Overcoming barriers to clinical trial enrollment in patients with bone and soft tissue sarcoma: a paradigm for an increasingly heterogeneous cancer population
Abstract
Background: Clinical trials remain a cornerstone in the development of new cancer therapies. Patients diagnosed with bone and soft tissue sarcoma typically have comparatively low rates of trial participation, which may contribute to lack of progress. This cross-sectional survey study was designed to characterize patient attitudes, knowledge, perceived ability (ie, self-efficacy), receptivity, and willingness to participate in trials. As well, we explored perceptions related to tumor molecular profiling (TMP).
Methods: Patients with sarcoma who were evaluated at Northwestern Medicine (NM) between 2012 and 2017 were identified through the Enterprise Data Warehouse (NMEDW). A link to an online self-administered survey was emailed to patients. Data were analyzed using Spearman correlations and the Mann-Whitney test.
Results: Surveys were e-mailed to 750 patients, of which 20 emails bounced back and 309 were opened; 283 patients completed at least a portion of the survey and this population was used in this analysis (37.7% of total and 91.6% of opened). Of the responding patients, median age was 56 years, 59.4% were female, and 26.8% reported metastatic disease. Greater knowledge of trials correlated with increased positive attitudes toward trial participation (r=0.5; P<0.001) and positive attitudes correlated with greater trial perceived ability (r=0.4; P<0.02). Patients with metastatic disease had more positive attitudes compared with patients with non-metastatic disease (P=0.03). Trial enrollment was associated with greater knowledge (P=0.002) and positive attitudes (P=0.001). Among patients who reported knowledge of TMP (n=46), 65% credit TMP with a >50% chance of isolating a targetable result. Of patients who had TMP performed (n=18), important considerations included wanting to live as long as possible and helping future cancer patients, but not wanting to be part of research.
Conclusions: Increasing awareness, knowledge, and attitudes towards trials among patients with sarcoma may lead to increased trial enrollment and greater progress in cancer treatment. Patient-focused interventions and research-site optimization are critical to maximizing accrual rates and biomarker-driven therapeutics. Lessons from a sarcoma patient population can be used to optimize trial enrollment in an era of increasingly heterogeneous cancer populations.
In our study, both knowledge and at titudes were increased in patients with previous trial exposure. This suggests that either patients with greater knowledge and more positive attitudes are more likely to enroll in trials, or that patients with direct trial exposure are more knowledgeable and develop more positive attitudes. Our patient population was overall receptive to learning more about clinical trials (85.4%) and willing to participate (65.8%). At the same time, our study demonstrated low to medium correlations between attitudes and perceived ability to take steps towards making an informed decision to enroll in a trial (r=0.4), which may partially be explained by the absence of a tangible trial opportunity. While we did not assess specifically whether patients in our study were offered a trial, there was a substantial trial menu at NM with limited screen failures and decent trial accrual over the time frame of our study. This underscores the importance not only of patient-focused strategies to increase educational and attitudinal resources, but also a need to focus on research-site optimization that includes opening of multiple trials in various settings, systematic pre-screening of patients, and eligibility criteria that are inclusive and rational.5
The patient population with metastatic disease demonstrated more positive attitudes towards enrolling in clinical trials. This cohort accrued well to clinical trials, with 21 of 24 trials enrolling specifically patients with metastatic disease. Of the patients who responded to our survey, patients with previous trial exposure were enriched for patients with metastatic disease (53.3% metastatic among previous trial exposure versus 26.8% metastatic overall). These observations are likely reflective of the need for novel therapies in this disease setting. At the same time, approximately 25% of patients with localized soft tissue sarcoma will develop distant metastatic disease after successful treatment of their primary tumor, which increases to 40% to 50% in larger and higher-grade tumors.18 Three of 24 trials were open for patients with non-metastatic disease, of which one managed to accrue patients. Patients with non-metastatic disease had more negative attitudes towards trial enrollment. These disproportionate findings suggest a need for interventions to increase patient awareness and attitudes towards trial enrollment among this patient population and the importance of research-site optimization for trial opportunities across disease states.
Molecular profiling of tumors and biomarker identification has become a critical component of further characterizing cancer subtypes. In our study, a majority (65.2%) thought there would be a 50% or greater likelihood of finding a targetable result in their molecular profile. Molecular data on 5,749 bone and soft tissue sarcomas suggested that 9.5% of tumors demonstrate a “targetable result,” defined as a new molecular finding for which there is an FDA-approved drug for malignancies other than sarcoma (eg, BRAF V600E, Her2, etc.),19 suggesting an overestimation in our patient cohort of the likelihood of benefit of molecular profiling. These results highlight that the growing use of molecular profiling has increased the need for educational and supportive resources to help patients understand the utility of molecular profiling and aid in shared decision-making surrounding the results.
At the same time, the importance of identifying a targetable mutation in patients with sarcoma cannot be understated. As a recent example of this paradigm, tumors that harbor fusions with the neurotrophic receptor tyrosine kinase 1, 2, or 3 (NTRK1, 2, and 3) have a high response rate (~75%) to drugs that target these fusions, such as larotrectinib and entrectinib.13 Molecular profiling and identification of predictive biomarkers in small patient subsets has led to great challenges in trial design and research-site optimization. Novel designs that incorporate molecular profiling,20 such as the Lung- MAP trial21 and NCI’s Molecular Analysis for Therapy Choice (MATCH) trial,22 are emerging to identify new therapies for small patient subsets. As a rare and increasingly heterogeneous cancer, sarcoma represents a paradigm to provide insight into optimizing patient perceptions and research enterprises to maximize clinical trial enrollment.
Some limitations of our study include a homogeneous and selected patient population that was predominantly Caucasian and highly educated. Therefore, these findings should not be extrapolated to other populations with barriers to trial accrual, such as lower socioeconomic or minority populations. The low response rate and failure of some to complete the survey may have introduced some bias. Additionally, our data include self-reported outcomes, which could have affected our results. Finally, the limited number of patients who had undergone or heard of molecular profiling limited our ability to draw definitive conclusions, and should be assessed in larger patient cohorts.
While our paper addresses a unique population—the sarcoma patient—similar themes and issues pertain to all oncology patients. A recent review was published in the American Society of Clinical Oncology Educational Book23 looking at methods to overcome barriers to clinical trial enrollment. Their paper clearly illustrates mechanisms to assist with overcoming financial burdens associated with cancer clinical trials, overcoming barriers as they relate to patient and clinician difficulty in coping with the uncertainty inherent in clinical trial participation, and highlight the role of a patient navigator in clinical trial participation.
Conclusions
Interventions aimed at increasing awareness, knowledge, and attitudes towards clinical trials among sarcoma patients may lead to increased trial enrollment and greater progress in cancer treatment in this population. In addition to patient- focused interventions, thoughtful and strategic clinical trial designs that allow for the development of biomarker- driven therapeutics, while at the same time optimizing patient accrual rates, should be developed. Evaluation of barriers to clinical trial enrollment and molecular profiling of tumors among bone and soft tissue sarcoma patients at an academic center can serve as a paradigm to overcome barriers to enrollment in the era of an increasingly heterogeneous cancer population. TSJ
