Malignant Melanoma Worldwide, the incidence of melanoma of the skin continues to
increase. Cutaneous melanoma is the most lethal skin cancer worldwide. In alignment with
the global trend, the number of Danes who are diagnosed with malignant melanoma has also
increased significantly during the last 50 years. In Denmark, approximately 400 persons
are diagnosed with metastatic disease each year. Although more people are diagnosed with
melanoma, there has only been a minor increase in the number of people who die from the
disease. This is primarily due to improved treatment modalities. The development of
immunotherapy and targeted therapy have been the most important breakthroughs in melanoma
treatment. In the last decade, immune checkpoint inhibitors (CPIs) have improved survival
significantly for patients with metastatic melanoma. However, the immune-related adverse
events (irAEs) that patients may experience can be severe and potentially
life-threatening.
Adjuvant therapy When it comes to the treatment of malignant melanoma, it is not only in
the metastatic setting that treatment options have improved disease control. The scene
has also changed when it comes to adjuvant treatment where CPIs also play an increasingly
important role. Until recently, the standard of care after completely resected stage III
melanoma was active surveillance. In stage III melanoma the cancer has spread from the
skin cells to the lymph nodes, which means that these patients are considered to have a
high risk of recurrence; a part of them will at some point experience a relapse with
metastatic disease. Consequently, several drugs to prevent recurrence after surgery have
been tested in melanoma over the years, but until recently none had proven effective. The
first drug to change this was the CPI, Ipilimumab. In 951 patients with resected melanoma
at high risk of recurrence stage (IIIa, IIIb, or IIIc disease), the effectiveness of
Ipilimumab as adjuvant therapy was tested. The recurrence-free survival was significantly
improved in favor of the patients who had received Ipilimumab compared with placebo.
5-year rate of recurrence-free survival was 41% in the ipilimumab group, as compared with
30% in the placebo group. However, more than half of the patients experienced severe
irAEs. Ipilimumab was never approved as a standard adjuvant treatment in Denmark due to
the high risk of severe irAEs. However, in December 2018 two other CPIs, Nivolumab and
Pembrolizumab, were approved as adjuvant treatment (for stage IIIa, IIIb, or IIIc
resected disease). Nivolumab has proved to increase recurrence-free survival when
compared to ipilimumab. 4-year recurrence-free survival was 52% in the Nivolumab group
and 41% in the ipilimumab group. In addition, only around 14% of the patients who receive
monotherapy with Nivolumab experience a grade 3 or 4 adverse events (AE). Similar results
were found in another study investigating the CPI, anti-PD1 antibody, Pembrolizumab. The
overall risk of recurrence was reduced by approximately 40% across stages as a result of
adjuvant therapy with Pembrolizumab after 3 years [12]. Despite the gain in
recurrence-free survival, there I not always a best/right decision regarding adjuvant
treatment. In the following the pros and cons for starting adjuvant treatment will be
described in more detail, illustrating the inherent dilemma between clinical benefit and
irAEs.
The challenges of adjuvant therapy
- - to treat or not to treat There is prognostic
heterogeneity within the group of stage III melanoma patients.
The risk of experiencing a
relapse varies depending on whether a patient is diagnosed with stage IIIA disease or
stage IIIC disease (AJCC 7th Edition). Thus, some patients have a low risk of recurrence,
(stage IIIA), while others are at greater risk (stage IIIC) following complete resection.
Patients with stage IIIC also have more to gain from a prognostic perspective than
patients with stage IIIA disease if they receive adjuvant treatment. Even though all
patients with stage III disease are eligible for adjuvant therapy, the decision to
initiate treatment is not unproblematic. Furthermore, the number of melanoma patients who
are candidates for adjuvant treatment is likely to increase in the future. Randomized
controlled trials are currently investigating if patients with stage IIB/C melanoma can
also benefit from adjuvant therapy. The argument is that these patients have a prognosis
similar to patients with stage IIIB melanoma.
In addition to the fact that some patients are considered to be at low risk of relapse,
there is also the question of toxicity. Almost 80% of the patients who receive adjuvant
immunotherapy experience some kind of irAE, and approximately 14% of the patients
experience severe irAEs that in some cases can be fatal.
Moreover, severe toxicities can impact patients´ quality of life. O´Reilly et al conclude
in a paper published in 2019 that melanoma patients who had received immunotherapy have
potentially experienced significant irAEs during treatment resulting in chronic
conditions and exposure to significant doses of steroids. Accordingly, they had
significantly lower health-related quality of life scores about physical, social, and
physical role functioning and general health compared with healthy controls. Moreover,
if/when patients relapse with metastatic disease, they are often offered treatment with
the same drug as they would have received in the adjuvant setting, which may support the
argument that some of the patients are better off waiting. On the other hand, patients of
course prefer not to have a relapse. Thus, there is not always an obvious best treatment
and the decision to treat or not to treat can be challenging. It is currently not well
understood how patients eligible for adjuvant immunotherapy make their decision to accept
or not accept treatment, and careful consideration and discussion about the potential
risks and benefits must be carried out with each patient. In addition to disease
recurrence, physicians must keep several factors in mind such as patient age,
comorbidity, and personal preferences.
Patient involvement As it is impossible to predict which patients will benefit from the
treatment, international guidelines developed for other patient populations suggest that
adjuvant systemic treatment, particularly in cases where there is little to gain (for
example patients with stage IIIA disease), should be discussed with the patient. This
recommendation to include the patients when it comes to decisions about treatment and
care is in line with the general trend within the health care system. The Danish National
Survey of Patient Experiences (LUP) stresses that the dimension "patient involvement" is
the most poorly rated area of all dimensions rated by the patients in the survey.
Moreover, the Region of Southern Denmark decided in 2019 that Shared Decision Making
(SDM) should be deployed in all hospitals in the region. Thus both politicians as well as
patient organizations have an increased focus on involving the patients more engagement.
Shared Decision Making
- - a possible game changer According to the Danish Melanoma Group,
approximately 100 patients are eligible for adjuvant treatment annually at the Department
of Oncology, Odense University Hospital.
Patients and physicians face the difficulties
described above, when having to decide which melanoma patients are to receive adjuvant
therapy. Sometimes the choice may seem obvious because the patients may have a relatively
high risk of recurrence. In other situations where the patients have a low risk of
recurrence or comorbidities which may make treatment with immunotherapy risky, it is more
complex. In such cases, SDM could be useful to support this preference-sensitive
decision. SDM is defined as "an approach where clinicians and patients share the best
available evidence when faced with the task of making decisions, and where patients are
supported to consider options, to achieve informed preferences and in making treatment
decisions that align with these preferences". A Danish lung cancer study from 2019 showed
that patients who had been engaged in SDM had lower decisional conflict and regret.
Furthermore, they felt more confident about the decision and the process facilitated that
patients´ values played a more central role in decision-making. One way to increase the
level of patient-perceived involvement and make the consultations in the outpatient
clinic more uniform may be to use a patient decision aid (PtDA) to support shared
decision-making. If the patients experience that they are part of the decision process,
it may also result in a lower level of decisional regret as described above.
Patient Decision Aids In other countries such as the United States decision-support tools
have been developed, containing information on what the patients need to know about stage
III melanoma. The patients can find information about the disease, substages, adjuvant
therapy vs.#46;active surveillance, side effects, and outcomes. With this information in
mind, the patients may be able to weigh the options with their treating oncologist to
come to the right decision. Only a few decision aids have been developed and tested
scientifically in a Danish context. As mentioned, adjuvant therapy as standard treatment
is a relatively new treatment option for patients with melanoma, and no recipe
guides/describes how to reach the right shared decision for the individual patient.
However, a study carried out in oncology care and pulmonary medicine demonstrates how the
use of a patient decision aid (PtDA) enhanced SDM in two different settings and helped
increase focus on patient preferences [25]. This study used a generic patient decision
aid template, called "Decision Helper" developed by the Center for Shared Decision Making
in the Region of Southern Denmark (CFFB). Therefore, the center now offers a platform for
decision-aid templates that adhere to the certification and quality criteria set by the
International Patient Decision Aid Standards (IPDAS). Utilizing log-in, healthcare
providers have access to the platform and the template for building patient decision aids
(BESLUTNINGSHJÆLPER™) and will be able to build and develop PtDAs tailored to their
specific needs. The template is developed based on the IPDAS criteria.
Study 1
- - Development of the Patient Decision Aid.
Methods: As both patients and clinicians are the end-users of the PtDA, both groups will
participate in an iterative process to ensure that patient needs are prioritized and that
the PtDA is relevant, accurate, and easy to use. Thus, instead of just seeing the
patients as a source of data, they will play an active role in the design phase of the
PtDA. A qualitative approach will be applied using semi-structured interviews, as
recommended in IPDAS guidelines, where melanoma patients and clinicians will identify the
type and amount of information needed for creating relevant and appropriate PtDA. As a
supplement to this, another qualitative method (observational) will be used as a
researcher (the project manager) will observe the patient-clinician communication (before
the introduction of the PtDA) in a natural situation to collect data on the communication
between the patient and clinician, how the talk is organized and the level of patient
involvement.
Phase 1: Preparation of the Patient Decision Aid.
- - Observation by researcher in the outpatient clinic - 5 consultations.
- - An expert group consisting of physicians and nurses will look at PROs and CONs for
receiving treatment/not receiving treatment.
- - Interviews with melanoma patients, who have already decided whether to receive
treatment or not, about their views and preferences and what they see as advantages
and disadvantages.
An interview guide will be prepared to ensure uniformity and all
aspects are covered. Three patients who have accepted treatment and three patients
who have declined will be included.
Phase 2: Design of the Patient Decision Aid.The PtDA will be prepared following the views and preferences of patients and clinicians
with the following content:
- - Introduction: It must be clear to the patients that a PtDA is used in the
consultation for the patient and the clinician to make a decision together.
- - The choices must be clear to the patient (observation or treatment)
- Focus on patient preferences - what matters to the patient.
- - Description of the different choices using 4 cards describing:
- PROs and CONs/risks and benefits.
- - Patient stories (patients who have made the choice already, see phase 1)
- Statistics (risk of relapse)
- Timeline (Description of the trajectory for both choices (treatment or
observation).
Data entered into IT platform 1. Draft prepared Information/data from phase 2 is entered
into the IT platform BESLUTNINGSHJÆLPER and the first draft is ready. The Center of
Shared Decision-Making will provide support and feedback.
User test
draft prepared A user test is carried out, including individual interviews
with 3-4 patients and 3-4 clinicians. For the patients, a semi-structured interview guide
will be used that is based on the items from the Preparation for Decision-Making Scale.
Similarly, a guide will be prepared for clinicians. Based on the findings from the
interviews and usability testing, the decision helper will be refined, and changes will
be entered into the IT platform.
Trial period
draft prepared The final version is printed and a trial period of
approximately 12 weeks will take place. If no further adjustments are required, the PtDA
is ready for implementation.
Study 2
- - Evaluation of the PtDA Hypothesis: The implementation of the PtDA will result
in an increased level of patient involvement among melanoma patients eligible for
adjuvant immunotherapy.
In addition, the patients will experience less decisional regret.
Moreover, the consultations in the outpatient clinic will become more uniform and
consistent.
Aims: To investigate 1)the level of patient involvement and 2)decisional regret among
melanoma patients receiving adjuvant therapy before and after implementation of the PtDA.
In addition, 3) to examine if the consultations become more uniform and consistent.
Methods: Since the aim was to examine the level of patient involvement, decisional
regret, and the uniformity and consistency of consultations before and after the
implementation of the PtDA, it has been decided to use a pre-post study design. Although
this design does not take other factors that may change during the study into account, it
may be able to suggest if the outcome is impacted by the intervention. A mixed method
approach will be used to evaluate the effect of the PtDA, using both quantitative data
and the Decision Regret Scale) and qualitative data (individual interviews and focus
group interviews.) A convergent design is selected, in which survey data and interview
data are collected in parallel over the same period. This will be described in more
detail for each of the three aims in the following.
- - Level of patient involvement Qualitative data: The level of patient involvement will
be examined using a qualitative approach, by conducting interviews with eligible
patients before and after implementation.
Due to the exploratory nature of the
study, the sample size cannot be determined in advance, but the aim is to include
10-15 patients for both pre and post-interviews depending on when data saturation
has been reached. A purposive sample of patients will be selected to ensure maximal
variation in gender, age, and treatment choice. A semi-structured interview guide
will be designed to make the interaction as smooth as possible and the interviews
will carried out by the same interviewer to ensure uniformity. Members of the
project group will participate in the coding and analysis of the interviews. Braun
and Clarke six step theory will be used for analysis.
Quantitative data:
Qualitative data: Focus group interviews will be carried out with clinicians who take
part in outpatient consultations before and after implementation to elucidate if the
consultations have become more uniform and consistent after the inclusion of the PtDA.
Due to the limited number of physicians and nurses caring for/treating the patient
population, it will only be possible to carry out two focus group interviews before and
after. The interviews will consist of approximately 5-6 clinicians each. As with the
individual interviews, an interview guide will be prepared and the interviews conducted
in a semi-structured manner. The same content analysis approach will be applied to the
group interview as described above.
Quantitative data: The plan is to measure the time spent on the individual consultation
to elucidate if the time consumption differs between the two groups i.e. if the length of
the consultations has been more uniform after implementation.
- - Decision regret Quantitative data: Patients who have not been exposed to SDM
(pre-implementation) and patients who have been exposed (post-implementation) will
be asked to complete the Decision Regret Scale (DRS).
The DRS is a questionnaire
that measures distress and remorse after a healthcare decision. The scale consists
of 5 questions. The scores are converted into a 0-100 scale following the user
manual. A score of 0 means no regret; a score of 100 means high regret.
Statistics:
Primary outcome: DRS (0-100 scale, 20 steps), mean before/after compared by linear
regression with bootstrapped standard errors (To take into account non-normality of
scores). Secondary analysis: Tested with Wilcoxon rank-sum test Secondary outcomes: DRS
above cutoffs for mild (5-25), respectively, moderate/strong regrets (≥ 30): Compared by
logistic regression.
Supplementary analysis: In supplementary analyses above regressions will be adjusted for
patient characteristics, which might have changed between the before and after periods.
Sample size calculations:
Collaborators The study is supported by the head of department at the Department of
Oncology at Odense University Hospital. Two patient representatives and the team
(physicians and nurses) that is responsible for the treatment will play a vital part in
developing the PtDA to ensure that all aspects are covered. Furthermore, the study will
be carried out in collaboration with "The Center for Shared Decision-Making". Finally, a
cross-sectional survey, including various questionnaires, was sent out to 427 melanoma
patients across Denmark in March this year. The Decision Regret Scale (DRS) is one of the
questionnaires in the survey and accordingly, it will be elucidated if the patients who
have received adjuvant treatment in 2019 and 2020 have had any decisional regret. The
results will be helpful as historical background data for our project.
Perspectives The studies will be based at the Department of Oncology, OUH, but the
project is highly relevant for all melanoma patients in Denmark. It is expected to change
how outpatient consultations take place, enabling the patients to participate in
important decision-making regarding their treatment and care. It is currently not well
understood how patients eligible for adjuvant immunotherapy make their decision to accept
or not accept treatment. It is expected that the PtDA for melanoma patients receiving
immunotherapy in the adjuvant setting can be used nationwide and serve as an example for
other researchers/clinicians who wish to design a similar tool for other patient
populations receiving immunotherapy. Moreover, because the researchers also aim to
evaluate the tool by comparing the level of patient involvement before and after
implementation of the "Decision Helper", it will be elucidated if the designed tool makes
a difference.
