Background
Neuroendocrine tumors (NETs) are rare forms of cancer arising from hormone-producing neuroendocrine cells throughout the body.1 The incidence of NETs in the United States is rising, with 8.3 cases per 100,000 individuals diagnosed in 2018 compared with 6.98 cases per 100,000 individuals diagnosed in 2012.2,3 Furthermore, nonspecific symptoms can cause significant delays in diagnosis.4 As a result, most patients with NETs are diagnosed with metastatic disease,1 at which point curative surgery is no longer a treatment option in most cases.5 Additional treatment strategies focus on symptom relief and/or slowing tumor progression.4–6
Given the indolent nature of many NETs, overall survival rates and treatment durations tend to be long; the median overall survival for all patients with NETs is 9.3 years.3 Therefore, it is important to consider the impact of potential treatment-related toxicities on the quality of life (QoL) of these patients. Patients with NETs tend to report worse health-related QoL than the general population, indicating the need for closer examination of their treatment goals and preferences.7 Patient preference studies in early-stage breast cancer, non–small cell lung cancer, and advanced melanoma revealed that these patients place the most importance on overall survival and symptom reduction when considering treatment preferences.8–10 Although these studies showed that patients with more aggressive malignancies value survival and symptom relief, another study of older adults with solid tumors starting chemotherapy suggested that older adults may value other outcomes instead of survival.11 The role of patient preferences in NETs has not yet been studied.
Clinical trials in recent years have established new treatment options for patients with advanced NETs, including somatostatin analog therapy,12–15 molecular targeted therapy,16–18 and peptide receptor radionuclide therapy.19–21 However, patient-centered outcomes are rarely included.5,21–26 To address this knowledge gap, we performed a cross-sectional survey study to assess values and preferences held by patients with NETs regarding competing health outcomes (quantity vs quality of life and present vs future health) using the Health Outcomes Tool,27–29 Attitude Scale,27,30 Now versus Later Tool,27,30 and Prognosis and Treatment Perceptions Questionnaire (PTPQ).31,32
Patients and Methods
Patient Population
Between March 2019 and August 2020, 60 English-speaking patients aged ≥18 years with pathologically confirmed, advanced (metastatic or unresectable), functional or nonfunctional, well-differentiated (grade 1 or 2) NETs of gastrointestinal, pancreatic, thoracic (including lung and thymus), or unknown primary and starting any new line of systemic therapy were consecutively recruited at an NCI-designated Comprehensive Cancer Center. To study the potential effects of age on patient responses, we recruited 30 patients aged <65 years and 30 patients aged ≥65 years. The City of Hope Institutional Review Board approved this study, and all patients signed an informed consent form. Study participation was voluntary, and no compensation was provided.
Measures
Patients completed the following study measures before starting their new line of systemic therapy: (1) Health Outcomes Tool,27–29 which ranks the importance of 4 outcomes (survival, maintaining independence [function], freedom from pain, and freedom from symptoms) using a visual analog scale; (2) Attitude Scale,27,30 which identifies the extent to which patients agree with health outcome–related statements; (3) Now versus Later Tool,27,30 which ranks the importance of QoL today vs 1 year or 5 years from today using a visual analog scale; and (4) PTPQ,31,32 which identifies the amount of information patients prefer to receive about their disease or treatment, patient’s treatment goal, patient’s perception about physician’s treatment goal, and self-reported health status. Additional assessments, including the Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30),33,34 EORTC Quality of Life Questionnaire Neuroendocrine Carcinoid Module (QLQ-GINET21),35,36 and Cancer & Aging Research Group Geriatric Assessment Tool37,38 were obtained for exploratory analyses. Data were entered into a secure, HIPAA-compliant database.
Statistical Analysis
Descriptive statistics were calculated for patient demographics and baseline tumor/treatment characteristics. The proportions and 95% confidence intervals of patients choosing survival, function/independence, freedom from pain, or freedom from symptoms as their most important treatment goal on the Health Outcomes Tool were calculated. Patient opinions on the Attitude Scale were captured using a 5-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree). Responses were categorized into 3 groups: “agree” (“strongly agree” and “somewhat agree”), “disagree” (“strongly disagree” and “somewhat disagree”), and “neither disagree/agree,” and their proportions and 95% confidence intervals were calculated. The proportions and 95% confidence intervals of patients who considered future QoL as more important than current QoL on the Now versus Later Tool were calculated. Chi-squared and Fisher’s exact tests were used to assess whether there were significant differences between younger (age <65 years) and older (age ≥65 years) patients regarding choice of primary treatment goal on the Health Outcomes Tool, agreement with statements on the Attitude Scale, and responses on the Now versus Later Tool.
Multinomial logistic regression was used to explore associations between age (<65 years vs ≥65 years), sex, race/ethnicity (non-Hispanic White vs all others), education (high school or less vs college or higher), marital status (married/partnered vs others), living situation (alone vs with someone), primary NET location (gastroenteropancreatic NET or unknown vs thoracic), lines of prior treatment (0 vs ≥1), tumor grade (grade 1 vs 2), and planned therapy (somatostatin analog vs other) and patient preferences (responses on the Health Outcomes Tool, Attitude Scale, and Now versus Later Tool). Odds ratios and 95% confidence intervals were calculated for all variables. A 2-sided P value <.05 was considered statistically significant. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc.).
Results
Patient Characteristics
Patient demographics and baseline tumor characteristics are summarized in Table 1. A total of 28 (46.7%) patients were female, 30 (50.0%) were non-Hispanic White, and the median age was 64.5 years (range, 34–94 years). Most patients were married/partnered (61.7%), had completed postsecondary education (53.3% college, 23.3% graduate/postcollege), and were either retired/unemployed (41.7%) or disabled/on medical leave (33.3%).
Patient Demographics and Tumor/Treatment Characteristics (N=60)
A total of 96.7% of patients had stage IV disease, and 75.0% had nonfunctional tumors (Table 1). Common primary tumor locations included the pancreas (30.0%), small bowel (26.7%), and lung (21.7%). Sixty percent of patients had received ≥1 line of prior therapy, and the most common planned therapies were somatostatin analog therapy (46.7%) and peptide receptor radionuclide therapy (31.7%). Most patients reported high levels of functioning and low levels of symptoms in the EORTC QLQ-C30 and QLQ-GINET21 (supplemental eTable 1, available online with this article at JNCCN.org). There were no significant differences in demographics or baseline tumor characteristics between younger (age <65 years) and older (age ≥65 years) patients (data not shown).
Patient Preferences
When choosing between maintaining independence (“maintaining your current ability to do your daily activities”), survival (“keeping you alive for as long as possible, regardless of what kind of health you are in”), reducing or eliminating pain, or reducing or eliminating dizziness, fatigue, and/or shortness of breath as their most important health outcome on the Health Outcomes Tool, 46.7% (95% CI, 34.0%–59.3%) of patients chose maintaining independence as their most important health outcome (Table 2). Only 30.0% (95% CI, 18.4%–41.6%) chose survival as their most important health outcome. The remaining patients chose reducing or eliminating pain (11.7%; 95% CI, 3.5%–19.8%) or reducing or eliminating dizziness, fatigue, and/or shortness of breath (11.7%; 95% CI, 3.5%–19.8%) as their most important health outcome. Maintaining independence was the most valued outcome in younger and older patients (46.7% for both), followed by survival (36.7% vs 23.3%), reducing or eliminating pain (16.7% vs 6.7%), and reducing or eliminating dizziness, fatigue, and/or shortness of breath (0% vs 23.3%) (P=.36). In multinomial logistic regression, no associations were observed between age, sex, race/ethnicity, education, marital status, living situation, primary NET location, receipt of prior therapy, tumor grade, and planned therapy and patients’ preferences (supplemental eTable 2).
Health Outcomes Tool (N=60)
On the Attitude Scale, 85.0% (95% CI, 76.0%–94.0%) of patients agreed they would rather maintain their thinking ability than live as long as possible, and 66.7% (95% CI, 54.7%–78.6%) of patients agreed they would rather live a shorter life than lose the ability to take care of themselves (Table 3). Similar proportions of younger and older patients agreed that they would rather maintain their thinking ability than live as long as possible (90.0% vs 80.0%; P=.56), and that they would rather live a shorter life than lose the ability to take care of themselves (63.3% vs 70.0%; P=.86). In terms of QoL versus survival, 36.7% (95% CI, 24.5%–48.9%) of patients agreed that they would rather live as long as possible, regardless of their QoL, and 45.0% (95% CI, 32.4%–57.6%) disagreed. When choosing between living as long as possible or being free from pain, 35.0% (95% CI, 22.9%–47.1%) of patients agreed they would choose living as long as possible, and 36.7% (95% CI, 24.5%–48.9%) disagreed. However, 93.3% (95% CI, 87.0%–99.7%) of patients agreed that they were willing to tolerate more doctor visits and dietary restrictions if it meant they would be less likely to develop new disease. Ninety-three percent of patients were also willing to endure adverse effects now if it meant they would have a better QoL in the future. Multinomial logistic regression did not identify any associations between patient demographics/tumor characteristics and patients’ responses (data not shown).
Attitude Scale (N=60)
When asked to choose between current QoL versus QoL 1 year or 5 years in the future as more important on the Now versus Later Tool, 48.3% (95% CI, 35.7%–61.0%) of patients considered QoL 1 year in the future more important than their current QoL, and 40.0% (95% CI, 27.6%–52.4%) of patients considered QoL 5 years in the future more important than their current QoL. Only 4 (6.7%) patients considered both QoL 1 year in the future and QoL 5 years in the future equally as important as their current QoL (Figure 1). No associations between patient demographics/tumor characteristics and patients’ choices were identified on multinomial logistic regression (data not shown).
Now versus Later tool (N=60). Relative importance of QoL compared with now: 1 year from now versus 5 years from now.
Abbreviation: QoL, quality of life.
Citation: Journal of the National Comprehensive Cancer Network 20, 12; 10.6004/jnccn.2022.7059
On the PTPQ, 90.0% of patients perceived themselves as relatively healthy (55.0% relatively healthy, 35.0% relatively healthy and terminally ill), and 86.7% preferred to hear as many details about their cancer and its treatment as possible. Similar to Health Outcomes Tool responses, 70.0% of patients indicated that their primary treatment goal was not survival (Table 4). In addition, 40.0% (24/60) of patients believed their oncologist’s primary treatment goal was “to extend their life as long as possible.” A total of 31 (51.7%) patients believed they shared the same primary treatment goal as their oncologist. Details on the discordance between patients’ primary treatment goals and patients’ perception of their oncologist’s primary treatment goal are shown in supplemental eTable 3.
Prognosis and Treatment Perceptions Questionnaire (N=60)
Discussion
To our knowledge, this is the first study designed to evaluate the treatment goals and preferences of adult patients with NETs starting a new line of systemic therapy using the Health Outcomes Tool, Attitude Scale, Now versus Later Tool, and PTPQ. We found that most patients with NETs who participated in this study valued maintaining independence and cognition over survival and that only half of patients believed they had the same primary treatment goal as their physician.
Data regarding patient preferences and patient-centered outcomes among those with NETs have been sparse. Mühlbacher and Juhnke39 asked patients with NETs to rank hypothetical therapies based on their proposed benefits (overall survival, tumor response, and stabilization of tumor growth) and adverse effects (nausea/vomiting, diarrhea, and abdominal pain). They reported that patients valued overall survival most. However, they did not present alternative endpoints, such as maintenance of independence and/or cognition. In contrast, we presented patients with a wide range of endpoints, allowing us to better determine the extent to which patients with NETs value survival relative to other outcomes. A total of 46.7% of patients indicated on the Health Outcomes Tool that maintaining their independence was a more important health outcome than living as long as possible. This was further emphasized by patient opinions on the Attitude Scale, in which 66.7% agreed that they would not want to lose their ability to take care of themselves in exchange for a longer life. Inclusion of these alternative endpoints may explain why many patients in our study did not choose survival as their most important health outcome, suggesting that patients with NETs may value QoL-related outcomes to a greater extent than survival.
The life expectancy of patients with NETs differs from that of patients with aggressive tumor types because patients with NETs are often faced with a more indolent, chronic, incurable disease. For example, the median overall survival for patients with recurrent/metastatic head and neck squamous cell carcinoma, advanced pancreatic ductal adenocarcinoma, and metastatic colon cancer is approximately 10.1 to 13.0 months, 11.1 months, and 13 to 18 months, respectively,40–42 compared with 112 months for patients with NETs.3 Moreover, the QoL and functional status of patients with aggressive tumor types tend to be poor.43–45 Compared with these aggressive tumor types, patients with NETs in our study reported relatively good baseline QoL and few symptom-related complaints. Given that the baseline QoL of patients with more aggressive tumor types may be lower than that of patients with NETs, these patients could be more willing to accept a reduced QoL during a defined treatment period to potentially improve their future QoL. Adkins et al43 reported that health-related QoL for patients with head and neck squamous cell carcinoma declined from baseline to the end of chemoradiation; however, patient-reported outcomes returned to baseline levels 6 to 12 months after the end of treatment. Similar trends of patient-reported QoL declining and improving during and after chemotherapy, respectively, were reported by Domati et al44 for patients with colon cancer. In contrast, NETs often require long-term treatment aimed at managing symptoms or slowing tumor progression.4,5 This alternative treatment approach may explain why patients with NETs value current QoL, even at the start of a new line of systemic therapy. On the Now versus Later Tool, 45.0% of patients stated that their current QoL was more important than their QoL 1 year in the future, and 53.3% stated that their current QoL was more important than their QoL 5 years in the future. This emphasis on current QoL may explain choices of other outcomes by patients with NETs as more important than survival. This phenomenon of valuing present outcomes over future outcomes has been described previously in other decision science studies.46,47
Although preferences of patients with NETs appear to strongly favor QoL compared with overall survival, this preference may not be adequately communicated with their physicians. On the PTPQ, only 51.7% of patients believed they had the same treatment goal as their physician. This disparity is concerning. Nelson et al48 reported that 20% of 276 patients with lung cancer stated that their physician communicated “not at all” or “a little bit” on topics related to their diagnosis and treatment, including practical needs and living well, suggesting that effective patient–physician communication is challenging and that difficulties in this area are not limited to patients with NETs. This disparity could possibly be alleviated by implementing shared decision-making. Wagner et al49 created a multicriteria decision analysis framework for patients with NETs and physicians to use in support of shared decision-making during treatment choice and planning. Although the model of Wagner et al49 only included 2 treatment options (somatostatin analog therapy and watchful waiting), such a framework could be helpful for patients with NETs and their physicians in deciding which treatment options to pursue.
Limitations of our study include our modest sample size (N=60) from a single institution, which may have prevented us from identifying significant associations between patient demographics/tumor characteristics and patient preferences. Although our study population included a relatively equal distribution of tumor types, including pancreatic, small bowel, and lung NETs, the patient population recruited for our study may not be representative of the national or global population of patients with NETs, limiting the generalizability of our results. Future studies containing a broader population of patients with NETs are needed to investigate the results described here. In addition, our study population included patients who were treatment-naïve and those who had received prior lines of therapy. Although these differing experiences may have influenced patients’ responses, all patients were about to start a new line of systemic therapy. This allowed us to capture responses from patients at a critical juncture in their treatment journey and provided a similar baseline perspective. Moreover, we did not find any associations between line of therapy (first-line vs second-line and beyond) and patient preferences for any health outcomes. In terms of treatment goals, the PTPQ did not specifically ask the physician what their goal of treatment was. Future studies will ask both the patient and the physician for their treatment goals.
Conclusions
Most patients with NETs who participated in this study value QoL-related factors, such as independence and cognition, more than survival as a primary outcome of their treatment. Concerningly, almost half of patients with NETs believe that they do not have the same treatment goals as their physician. Future studies of patients with NETs and their physicians are required to better understand the impact of patient preferences on treatment choice and improve communication between patients with NETs and physicians. Considering values and goals of patients with NETs when developing treatment plans will allow physicians to create a supportive environment for patients with NETs as they navigate their diagnosis and treatment journey.
Acknowledgments
Arti Hurria, MD, helped to conceptualize the study but died suddenly before the acquisition of data, preliminary analysis, and drafting of the manuscript. We dedicate this article to her legacy and mentorship. In addition, we acknowledge the patients who participated in the study and are grateful for their contributions to this work.
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