Patient-Reported Outcome Measure for Meningiomas study

Meningiomas are the most prevalent tumors of the central nervous system with an
incidence of 7.86 per 100.000 persons. As these tumors originate from the
arachnoid cap cells, frequent sites of development are the skull convexity/falx
cerebri (56%) and skull base (40%) and a less frequent site is the spinal canal
(< 1%). Based on the location of the tumor, patients may suffer from a wide
variety of signs and symptoms in the physical (e.g. hemiparesis), psychological
(e.g. depression and anxiety) and social domain (e.g. lack of initiative). In
addition patients may suffer from the side effects or complications of
anti-tumor treatment.

These signs and symptoms may result in dysfunction of patients on three
distinct levels, as described by the World Health Organisation International
Classification of functioning, Disability and Health (ICF, 2001) criteria:
impairment (e.g. visual problems), activity limitations (e.g. not able to
drive) and participation restrictions (e.g. not able to drive to work, family
and friends). Health-related Quality of Life (HRQoL) is a multidimensional
outcome measure, including domains on physical, psychological and social
functioning as well as symptoms induced by the disease and its treatment. HRQoL
is therefore an unique outcome measure, assessing functioning on all three
levels.

HRQoL can be physician-, proxy- or patient-reported, but is usually assessed
with patient-reported outcome measures (PROM), reflecting the patient*s
perspective. Indeed, patients are thought to be the best source to rate their
own health status. HRQoL can be measured using generic (e.g. SF-36, EQ-5D,
FACT-G, EORTC QLQ-C30, MDASI) or disease-specific questionnaires (e.g. FACT-BR,
EORTC QLQ-BN20, MDASI-BT) and can be used both in clinical trials and practice.
In clinical trials it can be used as primary or secondary outcome measure,
which in combination with survival rates can be used to measure the net
clinical benefit of different treatment modalities. Treatment may benefit or
harm both the quantity and quality of survival and when these outcomes are
conflicting a trade-off discussion will arise. In clinical practice on the
other hand, HRQoL can be used as a facilitating tool for doctor-patient
communication, for monitoring patients* problems and functioning during the
disease trajectory, and as quality indicator of healthcare.

A recent systematic review showed that existing HRQoL questionnaires used in
meningioma research are not developed for and/or validated in meningioma
patients. This study also showed that in contrast to the current impression of
patients and physicians, data are still insufficient and not conclusive on the
effect of interventions on HRQoL in meningioma patients. In addition, results
of a recently conducted pilot study suggest that existing HRQoL questionnaires
used in meningioma research cover issues that are not relevant for meningioma
patients and that these questionnaires miss relevant issues for this patient
group. Therefore, the development and validation of a meningioma specific
questionnaire is warranted.

Because of the great variety in symptoms and disease course of meningioma
patients, it is difficult for physicians to systematically discuss patients*
problems, and consequently their needs, during the short visits to the
outpatient clinic. More than 60% of meningioma patients (n=50) reported in a
survey study by *Integraal Kankercentrum Nederland* (Netherlands Comprehensive
Cancer Organisation) to have experienced issues or obstacles with the
patient-doctor communication (e.g. patients feel themselves unheard, no
attention for psychosocial problems and poor involvement of patients in the
decision making process around their treatment). It is known that routinely use
of PROMs in clinical practice can facilitate doctor-patient communication and
probably solve some of the obstacles in the communication.

Primary objective
The primary objective of this study is to develop and validate a
disease-specific PROM, which measures HRQoL in meningioma patients.

STUDY DESIGN
This study design consists of 2 parts.
- Part A: Development of a meningioma-specific PROM, measuring HRQoL
- Part B: Validation of a meningioma-specific PROM, measuring HRQoL

For the development of the meningioma-specific PROM, measuring HRQoL, we will
follow the guidelines of the European Organisation for Research and Treatment
of Cancer (EORTC) for the development of questionnaires. The EORTC guideline
consists of four phases: (1) generation of relevant HRQoL issues, (2)
construction of an item list, (3) pre-testing the provisional questionnaire and
(4) large-scale field-testing (see figure 1). In all four phases a
heterogeneous group of meningioma patients will be included, based on
demographic characteristics, tumor location and moment in the disease course
(preoperative and short- and long-term postoperative). By doing so, we will
ensure that the questionnaire is relevant for all meningioma patients during
the entire disease course. To ensure cross-cultural validation, patients will
be included from hospitals in the Netherlands, Italy and the United States.

Part A: development of a meningioma specific PROM, measuring HRQoL
Part A comprises the first three phases: (1) generation of relevant HRQoL
issues, (2) construction of an item list, (3) pre-testing the provisional
questionnaire.

Phase 1, generation of relevant HRQoL issues
In phase I, we will generate an exhaustive list of HRQoL issues by conducting a
systematic literature search, semi-structured interviews with patients (n=40)
and health care professionals (HCPs, n=18).
1. A literature search will be conducted to find relevant (HRQoL)
questionnaires for this patient group. The following electronical databases
will be searched: MEDLINE, Embase, Web of Science, CINAHL, PSYCHINFO, Academic
Search Premier, Cochrane and ScienceDirect. Search terms will be used for
meningioma, questionnaires and HRQoL.
2. The domains and issues covered by the found questionnaires will be extracted
by two researchers and will be used in the semi-structured interviews with
patients and HCPs.
3. The aim of these semi-structured interviews is threefold: (1) to identify
relevant quality of life issues (the interview will continue until no new
issues arise), (2) to determine the relevance of all issues identified in the
literature search, including those in the existing HRQoL questionnaires, and
(3) to determine the 5 most important issues.
4. Based on the literature search and semi-structured interviews with patients
and HCPs, we will generate an issue-list. All issues will be first translated
into English.

Phase 2, construction of an item list
1. In phase II, the list of HRQoL issues will be converted into questions in
English with the same format and time frame as the EORTC questionnaires.
a. Questions will refer to patient*s experience of the last week or last month,
based on the average frequency of the issue.
b. Responses will be recorded on a 4 point Likert scale (1 not at all - 4 very
much).
c. Questions related to functioning will be positively formulated and questions
related to symptoms and side effects will be negatively formulated.
2. The generated questions will be mailed to all the principal investigators to
come into consensus on the formulation of the questions.
3. The questions will be translated into Dutch and Italian through a
forward-backward translation, following the EORTC translation guidelines.
4. Cognitive debriefing interviews will be organised with 10 meningioma
patients to assess the construct validity of the provisional questionnaire and
whether the questions are clearly formulated.
Preliminary decision rules for phase 1 and 2
All issues identified in phase 1 will be included to the preliminary
questionnaire, with exception of:
- Issues with a mean relevance score less than 1.5 (4 point Likert scale).
- Issues which are fairly similar to each other; the issue with the highest
mean relevant score will be included to the preliminary questionnaire.
- Issues that are not applicable in all three countries.


Phase 3, pre-testing the provisional questionnaire
The aim of pre-testing the provisional questionnaire is to identify and solve
potential problems in its administration (e.g. the phrasing of questions, the
sequence of questions) and to identify missing or redundant questions. In phase
3, 120 meningioma patients (see, paragraph 5.4 for sample size calculation)
will be asked to complete the questionnaire and to score the relevance of each
issue and to assess whether the questions are clearly formulated. In addition,
preliminary psychometric testing will be conducted. This will result in a
preliminary questionnaire, which will be used in phase 4.
1. Patients complete the provisional questionnaire before the interview.
2. Patients will score the relevance of each question on a 4 point Likert scale
ranging from *not at all* to *very much*.
3. Semi-structured interviews are organised aiming to assess completeness and
acceptability of the questions. Based on these comments, the provisional
questionnaire will be adapted.
4. Preliminary psychometric testing will be conducted.
Preliminary decision rules for phase 3
Questions are retained in the final questionnaire if they meet 5 of the
following 7 criteria:
- Questions with a mean relevance score > 1.5 points
- Questions with a prevalence ratio > 30% (number of subjects assessing a
question as relevant divided by the total number that completed the question)
- Questions with a range > 2 points
- Questions with minimal floor and/or ceiling effects
- Issues that are not applicable in all three countries.
- Issues that are upsetting and potentially distressing.
- Issues with a high compliance of at least 95%
New issues are included when at least 30% of patients reported this issue as
relevant in phase 3.
Questions will be rephrased when 2 or more patients have any difficulty with
the question.


4.2 Part B: validation of a meningioma specific PROM, measuring HRQoL
Phase 4, large scale field testing
In phase 4, patients from multiple centres will complete the questionnaire at
multiple time points (for each item in the questionnaire, 10 patients will be
included) to assess its validity, reliability, responsiveness and
interpretability (i.e. minimal important change) in accordance to the
COnsensus-based Standards for the selection of health Measurement Instruments
(COSMIN) criteria, see figure 2.18
1. Patients complete the questionnaire at three time points: baseline, 12 weeks
and 14 weeks (patients who complete the questionnaires before surgery should
have their first interview no earlier than a week before surgery).
2. In addition, patients will complete three other questionnaires the first
time to assess concurrent validity: the EORTC QLQ-C30 and its brain
tumor-specific module (QLQ-BN20) and the SF-36.
3. Patients complete a debriefing questionnaire. Based on these comments, the
preliminary questionnaire may be adapted.
4. Psychometric analyses will be conducted in according to the COSMIN criteria.

During the semi-structured interviews, patients may be confronted with all
issues and problems that meningioma patients could have, which could impose a
psychological burden on them. Moreover, it will cost the patients time to
attend the interviews and complete the questionnaires, although this is not
substantial ( max: 60 minutes). Previous experience with the development of
HRQoL questionnaires is that the respondent burden is limited and that patients
like to discuss these issues/problems with a health care professional.