In this retrospective study of 298 patients with brain metastases undergoing surgical excision, there was no significant difference in overall survival between patients with CKP and CUP (9 versus 6 months p = 0.113). This study has not identified the reasons for this, but our findings suggest that (a) metastatic disease and (b) cerebral disease and not necessarily the type of cancer, are the major factors that determine a patient’s length of survival.
The median survival for patients with untreated cerebral metastases is 1–2 months, which may be extended to 6 months with surgery, radiotherapy, and chemotherapy [6]. Riihimaki et al. (2013) analyzed a large series comparing 6,745 patients with metastatic CKP at diagnosis and 2,881 patients with metastatic CUP [29]. They observed that CUP patients had poorer survival than patients with CKP, a finding that was not replicated in our cohort. D’Ambrosio and Agazzi found that there was no significant difference in survival between CUP and CKP patients, suggesting that delayed treatment whilst attempting to locate a primary cancer is inappropriate [4]. Whether the primary is eventually found also did not have a statistically significant impact upon survival outcome, an observation replicated in our study [10]. Positive prognostic indicators examined included age < 65 years and treatment modality used [4]. Polyzoidis et al. reached a similar conclusion that identification of the primary tumor does not affect prognosis and survival. Instead, age, Karnofsky Performance Score (KPS), number of metastases, treatment modality, and extent of extracranial pathology [26] were observed to be more favorable prognostic indicators. Unsurprisingly, provision of any postoperative adjuvant therapy has been shown to improve survival outcomes in this series, which is consistent with other studies in the literature [10].
Median survival among CUP patients with brain metastases has been reported to lie anywhere between 4.8–27 months [1, 11, 15, 34]. CUP patients were found to have longer median overall survival than the group containing all known primary brain metastases patients in the series by Bartelt et al. (4.8 and 3.4 months, respectively; p = 0.05) [1]. This wide range of outcomes exemplifies the need to obtain further prospective epidemiological data and analysis including stratification of tumor types and treatment modalities as the management of most primary cancers has become varied and complex. Recently Fureder et al. reported no statistical difference in survival between CUP and CKP patients within 3 months of presentation [16] adding further weight to the hypothesis that there is no difference in survival outcomes between CKP and CUP groups undergoing cranial metastasis excision [1, 7, 15, 23, 26]. Interestingly, one study points out that median survival was significantly higher for treated as opposed to untreated CUP patients (3.6 and 1.1 months, respectively; p = 0.0001) [10]. This supports the aforementioned conclusions that surgery should not necessarily be deferred for CUP patients if it is deemed potentially efficacious in the initial management phase.
Previous reports have indicated that surgical intervention contributes towards improved survival in CKP brain metastases patients [3, 13, 31, 32]. These demonstrated that neurosurgery coupled with whole brain radiotherapy (WBRT) leads to favorable survival outcomes when compared to the use of WBRT alone (median survival 9–10 months and 3–6 months, respectively) [14] with a lower recurrence rate in those patients undergoing neurosurgical intervention compared to those who did not (20% and 52%, respectively) [18]. Our study has demonstrated that there was no significant difference in survival outcomes between CKP and CUP patient groups following surgical excision. Further research of larger CUP patient populations, via strategies such as national and international databases, is required to elucidate the factors contributing to this finding. Furthermore, we also observed that adjuvant therapy improved survival for patients with CKP and CUP.
Recently ECOG status (0-1) and absence of extra-cranial metastases were shown to be significantly associated with better survival outcomes after irradiation for CUP brain metastases [28], corroborating results from other studies examining brain metastases from various types of primary tumors and treatment modalities [9, 25, 27]. Most of these studies focus on whole brain radiotherapy (WBRT) with or without neurosurgical resection. Our results concur with those pertaining to the influence of ECOG status on survival for the CUP group. That is, lower ECOG status is statistically associated with improved survival outcomes. Similarly, age consistently inversely correlates with survival parameters [5], (Fig. 4).
The study is limited in a number of respects. First, precise data pertaining to the mode of surgical excision (en bloc versus piecemeal excision) extent of metastasis resection (gross total versus subtotal) was not recorded. Whilst differentiating the cohort further based on operative techniques and extent of resection would have been ideal this would have led to smaller cohort sizes precluding meaningful statistical comparisons. Similarly, sub-groups based on modality of radiation treatment were not created based on the same rationale. Second, this study is based on a small sample size, particularly the CUP cohort. Such a limitation is not unique to studying this patient population, particularly as neurosurgical treatment for patients with CUP metastases is relatively less common. This is one of the many drawbacks of retrospective studies as typically large sample sizes are necessary to examine for rare outcomes. In addition, our observations are limited by the inherent selection and information biases typical of retrospective studies. The evidence base concerning neurosurgical treatment of CUP metastases is not wide with differing methodologies; therefore, meaningful comparison of epidemiological data from this study with those undergoing similar treatment in other studies may be limited. Nevertheless, our study adds valuable insights to the evolving CUP brain metastases knowledge base.
These data reflect clinically relevant information gleaned during the transition to precision-era medicine, and before its latent effects are fully manifest. The National Research Council defines precision medicine as a means to tailor medical treatment to the individual qualities of individuals and the diseases of which they suffer. Furthermore, it is a means to stratify patients into subgroups differing in their responses to specific diseases as well as their varying responses to treatment [17]. Whilst the laudable goals of precision medicine are slowly becoming more achievable, particularly in oncological practice, in reality the unavailability of effective treatments for the many usually unfortunately means that precision medicine can rarely be practiced. The neurosurgeon and oncologist working today are still forced to act promptly to manage the often-deteriorating patient with CUP with a brain metastasis. In light of this, based on our data and others [12, 30], we would advocate the early consideration of metastasis excision surgery, even when a primary diagnosis remains undetermined.