Placing a Cancer Diagnosis in Clinical Context: Applying Functional Trajectories to Advanced NSCLC.

Advances in molecular diagnostics, treatment, and supportive care have brought much-needed hope to the landscape of care for advanced NSCLC. A disease that once had few therapeutic options for late-stage diagnoses now has better-tolerated chemotherapy regimens, molecularly targeted agents, and immune checkpoint inhibitor therapy, along with evidence-based supportive care interventions to manage side effects and improve quality of life. In fact, a recent report from 2018 data noted that 67% of oncologists felt that they had adequate treatment options for advanced lung cancer, up from 36% in 2008. Despite this progress, clinical care for advanced NSCLC remains accompanied by challenges in maintaining functional status, minimizing disability, and maximizing patient resilience during and after active treatment. With the advent of molecularly targeted therapies and immune checkpoint inhibitors, rendering treatment recommendations based on functional status is arguably less clear than ever. Compared with conventional chemotherapy, these treatments may be both less toxic and more effective. As a result, patients who may not have been candidates for systemic therapy in the past may both tolerate and benefit from these newer options.

It is this prognostic challenge that Presley et al. address in their paper, “Functional trajectories and resilience among adults with advanced lung cancer.” Here the authors detail findings from longitudinal data of the prospective cohort study Beating Lung Cancer in Ohio. Functional status (measured by the EQ-5D-5L patient-reported outcomes survey) of 207 patients with advanced NSCLC was assessed monthly for up to 8 months after diagnosis. From these data, the researchers identified three distinct trajectories: none/mild disability (38%), moderate disability (48%), and severe disability (14%). Most demographic characteristics, baseline presence of brain metastases, and treatment types were not statistically different across trajectory groups, but baseline Eastern Cooperative Oncology Group performance status (ECOG PS) greater than 1, along with certain worse physical (e.g., dyspnea, pain) and psychological (e.g., depressive, anxious) symptoms, were associated with the severe disability trajectory. The majority of participants (74%) demonstrated functional resilience—defined as maintenance or improvement of the baseline EQ-5D-5L score—after 1 month, but that proportion declined to 46% at month 8, by which point one-third of the sample had died.

The Presley et al. study has the potential to improve advanced NSCLC patient care by providing another tool for oncology clinicians and patients to use in shared decision-making about treatment and supportive care needs. As the authors note, a clinician may be able to consider and discuss a more active treatment regimen for an individual who is older but otherwise able to maintain self-care and reports few physical and psychological symptoms. Indeed, this recommendation represents a tenet of oncology practice, namely that physiological fitness rather than chronological age be used to determine treatment candidacy. In addition, the study expands our understanding of prognostic factors beyond the use of performance status assessments, which have been critiqued as overly subjective, inconsistently applied, and inadequately predictive of treatment outcomes. Overall, the findings of this study may support a more inclusive approach to advanced NSCLC treatment, consistent with recent calls to expand guidelines for clinical trial eligibility and other aspects of lung cancer care.

Despite general enthusiasm about more precise data informing care for advanced NSCLC, we urge caution in using prognostic models as rationale to withhold treatment altogether. We appreciate concerns about needlessly continuing anticancer therapies toward the end of life. Nevertheless, we must remember that the toxicities of medical cancer therapies rarely manifest as an acute, life-threatening event. Unlike the risks of surgery—which are largely encapsulated in same-day anesthesia considerations and near-term postoperative events such as infection and thrombosis—the adverse effects of medical cancer therapy reflect the longitudinal nature of these treatments. Toxicities emerge and fluctuate over months, often providing clinicians numerous opportunities to modify dose, schedule, or supportive care regimens. Contemporary supportive care options, such as multiagent antiemetic regimens or myeloid growth factors, arguably represent one of the greatest advances in medical oncology, shifting the determination of treatment candidacy as much as new therapies have. Given these considerations, a potential role for functional trajectory assessment might be to individualize efficacy and toxicity monitoring for patients rather than making a simple go/no-go decision about offering treatment. Furthermore, disproportionately low rates of treatment initiation for advanced NSCLC continue to be concerning. For example, analyses from the National Cancer Database revealed that cancer-directed treatment rates for advanced NSCLC actually decreased between 1998 and 2012 and were significantly lower than other stage-matched solid tumors. These statistics highlight the need for increased scrutiny of and attention to potentially exacerbating factors of unconscious bias, stigma, nihilism, and system-level inequities. Interpreting and applying findings based on functional trajectory assessments requires consideration of this complex context.

Importantly, the results from this study emphasize the need to address modifiable risk factors, including psychological symptoms such as depression and anxiety, as an integrated component of advanced NSCLC care. The authors astutely note that the temporal relationship between psychological symptoms and functional status is not clear; that is, which precedes the other and how they are inter-related remain uncertain and likely vary among patients. Regardless, the robust correlations add to a growing understanding that evidence-based psychological treatments, in conjunction with other behavioral interventions such as smoking cessation services, physical therapy, respiratory therapy, nutritional services, pain management, and supervised exercise interventions, are crucial elements of integrated supportive and palliative care programs for lung cancer. In fact, a number of supportive care interventions are of low cost, high value, and have demonstrated impact on therapeutic outcomes. Although there are widespread professional guidelines focused on supportive and palliative care interventions in oncology, actual implementation and referral patterns for supportive care interventions in clinical trials and cancer centers are highly variable. In large-scale surveys, individuals with lung cancer continue to report disproportionately high levels of unmet supportive care and psychosocial needs, indicating suboptimal identification and treatment in many clinical settings. Serious and sustained investment in personnel and delivery of evidence-based psychological treatments and other behavioral interventions should be an important priority of value-based care standards.

Overall, authors' success in establishing this advanced NSCLC cohort (with significant rural [35%] representation), gathering monthly patient-reported outcomes, and identifying functional status trajectories represents an important step in identifying personalized care needs. Indeed, if telehealth visits remain a regular feature of oncology clinical care in the future, assessing functional status trajectory through straightforward questionnaires might provide some of the information lost when physical examinations are not performed. Further investigations should include patients with advanced NSCLC treated in community-based oncology centers, settings in which many patients with cancer receive care and potentially face treatment choices/outcomes that vary from academic centers. It is also crucial to focus on samples with higher proportions of racial/ethnic minorities (the current sample only included 7% Black/African American and 1% Hispanic patients) given the disparities faced especially among Black individuals diagnosed with advanced NSCLC. Finally, real-world consideration should be given to patient and clinician burden of completing and interpreting frequent PRO assessments. Although the data are valuable and contemporary interpretative tools can streamline these approaches, alert fatigue and the electronic health record more generally have emerged as key causes of clinician burnout. Moving forward, it will be critical to consider not only the validity and generalizability of functional status trajectory tools, but also the clinical logistics and perceived burden of use.

CRediT Authorship Contribution Statement

Heidi Hamann: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Roles/Writing—original draft; Writing—review and editing.

David Gerber: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Roles/Writing—original draft; Writing—review and editing.