Prognostic factors of brain metastases from colorectal cancer

Brain metastases, the most common intracranial tumors in adults, accounts for more than half of all brain tumors [1, 2]. The incidence of brain metastases is on the rise, likely due to improved detection of small metastases by magnetic resonance imaging and improved management of extracerebral disease by progress of systemic therapy. The incidence of brain metastases by origin was reported as follows [1, 2]; lung cancer – 16 to 20%, melanoma – 7%, renal cell cancer – 7 to 10%, breast cancer – 5%, and colorectal cancer (CRC) – 1 to 2%.

Regarding prognostic factors of brain metastases, the Radiation Therapy Oncology Group (RTOG) proposed and validated recursive partitioning analysis (RPA) using Karnofsky performance status (KPS) score, which reflects a patient’s functional status [3, 4]. RPA consists of the following three classes: Class 1: patients with a KPS score ≥ 70 (score of 70: cares for self) [5] and age < 65 years with controlled primary tumor and no extracranial metastases; Class 3: KPS score < 70; and Class 2: all others [3]. KPS score, age, adequate control of primary tumor, and presence of extracranial metastases are currently considered reliable prognostic factors of brain metastases from non-specific primary cancer [3, 4, 6‐9]. With respect to the establishment of criteria by origin, the diagnosis-specific graded prognostic assessment (DS-GPA), which adds the number of brain metastases to the four prognostic factors reported by RPA as covariates for multivariate analysis, was proposed and validated for non-small cell lung cancer, breast cancer, renal cell carcinoma, melanoma, and gastrointestinal cancer [10, 11]. In the DS-GPA model, KPS was the only significant prognostic factor for gastrointestinal cancer, which includes CRC, gastric cancer, and esophageal cancer [10, 12, 13].

Since survival following the treatment of brain metastases is highly variable and partly dependent on the clinical course of the primary tumor, investigating prognostic factors of brain metastases from CRC is important. While a number of reports have examined prognostic factors of brain metastases from CRC [14‐18], these studies did not adopt KPS as a covariate, which as mentioned above is a significant prognostic factor in the DS-GPA model. To this end, the present study aimed to investigate prognostic factors of brain metastases from CRC, including KPS as an essential covariate, in order to provide insight that could help in the development of appropriate treatment strategies for brain metastases.

In this study, we demonstrated that KPS, the number of brain lesions, and history of chemotherapy are independent prognostic factors for OS in patients with brain metastases from CRC. Our finding that KPS is an independent prognostic factor is consistent with what was suggested by DS-GPA for patients with brain metastases from gastrointestinal cancers (i.e., CRC, gastric cancer, esophageal cancer), non-small cell lung cancer, breast cancer, renal cell cancer, and malignant melanoma [10, 11]. Similarly, our finding that the number of brain metastases is a prognostic factor is consistent with the results of another study of brain metastases from gastrointestinal cancers [23]. History of systemic chemotherapy before brain metastases was found to be the strongest prognostic factor (HR: 2.39; p = 0.006), and patients with this history had poor survival. Although the presence of extracranial metastases and control of primary tumor were not prognostic factors, the cause of death was systemic progression of primary CRC rather than neurologic death for the majority of patients (75% versus 18%) in this study. Taken together, these results suggest the possibility that patients who have more chemotherapy regimens available to try have opportunities to undergo various regimens against systemic progression and thus can achieve a better prognosis. This is consistent with two studies reporting that patients who underwent less chemotherapy prior to the development of brain metastases from CRC survived longer [24, 25].

WBRT, the standard treatment for brain metastases, is associated with late adverse events, such as leukoencephalopathy, hydrocephalus, and cerebral atrophy, which can lead to cognitive dysfunction in 10 to 20% of mpatients who undergo the procedure [26]. Since many patients now live longer after the diagnosis and treatment of brain metastases, there have been increasing concerns regarding treatment-related toxicities associated with WBRT. In the last few decades, SRT, less neurotoxic than and not as invasive as WBRT, is gaining wide acceptance in clinical settings [27]. In a recent phase III randomized controlled trial (JCOG0504) that compared the effects of salvage stereotactic radiosurgery versus surgery with WBRT in patients with 1–4 brain metastases, the median OS was 15.6 months in both the WBRT arm and salvage stereotactic radiosurgery arm; 16% of patients in the WBRT arm experienced grade 2 to 4 cognitive dysfunction, whereas the rate was only 8% in the salvage stereotactic radiosurgery arm (p = 0.048) [28]. The JCOG0504 study concluded that ‘salvage stereotactic radiosurgery is noninferior to WBRT and can be established as a standard therapy for patients with ≤4 brain metastases’ [28]. In the present study, treatments performed for brain metastases significantly differed between the first half (1997–2005) and second half (2006–2015) of the study period (Table 3). Notably, WBRT alone was rarely performed in the second half (3%). In contrast, SRT alone was performed in 41% of patients in the second half, but in only 11% of patients in the first half.

In the present study, 1.2% of all Stage IV patients had synchronous brain metastases, which corresponds to 0.20% (14 of 7047 patients) of the entire patient cohort at the time of CRC diagnosis. These results are similar to those of a recent large population-based study [29], in which roughly 1.0% of all patients with CRC were found to have brain metastases, as well as those reported from the Metropolitan Detroit Cancer Surveillance System [1] and a Dutch series [2]. Thus, our study population is considered representative of the global CRC patient population.

This study has potential limitations. First, biases may exist given the retrospective design. Second, the sample size was relatively small. However, to our knowledge, the number of patients with brain metastases from CRC with sufficient background records, including KPS, was one of the largest reported to date. Third, the study period spanned 1997 to 2015. During this long period, treatment strategies as well as the detectability of brain metastases have dramatically changed. Thus, these data will be difficult to compare with other studies focused on novel approaches. Despite these limitations, our findings warrant further studies in a larger patient series of CRC with brain metastases.

In addition to KPS, the number of brain lesions and history of chemotherapy were found to be independent prognostic factors for OS in patients with brain metastases from CRC. An awareness of these factors may help gastrointestinal surgeons make appropriate choices in the treatment of these patients.