Validity and Reliability of the Turkish Version of National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Ovarian Symptom Index-18 (NFOSI-18) and Neurotoxicity-4 (NTX-4) for Patients with Advanced Ovarian Cancer

the Turkish version of the National Comprehensive Cancer Network/Functional Assessment of Cancer Terapy Ovarian Symptom Index-18 (NFOSI-18) and Functional Assessment of Cancer Terapy/Gynecologic Oncology Group Neurotoxicity 4-item (NTX-4) in patients with advanced ovarian cancer (OC). Methods . Ninety-four women with OC were included. Pearson correlation coefcients were used to examine the convergent validity between the European Quality of Life Survey-5 Dimension-3 Level (EQ-5D-3L) and the Turkish NFOSI-18 and NTX-4. Te internal consistencies of the Turkish NFOSI-18 and NTX-4 were calculated using Cronbach’s alpha. Turkish NFOSI-18 and Turkish NTX-4 were readministered to 62 (67.4%) patients with OC after 14–21 days to evaluate test-retest reliability. Results . Turkish NFOSI-18 and Turkish NTX-4 showed excellent internal consistency (Cronbach’s alpha: 0.919 and 0.917, respectively). Te test-retest reliability of Turkish NFOSI-18 and Turkish NTX-4 was detected as good to excellent for total score (ICC [95%] = 0.93 [0.88-0.95] and ICC [95%] = 0.90 [0.85-0.94], respectively). Signifcant correlations were detected between the EQ-5D-3L total score, NFOSI-18 ( r = 0.648, p < 0.01), and NTX-4 ( r = 0.694, p < 0.01) indicating sufcient convergent validity. Conclusion . Te Turkish NFOSI-18 and Turkish NTX-4 are reliable and valid tools to assess disease-related symptoms in patients with advanced OC.


Introduction
Ovarian cancer (OC) is the most life-threatening malignancy with a high mortality rate among gynecologic cancers [1].
Only 45.6% of patients with OC survive 5 years [2] and about 70% of patients have a relapse within three years, despite initial treatment yielding signifcant treatment outcomes [3].Almost 60% of women with OC are not diagnosed until the disease has progressed to stage III or IV due to a lack of efective screening and the absence of specifc symptoms [4].In fact, the rate of early diagnosis for patients with OC is reported as low as 20% [2].Patients with OC experience a variety of physical symptoms due to chronic disease processes and side efects of the treatment, including neuropathy, fatigue, alopecia, pain, swelling, anemia, nausea, and vomiting [5].Moreover, patients with advanced OC may present emotional manifestations such as anxiety and depression due to repetitive cycles of long-duration treatments [6].Additionally, the primary aim of clinical management of advanced OC is generally based on symptom management, functional preservation, and maintaining or enhancing the quality of life of a patient [7,8].Tus, evaluating health-related quality of life (HRQoL) which is a biopsychosocial concept emerges as important as a clinical and research endpoint [9,10].
Te Quality of Life Subcommittee of the Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee has emphasized that HRQoL should be assessed for the clinical beneft of patients in oncology drug trials [11].Functional Assessment of Cancer Terapy-Ovarian (FACT-O) questionnaire which was developed based on expert opinion is frequently used to evaluate HRQoL in patients with OC [12].Te FACT-O is a reliable and valid instrument for assessing HRQoL in women with OC [13].European Organization for Research and Treatment of Cancer the Ovarian Cancer Module (EORTC-QLQ-OV28) is also a psychometrically accepted questionnaire designed to assess HRQoL in patients with OC [14].However, FDA Oncologic Drugs Advisory Committee recommends including items regarding particular symptoms depending on the stage of the disease for measurement tools developed for cancer patients [11].Besides, recent fndings highlight the importance of involving patients during the development of disease-specifc patient-reported outcome measure (PROM) as patients' opinions and the importance given to particular topics by them may difer from oncology experts [15,16].
Te National Comprehensive Cancer Network Functional Assessment of Cancer Terapy Ovarian Symptom Index-18 (NFOSI-18) was developed as a PROM to assess the impact of the symptoms and concerns of advanced patients with OC by gathering opinions from both experts and patients [17].Te original NFOSI-18 demonstrated good internal consistency (Cronbach's alpha: 0.80) [17] and content validity [18].However, there are no items in NFOSI-18 evaluating neuropathy even though neurotoxicity was frequently reported by patients with OC [19].Tus, either the 11-item (NTX-11) or 4-item (NTX-4) Functional Assessment of Cancer Terapy/Gynecologic Oncology Group Neurotoxicity subscales should be used alongside NFOSI-18 to evaluate the HRQoL in a more comprehensive manner by assessing the symptoms of neurotoxicity [20,21].Te original version of NFOSI-18 and NTX-4 was developed in English, and their validity and reliability were assessed in Korean according to the Functional Assessment of Chronic Illness Terapy (FACIT) organization guidelines [22].Te aim of this study was to investigate the validity and reliability of Turkish forms of NFOSI-18 and NTX-4.4) currently receiving chemotherapy or radiotherapy.Refusing to participate in the study was the exclusion criterion.Signed informed consent was obtained from all the participants before the study.

Study Sample.
G * Power software (version 3.1.9.2, Düsseldorf University, Germany) was used for the calculation of the sample size.Te minimum sample size was estimated as 93 patients with a 5% type I error rate, a minimum power of 80%, the hypothesized minimum correlation coefcient of 0.3 [23], and the assumed correlation coefcient of 0.5 (the value was reported in a previous study investigating NFOSI-18 Korean language validation) [22].

Procedures.
Te Turkish version of the NFOSI-18 and NTX-4 available at https://FACIT.org was used with the permission from FACIT Group [24,25].A detailed medical history including demographic information (i.e., age, height, weight, body mass index (BMI), and disease-related characteristics (OC subtype, OC stage, adjuvant treatment, and disease duration)) of each participant was recorded.Ten, the patients flled out the HRQoL questionnaires.All assessments lasted approximately 30-45 minutes.All assessments were conducted by the same assessor to ensure consistency and reduce interassessor variability.A test-retest reliability analysis was performed with 62 (66% of total sample) patients for a second time within a 14 to 21-day period [26].

Te National Comprehensive Cancer Network Functional Assessment of Cancer Terapy Ovarian Symptom
Index-18 .NFOSI-18 comprises 18 items consisting of four subscales: disease-related symptoms-physical 2 European Journal of Cancer Care (DRS-P; nine items), disease-related symptoms-emotional (one item), treatment side efects (fve items), and general function/well-being (three items) [17].Each item is assessed using a fve-point Likert scale, with 0 "not at all" and 4 "very much."Te individual item scores were summed to calculate the fnal score or related subscale scores.Te total score range between 0 and 72, and higher scores indicate better HRQoL [17].

Functional Assessment of Cancer Terapy/Gynecologic
Oncology Group Neurotoxicity 4-Item (NTX-4).NTX-4 was used for the assessment of peripheral neuropathy symptoms, including sensory, motor, and auditory problems and sensitivity to cold.It consists of four items: numbness or tingling in the feet, numbness or tingling in the hands, discomfort in the feet, and discomfort in the hands [22].NTX-4 is fve-point Likert-type scale, and each item gets a score between 0 "not at all" and 4 "very much."Te total score is calculated by summing up the scores of each item, which ranges from 0 to 16.A higher score indicates higher level of neurotoxicity [22].

European Quality of Life Survey-5 Dimensions-3 Levels (EQ-5D-3L
). Generic HRQoL was evaluated using the EQ-5D-3L which essentially consists of two sections: the EQ-5D-3L descriptive system and the visual analogue scale (VAS) [27].Te EQ-5D-3L comprises fve dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.Te VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are captioned "Te best health you can imagine" and "Te worst health you can imagine."Te fnal scores vary from 0 to 100, and higher score indicates a good HRQoL EQ-5D-3L has shown high reliability, content validity, construct validity, and responsiveness for oncologic patients [28].It has been established that the Turkish version of EQ-5D-3L is a valid and reliable instrument [29].

Floor-Ceiling Efects.
To examine foor/ceiling efects, the percentage of participants that received minimum and maximum scores is used.Values greater than 15% were interpreted as indicating the presence of a foor or ceiling efect [33].Additionally, the presence of the foor ceiling efect was expected to have an absolute skewness value (c1) > 1.As a result, c1 > +1 was thought to be an indicator of the foor efect, whereas c|<-1 was assumed to be an indicator of the ceiling efect [34].

Results
Te study was completed with 94 women with OC.Te physical characteristics, disease-related characteristics, and generic HRQoL of participants are displayed in Table 1.

Internal Consistency.
Turkish NFOSI-18 and Turkish NTX-4 had excellent internal consistency (Cronbach's alpha: 0.919 and 0.917, respectively).Variation in internal consistency was acceptable with the exclusion of individual items (lower than 10%), and corrected item-total correlations were higher than 0.3 for both questionnaires (Table 2).Tus, all items, in both questionnaires, were retained for further analysis.
European Journal of Cancer Care

Reliability of Items. Te reliability of individual items
was detected as substantial to excellent for the Turkish NFOSI-18 (0.612 to 0.850) and as excellent for the Turkish NTX-4 (0.805 to 0.848) (Table 2).

Floor-Ceiling Efects.
Only one patient (1.06% of the study sample) had a total NFOSI-18 score of 0, and none of the patients had a total NFOSI-18 score of 72.For the total NTX-4 score, no patient had a score of 0, and three patients (3.20% of the study sample) had a score of 16.Tese scores were signifcantly less than the pre-decided cut-of scores of 15% for foor and ceiling efects.For NFOSI-18 and NTX-4 total scores, γ1 was calculated as −0.048 and −0.827, respectively, indicating absence of foor/ceiling efect.

Discussion
Our results demonstrated that the Turkish NFOSI-18 and Turkish NTX-4 had adequate internal consistency, item reliability, test-retest reliability, and convergent validity.Turkish NFOSI-18 and NTX-4 did not demonstrate any foor or ceiling efects.Turkish NFOSI-18 and Turkish NTX-4 questionnaires showed high ICC values in terms of total scores indicating sufcient test-retest reliability for these questionnaires.Tese fndings are in line with the results for Korean version of NFOSI-18 (ICC = 0.77) and NTX-4 (ICC = 0.84) [22].Te test-retest reliability of Treatment Side Efects and Functioning/Well-Being subscales of NFOSI-18 were shown to be lower than acceptable levels (ICC < 0.70) [35] while the other subscores had adequate test-retest reliability.Te possible reason may be the reduced side efects associated with cyclespecifc chemotherapy treatment.As the treatment parameters change during the course of chemotherapy, this may have led to alterations in patients' perceptions in terms of burden of the treatment and general well-being [36].Dose adjustments due to the toxicity, patient's tolerance, or adverse efects are common in clinical practice and may cause variations in experienced complications or present symptoms [37].As the interpretation of these subparameters in patient follow-up may be unreliable, using the changes in other subscores or total scores may be more benefcial.Another possible reason for obtaining low ICC values in some subscales may be due to the 14-21-day interval between the test and retest measurements.Tis relatively long duration was used to prevent the learning efect; however, some aspects related to disease status may have changed during this time and afected the reliability outcomes.
Our results of SEM value were less than 10% of the NFOSI-18 total score and were similar to the results by Trigg et al. [38] which yielded SEM values of 4.93 [36].Additionally, previous research found a minimal clinical important diference of NFOSI-18 in the range of 5 to 7. Correspondingly, the calculated SEM values for the Turkish version of NFOSI-18 were lower than the minimal clinical important diference.
Two previous studies that investigated the internal consistency of original NFOSI-18 calculated Cronbach's alpha coefcient as 0.80 [17] and 0.82 [38].Korean 4 European Journal of Cancer Care NFOSI-18 (α � 0.84) and Turkish NTX-4 (α � 0.89) were also shown to have sufcient internal consistency [22].Te present research demonstrated the Turkish NFOSI-18 and Turkish NTX-4 to have adequate internal consistency similar to the outcomes of prior research as all questions contributed to total score and all original items were also retained in the Turkish version.Te EQ-5D-3L developed by World Health Organization is a generic HRQoL questionnaire frequently used to assess patients with OC by health professionals [27].Lee et al. [22] employed the EQ-5D-3L to validate the Korean NFOSI-18 and Korean NTX-4.Tey detected poor-to-moderate correlations between NFOSI-18, NTX-4, and EQ-5D-3L [22].Similarly, we obtained signifcant correlations between all EQ-5D-3L scores and NTX-4 and NFOSI-18 scores/ subscores.Te patients with OC have been reported to experience difculties in the activities of daily living due to side efects of adjuvant therapy efects such as nausea, vomiting, loss of appetite, and fatigue [39].Te EQ-5D-3L consists of subscales that afect the patient's ability to sustain the activities of daily living.Terefore, our results are no surprise as NFOSI-18 and EQ-5D-3L both interrogate the potential impact of the disease on the activities of daily living.Neurotoxicity occurs in approximately half of the  European Journal of Cancer Care patients with OC during the frst two cycles of chemotherapy [40].Age and low HRQoL scores have been identifed as potential risk factors for the development of chemotherapyinduced peripheral neuropathy in patients with OC [40].
Neurotoxicity may lead to motor and sensory loss in hands and feet which may impair the daily living activities [41].In this context, a correlation may be expected between the EQ-5D-3L and the NTX-4.
Our results of the NFOSI-18 mean score were higher than the results of the study by Trigger et al. [38].Tis discrepancy might be explained by the diference between study samples.Trigger et al. [38] only included patients with stage 3-4 OC while the present study included patients with stage 2-4 OC according to FIGO.Recent FIGO consensus report suggests that patients with stage 2 OC cannot be classifed as early stage due to high risk of recurrence or metastasis [42].Additionally, adjuvant chemotherapy does not provide additional benefts in patients with stage 1 OC and is not indicated [43].Besides, all patients in the present study underwent primary cytoreduction surgery and received chemotherapy and may have still been afected by the side efects of adjuvant/surgical treatments and experience similar symptoms with stage 3-4 patients as previously reported [43].
Te strength of this study is rooted in its multicenter design, which may increase the generalizability of the fndings.Te most important limitation of this study is the insufcient number of patients to conduct more comprehensive analyses such as Rasch analysis or factor analysis.In the study by Trigger et al. [38], the validation of the NFOSI-18 was assessed by a multiple attribute analysis including 897 participants.However, our study did not achieve an adequate sample size for these analyses.Smaller representation of patients with stage 4 OC was another limitation of this study.
2.1.Study Design.Te present study was carried out as a multicenter, cross-sectional study that consists of three institutions (Dokuz Eylul University Hospital, Izmir Katip Celebi University Atatürk Training and Research Hospital, and Izmir Health Sciences University Tepecik Training and

Table 1 :
Physical characteristics, disease-related characteristics, and generic health-related quality of life.

Table 2 :
Internal consistency and item reliability of NFOSI-18 and NTX-4.-18: the National Comprehensive Cancer Network/Functional Assessment of Cancer Terapy Ovarian Cancer Symptom Index-18 Item Version; NTX-4: Functional Assessment of Cancer Terapy/Gynecologic Oncology Group Neurotoxicity 4-item.
r6European Journal of Cancer Care