Clinical outcome of stereotactic body radiotherapy for primary and oligometastatic lung tumors: a single institutional study with almost uniform dose with different five treatment schedules

The use of stereotactic body radiotherapy (SBRT) for the treatment of localized lung tumors, including early-stage non-small cell lung cancer and lung metastases, was introduced in the mid-1990s in Japan and Western countries [1‐8]. Although SBRT is generally performed with higher fraction sizes, the optimal fractionation schedule for SBRT remains unclear. SBRT is associated with excellent local control and minimal toxicity; however, fatal pulmonary bleeding following radiotherapy has been reported with the use of hypofractionated regimens for centrally located tumors [9]. Although a fraction size of 12 Gy is widely used in Japan [10], we started our dose escalation study of SBRT for localized lung tumor with a fraction size of 6 Gy from May 2003 in order to avoid serious late complications. We previously published our initial clinical experience of SBRT in patients with early-stage non-small cell lung cancer and lung metastasis, using a total dose of 54 Gy administered in 9 fractions [11], and has since performed a dose escalation study with increases in fraction size of 1 Gy.

The purpose of the present study was to evaluate clinical outcomes following stereotactic body radiotherapy for localized primary and metastatic lung tumor and assess the efficacy and safety of 5 regimens with varying fraction size and number at total doses of 50–56 Gy.

The median follow-up period for all patients and survivors were 44.8 and 51.1 months, respectively. Totally, 30 of 100 patients died during the follow-up period of 3–128 months. Causes of death in these patients were other diseases in 17 patients and disease progression in 13 patients. Of the 100 patients, 70 patients were alive at the last follow-up session. The actuarial 3- and 5-year overall survival rates for all patients were 77.9 % and 68.5 %, respectively.

The results of this study indicate SBRT at total doses between 50 and 56 Gy administered in 5–9 fractions was feasible for primary lung cancer and oligometastatic lung tumors. In our study, grade 2 pulmonary toxicity was observed in 2 patients with an overall 3-year local control rate of over 90 %, equivalent to rates previously reported for SBRT [1‐8]. Additionally, no significant difference was observed in BED₁₀ values between 86.4 and 102.6 Gy.

Nagata Y. et al. [10] evaluated the current status of SBRT in Japan and reported fractionation schedules. According to their survey, the commonest schedules for primary lung cancer were 48 Gy administered in 4 fractions (22 institutions), followed by 50 Gy administered in 5 fractions (11 institutions), and 60 Gy administered in 8 fractions (4 institutions). The use of 48 Gy administered in 4 fractions may be the commonest schedule in Japan, as a result of the impact of a recent Japanese Phase II clinical trial (JCOG0403) [14]. However, various fractionation schedules are currently being performed in many other institutions in Japan, as there is currently a lack of consensus regarding the optimal fractionation schedules for SBRT. Therefore, BED values for tumoral and normal tissues have been utilized to compare the efficacy of various fractionation schedules, with many investigators reporting the utility of BED.

There have been several reports of the correlation between BED₁₀ and local control. Onishi et al. [15] evaluated the clinical outcomes following stereotactic hypofractionated high-dose irradiation of stage I non-small cell lung carcinoma and found local control rates were better with BED₁₀ ≥ 100 Gy, compared with BED₁₀ < 100 Gy. Similar findings regarding the importance of BED₁₀ on local control have been reported by Nagata Y. et al. [16]. BED₁₀ appears to be useful in comparing the efficacy of treatment protocols with varying fraction sizes and total doses. On the other hand, Shibamoto Y, et al. [17] highlighted issues with the use of the LQ model and BED for estimating the efficacy of radiation schedules in SBRT. The LQ model has utility in the conversion of relatively low radiation doses used in conventional radiotherapy; however, it has been suggested that the LQ model is not applicable to higher daily doses or smaller fraction numbers [18]. In our study, the 3-year local control rate of over 90 % for BED₁₀ < 100 Gy was equivalent to the rate of over 95 % for BED₁₀ ≥ 100 Gy. This result indicates BED has no usefulness in estimating the efficacy of radiation schedules for SBRT. However, alternative mathematical models for estimating the efficacy of radiation schedules for SBRT are yet to be developed. Therefore, further research is necessary, focusing on the development of alternative mathematical models for SBRT.

Aside for the issues associated with use of the LQ model and BED, the higher local control rate in 40 patients with BED less than 100 Gy remains incompletely understood. In our study, despite 22.5 % (9/40) of tumors in the low-BED group (<100 Gy) with a maximum diameter of 3 cm or more, the 3-year local control rate was over 90 %. Additionally, in our study, the 3-year local control rate using competing risk analysis of 86 % for T2 tumors (≥3 cm) was almost equivalent to previous clinical studies that reported local control rates of 70 %–78 % for T2 tumors, following the use of higher fraction sizes (greater than 10 Gy) [19‐22]. Fraction sizes were smaller, overall treatment times were longer, and fraction numbers were larger in the low-BED group. From a radiobiological standpoint, these findings suggest that during SBRT, prolonged treatment periods and larger fraction numbers may have a positive effect on local control through reoxygenation or redistribution of cancer cells during treatment. A large amount of evidence suggests tumoral reoxygenation occurs 24–72 h following irradiation [23‐26]. The redistribution of cancer cells is believed to play an important role in enhancing the therapeutic effect of irradiation as a result of reoxygenation [27]. In other words, our study indicates increasing the number of fractions and extending the overall treatment duration of fractionation schedules are important for local control in addition to increasing the fraction size. However, medical expenses and the balance between local control and side effects are also important considerations for the development of optimal fractionation schedules. Jain S, et al. [28] conducted a randomized study in patients treated with four fractions of lung SBRT delivered over 4 or 11 days locking at acute toxicity and quality of life and concluded that grade 2 or higher acute toxicity was more common in the 4-day group. Although, local control rates for 4- or 11-day groups are not reported, long treatment times in Jain’s study is very interesting for future direction of SBRT schedules.

Dose/volume-effect relationships in SBRT for primary and secondary lung tumors have been discussed in recent papers. Guckenberger M, et al. [29] conducted a retrospective multi-institutional study in 399 patients with stage I non-small cell lung cancer and 397 patients with 525 lung metastases and concluded that the dose–response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary non-small cell lung cancers and lung metastases. Suzuki O, et al. [30] reported a dose-volume-response analysis in SBRT for early lung cancer among Japan and Western countries. The BED₁₀ at PTV periphery was 102 Gy in Western countries and 83 Gy in Japan. The local control was better in Western countries for larger tumors but was similar for smaller tumors. The dose was prescribed at the isocenter in our study; dose–response relationship was not observed in tumor size and primary and oligo-metastatic lung tumors.

The current study had the following limitations. First, the study was performed without upfront power and sample size calculations. Second, analysing dose but not tumor size as risk factor for local recurrence was the primary intent of the study, and additionally, most likely by chance, tumors had been larger in the first phase of the study (at the 6 Gy level). Third, the dose was prescribed at the isocenter, and the aperture was set at 5 mm beyond PTV; the peripheral dose for PTV was different to Western approaches [30]. Fourth, all tumors included in this study were peripherally located, meaning the efficacy of these fractionation schedules for the treatment of central lesions remains unclear. Fifth, the dose calculation was changed during the study period; this possibly affected the administered doses. Finally, patient and tumor characteristic differed for each fractionation schedule because this was not a randomized study.

This study, however, provides a novel perspective on future directions for the development of optimal fractionation schedules in stereotactic body radiotherapy for patients with primary lung cancer or oligometastatic lung tumor.

Regardless of fractionation schedule, stereotactic body radiotherapy with total doses between 50 and 56 Gy administered over 5–9 fractions achieved acceptable tumor control without severe complications. For stage IB primary lung cancer, however, more intensive regimen appear necessary to achieve local control. From a radiobiological standpoint, increasing the number of fractions and extending the overall treatment duration of fractionation schedules may also be important factors that influence local control.