{'fraction_non_alphanumeric': 0.033969966467415076, 'fraction_numerical': 0.018370024784954076, 'mean_word_length': 4.986038394415358, 'pattern_counts': {'":': 0, '<': 5, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Lung stereotactic radiotherapy for oligometastases: comparison of oligo-recurrence and sync-oligometastases†

The state of oligo-recurrence is the most valuable prognostic factor of pulmonary oligometastases treated by stereotactic body radiotherapy.

as the state in which patients with cancer have ≤5 metastatic or recurrent lesions with controlled primary lesions. Recently, the concept of sync-oligometastases was proposed as the state in which patients with cancer have ≤5 metastatic or recurrent lesions with active primary lesions (4). The major difference among oligometastases, oligorecurrence and sync-oligometastases was the status of the primary lesion; oligo-recurrence has been considered to show a better prognosis than sync-oligometastases among some researchers including us. However, there was no evidence until now.
For cases with oligo-recurrent cancer in the lung, controversy exists regarding the optimal approach for these metastatic sites. Although a surgical approach is considered an alternative for a single metastasis, there are many patients with lung oligo-recurrence who are not amenable for metastasectomy. For them, less invasive techniques such as stereotactic body radiotherapy (SBRT) have been used to treat lung oligo-recurrence. In cases considered to have a favorable prognosis, radical treatment with SBRT seems to prolong the survival time. However, the role of radiotherapy and the prognostic factors for oligo-recurrence have not yet been clearly elucidated (5). This retrospective study investigated SBRT for lung oligometastases. At the same time, the difference in prognosis between oligo-recurrence and sync-oligometastases was examined.

Methods
A total of 96 patients (65 males, 31 females) who received SBRT for oligometastatic lung tumors between January 2004 and April 2014 at four high-volume institutions in Japan were enrolled in this retrospective study (Table 1). This retrospective study was approved by the ethical committees of all institutions.
As to systemic chemotherapy, no concurrent chemotherapy combined with SBRT was performed. Induction chemotherapy before SBRT was given in four cases. Three cases were given carboplatin plus paclitaxel for ovary, uterine cervical and uterine body cancer, and the other was given S-1 for colon cancer. Adjuvant chemotherapy after SBRT (which was started within 8 weeks) was performed in one case. S-1 was given for colon cancer.
Overall survival (OS), the local control rate (LCR) and relapsefree survival (RFS) were calculated using Kaplan-Meier curves, and the log-rank test was used to compare the curves. Significance of univariate analyses was set at P < 0.05. The 95% confidence interval (CI) range of survival was calculated using Greenwood's formula. Multivariate analyses for OS and RFS were performed using a Cox proportional hazards model. Three factors, DFI (<24 vs. ≥24 months), oligometastatic state (sync-oligometastases vs. oligo-recurrences) and number of metastatic tumors (multiple vs. single), were included in the multivariate analysis. Significance of the multivariate analysis was set at P < 0.017 using the Bonferroni method.

Results
The median follow-up period for all patients was 21 months (range, 1-119 months) and that for survivors was 32 months (range, 1-110 months). During follow-up, local recurrence occurred in 18 lesions, 43 patients (45%) died and relapse or death occurred in 70 patients (73%). Radiation pneumonitis of Grade 3 was found in two patients, and gastrointestinal toxicity of Grade 4 was found in one patient. No Grade 5 toxicity occurred.

Discussion
The Japanese guidelines recommend local therapy with curative intent for lung oligometastases from colorectal cancer (6). In the NCCN guidelines version 1.2015 for non-small-cell lung cancer, it is stated that aggressive local therapy may be appropriate for selected patients with limited-site involvement, such as brain oligometastatic disease. SBRT for lung oligometastases without other active disease is also covered by insurance in Japan.
In this study, 3-year OS and the LCR were 53% and 74%, respectively, for the whole patient group. The present results are comparable to other studies of lung oligometastases (7-9). Norihisa et al. (10) also previously reported the results of SBRT for 43 metastatic lung cancers. In their series, the survival rates and LCR at 2 years were reported to be 84.3% and 90%, respectively. Ricardi et al. (11) also reported a study of SBRT for oligometastatic lung tumors. In 61 patients treated with SBRT, local control was achieved in 89% and 2-year survival was 66.5%. Onishi et al. (12) reported an excellent case report about sequential oligo-recurrence.
Several studies (10,13) have shown that local control after SBRT for lung metastases from colorectal cancer is worse than that from other origins. However, in this study, lung metastases from colorectal cancer were not significantly worse, but the statistical power might be low since there were only 96 patients and only 25 colorectal cancers.
Takahashi et al. (14) reported that a shorter DFI of less than 31.9 months was the prognostic factor in a study of SBRT for pulmonary oligo-recurrence. In another study, a DFI ≥36 months was associated with better prognosis than that of <36 months (15). The 3-year OS was 69 vs. 30% for a DFI of ≥24 vs. <24 months, respectively. A longer DFI was also found to be associated with a good prognosis in this study.
In SBRT for lung metastases, limited toxicity rates have been reported by several authors. In the present series, no patient had serious late toxicities.
Several limitations of this study warrant mention. First, it was a retrospective review from multiple institutions with a limited number of patients and limited follow-up. There was a wide range of doses prescribed and a variety of fractionation schema at each institution. SBRT for lung oligometastatic disease without controlling the primary tumor is not covered by insurance in Japan. In other words, SBRT for synchronous pulmonary metastases is not justified in general clinical setting. Furthermore, in this study, only in special situations, such as if lung metastases were controlled by SBRT, was the primary tumor surgically removed and SBRT was performed. Briefly, SBRT for lung metastases was performed for only patients with schedule of surgery for the primary tumor in some institutions. Nevertheless, the clinical outcome of SBRT for sync-oligometastases was dismal. In these situations, systemic therapy is more important than local treatment.

Conclusions
Patients with single oligo-recurrent tumor in the lung could be good candidates for SBRT. Clinicians might consider SBRT in cases of single oligo-recurrence because this powerful local therapy could benefit such patients.

690
Oligo-recurrence is the best prognostic factor