Are We Expanding Oligometastatic Non–Small-Cell Lung Cancer Using Advanced Radiotherapeutic Modalities?

Whether local therapy in the setting of metastatic cancer can affect overall survival is a matter of debate in oncologic practice. For a cancer to metastasize, it should be microscopically present in the systemic circulation, rightfully justifying the need for systemic treatment, and perhaps questioning the utility of local therapy. Nevertheless, it has been demonstrated that the reduction of disease burden through local treatment in some disease settings does improve overall survival and can lead to long-term disease control; examples include the use of radical nephrectomy in patients with diffuse renal cell carcinoma, surgical extirpation of hepatic metastases from colorectal cancer and resection of lung metastases from a variety of primary tumor sites. In the article by Iyengar et al that accompanies this editorial, the authors highlight the importance of local therapy in previously treated metastatic non–small-cell lung cancer (NSCLC). These investigators illustrate dramatic survival outcomes using stereotactic body radiation therapy (SBRT) combined with erlotinib in 24 patients who had six or fewer sites of extracranial disease and for whom platinum-based therapy had failed. With a progression-free survival of nearly 15 months and an overall survival of 20 months (improved from traditional survival rates of 2 to 4 months and 6 to 9 months, respectively), the results seem unexpected at first glance. However, when considered in the context of oligometastatic NSCLC treated with aggressive thoracic radiotherapy, these results may not be surprising, given that other series evaluating one to two sites of extrathoracic metastases have similarly revealed prolonged median survival rates of 20 to 28 months. Likewise, there are series that have incorporated a variety of primary tumor sites (ie, breast or renal) that demonstrate remarkable survival results with SBRT for five or fewer sites of metastases. Yet the single-arm nature of these studies, none of which were randomized, confounds interpretation of these results because of potential selection bias. Selecting patients who could tolerate at least one regimen of chemotherapy and were eligible for SBRT, focal and intensified radiation therapy, to all sites of disease, implies the absence of negative prognostic factors such as pleural effusion, active brain metastases, and large tumors. Patients with large tumors ( 6 cm) would have been excluded from SBRT by virtue of the conformality and dose escalation that must be achieved; in addition, tumors of this size generally fare worse. Such criteria may indicate that the favorable selection of patients can positively affect survival measures. A similar phase II study incorporated SBRT and demonstrated a lesser median survival of 14.8 months, but patients did not uniformly receive upfront chemotherapy. Chemotherapy sensitivity may likewise select for favorable disease biology. Iyengar et al used systemic therapy that consisted of erlotinib beginning 1 week before SBRT and continuing during and after SBRT until disease progression or unacceptable toxicity. Because evaluation of epidermal growth factor receptor (EGFR) mutation status was not mandatory for this clinical trial, only 54% of patients had a mutational status determined, and none harbored an EGFR mutation. However, uncertainty exists about the impact of erlotinib on the survival of the remaining patients who did not undergo mutational status determination. Although it is unlikely that targeting the EGFR mutation influenced survival outcomes and that the main source of the survival benefit was SBRT, one cannot discern the relative benefits of SBRT and the possibility that an actionable EGFR mutation affected survival in some proportion of untested patients. The authors point out that there were no significant differences in survivals between the group that had their mutational status determined versus that which did not. This is contrary to RTOG 0324, in which cetuximab was combined with chemoradiotherapy for NSCLC, and approximately 52% of patients had a specimen analysis for EGFR testing. Komaki et al showed here that patients without EGFR immunohistochemistry (IHC) had worse overall and progression-free survival compared with those with IHC data, which suggests the importance of obtaining biopsy samples for mutational analysis. This prospective phase II trial by Iyengar et al took 6 years to reach its accrual goal. The reasons for prolonged accrual at most institutions are complex, but in this situation, it calls into the question the incidence of oligometastatic NSCLC, or more importantly, how oligometastatic disease is defined. Hellman and Weichselbaum coined the term oligometastases in Journal of Clinical Oncology in 1995 to explain a clinically significant state in which there were metastases to a single or limited number of organs, an intermediary state between locally advanced disease and widespread metastatic disease. In a series by Thibault et al, the incidence of patients able to undergo SBRT for oligometastases was 17%. Mehta et al report that 74% of patients JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 34 DECEMBER 1 2014