Is stereotactic radiosurgery a rational treatment option for brain metastases from small cell lung cancer? A retrospective analysis of 70 consecutive patients

Advances in the development of systemic treatments, together with judicious use of surgical resection, WBRT and SRS, have led to increases in the number of long-term survivors and the MST. The long-term control of CNS disease has become increasingly important not only for overall disease control but also for the patient’s quality of life. The risk of developing BM in SCLC is higher than with other histologies. Seute et al. reported the cumulative risk of BM at 2 years after the diagnosis to be 49% to 65% in SCLC [1]. Thus, PCI has long been advocated to reduce the incidence of BM development [2-5]. The survival advantage in previous randomized trials supporting PCI as the standard of care is widely recognized as level 1 evidence. This approach may, however, at least theoretically increase the potential risk of leukoencephalopathy in patients without any known intracranial disease, but with a 50% probability that at some point CNS disease will appear [21,22]. In addition, intracranial disease control failure will continue to occur despite the relatively radiosensitive nature of SCLC [3,4,23]. Certainly, WBRT only treats existing disease and there is no evidence indicating that PCI prevents new BM from developing in patients with active systemic disease.

SRS for BM from SCLC has been relegated to use mainly after failed WBRT probably due to lack of evidence of the efficacy of SRS for this malignancy [9-13]. However, recent refinements in diagnostic and therapeutic modalities may impact the modern management of BM. High-resolution neuroimaging such as 3-dimensional volumetric imaging and the 3-tesla unit might become routinely available for visualizing lesions that used to be undetectable with older imaging modalities [24,25]. Recent technological breakthroughs in the SRS apparatus [26] have made it possible to safely treat 20, or even more, BM, provided that the lesions are small, in a one-day session. The delivery of highly focused radiation with a sharp dose fall-off is theoretically expected to reduce delayed neurotoxicity, and this feature makes it applicable both in the upfront and the salvage setting after recurrence or progression after prophylactic or therapeutic WBRT. A recent Japanese multi-institutional prospective study including 1194 patients (76% with lung cancer) suggested that the upfront SRS strategy is reasonable for patients with up to 10 lesions [15]. However, a critical argument can be made that the pathology of SCLC is unsuitable for SRS because of the disseminated nature of this malignancy. Thus, in our view, the efficacy and limitations of a focal therapeutic approach for BM from SCLC have yet to be determined.

The survival results after SRS in the present study are comparable to those of previous studies [9-11,13] (Table 1). What makes the present study different from the previous series is the ratio of upfront to salvage intervention. Upfront treatment accounts for almost two-thirds of our cohort, while salvage treatments were most numerous in previous series. We had anticipated before this investigation that the survival results would be worse in patients undergoing salvage treatment than in those receiving upfront treatment, but there was, in fact, no significant difference between these two groups (Table 3). We speculate that this might, at least in part, be attributable to patients receiving SRS as salvage having been self-selected to do well by virtue of having had time to develop recurrent BM and not dying of their systemic disease. Patient survival could be stratified employing validated prognostic grading systems. The DS-GPA index is one of the most relevant diagnostic tools for predicting the survival of patients with newly diagnosed BM [27]. In the original DS-GPA study, where the majority of patients (82.6%) received WBRT as the sole treatment, the survival of those with newly diagnosed BM from SCLC was 4.9 months, which was worse than those for patients with tumors at other primary sites. If confined to DS-GPA scores not exceeding 1.0, the MST was as short as 2.8 months. Considering that half the patients had DS-GPA scores of 1 or less in our cohort, the survival outcomes after SRS appear to be acceptable. Rades’s survival scoring system [20] also predicted the survival rates in our cohort, with the survival rates in the present study being higher in the lower score classes than in the original dataset. With regard to prognostic factors, high KPS and solitary BM were associated with improved patient survival in multivariate analyses (Table 3). Both variables were actually incorporated into the above survival scoring systems and these findings were also reproduced in prior studies focusing mainly on salvage treatment [9,13]. Identifying prognostic factors for longer survival in patients with BM would be critically important for assigning patients to the optimal treatment modality. This observation suggests that selected subsets of patients can be expected to experience prolonged survival, though the expected survival of patients with BM from SCLC may be limited in the majority of cases.

In the curve of local tumor control failure, an irregular elevation was observed around 8 months after SRS (Figure 2B). We speculate that the following factors may account for this observation. In a male patient who had received WBRT for multiple BM, multiple recurrent tumors initially responded well to SRS but the enhancement subsequently enlarged in most of these lesions. They were eventually diminished again by salvage re-SRS. Considering that salvage was successful, these lesions should be regarded as true local recurrence. The reason for the higher rate of local tumor control failure in patients with prior WBRT demonstrated herein remains unknown. However, it might be attributable to selective regrowth of radio-resistant tumor cells or to the surrounding brain tissue being predisposed to radiation injury. Thus, we recommend a high marginal dose (≥20 Gy), when possible, being given even for recurrent BM after WBRT, by referring to the results of multivariate analysis for local tumor control (Table 5).

Nearly half of our patients eventually experienced metachronous recurrence outside the treated area after the initial SRS. Subsequent SRS was needed in as many as 30 patients (43%), mostly because of remote BM recurrence. These patients were successfully managed with minimal toxicity. Only eight patients without prior WBRT eventually underwent salvage WBRT because of miliary metastases or leptomeningeal dissemination. Considering that remote recurrence frequently developed, meticulous clinical and neuroimaging follow-up and salvage SRS in a timely manner should be considered essential for assuring the relevance of SRS management. Such a continued radiotherapeutic management protocol might contribute to reducing the neurological death rate, though OS results after SRS were comparable to those of previous studies (Figure 1). This finding is not consistent with the previous study by Harris et al. showing the rate of neurological death to be as high as 53% [13]. In our country, nation-wide availability of advanced diagnostic imaging facilities and radiosurgical equipment as well as the public healthcare system may, fortunately, be making it possible to provide cancer patients with easy access to necessary advanced medical services [28].

The present results must be interpreted with caution. Although the treatment results in our cohort suggested survival similar to that obtained with WBRT in properly stratified populations, a patient selection bias inherent to the retrospective approach is unavoidable. One of the critical issues in the present study is that the reason for PCI having been omitted could not be specified for all cases. It must be appreciated that we cannot address the potential role of SRS in comparison to WBRT because this was a small retrospective observational study. The survival advantage in previous randomized trials supporting PCI as the standard of care also cannot be ignored. The evidence for the clinical efficacy of SRS for BM from SCLC remains insufficient and more evidence-based information and additional research are needed to confirm the therapeutic benefits of SRS. We consider the present retrospective study to have been necessary as a means of hypothesis generation for future investigations.