Repeat stereotactic body radiotherapy (SBRT) for local recurrence of non-small cell lung cancer and lung metastasis after first SBRT

Stereotactic body radiotherapy (SBRT) has been established as one of the standard treatments for stage I non-small-cell lung cancer (NSCLC) and solitary lung metastasis. Excellent survival rates have been reported, especially following SBRT for stage I NSCLC, with a high quality of life and a high local control rate of 70–90% [1‐3]. In our previous studies, the 5-year local control rate was 83–85% [3, 4]. A recently published report involving combined analysis of two randomized studies of SBRT versus surgery for stage I NSCLC revealed that SBRT yielded better survival rates than surgery [5]. Nevertheless, a proportion of patients develop recurrence or metastasis, and local in-field recurrence remains one of the major patterns of failure.

Treatment of local recurrence of tumors after SBRT has not yet been established. Since many patients were judged inoperable before SBRT, surgery is generally considered difficult, except for in a minority of cases. Chemotherapy may be applied, but cure of the recurrent tumors may be difficult. Traditionally, reirradiation has been considered to be high-risk for most late-responding normal tissues, since damage caused by radiation therapy tends to remain for a long time [6, 7]. However, recent investigations have revealed that re-irradiation could be relatively safely applied to tumors at various sites, especially when the treatment volume could be limited to a small one [8‐10]. Previous studies suggested that late radiation damage that was previously considered unrecoverable may recover to some extent [11], and this may especially be the case for the lung [12].

Since SBRT is quite a localized treatment, we hypothesized that retreatment for local recurrence of stage I NSCLC and solitary lung metastases with SBRT using doses similar to those employed in the first-line treatment might be safely delivered. Thus, we used repeat SBRT for such patients. In this report, we describe our results in 31 patients. To our knowledge, our series is the largest one with the longest follow-up periods among studies of second SBRT for lung tumors.

Surgery and SBRT are now considered as two major definitive treatments for stage I NSCLC and solitary lung metastasis. So far, the majority of patients undergoing SBRT have been medically inoperable, and so surgery is impossible for patients when they develop local recurrence. On the other hand, numbers of medically operable patients who refuse surgery seem to be increasing, and when they develop local recurrence, surgery may be a second-line treatment option. Successful performance of salvage surgery has been reported [16‐18]. Nevertheless, none of the 8 patients who were considered operable desired surgery. Thus, surgery is not indicated for the vast majority of such patients, so repeat SBRT may be a good option to retreat their disease.

Patients retreated with SBRT have been reported in the literature, but the numbers of patients are smaller than ours [19‐28]. The previous reports suggested the feasibility and relative safety of second SBRT, and our larger study confirmed the findings. None of our patients developed severe complications. However, three Grade 5 toxicities due to bleeding, one from aorto-esophageal fistula, and one from perforation of gastric ulcer have been reported [19, 22, 29]. The former 4 patients had a central tumor, while the latter one patient had a peripheral tumor. In most of our patients, dose limits recommended in previous SBRT trials for the trachea, major vessels, and esophagus are exceeded when doses for all treatments are summed. In this study, the dose was prescribed to the isocenter, so the delivered dose was lower than with the dose prescription to the isodose line. Nevertheless, recovery from normal tissue damage between SBRT sessions may largely account for the absence of toxicity, and further investigations on the extent of the recovery seem to be warranted. On the other hand, the recommended dose limits would absolutely represent the safe doses below which major complications rarely occur, and dangerous zones may exist at much higher levels. In our patient undergoing 4 sessions of SBRT to the same site and another session to a neighboring site, the Dmax to the trachea, main bronchus, and aorta were > 130 Gy, but no apparent complications developed in these tissues. Our results would suggest relative safety of repeat SBRT; however, considering the potential risk of overdoses, proton beam therapy may be a better option to reduce the doses to the organs at risk.

The efficacy of repeat SBRT was not clarified in previous studies due to the small patient numbers and short follow-up periods. According to the limited previous data, the local control rates at 5 months to 2 years after second SBRT were 50–75% [18‐22], but longer-term local control data were not available. Some of the previous investigators employed lower doses at second SBRT, and they might have treated their patients rather palliatively. On the other hand, we used similar doses at both first and second SBRT, and the 3-year OS and local control rates were 36 and 53%, respectively. It should be noted that these rates might possibly be falsely elevated because 55% of our patients had no histological proof of recurrence at second SBRT. However, the present study suggested long-term (> 5 years) tumor control in at least 4 patients. Generally, tumors recurring after radiotherapy may be considered to be radioresistant, since they have not been cured with the first radiation therapy. Therefore, it may be a concern that recurrent tumors cannot be cured with similar treatment. However, this was not necessarily the case in our study. Four tumors were considered cured by second SBRT. Treatment intensities were similar between the first and second SBRT, but the recurrent tumors were slightly smaller than the original tumor in 3 patients and of a similar size in 1 patient. Our study suggests that recurrent tumors are not necessarily more radioresistant, and that patients still have a chance of cure when the recurrence is diagnosed early. Experimental studies with rodent tumors indicated that recurrent tumors were not necessarily more radioresistant and sometimes were more radiosensitive than the original tumors [30, 31].

One of the issues in the retreatment of lung tumors recurring after SBRT is the difficulty in correctly diagnosing recurrence based on imaging studies. It is now well-known that post-radiotherapy changes in the lung may mimic recurrence [32, 33]. Positive FDG-PET findings also do not necessarily indicate tumor recurrence. We used a criterion of SUVmax ≥ 5 to suspect recurrence, but we experienced a number of false-positive cases. Therefore, obtaining a histological diagnosis is desirable. However, bronchoscopic and CT-guided biopsy may yield false-negative results, the case in 1 of our patients. In addition, post-SBRT changes in the lung occasionally involve vascular-rich atelectasis so that CT-guided biopsy may be considered hazardous. This applied to 5 patients in our study. Although repeat SBRT is a relatively safe treatment, delivery of retreatment should be conducted carefully if histological diagnosis cannot be established. Occasionally, enlargement of a tumor-like shadow and a positive FDG-PET finding are not sufficient to diagnose recurrence. If obtaining histology is difficult in such cases, a strategy of watchful waiting may be an option.

Repeat SBRT appears to be a relatively safe treatment in patients not developing grade 2 or higher radiation pneumonitis after their first SBRT, although grade 5 toxicities have been reported especially in patients with a central tumor. Patients with local recurrence still have a chance of cure by repeat SBRT.