This study reports our experience of hypofractionated Tomotherapy for the treatment of oligometastatic primary or secondary lung cancer. We found that HRT in combination with systemic treatment may be effective without causing major toxicities. EPD status strongly predicted survival. To date, few studies have investigated the use of hypofractionated Tomotherapy for advanced-stage primary lung cancer. Adkison et al.
 reported the effectiveness of hypofractionated Tomotherapy for inoperable NSCLC with 2.28–3.22 Gy per fraction, for a total of 25 fractions in 46 patients. The median survival time was 18 months, with an actuarial 2-year survival of 46.8% and a 6.5% in-field progression rate. However, 80% of their patient population had stage III cancers. Song et al.
 reported a 2-year survival rate of 56% and a 2-year LC rate of 63% in 37 NSCLC patients after hypofractionated Tomotherapy with 2.0–2.4 Gy per fraction, at a total dose of 60–70.4 Gy. Again, 75.7% of their patients had stage III cancer, 13.5% had stage I and II cancers, and 10.8% had recurrent disease. However, all of the patients in our study population had stage IV cancer and achieved a 2-year survival rate of 55.9% and a median survival of 32.1 months. We believe that one of the reasons for our results is that most of our lung cancer patients responded to the systemic targeted therapy.
Patients with oligometastatic lung tumors without extrapulmonary disease (EPD) had better survival than those with EPD, regardless of treatment modality. Zhang Ye et al.
 reported that in patients with secondary lung cancers who underwent SBRT, the 5-year survival rate (33.2% vs 12.5%), median survival time (37.3 months vs 18.2 months, p = 0.012), and hazard ratio (HR, 1.894; p = 0.024) all favored negative EPD. Yamakado et al.
 presented a study of colon cancer with lung metastasis treated with radio frequency ablation (RFA). They found that the 5-year survival rate for the patients without EPD was 57%, whereas that for the patients with EPD was 0% (p < 0.0001). Surgical management of oligometastases in esophageal cancer patients by Ichikawa et al.
 also revealed that EPD was the most important prognostic factor. The 3-year survival rates were 54.7% for EPD-negative patients and 0% for EPD-positive patients (p = 0.0411). A large series of pulmonary metastasectomy for CRC conducted by Kanemitsu et al.
 also demonstrated that EPD was a poor prognostic factor, with HRs of 1.73 (univariate, p = 0.001) and 1.55 (multivariate, p = 0.021). The study conducted by Schuhan et al.
, which evaluated survival after pulmonary metastasectomy in malignant melanoma, disclosed that before surgery, EPD-negative patients had a median survival time of 39.8 months, compared with the 15.7 months (p = 0.23) in those with EPD. All of these studies generated the same conclusion as ours: that the median survival time of patients with EPD was 11.2 months, as compared with the >50 months (not reached) in patients without EPD (p < 0.001).
The importance of the involved numbers of organs or lesions in survival outcome was reported in 2 studies
[20, 21]. On the contrary, a pilot study for SBRT conducted by Milano et al.
 disclosed that neither the numbers of organs nor lesions involved could predict survival (univariate, p = 0.43; multivariate, p = 0.50). Kim et al.
 reported that treatment of oligometastatic lung tumors with Tomotherapy resulted in better overall survival in patients with ≤5 intrapulmonary lesions than those with >5 lesions, but the difference was not statistically significant (17 months vs 10 months, p = 0.2323). We observed a median OS time > 40 months versus 26 months in those with ≤2 versus those with ≥3 intrapulmonary lesions, respectively (p = 0.065).
 prospective study also concluded that smaller GTVs were significant for LC, distant control, and survival benefit. Another long-term follow-up study by Milano
 also showed that greater SBRT target volume in non-breast cancer was a poor prognostic factor for OS (p = 0.012). Our study also revealed that a small intrapulmonary GTV (≤27.89 cm3) correlated with better survival than a large GTV (≥27.89 cm3): >40 months versus 12.85 months (p = 0.047). These results are in accordance with the rationale of oligometastasis that higher tumor burden beyond the threshold size leads to an exponential rise in cell proliferation and the risk of distant metastasis. GTV has proved to be more significant than the number of metastatic lesions or organs for predicting survival.
Stage IV lung cancer is a systemic disease. The survival benefit from good LC should be based on good systemic control, and high LC rate alone would be meaningless in systemic disease. We have previously reported
 that patients with mainly stage IV lung adenocarcinoma may gain longer survival by taking concurrent TKI plus multi-target Tomotherapy with a smaller fraction size, that is, 250 cGy/fx, for a total of 20–25 fractions. The 3-year overall survival rate reached 62.5%, and the progression-free survival (PFS) time was 16 months. The results of this study implied that early intervention of oligometastasis by radiotherapy in patients with fair systemic control may prolong progression-free survival and probably offer a greater survival benefit than systemic therapy alone. In the present study, we reviewed patients treated with Tomotherapy with a higher fraction size (450–700 cGy per fraction) and found a similar long survival rate but a more impressive LC rate.
The outcome of oligometastatic primary or secondary lung cancer treatment depends mainly on the nature of the tumor and the response to systemic treatment. Ideally, the oligometastatic state should be more indolent in nature. Metastases that are limited in number and location may be due to the fact that the metastatic machinery has not matured at that time. Disease progression is just a matter of time, and tumors detected in the oligometastatic state may be more vulnerable to therapy. An aggressive approach such as early intervention by local or multi-target radiotherapy in addition to mainstream systemic therapy is important to avoid malignant progression and drug resistance in response to systemic therapy alone.
In our study, the RP grade was quite low, with only 2 patients (6.1%) having ≥3 RP and most patients having grade 0 or 1 RP (81.8%), which is comparable with other studies. Park et al.
 evaluated the early CT findings in 25 patients with pulmonary malignancies treated by Tomotherapy. The median total dose was 50 ± 4.99 Gy in 3–20 fractions. They reported that none of the patients developed ≥ grade 3 RP. Adkison et al.
 treated 46 lung cancer patients with hypofractionated Tomotherapy with 2.28–3.22 Gy per fraction, for a total of 25 fractions. They also reported a ≥ grade 3 RP rate of 0%. Song et al.
 described a trial in which 37 NSCLC patients treated with Tomotherapy with 2.0-2.4 Gy per fraction, up to total 60–70.4 Gy, exhibited a higher ≥ grade 3 RP rate (19%). Generally, SBRT of smaller GTV yields a lower ≥ grade 3 RP rate of 1.2–4%
[25, 26]. Referring to the report from Vofelius et al., Tomotherapy is particularly safe in the range of 7 to 20 fractionation schedule (RP risk ≦8%), while RP rate by 3D-CRT technique would be 10-12% in 7 to 20 fractions and even up to 13-16% in ≦5 fractions
The median fraction size of 4.5–6 Gy/fx to a median total dose of 49.5 Gy was performed in our study. We had a lower BED (median estimated BED10 was 71.78 Gy) than that provided by the widely used high-fraction size SBRT technique (median BED10 ≥ 100 Gy in most studies). Nonetheless, a 94.7% 2-year LC rate and a 6.1% severe RP rate make our protocol quite attractive. Tomotherapy with conventional immobilization casts is much more convenient than SBRT with a stereotactic body frame. Furthermore, hypofractionated Tomotherapy can treat a larger tumor size. It can also treat multitargets in the thorax and extrapulmonary regions at the same time.