools.
                                                                   in issue, given its high consistency in literature [3,7,8]. Such
                                                                   questionnaire consists of 18 items exploring taste alterations,
Objectives                                                         nausea/discomfort, food temperature intolerability and ol-
                                                                   factory disturbs [7]. The Citas scale was administered by
In detail, dysgeusia occurring during treatment with
                                                                   5 investigators (EC, AV, MS, SS OG, MM) to enrolled pa-
Smoothened (SMO) inhibitors results from the blockade of
                                                                   tients together with broader and open questions to better
the Sonic Hedgehog (SHH) pathway, that has been proven
                                                                   define the quality and severity of dysgeusia and any po-
to be a fundamental regulator of the gustatory functioning
                                                                   tential impact on eating habits. Interviews were conducted
without impacting the olfactory one [4,5]. For this reason, we
                                                                   ­in-person every 8 weeks from study start and patients an-
developed a new and specific patient-reported outcome mea-
                                                                   swers were recorded and transcribed verbatim.
sure (PROM) to characterize it: the SMO inhibitors-induced
Dysgeusia (SMO-iD) questionnaire.
                                                                   The Validation Phase (July 2020-December 2020)
                                                                   All enrolled patients took part in the second phase of PROM
Methods                                                            development. They were administered the SMO-iD question-
                                                                   naire by the same investigators with the same schedule and
The COSMIN (COnsensus-based Standards for the selec-
                                                                   procedure of the previous one (the CiTas), ie, every 8 weeks,
tion of health Measurement Instruments) ‘study design for
                                                                   and answers recorded. The validation process of PROM went
PROMs’ checklist was followed during the process of ques-
                                                                   through qualitative and quantitative analysis as follows.
tionnaire creation [6]. A prospective study was conducted on
patients affected by locally advanced basal cell carcinomas
(laBCCs) treated with Smoothened inhibitors (Sonidegib             Results
and Vismodegib) referring dysgeusia, that were admitted to
the University Hospital Federico II of Naples, Italy, between      Preliminary Results of the Development Phase
January 2020 and December 2020. Informed consent was               Thirty-nine patients meeting the inclusion and exclusion
required before participation. Inclusion criteria were laB-        criteria were enrolled in the study. Overall, 160 interviews
CCs treated with SMO inhibitors and age ≥ 18 years old. By         were made and recorded. From the answers analysis, some



2                                                                      Original Article | Dermatol Pract Concept. 2023;13(3):e2023177
questions of the Citas scale resulted redundant and inap-         as well as overall approval of the questionnaire. A total of
propriate: indeed, they explored aspects not reported by the      195 SMO-iD questionnaires were collected and analyzed. In
study population nor in literature concerning SMO inhibitors      general, the questionnaire was appreciated by patients and
side effects, such as olfactory impairment and food tempera-      defined as more focused to describe their taste alterations
ture intolerance [9,10]. Moreover, from the open questions,       compared to the previous one. Moreover, it was depicted as
patients referred variable impact of dysgeusia on social life     easily understandable, repeatable, and fast. Also, the quan-
and eating habits (appetite, nausea and weight) and better        titative validation was performed employing the Cronbach
detailed the quality and severity of their taste alteration.      alpha (CA), a test that measures the internal consistency
On this basis, a new and specific questionnaire consisting        of a survey, since it makes inferences about the health sta-
of 4 domains and 14 items was developed as illustrated in         tus of individuals (ie, dysgeusia), which is an unobservable
­Table 1: the SMO-iD questionnaire. The herein provided           variable for the practitioner, using available evidence (ques-
version was translated from Italian into English according to     tions), which instead is observable. The test gave an alpha
the COSMIN-principles. No scoring was provided since the          coefficient of 0.89 which indicates high internal consistency
questionnaire is intended to give physicians a toll to screen     (note that a reliability coefficient of .70 or higher is consid-
for and monitor the occurrence of dysgeusia and related           ered “acceptable” in most social science research situations).
symptoms in patients under SMO inhibitors. Moreover, as           Also, the 95% confidence intervals were computed based on
displayed in the last domain, patients’ self-assessment of dys-   1000 bootstrapped samples which resulted in [0.83, 0.950].
geusia severity may guide physicians in changing drug posol-      The narrow bands, small standard errors, also supported the
ogy or eating behaviors during treatment to improve their         accuracy of the survey. In addition to computing the alpha
quality of life and increase compliance.                          coefficient of reliability, the dimensionality of the scale was
                                                                  investigated, since the unobservable variable was assumed
Preliminary Results of the Validation Phase                       unidimensional. Factor analysis is one method of checking
The qualitative validation of the PROM in issue derived           dimensionality (Table 2). Looking at the table labeled “To-
from investigators interviews recording participants’ opin-       tal Variance Explained”, the eigenvalue for the first factor
ion about accuracy of questions and standardized answers          is significantly larger than the eigenvalue for the next factor




     Table 1. Smoothened inhibitors-induced dysgeusia (SMO-iD) questionnaire: it is composed by
      4 domains that investigate the quality of taste perception and distortion, the impact on food
                    habits and an overall patient self-assessment of dysgeusia severity.
     Assessing taste perception
     Do you perceive the salty taste?                            □ no □ little □ tolerably □a lot
     Do you perceive the sweet taste?                            □ no □ little □ tolerably □a lot
     Do you perceive the bitter taste?                           □ no □ little □ tolerably □a lot
     Do you perceive the sour taste?                             □ no □ little □ tolerably □a lot
     Do you perceive the umami taste?                            □ no □ little □ tolerably □a lot

     Assessing taste distortion
     Do you have a metallic taste in your mouth?                                           □ yes     □no
     Do you have a bitter taste in your mouth?                                             □ yes     □no
     Do you have a foul taste in your mouth?                                               □ yes     □no
     Do you have a salty taste in your mouth?                                              □ yes     □no
     Do you have a sickly-sweet taste in your mouth?                                       □ yes     □no

     Assessing impact on food habits
     Do you have nausea?                                                                   □ yes     □no
     Have you lost appetite?                                                               □ yes     □no
     Have you lost weight?                                                                 □ yes     □no

     Assessing severity of dysgeusia
     How would you grade your dysgeusia?                                       □ mild      □moderate □severe




Original Article | Dermatol Pract Concept. 2023;13(3):e2023177                                                                  3
    Table 2. Principal component analysis: the table shows the results of principal component analysis
                                      applied to domains survey.
      Components             Eigenvalues              Percentage variance %                       Cumulative percentage%
           1                      3.10                             76.23                                       76.23
           2                      0.52                             11.22                                       87.45
           3                      0.20                              9.40                                       96.85
           4                      0.18                              3.15                                      100.00




(3.10 versus 0.52). Additionally, the first factor accounts for       and frame [3,7,8]. On the basis of the answers given by in-
76.23% of the overall variance. This suggests that the scale          terviewed patients, the CiTas questionnaire was restructured
domains are unidimensional, that is, the questions in the sur-        and modified, reducing the number and topic of items as
vey are inherent to one single common factor, ie, the presence        to make it more focused and specific. Moreover, such new
of dysgeusia.                                                         version, the SMO-iD, gives the possibility to have a direct es-
                                                                      teem of patients self-assessment of dysgeusia, that may guide
                                                                      the development of tailored treatment strategies. Hence, the
Conclusions                                                           SMO-iD questionnaire was developed and subsequently val-
The rationale of creating a new questionnaire to investigate          idated, showing high face and content validity as well as high
chemotherapy-induced dysgeusia derives from development               internal consistency and reliability. Such results suggest its
of the so called “target therapies”- ie, agents that selectively      potential important applicability in daily clinical practice to
target a specific pathogenetic mechanism that sustains an             collect, monitor and screen for such side effect with a specific
oncological disease [11]. Hence, the concept of chemother-            tool. Hence, further and real-life studies are needed to sup-
apy -induced side effects has changed dramatically as they            port our findings.
are not the result of a generalized antimitotic effect common              The SMO-iD questionnaire has been proven to be char-
to the category of traditional antineoplastics but appears to         acterized by high face and content validity as well as high
be class-specific [11]. Moreover, the development of target           internal consistency e reliability. Hence, it may be promis-
therapy implies a complete knowledge of the role of certain           ingly introduced in daily clinical settings to help physicians
molecules in the pathogenesis of the disease and in some way          screen for and monitor the occurrence and the social impact
may foresee its side effects [11]. Concerning the SMO in-             of dysgeusia in patients under SMO-inhibitors.
hibitors, the SHH pathway has been proven to be crucial
for taste functioning maintenance, and its tackle predictably
leads to gustatory impairment [5,12]. In fact, an alteration          References
of the morphology of fungiform papilla, a reduction in the
                                                                       1. Jafari A, Alaee A, Ghods K. The etiologies and considerations of
number of taste buds and an impairment in the chorda tym-
                                                                          dysgeusia: A review of literature. J Oral Biosci. 2021;63(4):319-
pani response to all taste quality has been described in pa-
                                                                          326. DOI: 10.1016/j.job.2021.08.006. PMID: 34487857.
tients with laBCCs treated with such agents [4]. By contrast,          2. Malta CEN, de Lima Martins JO, Carlos ACAM, et al. Risk
SHH pathway is not involved in olfactory functioning, that                factors for dysgeusia during chemotherapy for solid tumors: a
is not affected [4,5]. In those patients, taste alterations have          retrospective cross-sectional study. Support Care Cancer. 2022;
been proven to affect quality of life as well as therapeutic              30(1):313-325. DOI: 10.1007/s00520-021-06219-4. PMID:
                                                                          34283319.
compliance and efficacy [13,14]. In literature, no PROMs
                                                                       3. Sözeri E, Kutlutürkan S. Taste Alteration in Patients Receiving
or questionnaire on target-chemotherapy induced dysgeusia
                                                                          Chemotherapy. Breast Health. 2015;11(2):81-87.DOI: 10.5152
exist, as the available questionnaires relate to conventional             /tjbh.2015.2489. PMID: 28331697. PMCID: PMC5351492.
chemotherapies or radiotherapy, and do not perfectly apply             4. Kumari A, Ermilov AN, Allen BL, et al. Hedgehog pathway
to the condition in issue, with the risk of not completely                blockade with the cancer drug LDE225 disrupts taste organs
understanding patients’ discomfort. For this reason, we de-               and taste sensation. J Neurophysiol. 2015;113(3):1034-1040.
                                                                          DOI: 10.1152/jn.00822.2014. PMID: 25392175. PMCID:
cided to create a target-therapy specific questionnaire to in-
                                                                          PMC4312875.
vestigate the peculiarity of dysgeusia under SMO inhibitors,
                                                                       5. Hall JMH, Bell ML, Finger TE. Disruption of Sonic hedgehog
that manifests with different characteristics compared to                 signaling alters growth and patterning of lingual taste papil-
conventional antineoplastic agents. A validated and certified             lae. Dev Biol. 2003;255(2):263-277. DOI: 10.1016/s0012
questionnaire, the CiTas, has been used as theoretical model              -1606(02)00048-9. PMID: 12648489.



4                                                                          Original Article | Dermatol Pract Concept. 2023;13(3):e2023177
 6. Mokkink LB, Patrick DL, Alonso J, et al. COSMIN Study De-            11. Alam A, Farooq U, Singh R, et al. Chemotherapy Treatment
    sign checklist for Patient-reported outcome measurement instru-          and Strategy Schemes : A Review Chemotherapy Treatment and
    ments. 2019. Available at: https://www.cosmin.nl/wp-content              Strategy Schemes : A Review. Open Acc J of Toxicol. 2018;2(5):
    /uploads/COSMIN-study-designing-checklist_final.pdf.                     555600. DOI: 10.19080/OAJT.2018.02.555600.
    Accessed January 2022).                                              12. Gutzmer R, Solomon JA. Hedgehog Pathway Inhibition
 7. Kano T, Kanda K. Development and validation of a                         for the Treatment of Basal Cell Carcinoma. Target Oncol.
    chemotherapy-induced taste alteration scale. Oncol Nurs Forum.           2019;14(3):253-267. DOI: 10.1007/s11523-019-00648-2.
    2013;40 (2):E79-85. DOI: 10.1188/13.ONF.E79-E85. PMID:                   PMID: 31243642. Target Oncol [Internet]. 2019;14:253–267.
    23448748.                                                                DOI:10.1007/s11523-019-00648-2.
 8. Simeone S, Esposito MR, Gargiulo G, et al. The CiTAS scale for       13. Villani A, Costa C, Fabbrocini G, et al. Dose reduction during
    evaluating taste alteration induced by chemotherapy: state of the        routine treatment of locally advanced basal cell carcinoma
    art on its clinical use. Acta Biomed. 2019;90:17–25. doi: 10.23750       with the hedgehog inhibitor sonidegib to manage adverse
    /abm.v90i6-S.8278. PMID: 31292411; PMCID: PMC6776177.                    effects: a retrospective case series. J Am Acad Dermatol.
 9. Erivedge, INN-Vismodegib - European Medicines Agency:                    2021;84(4):e211-e212. DOI: 10.1016/j.jaad.2020.12.006.
    Summary of Product Characteristics [Internet]. Available from:           PMID: 33301802. 14. Villani A, Megna M, Fabbrocini G,
    https://www.ema.europa.eu/en/documents/product-information               et al. Long-Term Efficacy of Vismodegib After its With-
    /erivedge-epar-product-information_en.pdf. Jan 2022.                     drawal and Patients’ Health-Related Quality of Life Us-
10. Odomzo, INN-Sonidegib - European Medicines Agency: Sum-                  ing the Dermatology Life Quality Index (DLQI). Dermatol
    mary of Product Characteristics [Internet]. Available from:              Ther (Heidelb). 2019;9(4):719-724. DOI: 10.1007/s13555
    https://www.ema.europa.eu/en/documents/product-information               -019-00323-4. PMID: 31506916. PMCID: PMC6828856.9
    /odomzo-epar-product-information_en.pdf. Jan 2022.                       :719–724.




Original Article | Dermatol Pract Concept. 2023;13(3):e2023177                                                                           5
