The standard treatment for metastatic NSCLC is systemic therapy. However, in those patients with metastases limited in number and location, local surgical or ablative treatments have shown to be beneficial. Series describing surgical metastectomy have the largest patient numbers and longest follow up [12
]. Surgical metastatectomy is proposed to be a curative therapy, resulting in prolonged disease-free survival [15
]. Recently, there is an expanding experience with stereotactic radiotherapy as effective local therapy for metastatic lesions from any primary cancer. Local control rates of 60-90% have been reported for metastatic tumors involving spine, lung, and liver [16
In this study, patients with initial stage IV NSCLC treated with aggressive local therapy had a higher 5-year OS when compared to stage III NSCLC patients treated with curative intent (14% and 7%, respectively). Although our 5-year survival rate of 7% for Stage III NSCLC patients is lower than what is reported in Phase II-III studies of definitive radiation, our Stage III patients represent an unselected cohort of all patients seen in our clinic, many of whom had adverse prognostic factors such as poor performance status and/or significant weights loss, unlike most patients receiving chemoradiation/radiation on prospective studies [21
]. Most of our patients with Stage III NSCLC had bulky disease, and many would not qualify for prospective studies because of poor performance status and/or > 5% weight loss (Additional file 1
). The 5-year OS rate of patients presenting with limited stage IV NSCLC, which is a selected cohort of patients with disease amenable to SBRT, was similar to those with stage III NSCLC that did not metastasize, suggesting that a number of patients in AJCC stage IV group would be more appropriately classified as stage III NSCLC in future AJCC staging. These data support the hypothesis that select patients with stage IV NSCLC have excellent outcomes comparable to unselected patients with stage III disease when treated aggressively with SBRT.
Patients with initial limited stage IV NSCLC fared better than those with stage I/II or III NSCLC who later progressed to stage IV (5-year OS 22% versus 0% from time of metastatic diagnosis). Perhaps limited metastases presenting as Stage IV NSCLC is biologically more responsive to cancer therapy than recurrent disease.
There may be a period during which local therapy may be most beneficial for patients who initially present with limited metastatic disease. Studies have shown that effective chemotherapy can reduce the number and sites of metastatic tumors at which time, local therapy may be considered [23
]. Rusthoven et al reported that after NSCLC patients receive systemic chemotherapy for limited metastases, the majority (64%) progressed with local failure only; the time to progression in these patients was 3 - 4 months, thereby providing a critical window during which curative local therapy could be offered. Researchers from the University of Chicago analyzed the patterns of recurrence among 38 patients with stage IIIB and IV NSCLC who were enrolled on a Phase II trial of oxaliplatin and paclitaxel [24
]. Half of the patients (19/38) had stable disease or progressed in the original sites only without developing new lesions after the completion of chemotherapy. Seventeen patients who had limited disease (≤ 4 metastatic sites) at initial presentation had a higher propensity to have stable disease or progress only at the initially involved sites. These studies demonstrate that there is a point at which progression of metastatic disease (i.e., development of new lesions) may be suppressed by systemic chemotherapy, allowing for aggressive local treatment to address residual disease.
The role of combined modality treatment for metastatic NSCLC patients was investigated by Khan, et al in a retrospective series of 23 patients with oligometastatic (1-2 sites) NSCLC disease [25
]. These patients received curative treatment for their primary thoracic disease and subsequently received local treatment for their metastatic sites. At 28 months, overall survival was 22% with median survival of 20 months. In our study, patients with initial limited metastatic NSCLC treated with SBRT had a 2-year OS of 48% - this difference could be attributed to differences in patients or cancer characteristics or perhaps recent improvements in systemic chemotherapy and local treatment techniques. With a combined modality approach, the potential for further metastatic disease dissemination may be minimized, thus potentially translating to improved OS.
Among patients with recurrent metastatic NSCLC, those with limited metastases (2-year survival of 24%) had superior outcomes compared to those with extensive disease (no survivors beyond 11.0 months). This is consistent with the hypothesis that a larger tumor burden may predict for increased risk of local failure and metastatic potential. Among patients with limited metastases treated with curative intent SBRT, there were not significant differences in survival between those with ≤ 5 metastases versus 6-8 metastases, and in fact their survival is equivalent at 47 months. While small patient numbers limit analyses, this suggests that other variables such as tumor bulk and/or tumor location are more critical than number of lesions. Previous studies from our group of patients who underwent SBRT for limited metastases (not necessarily from NSCLC) [10
] have shown net GTV to significantly impact disease control and survival outcomes.
In patients with non-metastatic NSCLC, numerous studies suggest that tumor burden correlates with prognosis [27
]. In a small cohort of 19 patients with stage I-III NSCLC, Lee et al reported that tumor volume > 25 cc measured on PET CT scan was associated with increased risk of disease progression and was postulated to be a poor prognostic factor in lung cancer. Similarly, Bradley et al. demonstrated the prognostic value of GTV determined on planning CT scans to be associated with OS and local tumor control. This correlation appears to persist for patients with metastatic NSCLC [31
] as reported by Oh et al and our present observations in which net GTV predicted for improved OS (MVA p < 0.0001). However, GTV of metastatic sites treated with SBRT was not significantly correlated with OS. The GTV of metastatic sites included patients with initial Stage III who developed limited metastases.
Weaknesses of our study include the retrospective nature of the analyses, heterogeneity of patient treatment, including various systemic therapy regimens (which was not presented), heterogeneity of involved metastatic sites (which was not analyzed) and, for some patient subgroups, relatively small patient numbers. Strengths of our study include an overall relatively large study population (particularly unselected Stage III patients and select patients with limited metastases from NSCLC) allowing for the analysis of several prognostic variables.
Stage IV NSCLC represents a heterogeneous patient population. Those patients with limited tumor burden in terms of volume and number of lesions are amenable to, and may benefit from focal ablative therapy to known sites of disease. In our study, select patients with limited stage IV NSCLC treated with curative-intent SBRT, have similar outcomes compared to those unselected patients with stage III NSCLC. While the benefit of SBRT (or other ablative therapies) for limited metastatic NSCLC has not been definitively proven from controlled randomized studies, even with the possibility of no benefit from ablative therapies, select patients with Stage IV NSCLC fare relatively well, and perhaps warrant unique consideration in future AJCC stage groupings. It reasonable to postulate that these patients fare well by virtue of a less indolent disease process in conjunction with a therapeutic benefit from ablative therapy. Given the relatively poor prolonged NSCLC disease control from systemic therapy, it is difficult to postulate that ablative therapies are not benefiting patients. Nonetheless, the favorable outcomes reported here warrant consideration of further investigation of local treatment for patients with limited tumor burden. The University of Chicago has launched a randomized Phase II trial of patients with 1-5 metastases from NSCLC to assess the survival with the addition of hypofractionated image guided radiotherapy concurrently with docetaxel and cisplatin. The NCCTG is also randomizing patients with 1-5 metastases from NSCLC, to undergo or not undergo radiation (with standard fractionation) to metastatic sites.