Stereotactic body radiotherapy for pulmonary oligometastases as an initial metastasis‐directed therapy: patterns of relapse and predictive factors for early mortality

This study aimed to analyze the early mortality rates and patterns of relapse after stereotactic body radiotherapy (SBRT) as an initial metastasis‐directed therapy.


Data acquisition and inclusion criteria
This study was a retrospective, multicenter study conducted in Japan.
The primary end-point of the study has already been reported, and the current study was performed as a subset analysis. 17 The study was approved by the ethics committee of a representative facility (Ethics Committee of Toho University Omori Medical Center, reference number: . The requirement for informed consent was waived due to the retrospective nature of the study. All participating institutions had health insurance and catered to all citizens in Japan. The institutions were given the chance to opt out of this study, and were informed about the aim and significance of the study through the Internet or posters; opt-out consent was obtained from all patients.
Patients with five or fewer detectable metastases, controlled primary lesion, and controlled extrathoracic metastatic lesion at the time of SBRT; who underwent SBRT from January 2004 to June 2015; and who received a biological effective dose (BED 10 ) of ≥75 Gy were included in the study. The following formula was used to calculate the BED 10 : BED 10 = nd [1 + d / (α/β)], where n is the number of fractions, d is dose per fraction, and the α/β ratio is applied for 10 Gy for the tumors. A total of 1378 patients were enrolled in the study, of whom those with no history of metastasis-directed therapy were included in the final analysis.

Patients
A total of 720 patients with 793 oligometastatic tumors were identified from the entire cohort. The characteristics of patients, oligometastatic tumors, SBRT, and chemotherapy at the time of SBRT are summarized in Table 1. The performance status (PS) and tumor diameter were also evaluated at the time of SBRT. The disease-free interval (DFI) was defined as the interval between the date that the primary site was controlled and the date that metastasis was confirmed. The DFI was measured from the day of surgery or on the last day of radiotherapy.
Adjuvant chemotherapy and hormonal therapy were not considered as treatments for primary lesions. The DFI was regarded as zero in patients with simultaneous metastases at the time of initial treatment.
Oligo-recurrences, sync-oligometastases, and unclassified oligometastases had DFI values of ≥6 months, 0 months, and <6 months, respectively. The majority of patients had single pulmonary oligometastases and experienced oligo-recurrence (Table 1). The BED 10 ranged from 75.0 to 233.0 Gy, the dose per fraction ranged from 4 to 20 Gy, and the number of fractions ranged from 2 to 15.

Events definitions and analyses
The time-to-event outcomes and follow-up periods were calculated from the first day of SBRT to the occurrence of the event.

Relevant factors for early mortality
The results of univariate analyses for 90-, 180-, and 360-day mortality rates are summarized in

DISCUSSION
The present study is one of the largest-scale analyses of SBRT as an initial metastasis-directed therapy for pulmonary oligometastases under a controlled primary site (oligo-recurrence) and a simultaneous control of the primary site (sync-oligometastases). 17 The results showed extremely low 90-and 180-day mortality rates (1.1% and 2.4%, respectively), as expected from the experience of SBRT for NCSLC. 5 In a pulmonary oligometastases setting, high safety and low mortality soon after SBRT were confirmed, although some patients received chemotherapy during the course of SBRT ( However, the number of pulmonary metastases is not related to early mortality. Therefore, the number of pulmonary metastases might make a lower contribution to early mortality compared with the maximum tumor diameter. The number of metastases might have a lesser effect on a few patients with three or more oligometastases or all patients with metastases limited to the lung. The results related to BED 10 were interesting. In SBRT for metastatic targets, a higher BED resulted in a higher local control rate. 22 However, as for early mortality, a higher BED resulted in a significantly higher rate of 180-day mortality, a trend that was also observed in the 90-day mortality. Although the date of SBRT toxicity was not investigated in this survey, reports of previous studies could explain the possible association between 180-day mortality and the timing of emergence of radiation-induced lung toxicity. As an abnormal shadow in the lung caused by SBRT occurred within 6 months in most patients (i.e. radiation pneumonitis), and early radiation pneumonitis was reported to correlate with severe radiation pneumonitis, SBRT toxicity may influence early mortality. 25 Actually, two of 20 patients with grade ≥3 radiation pneumonitis died within 180 days after SBRT, although a grade 5 radiation pneumonitis did not occur within 180 days after SBRT. In SBRT for NSCLC, the percentage of lung volume receiving ≥20 Gy and the mean lung dose were associated with lung toxicity. 24 Furthermore, patients with central lung tumors treated with high doses of SBRT showed a high rate of toxicity. 26 Thus, it is possible that higher doses provide better local control, but do not always contribute to lower early mortality. However, considering the very low 90-and 180-day mortality rates, and the importance of metastasis-directed therapy, this is a risk-benefit problem, and excessive hesitation to deliver ablative radiation doses would be over-cautious. 13 TA B L E 2 Results of univariate analyses for 90-, 180-, and 360-day mortality rates  The DFI and oligo-recurrences, which are common prognostic factors after SBRT for oligometastases, were not independent significant factors for early mortality. [27][28][29] It is likely that these factors reflect the state of malignancies, including the aggressiveness of the primary disease and the tendency for the primary disease to spread throughout the body. These factors may be used to determine the effectiveness of metastasis-directed therapy, but they do not have significant relevance to early mortality, given the relatively low ratio of deaths from primary disease in the early period after SBRT. Control of primary lesions and true single organ oligometastases with no history of prior metastasis-directed therapy, which resulted in the first relapse of cancer in the lung (the most common site of relapse), contributed to the prolongation of survival and reduction in the rate of early mortality. Furthermore, successful control of the primary lesion, which led to the recurrences of eight primary lesions at first relapse, also contributed to the excellent survival outcomes and minimized the effect of oligo-recurrence; conversely, the effectiveness of metastasis-directed therapy was maximized. DFI and oligo-recurrences showed prognostic significance, as deaths from primary disease increased; these factors are useful to identify long-term survivors and long-term relapse-free survivors after metastasis-directed therapy.

Factors Alive (n) D e a t h( n) P-value Alive (n) D e a t h( n) P-value Alive (n) D e a t h( n) P-value
The present retrospective study had several limitations. The retrospective nature of the study has inherent selection biases.
Furthermore, some missing data were reported, various or short follow-up procedures were performed, and various treatment protocols in addition to SBRT were used, all of which may have affected the results. Possible factors, such as comorbidity and operability, were not investigated. Finally, the 90-day and 180-day mortality rates were low.
In conclusion, SBRT for pulmonary oligometastases resulted in good OS with a median survival of 53.2 months, which is comparable to that after surgical resection. Furthermore, the rate of early mortality after SBRT was very low (1.1% at 90 days and 2.4% at 180 days after SBRT), even in patients who were not candidates for surgery. SBRT is a good alternative to metastasectomy considering its effectiveness and reduced invasiveness. Some factors affecting the early mortality rate and patterns of failure were reported; these findings will be helpful in the selection and follow up of patients after SBRT.