In a study reported in a research letter in JAMA Oncology, Corbett et al found that the majority of phase III trials investigating systemic therapy in patients with advanced lung cancer, breast cancer, and melanoma over the past 20 years have excluded or restricted enrollment of those with brain metastases. Additionally, a small minority of these studies reported central nervous system–specific outcomes.
As stated by the investigators, “Brain metastases are among the most common neurologic complications of cancer. In fact, up to 40% of patients with a metastatic malignant tumor will develop brain metastases during their lifetime. Historically, patients with brain metastases have been excluded from clinical trials due to concerns about poor prognosis and increased risk of neurologic toxic effects. This has resulted in a scarcity of evidence for the efficacy of systemic therapies in the central nervous system.”
The study involved a search of the ClinicalTrials.gov database in January 2020 to identify eligible studies. A total of 223 studies were included in the analysis, including 117 in lung cancer, 81 in breast cancer, and 25 in melanoma.
Among the 223 trials, 52 (23%) excluded all patients with preexisting brain metastases and 124 (56%) permitted enrollment of patients with brain metastases under particular conditions; among the 124 trials, the most common conditions for enrollment were stable/nonprogressing brain metastases (83 trials, 67%), prior treatment for brain metastases (62 trials, 50%), and lack of neurologic symptoms (49 trials, 40%).
Complete exclusion of patients with brain metastases decreased over 5-year increments between 2000 and 2019 (overall P = .006); for example, patients with brain metastases were completely excluded in 8 (50%) of 16 studies from 2000 to 2004 compared with 3 (11%) of 27 studies in 2015 to 2019.
Disease site was also significantly associated with complete exclusion of patients with brain metastases (overall P < .001), with complete exclusion in 15 (13%) of the lung cancer trials, 5 (20%) of the melanoma trials, and 32 (40%) of the breast cancer trials.
Factors significantly associated with conditional exclusion of patients with brain metastases included years of trials (overall P < .001), with rates of conditional exclusion ranging from 31% in 2000 to 2004 to 81% in 2015 to 2019; and disease site (overall P <.001), with rates of 35% for breast cancer trials, 67% for lung cancer trials, and 72% for melanoma trials.
There was no association between inclusion of patients with brain metastases in trials and reporting of central nervous system–specific endpoints.
Of 223 trials, central nervous system–specific outcomes were assessed in 13 studies (6%). In the 13 studies, the most commonly reported central nervous system–specific outcomes were presence vs absence of central nervous system progression (7 studies, 54%), time to central nervous system progression (7 studies, 54%), central nervous system–specific response (4 studies, 31%), and duration of central nervous system response (3 studies, 23%). Studies including central nervous system–specific outcomes showed marked heterogeneity in selection and definition of endpoints. Only two studies reported on the effect of systemic therapy on neurologic quality of life and only one study evaluated neurocognitive outcomes.
The investigators concluded, “The majority of phase III clinical trials for patients with advanced breast cancer, lung cancer, and melanoma excluded or restricted enrollment of patients with brain metastases. Furthermore, collection of central nervous system–specific outcomes is rarely specified in trial protocols, highlighting challenges in assessing central nervous system response to systemic therapies. It is important to unify the definitions of central nervous system–specific endpoints across trials, particularly in the modern era of stereotactic radiosurgery and immunotherapy. [S]ince central nervous system–penetrating systemic therapies may impact neurologic-specific quality of life and neurocognition, efforts must be made to measure these patient-reported outcomes using validated tools.”
Katarzyna J. Jerzak, MD, MSc, of the Department of Medicine, University of Toronto, is the corresponding author for the JAMA Oncology article.
Disclosure: For full disclosures of the study authors, visit jamanetwork.com.