FormalPara Key Summary Points

Why carry out this study?

Qualitative literature on the direct experience of patients with advanced basal cell carcinoma (aBCC) who discontinue first-line treatment with a hedgehog pathway inhibitor (HHI) is sparse.

To better understand the patient experience, this study aimed to identify the reported symptoms and impacts on health-related quality of life (HRQoL) that are most important to patients with aBCC who were previously treated with an HHI.

What was learned from the study?

Patients described a significant disease burden in aBCC, even after previous treatment with an HHI. The most commonly discussed concepts were fatigue and tiredness, itch, anxiety, worry, and fear, such as day-to-day anxiety and fear about the future. Of these, fatigue and tiredness, anxiety, worry, and fear were considered the most bothersome concepts.

Introduction

Basal cell carcinoma (BCC) is the most common form of non-melanoma (keratinocyte) skin cancer in the USA, with approximately 3.6 million cases and more than 3000 deaths per year [1]. In 2017, the global incidence of reported BCC was 5,884,759 cases, reflecting a 77.4% increase in new diagnoses between 1990 and 2017 [2].

Surgical excision, when possible, is the standard treatment of BCC. However, inadequate or incomplete excision increases the risk of recurrence, and such tumors may require re-excision [3,4,5]. Fewer than 1% of cases progress to locally advanced or metastatic disease, collectively referred to as advanced BCC (aBCC) [6], and may consequently require systemic therapy [7]. European Medicines Agency (EMA) and US Food and Drug Administration (FDA)-approved and guideline-recommended therapies that target the hedgehog signaling pathway (hedgehog pathway inhibitors, HHIs) have been used as a first-line systemic therapy against aBCC not amenable to curative surgery or radiotherapy. Eventual discontinuation of first-line HHI therapy is common because of progression of disease or adverse events [3,4,5, 8,9,10,11,12,13,14]. In 2021, the FDA and EMA approved the use of cemiplimab, a programmed cell death-1 inhibitor, for the treatment of patients with aBCC previously treated with an HHI or for whom an HHI is not appropriate [15].

Qualitative literature is sparse on the experience of aBCC from the patient perspective. Shingler et al. [16] explored the psychological and cosmetic burden to patients with aBCC by constructing a series of health state vignettes based on clinician input. Mathias et al. [17, 18] developed a patient-reported outcome (PRO) questionnaire describing BCC-related impacts, stratified by basal cell nevus syndrome versus aBCC. However, these methods did not provide patients the opportunity to describe how they experienced their disease in their own words. Steenrod et al. [19] conducted qualitative interviews with patients with BCC and identified high-level information on symptoms and impacts, but this work did not develop a more detailed understanding of the lived experience of patients with this condition, and less than a third of patients included had previous exposure to HHI therapy.

There are a few validated PRO scales that characterize the complex burden of oncologic skin conditions. These include the European Organization for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) questionnaire, a health-related quality of life (HRQoL) measure developed for patients with cancer that assesses a range of physical limitations and mood [20], and the Skindex-16 questionnaire which was developed and validated to assess HRQoL in patients with BCC and cutaneous squamous cell carcinoma [21]. The EORTC QLQ-C30—the most commonly utilized instrument to assess HRQoL in patients with skin cancer [22]—and the Skindex-16 questionnaire provide valuable indicators of the impact of disease on symptoms, functioning, and quality of life, despite limiting the patient to a set of predefined questions that may not completely correspond with their experiences with aBCC. Although the EORTC QLQ-C30 and Skindex-16 questionnaires were previously included in BCC clinical trials [23, 24], the Skindex-16 questionnaire was not previously used to assess HRQoL in patients with aBCC post first-line HHI therapy.

The objective of this study, which is based on constructivist principles, was to capture, through semi-structured qualitative interviews, the specific symptoms and impacts on HRQoL that are most important to patients with aBCC who previously received HHI therapy and develop a conceptual model to better understand the patient experience.

Methods

This study was conducted in compliance with Good Clinical Practice guidelines, including the International Conference on Harmonization guidelines, and was consistent with the most recent version of the Declaration of Helsinki [25]. All applicable local laws and regulatory requirements were followed throughout the study.

Study Design

In-depth semi-structured interviews were conducted with US patients with metastatic or locally advanced BCC. The interviews were initially planned to be face-to-face but were replaced with telephone interviews owing to the severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic. To facilitate the opportunity for patients to mention concepts spontaneously, a discussion guide was developed based on informal literature searches [1, 19, 26,27,28] and the researchers’ experience with qualitative research and clinical outcome assessment research. The discussion guide was developed so that interviewers could maintain a level of consistency between patient interviews and ensure that all key topics were adequately covered. The discussion guide comprised of four sections: (1) the “overview of the interview” which stated the objective and schedule, (2) the “interview instructions” for the person conducting the interview, (3) the “introduction” where objectives and disclosures were discussed with the participant, and (4) the “interview” where concept elicitation took place, and the interview was concluded. Interviews were designed to last approximately 60 min and were conducted by two trained qualitative researchers who had substantial experience conducting qualitative interviews across numerous studies, including oncology. The interviewers received project-specific training to ensure that they were familiar with the project objectives, discussion guide, and disease area, including mock interviews prior to speaking with patients. To ascertain unbiased responses and encourage spontaneous discussion, interviewers were specifically instructed per the discussion guide to use open-ended questions, and use probes to follow-up without inadvertently leading a participant’s response. A list of example interview questions is provided in Table 1. Interviews were designed to be exploratory and semi-structured to allow for an in-depth understanding of individual experiences in living with metastatic or locally advanced BCC post HHI treatment. Specifically, semi-structured interviews allowed for the investigation of thoughts, experiences, and details volunteered by the participants that would not be possible with structured interviews [29].

Table 1 Example interview questions
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Interviews proceeded as follows: brief initial questions designed to establish rapport and open the conversation (e.g., “Could you tell me what symptoms you are experiencing now, related to your BCC? Thinking about how your BCC is now, can you tell me if it ever makes anything difficult to do, or prevents you from doing anything?”), a series of focused questions to explore topics of interest (e.g., “We would like to understand any other experiences you have had in terms of symptoms or how living with BCC affects your daily life. What we would like to do now is go through some other areas to see if there are things you are currently experiencing relating to your BCC”), probes to explore relevant issues not previously mentioned in the interview (e.g., “Some people with BCC experience [concept from table not previously mentioned]. Is this something that you have experienced due to your BCC?”), and a request for participants to rank the three most bothersome symptoms and impacts that had been discussed in the interview (e.g., “Thinking about all of the topics we have discussed relating to your BCC, which would you say are the three most important to you?”). All interviews were recorded and transcribed verbatim. All data were analyzed using thematic analysis. No therapeutic interventions or treatments were administered as part of this study.

Patient Selection Criteria

Patients were eligible for study enrollment if they had a clinical diagnosis of aBCC, prior HHI treatment, and met the inclusion criteria, as assessed by the treating physicians. Key inclusion criteria were age 18 years or older; ability to understand informed consent and to participate in the interview; being unlikely to benefit further from HHI treatment because of disease progression, treatment intolerance, or stable response while undergoing HHI treatment; and being treatment-naïve following the cessation of HHIs. Key exclusion criteria included eligibility of their BCC for curative surgery or curative radiotherapy, clinical diagnosis of cutaneous squamous cell carcinoma, untreated brain metastases, chronic drug or alcohol abuse, or significant uncontrolled psychiatric or physical comorbidities that would impact the ability of patients to participate in this study.

Recruitment

Recruitment was conducted through an agency that contacted oncologists to identify individuals who met the study eligibility criteria under a Health Insurance Portability and Accountability Act waiver. Prior to any study-related procedure, eligible patients who agreed to participate provided a signed and dated fully informed consent form and an Authorization to Use and Disclose Personal Health Information Form. Upon recruitment, the treating clinicians completed an Eligibility Assessment Form to screen each participating patient based on the inclusion and exclusion criteria. For each eligible participant, the treating clinicians completed a brief Medical History Form to document date of aBCC diagnosis, date of HHI therapy discontinuation, characterization of the patient’s disease as metastatic or local BCC, as well as a current and previous history of treatments with dosages, treatment/symptom target (e.g., pain reduction), treatment start date, and response to treatment. The clinicians worked with the participants to complete a Demographic Health Information Form that listed gender, ethnicity, race, education, and employment status.

Target quotas were used to obtain diverse representation of age, sex, ethnicity, education, metastatic versus locally advanced status, and length of time post HHI treatment. The minimum target quotas, which were intended to provide a broad representation of the second-line eligible aBCC patient population, included six patients of greater than 65 years of age, six men, four women, two patients who identified as Hispanic, two patients with a high school diploma as the highest level of education, two patients with metastatic BCC, eight patients with locally advanced BCC, and seven patients at least 6 months beyond the cessation of first-line HHI treatment.

Analysis

Transcripts of the interviews were entered into NVivo 10 (updated to NVivo 1.0 during analysis), a software package designed to facilitate the storage, coding, and analysis of qualitative data [30]. Thematic analysis is a well-accepted and widely used approach for interpreting qualitative data [31] that uses both inductive and deductive coding and was considered the most suitable methodology for the present study. In thematic analysis, line-by-line coding is used to identify meaning in the transcripts and to identify any themes, patterns, or features of interest within the data relating to the research aims. The initial pass of the data focused on inductive coding methods which were then followed up using a deductive approach.

The data were also subjected to concept saturation analysis [32], which was undertaken by splitting the study sample into three equal groups of five based on the order in which they were interviewed. If a concept was discussed spontaneously or endorsed after probing by at least one patient within a group, it was noted as having been raised as relevant within that specific group. Concept saturation was considered met when no new themes or descriptions of concepts were identified in the final group of interviews.

Following coding, the signs, symptoms, and impacts reported by patients during the interviews were used to generate a patient-led conceptual model [33, 34]. The conceptual model was a visual representation of aspects of patients’ experience living with aBCC. Impacts reported by patients were categorized into emotional/psychological, physical, and social domains. As an exploratory and deductive exercise, concepts covered by the EORTC QLQ-C30 [20] and Skindex-16 [21] questionnaires, two widely used measures in oncology and skin condition clinical trials, were mapped to those identified during the interviews to descriptively assess the adequacy of the concept coverage of these PRO measures in assessing the burden of aBCC.

Results

Patient Characteristics

The quotas for age, gender, ethnicity, education, and condition status were all met or exceeded during the study. However, the target quota (n = 7) for participants at least 6 months beyond cessation of HHI therapy was met by only two patients. This in part was due to recruitment delays associated with the COVID-19 pandemic, and recruiters were unable to identify sufficient patients to meet this quota. After the recruitment of the first ten participating patients, feedback from the recruiter was reviewed, and the study team agreed that this quota could be removed.

There were 15 participants enrolled in the study with a median age (range) of 63 (38–73) years. Most participants identified as White race (66.7%) and non-Hispanic/Latino ethnicity (73.3%) and were predominantly female (60%) (Table 2). Sixty percent of participants had locally advanced BCC and 40% had metastatic BCC. Median (range) time since initial diagnosis of BCC was 10.1 (4.1–61.2) months, the median (range) time from initial BCC diagnosis to aBCC diagnosis was 6.8 (0.3–56.4) months, and median (range) time since cessation of HHI treatment was 2.8 (0.7–9.1) months (Table 2). All participants had received previous HHI treatment, most commonly sonidegib (n = 10), and 12 patients reported prior Mohs surgery. No other treatments were reported. No differences were seen in the data between any of the compared subgroups (sex, race, ethnicity, or clinical status).

Table 2 Patient demographics and baseline characteristics
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Main Findings

Concept saturation for reported signs, symptoms, and impacts were considered met, with no new concepts identified in the final round of five interviews. A patient-centered conceptual model was developed based on ten reported symptoms and 15 reported impact categories (divided into emotional/psychological, social, and physical domains) that were most commonly discussed and considered important to patients (Fig. 1). Four concepts were each discussed by only one participant, namely vomiting, difficulties with memory, feeling generally ill, and financial difficulties. These concepts were thematically determined to not be core concepts and were subsequently excluded in the conceptual model. For all concepts, no clear qualitative differences could be discerned across any subgroup (sex, ethnicity, or metastatic versus locally advanced BCC).

Fig. 1
figure 1

Patient-centered conceptual model of aBCC after first-line HHI therapy discontinuation. BCC basal cell carcinoma, HRQoL health-related quality of life

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Patient-Reported Symptoms

The most commonly discussed symptom, reported by all but one participant (n = 14; 93%), was fatigue and tiredness (Table 3). This symptom was reported spontaneously by 12 participants, with an additional two participants reporting it after some probing. Various terms were used by participants to describe their fatigue and tiredness, including “lack of energy” (n = 9) and “mentally and physically exhausted” (n = 7). One participant commented, “Saying tired, that’s putting it a little mildly. I would say it’s an exhaustion. I feel like I’m exhausted. Sometimes I wake up and I feel like I didn’t sleep.” Fatigue and tiredness were classified as important by 12 of the 14 participants, with one participant stating, “It’s important, ’cause there’s so much that I wanna do but my body just won’t let me do it.” The remaining two participants indicated it was not important and had little impact on their day-to-day life, e.g., “[Fatigue and tiredness] doesn’t bother me. It’s not severe enough to bother me right now.” Consistency of fatigue and tiredness was discussed by 12 participants, and results varied; six participants described feelings of tiredness as generally constant, and six spoke about how it was more variable. Feelings of fatigue and tiredness were considered to impact other aspects of their day-to-day lives, including sleep (n = 7), social interactions and activities (n = 5), household tasks (n = 4), and personal hobbies and activities (n = 4).

Table 3 Reported symptoms and areas of impact
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Itch was the second most commonly discussed symptom of aBCC (n = 13; 87%), arising spontaneously in discussion with 11 participants, and after probing with an additional two participants. The location of the itch was dependent on the location of the participant’s BCC, with the most common locations being the back (n = 5) and neck (n = 4). Itch was described as important to their experience of the condition by nine of the 13 participants, and those who described it as unimportant stated it was not important at the moment, or that it was not currently bothersome. As with fatigue and tiredness, the consistency of itch also varied between participants, with five participants describing their itch as constant, and seven as more variable.

Less commonly discussed symptoms included the physical appearance of BCC on the skin (scarring, open wound, etc.; n = 9; 60%), lack of appetite (n = 8; 53%), pain (n = 7; 47%), lack of physical strength (n = 5; 33%), nausea (n = 4; 27%), diarrhea (n = 4; 27%), constipation (n = 2; 13%), and shortness of breath (n = 2; 13%) (Table 3).

Patient-Reported Impacts

Impacts were more commonly discussed by participants than symptoms. Anxiety, worry, or fear were discussed by all but one of the enrolled participants (n = 14; 93%), 13 spontaneously and one after probing. These three emotional impacts were grouped based on participant feedback on similar concepts that captured different aspects of the same feelings. Most participants (n = 11; 73%) discussed being worried, anxious, and afraid about the future, with 5 (33%) feeling generally anxious from day to day. One participant described the emotional impact of BCC, “[My BCC] gives me a lot of anxiety, I would, I would say… Just because I know at this point that it has locally advanced in the same region. Um, and there’s nothing that we can do about it right now, or ever, at this point.”

The second most common reported emotional impact was low mood or depression related to aBCC (n = 12; 80%). This was discussed spontaneously by six participants and by the remaining six participants after probing. All participants who reported emotional impact identified it as important to them, and six described it as intermittent based on the reported symptoms they were experiencing at any given time. Terms used to describe these feelings included “emotional,” “emotional wreck,” and “feeling vulnerable and worthless.” Emotional impacts, which were less commonly reported, included skin cancer perception by others (n = 9; 60%), difficulties concentrating (n = 8; 53%), frustration, anger, and irritability (n = 8; 53%), and embarrassment (n = 7; 47%).

The most discussed physical impact of aBCC was the limitation of hobbies or leisure activities. Thirteen participants discussed this concept, nine spontaneously and four after probing. Fatigue and tiredness was found to impact the hobbies or leisure activities of four participants, and two identified a lack of physical strength as the symptom causing this impact, e.g., “I used to love to cook… I don’t have the strength to stand over a stove, or a barbecue, or anything to, for a long period of time to cook a meal.” Other physical impacts of aBCC that were discussed less commonly included needing to rest more often (n = 10; 67%), difficulties doing strenuous activities (n = 9; 60%), needing help with day-to-day activities (n = 8; 53%), trouble sleeping (n = 8; 53%), work limitations (n = 4; 27%), and difficulties walking (n = 3; 20%).

Social impacts of aBCC were discussed less commonly than physical or emotional/psychological impacts. Challenges with social interactions and modifications to activities to avoid the sun were described by eight (53%) and seven (47%) participants, respectively.

Most Bothersome Patient-Reported Symptoms and Impacts

As part of the interview guide, participants were also asked to identify the top three symptoms and/or impacts associated with their aBCC condition which were considered to be the most bothersome (Table 4). Most participants tended to pick impacts rather than symptoms as their most bothersome concept, consistent with the finding that participants were more likely to discuss impacts than symptoms during the interviews. In total across all categories, the most commonly selected symptom was fatigue and tiredness (n = 7) and the most commonly selected impact was the emotional impact of anxiety, worry, and fear (n = 6). Some participants selected overarching rather than specific concepts as the most bothersome, such as the inability to “live a normal life” because of their aBCC (n = 3).

Table 4 Most bothersome patient-reported symptoms and impacts
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Discussion

Most patients with aBCC discontinue the currently recommended first-line treatment comprising HHIs (vismodegib or sonidegib) because of adverse events or disease progression [5, 13, 14]. To our knowledge, there is limited literature examining the experiences of patients living with aBCC post HHI treatment. Through in-depth interviews and qualitative thematic analysis, we were able to determine the reported symptoms and impacts most important to this patient population. We developed a conceptual model and identified whether concepts important to patients with aBCC were captured by widely used instruments that measure HRQoL: the EORTC QLQ-C30 and Skindex-16 questionnaires.

Qualitative interviews with patients who have aBCC and prior HHI treatment identified that the condition has a substantial impact on daily life. The reported impacts of aBCC were discussed more commonly than the reported symptoms, with the most commonly discussed impacts related to emotions and physical function. The reported impacts of aBCC could consistently be mapped back to two concepts: anxiety, worry, and fear, and fatigue and tiredness, consistent with these domains being listed most commonly as bothersome (Table 3). That there were no differences in the data between any of the compared subgroups (sex, race, ethnicity, or clinical status) indicates the concepts are likely to apply to a full range of patients with aBCC.

To our knowledge, the only other qualitative interview study assessing the experience of patients with BCC was conducted by Steenrod et al. [19]. Steenrod et al. and our study identified a number of reported symptoms and impacts in common such as fatigue, itch, pain, impacts on daily activities, and depression. The Steenrod et al. study interviewed patients with nonadvanced and advanced disease in separate cohorts and established that patients with advanced disease experienced a greater impact on their emotional well-being and daily functioning than patients with nonadvanced disease. Unlike in the Steenrod et al. study, participants in our study were mostly female and, per eligibility criteria, all had previously received HHI therapy for aBCC. Owing to differences in the baseline characteristics of the patient populations, comparisons across these studies must be made with caution, but both studies generally portray a significant burden to patients with aBCC.

Steenrod et al. recommended that while HRQoL domains should evaluate changes in daily activities among patients with nonadvanced disease, a broader assessment that captures changes in lifestyle is needed for patients suffering from advanced disease [19]. The results of our study have made it possible to begin addressing this need by identifying impacts in greater detail than has been done previously. The granularity of results reported in our study allowed for the development of a conceptual model that reflected the patient experience living with aBCC (Fig. 1). Although these concepts have variously been reported previously either in PRO measures or patient interviews, the conceptual model is a new addition that captures them in one place. Of note, the conceptual model is a visual representation of concepts important to patients, but not necessarily indicative of any theoretical underpinnings.

Consistent with previous findings, patients significantly changed their behavior to mitigate the reported impact of BCC symptoms [19]. For example, patients reported avoiding the sun, covering up, using sunblock, or staying indoors, which was burdensome and impacted their HRQoL. Such behavioral modifications were closely linked with the impact on social interaction, limitation on hobbies and activities, needing help with day-to-day activities, and work impediments. Some concepts described as “mild” or “not important” still had the potential to substantially impact patients, for example, pain, which although mild in intensity was nonetheless annoying and frustrating.

Recognition is growing for the need to include PRO measures in the clinical investigations of aBCC [35]. PRO measures such as the EORTC QLQ-C30 [20] and Skindex-16 [21], which are commonly used in clinical trials for aBCC, provide a list of symptoms and impacts which patients score to assess their quality of life. As a descriptive exercise, we mapped participant responses and the resulting conceptual model to these PRO questionnaires to examine where concept coverage exists or may require adjustment. Results from the current study validated the use of EORTC QLQ-C30 and Skindex-16 questionnaires for aBCC, but also provided patients the opportunity to identify new concepts that may not have been covered by these PROs. Skin cancer perception by others and modifications to activities to avoid the sun were not explicitly captured by these instruments, although sun avoidance was likely considered by patients while answering EORTC QLC-C30 Item 7 (hobbies or leisure activities) and Skindex-16 Item 16 (work or do what you enjoy). Overall, most of the core concepts identified during the qualitative interviews were appropriately captured between both the EORTC QLQ-C30 and the Skindex-16, when these two instruments were used together to assess a patient’s HRQoL. The Skin Cancer Index, a PRO instrument recently developed based on expert opinion, patient feedback, and existing literature [36], may also be useful to include in future investigations of patients’ experience living with aBCC. To date it has seen limited use in clinical trials for BCC.

Qualitative research is intentionally based on a small sample size with an emphasis on in-depth analysis of the patient experience. Therefore, no statistical testing was conducted as part of this study. Because saturation depends on homogeneity of the sample and the concepts under study, and since saturation was achieved at 15 patients, it is likely that the issues discussed were relevant to this patient group and that no pertinent issues were overlooked. However, one limitation to this study is that it was only conducted in the USA and may not represent a sufficiently heterogeneous population to reflect patients with aBCC worldwide. Also, recruiters were unable to meet the study quota for seven patients with aBCC who had progressed at 6 months post HHI cessation; only two (13%) were recruited for this quota. These patients may have a different experience of their disease and may be underrepresented in the study, although the time in months since HHI therapy discontinuation varied widely among the participants, with a median (range) of 2.8 (0.7–9.1) months (Table 2). Additionally, the reason for initial discontinuation of HHI therapy is unknown (e.g., tolerability, disease progression, etc.). Depending on the specific reason(s) for discontinuing HHIs, patients may have different lived experience with their aBCC. Face-to-face interviews would have enabled the interviewers to ascertain non-verbal cues in addition to verbal responses. Whilst observing these non-verbal cues may have further enhanced communication and discussions, our focus was on themes emerging from what was spontaneously said and thus empirically driven. In this respect, the change in mode of data collection is unlikely to have impacted the results.

Conclusions

This qualitative study highlights the substantial burden aBCC imposes on the daily lives of patients following first-line systemic therapy with HHIs. Patient-reported symptoms and impacts identified as most bothersome were fatigue and tiredness, anxiety, worry, and fear. A common theme expressed by patients was the inability to lead a normal life. Given that patients with aBCC often discontinue first-line systemic therapy with HHIs because of disease progression or intolerance, there is an unmet need for second-line therapies to address the needs of patients and improve their HRQoL.