Preferences for Immunotherapy in Melanoma: A Systematic Review

Abstract

Background

Immunotherapy improves overall survival for patients with metatstatic melanoma and improves recurrence–free survival in the adjuvant setting, but is costly and has adverse effects. Little is known about the preferences of patients and clinicians regarding immunotherapy. This study aimed to identify factors important to patients and clinicians when deciding about immunotherapy for stages 2–4 melanoma.

Methods

This study searched the Medline, EMBASE, ECONLIT, PsychINFO, and COCHRANE Systematic Reviews databases from inception to June 2018 for immunotherapy choice and preference studies. Findings were tabulated and summarized, and study reporting was assessed against recommended checklists.

Results

This investigation identified eight studies assessing preferences for melanoma treatment; four studies regarding nivolumab, pembrolizumab, or ipilimumab; and four studies regarding interferon conducted in the United States, Germany, and Australia. The following 10 factors were important to decision-making: overall survival, recurrence-free survival, treatment side effects, dosing regimen, patient or payer cost, patient age, clinician or family/friend treatment recommendation, quality of life, and psychosocial effects. Overall survival was the most important factor for all respondents. The patients judged severe toxicities to be tolerable for small survival gains. The description of information about treatment harms and benefits was limited in most studies.

Conclusions

Overall survival was of primary importance to patients and clinicians considering immunotherapy. Impaired quality of life due to adverse effects appeared to be a second-order consideration. Future research is required to determine preferences for contemporary combination therapies, extended treatment durations, and avoidance of chronic side effects.

Systematic review registration

PROSPERO registration number CRD42018095899.

Appendices

Appendix 1: MEDLINE search strategy with MeSH terms and text words

1	exp MELANOMA/
2	melano*.tw,kf.
3	(skin* adj4 cancer*).tw,kf.
4	1 or 2 or 3
5	adadjuvant*.tw,kf.
6	immunotherapy/ or radioimmunotherapy/
7	(immunotherap* or radioimmunotherap*).tw,kf.
8	(adjuvan* adj4 immunotherap*).mp.
9	5 or 6 or 7 or 8
10	Patient preference/
11	Decision-making/ or choice behavior/
12	exp “Patient acceptance of health care”/
13	((patient* or doctor* or clinician*) adj4 (preference* or accept* or participat*)).tw,kf.
14	((decision* or choice* or choose*) adj4 (treat* or therap* or mak* or behavio?r*)).tw,kf.
15	(“discrete choice*” or dce or “stated preference*” or “conjoint analys*” or “choice experiment*” or “discrete rank*” or “best worst” or “best best”).tw,kf.
16	10 or 11 or 12 or 13 or 14 or 15
17	4 and 9 and 16

Appendix 2: ISPOR Statement: a checklist for conjoint analysis applications in health care

1 Was a well-defined research question stated and is a conjoint analysis an appropriate method for answering it?

1.1 Were a well-defined research question and a testable hypothesis articulated?

1.2 Was the study perspective described, and was the study placed in a particular decision-making or policy context?

1.3 What is the rationale for using conjoint analysis to answer the research question?

2 Was the choice of attributes and levels supported by evidence?

2.1 Was attribute identification supported by evidence (literature reviews, focus groups, or other scientific methods)?

2.2 Was attribute selection justified and consistent with theory?

2.3 Was level selection for each attribute justified by the evidence and consistent with the study perspective and hypothesis?

3 Was the construction of tasks appropriate?

3.1Was the number of attributes in each conjoint task justified (i.e., full or partial profile)?

3.2 Was the number of profiles in each conjoint task justified?

3.3 Was (should) an opt out or status-quo alternative (be) included?

4 Was the choice of experimental design justified and evaluated?

4.1 Was the choice of experimental design justified? Were alternative experimental designs considered?

4.2 Were the properties of the experimental design evaluated?

4.3 Was the number of conjoint tasks included in the data-collection instrument appropriate?

5 Were preferences elicited appropriately given the research question?

5.1 Was there sufficient motivation and explanation of conjoint tasks?

5.2 Was an appropriate elicitation format (i.e., rating, ranking, or choice) used? Did (should) the elicitation format allow for indifference?

5.3 In addition to preference elicitation, did the conjoint tasks include other qualifying questions (e.g., strength of preference, confidence in response, and other methods)?

6 Was the data-collection instrument designed appropriately?

6.1 Was appropriate respondent information collected (e.g., sociodemographic, attitudinal, health history or status, and treatment experience)?

6.2 Were the attributes and levels defined, and was any contextual information provided?

6.3 Was the level of burden of the data-collection instrument appropriate? Were respondents encouraged and motivated?

7 Was the data-collection plan appropriate?

7.1 Was the sampling strategy justified (e.g., sample size, stratification, and recruitment)?

7.2 Was the mode of administration justified and appropriate (e.g., face-to-face, pen-and-paper, web-based)?

7.3 Were ethical considerations addressed (e.g., recruitment, information, and/or consent, compensation)?

8 Were statistical analyses and model estimations appropriate?

8.1 Were respondent characteristics examined and tested?

8.2 Was the quality of the responses examined (e.g., rationality, validity, reliability)?

8.3 Was model estimation conducted appropriately? Were issues of clustering and subgroups handled appropriately?

9. Were the results and conclusions valid?

9.1 Did study results reflect testable hypotheses and account for statistical uncertainty?

9.2 Were study conclusions supported by the evidence and compared with existing findings in the literature?

9.3 Were study limitations and generalizability adequately discussed?

10. Was the study presentation clear, concise, and complete?

10.1 Was study importance and research context adequately motivated?

10.2 Were the study data-collection instrument and methods described?

10.3 Were the study implications clearly stated and understandable to a wide audience?

Appendix 3: STROBE statement: a checklist of items that should be included in reports of cross-sectional studies

	Item no.	Recommendation
Title and abstract	1	(a) Indicate the study’s design with a commonly used term in the title or the abstract
		(b) Provide in the abstract an informative and balanced summary of what was done and what was found
Introduction
Background/rationale	2	Explain the scientific background and rationale for the investigation being reported
Objectives	3	State specific objectives, including any pre-specified hypotheses
Methods
Study design	4	Present key elements of study design early in the paper
Setting	5	Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection
Participants	6	(a) Give the eligibility criteria, and the sources and methods of selection of participants
Variables	7	Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable
Data sources/measurement	8a	For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group
Bias	9	Describe any efforts to address potential sources of bias
Study size	10	Explain how the study size was determined
Quantitative variables	11	Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why
Statistical methods	12	(a) Describe all statistical methods, including those used to control for confounding
		(b) Describe any methods used to examine subgroups and interactions
		(c) Explain how missing data were addressed
		(d) If applicable, describe analytical methods taking account of sampling strategy
		(e) Describe any sensitivity analyses
Results
Participants	13a	(a) Report numbers of individuals at each stage of study (e.g., numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analyzed)
		(b) Give reasons for nonparticipation at each stage
		(c) Consider use of a flow diagram
Descriptive data	14a	(a) Give characteristics of study participants (e.g., demographic, clinical, social) and information on exposures and potential confounders
		(b) Indicate number of participants with missing data for each variable of interest
Outcome data	15a	Report numbers of outcome events or summary measures
Main results	16	(a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (e.g., 95% CI). Make clear which confounders were adjusted for and why they were included
		(b) Report category boundaries when continuous variables were categorized
		(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period
Other analyses	17	Report other analyses done (e.g., analyses of subgroups and interactions, and sensitivity analyses)
Discussion
Key results	18	Summarize key results with reference to study objectives.
Limitations	19	Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias
Interpretation	20	Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence
Generalizability	21	Discuss the generalizability (external validity) of the study results
Other information
Funding	22	Give the source of funding and the role of the funders for the current study and, if applicable, for the original study on which the present article is based

1. ^aGive information separately for exposed and unexposed groups
2. An Explanation and Elaboration article discusses each checklist item and gives methodologic background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the websites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/)
3. Information on the STROBE initiative is available at www.strobe-statement.org

Appendix 4: Methodologic considerations of studies

Presentation of risk information	Choice survey designs	Analytical methods
Text only 19–21,23	Opt-out alternative included (if unable to chose between treatments) 17,24	Conditional and multinomial logit models 17,24
Pictorial aids plus % of risk 24	Treatment alternatives identified as unlabeled 17,22,24	Mixed logit models and hierarchical Bayesian model 22
Visual bars showing number out of 100 experiencing side effects 22
Text plus risk (%) of side effects 17

Appendix 5: Quality assessment of included studies using ISPOR tool^a

Author	Well-defined research question	Choice of attributes/levels evidence based	Task construction appropriate	Choice of design justified and evaluated	Preferences elicited appropriate	Data collection design appropriate	Data collection plan appropriate	Statistical analysis and model estimations appropriate	Results and conclusions valid	Study presentation clear concise complete
Beusterien et al. 17	✓	✓	Partial	Partial	✓	Partial	Partial	Partial	Partial	✓
Huynh et al. 22b	Partial	Unknown	Unknown	Unknown	Unknown	Unknown	Partial	Unknown	Unknown	Unknown
Stenehjem et al. 24	✓	✓	Partial	Partial	Partial	✓	✓	Partial	✓	✓

1. ISPOR International Society for Pharmacoeconomics and Outcomes Research
2. ^aISPOR statement: a checklist for conjoint analysis applications in health care
3. ^bHuynh study available only as an abstract, not as a full article

Appendix 6: Quality assessment of included studies using STROBE tool^a

First author surname, initials, publication year	Title and abstract	Introduction		Methods
		Background	Objectives	Study design	Setting	Participants	Variables	Data sources	Bias	Study size	Quan variables	Stat methods
Bramlette et al. 18	Partial	✓	✓	✓	✓	✓	Partial	✓	X	✓	✓	Partial
Kaehler et al. 19	Partial	✓	✓	✓	Partial	Partial	Partial	✓	X	X	✓	Partial
Kahler et al. 20	Partial	✓	✓	Partial	Partial	Partial	✓	✓	X	X	✓	Partial
Kilbridge et al. 21	Partial	✓	✓	✓	Partial	✓	✓	✓	✓	✓	✓	✓
Krammer and Heinzerling 23	Partial	✓	✓	✓	Partial	X	✓	✓	X	X	✓	Partial

First author surname, initials, publication year	Title and abstract	Results						Discussion			Other info
		Participants	Descrip data	Outcome data	Main results	Other analyses	Key results	Limit	Interpret	General	Funding
Bramlette et al. 18	Partial	✓	✓	✓	Partial	✓	✓	✓	✓	✓	✓
Kaehler et al. 19	Partial	✓	Partial	✓	Partial	✓	✓	✓	✓	Partial	✓
Kahler et al. 20	Partial	✓	✓	✓	Partial	X	✓	✓	✓	✓	✓
Kilbridge et al. 21	Partial	✓	✓	✓	Partial	Partial	✓	✓	✓	X	✓
Krammer and Heinzerling 23	Partial	Partial	✓	✓	Partial	X	✓	Partial	✓	✓	✓

1. STROBE statement—A checklist of items that should be included in reports of cross-sectional studies
2. ^aSTROBE Strengthening the Reporting of Observational Studies in Epidemiology, Quan quantitative, Stat statistical, Descrip descriptive; Limit limitations, Interpret interpretation, General generalizability, Info information