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  • br The effect of systemic therapy on

    2020-08-12


    The effect of systemic therapy on all-cause mortality was analyzed in 2 ways. In the first model (model IMP-1088 1), patients assigned to the post-SRS systemic therapy group received sys-temic therapy at any time before death, including after IMP-1088 relapse or systemic relapse. In the second model (model 2), patients assigned to the post-SRS systemic therapy group received systemic therapy before brain relapse and systemic relapse, if either occurred. Model 2 better assesses the prophy-lactic value of systemic therapy because it includes only patients who received systemic therapy in the context of stable intracra-nial and extracranial disease.
    As a secondary analysis, we assessed whether the type of sys-temic therapy and the ability of a drug to cross the BBB affected the risk of intracranial relapse, systemic relapse, and death. Sys-temic therapies were subdivided into the following categories based on their pharmacologic mechanism of action: agents that damage DNA or inhibit DNA synthesis, hormone receptor an-tagonists, immunotherapies, kinase inhibitors, microtubule an-tagonists, and angiogenesis inhibitors. The ability of a particular drug to cross the intact BBB was abstracted from the literature and was categorized as a binary variable (either BBB permeable or BBB impermeable). Cox proportional hazards regression was per-formed using the same predictor variables as the initial Cox pro-portional hazards regression models. All-cause mortality was analyzed according to model 2.
    P values <0.05 were deemed significant. Analyses were per-formed using the survival and survminer packages in R (v3.4.0, 2017 [R Foundation for Statistical Computing, Auckland, New Zealand]).
    RESULTS
    Patient Characteristics and Descriptive Statistics
    Sixty-seven patients met inclusion criteria. Patient characteristics are shown in Table 1. Median patient age was 65 years (interquartile range, 53.5e69 years) and the sample included more females (60%) than males (40%). The most common cancer types were breast carcinoma (25%), adenocarcinoma subtype of nonesmall-cell lung cancer (NSCLC) (22%), melanoma (13%), and squamous cell NSCLC (9%). Most patients (81%) received systemic therapy before SRS and slightly fewer patients (63%) received systemic therapy after SRS. However, among the 63% of patients receiving systemic therapy after SRS, only 31% received systemic therapy before systemic relapse or brain relapse; the other 32% received systemic therapy to treat brain or systemic relapse after it had occurred. Table 2 lists the systemic therapy agents received by patients after SRS.
    ORIGINAL ARTICLE
    TIMOUR AL-KHINDI ET AL. EFFECT OF POST-SRS SYSTEMIC THERAPY ON PATIENT OUTCOMES
    Table 1. Patient Characteristics
    Total Sample
    (first quartile, third quartile)
    (first quartile, third quartile)
    (first quartile, third quartile)
    Time between primary diagnosis and metastasis diagnosis 2.3 (1.2, 5.1)
    (years), median (first quartile, third quartile)
    Cancer histology, number of cases (%)
    Nonesmall-cell lung cancer, adenocarcinoma 15 (22)
    Nonesmall-cell lung cancer, squamous cell 6 (9)
    Renal cell carcinoma 5 (7)
    Ovarian serous carcinoma 3 (4)
    Colon adenocarcinoma 2 (3)
    Esophageal carcinoma 2 (3)
    Squamous cell carcinoma 2 (3)
    Endometrial carcinoma 1 (1)
    Uterine malignant mixed Müllerian tumor 1 (1)
    Adenoid cystic carcinoma 1 (1)
    Hypopharyngeal carcinoma 1 (1)
    Received systemic therapy after SRS but before brain 29 (43)
    Received systemic therapy after SRS but before systemic 27 (40)
    Received systemic therapy after SRS but before systemic 21 (31)
    relapse or brain relapse, if it occurred, n (%)
    SRS, stereotactic radiosurgery.
    Effect of Post-SRS Systemic Therapy on Brain Relapse, Systemic Relapse, and Death
    Table 3 shows prognostic factors for brain relapse after SRS. After controlling for other variables, systemic therapy after SRS was associated with a reduced risk of brain relapse; patients who received systemic therapy after SRS had a 78% reduced risk of brain relapse compared with those who did not (P ¼ 0.002). Another prognostic factor for brain relapse was cancer type; patients with squamous cell NSCLC had a 94% reduced risk of brain relapse compared with those with breast cancer (hazard ratio [HR], 0.06; P ¼ 0.02), whereas patients with renal cell carcinoma had a 7.7-fold higher risk of brain relapse compared with those with breast cancer (HR, 7.71; P ¼ 0.04). Time between primary tumor diagnosis and brain metastasis diagnosis (a proxy of cancer aggressiveness) was also prognostic for post-SRS brain relapse. The longer the time between primary tumor diagnosis and brain metastasis diagnosis, the lower the risk of post-SRS brain relapse (for every 1 month increase in time between primary tumor diagnosis and brain metastasis diagnosis, the risk of brain relapse decreased by 0.03%; HR, 0.9997; P ¼ 0.01).