Hematologic variables associated with brain failure in patients with small-cell lung cancer

Abstract

Background and purpose

We sought factors associated with the development of brain metastases after treatment of small cell lung cancer (SCLC) in patients without brain involvement at diagnosis.

Methods

We analyzed 293 patients with SCLC without brain metastases who received chemotherapy, thoracic radiation therapy (TRT), or both in 2001–2015. Pretreatment hematologic markers (platelet count, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lactate dehydrogenase) and other clinical characteristics were evaluated for correlation with brain metastases–free survival (BMFS). Cutoffs were established with receiver operating characteristics curves. Factors significant in univariate analysis were used to build a multivariate Cox model for BMFS.

Results

Median follow-up time was 14.3 months. Brain metastases developed in 115 patients (39%)—32% of those with low pretreatment platelet counts (PPC) (≤270 × 10⁹/L) and 46% of those with high PPC (>270 × 10⁹/L). Median BMFS time for all patients was 27.9 months. Two-year BMFS rates were worse for patients with high PPC (14.6% vs. 22.1% low, P = 0.009). High PPC was independently associated with inferior BMFS (P = 0.038), as were receipt of TRT <45 Gy and no prophylactic cranial irradiation (both P < 0.001).

Conclusions

High PPC was associated with increased rates of brain metastasis in patients with SCLC with no evidence of brain disease at diagnosis.

Introduction

Small-cell lung cancer (SCLC) is highly chemo- and radiosensitive given its propensity for rapid proliferation. Chemotherapy was the mainstay of treatment until the 1990s, when the advantage of adding thoracic radiation therapy (TRT) for patients with limited-stage (LS) SCLC was confirmed in two meta-analyses, which showed an absolute survival benefit of 5.4% at 3 years (from 8.9% with chemotherapy alone to 14.3% with chemotherapy and TRT) [1], [2]. The benefit of adding TRT for both disease control and survival has also been confirmed for patients with extensive-stage (ES) SCLC [3].

The therapeutic improvements associated with the inclusion of radiotherapy and the technologic advances in radiotherapy planning and delivery techniques over time undoubtedly contributed to the improvement in 2-year overall survival (OS) rates for patients with LS SCLC from 47% in the Intergroup 0096 study, published in 1999 [4], to 56% in the CONVERT trial, published in 2017 [5]. However, expectations of longer survival should prompt patients and clinicians to prepare for the need to manage disease recurrence, especially in the brain. The brain is considered a sanctuary site for relapse because of the blood–brain barrier, which blocks most chemotherapeutic agents from entry. Autopsy studies have shown that 50% to 65% of patients with SCLC have brain metastases at the time of death [6], [7]. Patients who live longer are at higher risk of developing brain metastasis, to a cumulative probability of 80% among patients who live for 2 or more years after treatment [7], [8]. The frequency of disease recurrence in the brain led to the advent of prophylactic cranial irradiation (PCI) for patients with SCLC in 1970s. After a meta-analysis revealed that PCI was associated with improvements in both survival and disease control in the brain [9], PCI is generally offered to patients with LS SCLC who respond to initial definitive treatment. Although PCI has not consistently been found to confer a survival benefit, most studies, including trials conducted in Europe and Japan, have shown that PCI improves control of brain disease among patients with ES SCLC [10], [11]. Some patients with SCLC who do not receive PCI die without brain metastases, but others experience relapse in the brain even after withstanding the physical and financial costs of PCI. Factors associated with the risk of a particular patient’s developing brain metastases would be valuable for improving the therapeutic management of SCLC.

Inflammatory and immune responses are integral to tumor development and metastasis [12]. Platelets are known to participate in both homeostasis and inflammation [13], and several studies have linked increased platelet counts with poor prognosis in lung cancer, among others [14], [15], [16], [17], [18]. Other inflammation markers that have been linked with prognosis in lung and other forms of cancer include the platelet-to-lymphocyte ratio (PLR) and the neutrophil-to-lymphocyte ratio (NLR) [19], [20], [21], [22], [23], [24], [25]. Total lymphocyte count (TLC) is considered an indicator of host immune status, and lymphopenia (i.e., reduced TLC) has also been associated with worse prognosis in lung and other types of cancer [26], [27], [28], [29], [30], [31], [32], [33]. Levels of platelets, lymphocytes, and neutrophils are easily measured via routine laboratory testing and can be measured repeatedly, at initial diagnosis as well as during follow-up. However, whether these markers reflect the risk of patients developing brain metastases after the initial treatment of SCLC is unknown.

We sought here to determine whether hematologic markers of inflammation and immune function (platelet count, neutrophil count, TLC, NLR, and PLR), evaluated before definitive treatment and before PCI, could be potential markers of brain metastases in patients with SCLC and no evidence of brain disease at diagnosis.