Stereotactic radiosurgery versus whole brain radiotherapy in patients with intracranial metastatic disease and small-cell lung cancer: a systematic review and meta-analysis

BACKGROUND
Patients with small-cell lung cancer (SCLC) are at high risk for intracranial metastatic disease (IMD). Although stereotactic radiosurgery (SRS) has supplanted whole brain radiotherapy (WBRT) as first-line treatment for IMD in most solid cancers, WBRT remains first-line treatment for IMD in patients with SCLC. We aimed to evaluate the efficacy of SRS in comparison with WBRT and assess treatment outcomes following SRS.

METHODS
In this systematic review and meta-analysis, we searched MEDLINE, Embase, CENTRAL, and grey literature sources for controlled trials and cohort studies published in English reporting on SRS for IMD treatment in patients with SCLC from inception to March 23, 2022. Studies were excluded that did not report on SRS for IMD secondary to SCLC. Summary data were extracted. The primary outcome was overall survival, presented as pooled hazard ratios (HR) through random-effects meta-analysis for studies comparing SRS with WBRT with or without SRS boost, and as medians for single-arm SRS studies. This study is registered with the Open Science Framework, DOI 10.17605/OSF.IO/8M4HC, and PROSPERO, CRD42021258197.

FINDINGS
Of 3823 identified records, 31 were eligible for inclusion; seven were included in the meta-analysis. Overall survival following SRS was longer than following WBRT with or without SRS boost (HR 0·85; 95% CI 0·75–0·97; n=7 studies; n=18 130 patients), or WBRT alone (0·77; 0·72–0·83; n=7 studies; n=16 961 patients), but not WBRT plus SRS boost (1·17, 0·78–1·75; n=4 studies; n=1167 patients). Using single-arm studies, pooled median overall survival from SRS was 8·99 months (95% CI 7·86–10·16; n=14 studies; n=1682 patients). Between-study heterogeneity was considerable when pooled among all comparative studies (I2=71·9%).

INTERPRETATION
These results suggest survival outcomes are equitable following treatment with SRS compared with WBRT in patients with SCLC and IMD. Future prospective studies should focus on tumour burden and differences in local and distant intracranial progression between WBRT-treated and SRS-treated patients with SCLC.

Karolina Gaebe, BMath, Alyssa Y Li, BA, Amy Park, BSc, Ambica Parmar, MD, Benjamin H Lok, MD, Prof Arjun Sahgal, MD, et al

© 2022 Elsevier Ltd. All rights reserved.

Lung cancer

Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND
21

METHODS
The CAPSTONE-1 study was a randomised, double-blind, placebo-controlled, phase 3 trial, done in 47 tertiary hospitals in China. Key inclusion criteria were patients aged 18–75 years, with previously untreated histologically or cytologically confirmed ES-SCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. Eligible patients were randomly assigned (1:1) to receive four to six cycles of carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m2 of body-surface area, on days 1–3 of each cycle) with either adebrelimab (20 mg/kg, day 1 of each cycle) or matching placebo, followed by maintenance therapy with adebrelimab or placebo. All treatments were given intravenously in 21-day cycles. Randomisation was done using a centralised interactive web response system with a block size of four, stratified by liver metastases, brain metastases, and lactate dehydrogenase concentration. The primary endpoint was overall survival in patients who received at least one dose of study medication. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov, NCT03711305.

FINDINGS
Between Dec 26, 2018, and Sept 4, 2020, 462 eligible patients were enrolled and randomly assigned: 230 (50%) patients received adebrelimab plus chemotherapy (adebrelimab group) and 232 (50%) patients received placebo plus chemotherapy (placebo group). At data cutoff (Oct 8, 2021), median follow-up was 13·5 months (IQR 8·9–20·1). Median overall survival was significantly improved in the adebrelimab group (median 15·3 months [95% CI 13·2–17·5]) compared with the placebo group (12·8 months [11·3–13·7]; hazard ratio 0·72 [95% CI 0·58–0·90]; one-sided p=0·0017). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (174 [76%] patients in the adebrelimab group and 175 [75%] patients in the placebo group), decreased white blood cell count (106 [46%] and 88 [38%]), decreased platelet count (88 [38%] and 78 [34%]), and anaemia (64 [28%] and 66 [28%]). Treatment-related serious adverse events occurred in 89 (39%) patients in the adebrelimab group and 66 (28%) patients in the placebo group. Four treatment-related deaths were reported: two each in the adebrelimab group (respiratory failure and interstitial lung disease and pneumonia) and placebo group (multiple organ dysfunction and unknown cause of death).

INTERPRETATION
Adding adebrelimab to chemotherapy significantly improved overall survival with an acceptable safety profile in patients with ES-SCLC, supporting this combination as a new first-line treatment option for this population.

FUNDING
Jiangsu Hengrui Pharmaceuticals.

Prof Jie Wang, MD, Prof Caicun Zhou, MD, Prof Wenxiu Yao, PhD, Prof Qiming Wang, MD, Xuhong Min, BS, Prof Gongyan Chen, MD, et al.

© 2022 Elsevier Ltd. All rights reserved.

Lung cancer

Expanded Lung and Colorectal Cancer Screening — Ensuring Equity and Safety under New Guidelines

In 2021, the U.S. Preventive Services Task Force (USPSTF) recommended major expansions of the populations that should undergo routine screening for lung or colorectal cancer. Both recommendations are evidence-based and, if implemented effectively, will most likely save lives. The changes were made with an eye toward reducing inequities in rates of early cancer detection among women and people who identify as Black, Indigenous, or Latinx. The guidelines, however, were released without adequate attention to how they would be implemented. Efforts to deploy complex, highly personalized screening methods using the patchwork approach that is typical of the U.S. health system could backfire, unless health care organizations, payers, and policymakers invest in preventive care infrastructure.

We believe regulatory and policy solutions are necessary to prevent unintended consequences associated with these important expansions in cancer-screening eligibility. To combat systemic racism and promote safety in ambulatory care, health care systems could collect and report data on disparities in preventive care, and they could design and deploy safety nets to ensure timely follow-up after abnormal screening results. In addition, we need policies that explicitly support equity and safety in preventive care.

When layered atop an already inequitable care delivery system, a substantial increase in the volume of preventive screening could exacerbate inequities in access based on race and other factors and lead to missed or delayed cancer diagnoses because of inadequate follow-up. Twenty million people between 45 and 49 years of age are newly eligible for routine colorectal cancer screening under the guidelines. Another 6.4 million people are newly eligible for lung cancer screening. The recommended age for starting lung cancer screening in current or former smokers dropped from 55 to 50 years, and the recommended number of pack-years of smoking history before screening is initiated dropped from 30 to 20 — which nearly doubles the population of eligible adults.1

Even before these changes, the preventive care system wasn’t functioning well. Under the previous USPSTF screening guidelines, only 5% of eligible people received lung cancer screening, and 69% of adults were up to date for colorectal cancer screening. Eligible populations now include younger people, who have historically had lower preventive-screening rates, are more racially and ethnically diverse, and are more likely to be underinsured than older people. Inequities in screening rates, cancer incidence, and mortality have persisted for decades, in part because health care systems haven’t invested in preventing systemic racism in the delivery of routine preventive care and don’t have functional systems to consistently follow up after test results indicating moderate or high cancer risk.2 Purposeful action will be required to overcome these challenges to meet the goals of the expanded USPSTF guidelines.

We believe the first step is for health care systems to create equity dashboards that report data on disparities in screening rates by race and ethnic group, sexual orientation and gender identity, and language. Because we can’t improve what we don’t measure, equity dashboards tracking key process and outcome measures should become part of the standard performance-management tools deployed throughout the U.S. health system. Our perspective could then shift from caring for only the individual patients who come into our offices to having a more complete understanding of the health of our populations, so that we can begin to systematically address the barriers our patients experience and promote the facilitators our patients need. Such an approach is critical to delivering on the potential of the new guidelines, and it will be required to begin addressing systemic racism and other inequities in our health care systems. Of course, reliable equity dashboards will not be possible unless health systems consistently ask patients to share key demographic data. This will require proactive education and outreach in close partnership with the community, as demonstrated in the “We Ask Because We Care” campaigns deployed by numerous U.S. health systems over the past decade.

Plans to address inequities in preventive care could be mandated by the Joint Commission, the National Committee for Quality Assurance, and other credentialing bodies. Health care systems will then need to focus on solutions for advancing equity, such as employing preventive care navigators, offering after-hours screening and diagnostic services to enhance access, supporting community-based screening sites, and broadly deploying programs offering home-based screening methods, such as fecal immunochemical testing or fecal DNA testing for colorectal cancer. By setting explicit goals regarding equitable access to preventive care and tracking improvement, we can avoid exacerbating health disparities and begin leveraging the USPSTF guidelines to correct long-standing inequities.

As health care systems reap the financial rewards of conducting the various diagnostic evaluations and surveillance tests that frequently follow screening, they could also be mandated to invest in a comprehensive cancer-screening safety-net program. Such a program could include registries and workflows to ensure that follow-up of abnormal test results is completed in a timely and highly reliable manner for all patients. Very few programs for colorectal cancer screening in the United States have a high-reliability system to track all patients who don’t follow up after an abnormal screening result. Although accredited facilities for lung cancer screening that bill Medicare are required to submit data to the Centers for Medicare and Medicaid Services using a registry, there’s no requirement that the registry then be employed to close the loop and ensure that follow-up occurs. An ideal cancer-screening safety-net program would track all patients for various preventive services, regardless of insurance status.

The goal of implementing equitable and safe cancer screening throughout the population will be difficult to achieve without payment and regulatory reform. Several types of reform would be beneficial. First, payers could recognize the role of health navigators as crucial members of the care team. Once navigators are funded, either by means of a fee-schedule adjustment or as part of a primary care subcapitation model, they could engage with the most marginalized patients in their communities to address social barriers to care, facilitate shared decision making, and order and schedule indicated tests. Navigators would also manage cancer-screening safety-net registries and perform patient outreach.

Second, the United States lacks the type of well-organized national screening program that has been adopted in many European countries.3 To address this gap, the federal government and state governments could enter into collaborative agreements with health care organizations to establish interoperable preventive care and safety-net registries that would allow the preventive-screening records of patients who move from one health care system or geographic region to another to be readily accessible to any clinician they see. Third, mandating that employers provide paid leave for preventive care is key to ensuring uptake among the younger populations that are included in the expanded USPSTF guidelines.4

Fourth, Congress could pass legislation that compels both commercial and government payers to immediately cover services that receive grade A or B recommendations from the USPSTF. The current 1-year lag before commercial payers must begin reimbursing providers for recommended services delays screening uptake and could therefore delay the diagnosis of new cancers. Finally, Medicaid expansion under the Affordable Care Act has driven substantial improvement in the provision of preventive care. We believe all efforts should be made to induce the 12 states that haven’t yet expanded Medicaid to do so.5

The expansion of eligibility for lung and colorectal cancer screening outlined by the USPSTF represents an opportunity for the United States to promote health equity, create safety-net registries to ensure adequate follow-up after screening, and implement regulatory and payment reform that facilitates rapid adoption of these and other preventive care guidelines. Given that we are building on a shaky foundation, all policy and regulatory levers should be pulled to generate incentives for the U.S. health system to invest in a more equitable and safer approach to preventive care.

Daniel M. Horn, M.D., and Jennifer S. Haas, M.D.

This article was published on January 8, 2022, at NEJM.org.

Lung cancer