The report is a product of the VA/HSR Evidence Synthesis Program.

Non-Surgical Therapies for Early-stage Non-small Cell Lung Cancer: A Systematic Review

Takeaway: This review found insufficient evidence on the comparative effectiveness and harms of surgery versus SBRT/SABR for adults with medically operable stage 1 lung cancer. Because of treatment outcome uncertainty, the increased implementation of lung cancer screening programs, and the fact that lung cancer remains one of the most common and lethal cancers globally, there is a critical need for robust evidence on comparative treatment effects for non-surgical treatment strategies for stage 1 lung cancer.

Lung cancer is the leading cause of cancer-related deaths in the United States. The majority of lung cancers are diagnosed at advanced stages, but with the advent of lung cancer screening, the number of individuals diagnosed with early-stage lung cancer continues to rise. Within VA, approximately 8,000 Veterans are diagnosed with and treated for lung cancer every year. Surgery, with or without the use of minimally invasive approaches, has been considered the standard of care for individuals with early-stage lung cancer who are deemed medically operable. Stereotactic body radiation therapy (SBRT)—or stereotactic ablative radiotherapy (SABR)—is frequently offered to individuals considered to be medically inoperable for various reasons (i.e., advanced age, comorbidities). Promising results with SBRT/SABR in medically inoperable patients have led to studies evaluating the efficacy and long-term outcomes of this therapy as an alternative to surgery in medically operable patients. These results raise questions about definitive treatment options for early-stage lung cancer.

HSR&D’s Evidence Synthesis Program (ESP) Center located in Minneapolis, MN conducted a systematic review to address questions regarding the comparative effectiveness and harms of surgery versus SBRT/SABR, as well as preparing an evidence map to describe studies evaluating ablative therapies (i.e., radiofrequency ablation, cryoablation, laser ablation) in the management of medically operable stage 1 lung cancer. ESP investigators searched relevant articles in Medline and Embase from inception to September 2022, supplemented with a review of relevant systematic review bibliographies. Investigators identified 3,850 potentially relevant articles, of which 27 advanced to a full-text review. Of those 27 articles, only 2 publications met inclusion criteria. For the evidence map, the investigators identified 3,095 potentially relevant citations, of which 131 were reviewed as full-text articles, and 18 met inclusion criteria.

Summary of Findings

Based on two randomized controlled trials (RCTs), which were both terminated early, investigators found insufficient evidence on the comparative effectiveness and harms of surgery versus SBRT/SABR for adults with medically operable stage 1 lung cancer. In addition, no RCTs were identified that examined if the benefits and harms of SABR/SBRT differed by patient, tumor, or intervention characteristics.

The evidence map highlighted the limited quantity of information on ablative therapies (e.g., radiofrequency, microwave, laser ablation, brachytherapy, and cryotherapy) for stage 1 lung cancer. The majority of identified studies were non-randomized comparative studies which grouped together ablation therapies and compared outcomes with respect to surgery or SBRT/SABR. Radiofrequency ablation was the most commonly studied ablative therapy.

Limitations

Investigators found limited studies and insufficient evidence to inform the comparative effectiveness of SBRT/SABR versus surgery for stage 1 medically operable lung cancer.

Implications

Because of treatment outcome uncertainty, the increased implementation of lung cancer screening programs—and the fact that lung cancer remains one of the most common and lethal cancers globally—there is a need for robust evidence on comparative treatment effects. Future research on patient preferences and values to inform the management of patients with medically operable stage 1 non-small cell lung cancer is imperative.

Future Research

The results of this systematic review underscore the recognition that data from RCTs, especially that of the VA Lung Cancer Surgery or Stereotactic Radiotherapy (VALOR) Cooperative Study, are critically needed to inform decisions around treatment for stage 1 lung cancer. The scarcity of RCT data is a major limitation in understanding the comparative effectiveness of treatment options, especially in the era of widespread lung cancer screening and whether willingness to undergo surgery should be a prerequisite for offering screening.

Future studies should:

• Use consistent terminology or definitions for medically operable disease using standardized protocols for enrollment to minimize selection bias or confounding by indication and provider bias for enrollment.
• Ensure adequate experience and training for minimally invasive surgery and ablative therapies.
• Ensure adequate enrollment and follow-up to have adequate sample size to detect clinically meaningful differences in overall and cancer-specific survival, tumor-free progression, adverse effects, quality of life, and long-term side effects.
• Be pragmatic in design to ensure that studies address the range of patients, tumors, and interventions under clinical consideration for individuals with newly diagnosed lung cancer.
• Recruit patient engagement groups to understand barriers and seek solutions to randomization in trials of these vastly different treatments, and examine values and preferences, acceptability, and feasibility.
• Assess potential expansion of treatment options for stage 1 lung cancer to include SABR/SBRT and/or ablative therapies (potentially as three-arm trials).
• Explore how screen-detected lesions might influence screening and treatment decisions. This includes use of less invasive therapies for small, indolent lung cancers among older, sicker adults who would otherwise not have been candidates for screening or treatment.

Sultan S, Ullman K, Ester E, et al. Non-surgical Therapies for Early-stage Non-small Cell Lung Cancer: A Systematic Review. Washington, DC: Evidence Synthesis Program, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs. VA ESP Project #09-009; 2023.

To view the full report, go to: Non-surgical Therapies for Early-stage Non-small Cell Lung Cancer: A Systematic Review (va.gov)

ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

This report is a product of VA/HSR&D's Evidence Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers –; and to disseminate these reports throughout VA.

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