Abstract
Aim: To retrospectively evaluate the efficacy and safety of definitive fractionated re-irradiation for local recurrence following stereotactic body radiotherapy (SBRT) for primary lung cancer. Patients and Methods: Between April 2003 and December 2011, 398 patients with primary lung tumor underwent SBRT at the Kyushu University Hospital, and 46 out of these developed local recurrence after SBRT. Definitive fractionated re-irradiation was performed for 17 out of the 46 patients. The median dose of re-irradiation was 60 Gy/ 30 fractions. Concurrent chemotherapy was given to four patients. Results: The median follow-up duration was 12.6 months. At one year post-re-irradiation, local progression-free survival was 33.8%; progression-free survival, 30.9%; cause-specific survival, 79.3%; and overall survival, 74.7%. No severe adverse events were observed during the follow-up. Conclusion: Definitive fractionated re-irradiation is thought to be a safe alternative therapy for local recurrence following SBRT, although its efficacy may be not entirely satisfactory.
Stereotactic body radiotherapy (SBRT) has been used to treat primary and metastatic lung tumors with excellent local control rates. The 3-year local control rate of SBRT for stage I non-small cell lung cancer has been reported to be 78-92% (1-10). However, therapeutic strategies for local recurrence following SBRT have not yet been established. Because most patients who are treated with SBRT are medically-inoperable for various reasons prior to SBRT, surgical resection or chemotherapy for local recurrence is not indicated, in most cases. Severe adverse events due to re-irradiation to the same site have been a concern, but a number of researchers have reported that palliative and definitive re-irradiation following fractionated radiotherapy for primary and metastatic lung tumors was safe and effective (11-16). The efficacy of fractionated re-irradiation for local recurrence following SBRT, in contrast, is still unknown.
The purpose of the present study was to explore the efficacy and safety of definitive fractionated re-irradiation for local recurrence following SBRT for primary lung cancers.
Patients and Methods
Patients' and tumor characteristics. Between April 2004 and December 2011, 398 patients with primary lung cancer underwent SBRT at the Kyushu University Hospital; 46 out of these patients (11.6%) subsequently developed local recurrence. Among these 46 patients, definitive fractionated re-irradiation was performed for 17 patients (37.0%) who were medically-inoperable or refused surgery. The median age of the 17 patients was 81 years (range=69-88 years). Fifteen patients were males, and two were females. The median size of the recurrent tumors was 41 mm (range=19-77 mm). Three patients had regional lymph node metastases and one had brain metastases. Three out of the 17 patients had regional nodal failure and one had two brain metastases, concurrently. Patients' and tumor characteristics are summarized in Table I.
Prior SBRT. The SBRT technique has been described (17). All patients were fixed with a Body Cast System composed of a thermoplastic body cast, a vacuum pillow, arm and leg support, and a carbon plate (Engineering Systems Co., Matsumoto, Japan). Computed tomography (CT) scans were performed at 2-mm intervals on the day of planning and on the first treatment day for verification of the set-up. Treatment planning was performed using the 3D RTP machine (Eclipse: Varian Medical Systems, Palo Alto, CA, USA). The gross tumor volume (GTV) was identified on relevant lung setting CT images. The internal target volume (ITV) was created individually according to the internal respiratory motion. The planning target volume (PTV) margin was 5 mm in all directions. Seven to eight multi-leaf-collimator (MLC)-shaped non-coplanar static ports of 4 or 6 MV X-rays were selected to reduce the percentage of total lung receiving more than 20 Gy (V20) to below 20% (Figure 1A). The prescribed dose was 48 Gy in four fractions, except for one patient (60 Gy in 10 fractions). When the range of respiratory tumor motion was 1 cm or more, irradiation was performed during breath-holding using a visual feedback-guided breath-holding system (18). No patients received chemotherapy before or after SBRT. No severe adverse events (i.e. grade 2 or greater) were observed after SBRT in any patient.
Patients' and tumor characteristics.
Fractionated re-irradiation. The length of time from the SBRT to recurrence and to re-irradiation was 4.8-32.9 months (median=11.6 months) and 6.3-35.5 months (median=12.4 months), respectively. Local recurrence was diagnosed by histological or cytological examination in five out of the 17 patients, and by clinical and radiological findings in 12 patients. Definitive fractionated re-irradiation was performed with a dose of 60-70 Gy in 30-35 fractions (median=60 Gy in 30 fractions). The irradiation fields were limited to the recurrent gross tumors without prophylactic lymph node coverage (Figure 1B).
One patient with brain metastases underwent stereotactic radiosurgery prior to re-irradiation to the local recurrence. The lung V20 values of the 17 patients were 3.9%-25.2% (median=9.2%). The cumulative dose (BED10) of the prior SBRT and fractionated re-irradiation ranged from 168 to 189.6 Gy (median=177.6 Gy). Four out of 17 patients (23.5%) received concurrent chemotherapy (carboplatin plus paclitaxel: n=3; S-1: n=1) with fractionated re-irradiation. One patient (5.9%) received hyperthermia treatment weekly during the radiotherapy. Thirteen patients (76.5%) were treated with radiotherapy alone.
Patient follow-up and evaluation. After the completion of re-irradiation, patients were assessed by examinations including chest X-ray and CT every four weeks for the first six months, every 2-3 months for the next 18 months, and every six months thereafter. Brain magnetic resonance imaging (MRI) and fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDG-PET/CT) were also performed, if needed.
Data analysis. We evaluated the patients' survival rates after re-irradiation, the pattern of failures, and toxicities. Overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS), and local progression-free survival (LPFS) rates were estimated with the Kaplan–Meier method. Toxicities were graded according to the Common Toxicity Criteria for Adverse Effect version 3.0 (CTCAE v3.0) (19).
Results
Survival and patterns of failure. The median follow-up was 12.6 months (range=4.3-31.1 months). Re-recurrence was observed in 11 patients (64.7%). Local re-recurrence was observed in nine patients (52.9%), one patient with local re-recurrence had lung metastasis also. Regional failure and pleural dissemination were each observed in one patient (5.9%). Nine patients (52.9%) died of recurrence, and two (11.8%) died from other diseases.
A computed tomographic (CT) image of a 79-year-old male with cT1aN0M0 squamous cell lung carcinoma of the lower right lobe. A: Stereotactic body radiotherapy (SBRT) was performed for primary lung cancer with a dose of 48 Gy in four fractions. B: Re-irradiation with doses of 60 Gy in 30 fractions was performed for local recurrence which was confirmed by CT-guided biopsy 14 months after SBRT. The patient died of another disease one year after re-irradiation, without disease progression.
At one year post-re-irradiation, the following rates were obtained for the 17 patients: LPFS, 33.8%; PFS, 30.9%; CSS, 79.3%; and OS, 74.7% (Figure 2). The median LPFS was 11.7 months; that for PFS was 9.7, for CSS, 19.0, and for OS, 17.0 months.
Adverse effects. One patient had a grade 2 rib fracture. No other adverse events of grade 2 or more were observed in any patient during the follow-up.
Discussion
In this study, the LPFS rate at one year after fractionated re-irradiation was 33.8%, an unacceptably low value. Two reasons may account for the low LPFS; the first is an insufficient dose of fractionated re-irradiation. The biological effective dose of 60 Gy in 30 fractions is smaller than that of 48 Gy in four fractions. In addition, the recurrent tumor might contain potentially radioresistant cells that survived prior SBRT. The second reason is that the recurrent tumor and the surrounding normal tissue might exhibit hypoxic changes due to microvascular dysfunction as a late effect of the prior radiotherapy (20, 21). In this respect, however, fractionated irradiation takes better advantage of the re-oxygenation phenomenon compared to hypofractionated irradiation, which may be reason for long-term local control being observed in only a few of our patients. Further investigation to determine the optimal dose and fractionation is necessary.
Survival curves after definitive fractionated re-irradiation. This Figure shows Kaplan–Meier curves for the overall survival rate (OS), cause-specific survival rate (CSS), progression-free survival rate (PFS), and local progression-free survival rate (LPFS) of patients after re-irradiation for local recurrence following stereotactic body radiotherapy.
To our knowledge, this is the first report of the feasibility of re-irradiation for local recurrence after SBRT. In previous studies of re-irradiation following fractionated irradiation (12-16), the incidences of grade 2 and 3 radiation pneumonitis were 3%-35% and 0%-21%, and those of esophagitis were 0%-24% and 0%-6%. There were no cases of grade 2 or more esophagitis in this study, unlike previous studies. We suspect that the reasons for the low incidence of esophagitis are that the irradiation dose to the esophagus was very low in the prior SBRT, and that the field of re-irradiation did not include a prophylactic area. In addition, no grade 2 or more pneumonitis was observed in the present study. One of the reasons is probably that none of the patients had severe radiation pneumonitis after the prior SBRT. If the patients had had severe radiation pneumonitis, re-irradiation would not have been performed. This selection bias was one of the limitations of this study.
The single patient who had a rib fracture received medication without surgical treatment and improved. For all these reasons, fractionated re-irradiation may be a safe treatment option for local recurrence following SBRT. However, if the disease in the patients is initially operable, we need to consider the indications for salvage lung resection prior to re-irradiation. Chen et al. reported that salvage surgical resection was feasible after SBRT in patients with initially operable disease (22). In addition, when a patient is epidermal growth factor receptor (EGFR) mutation-positive, re-irradiation can be avoided by using an EGFR-tyrosine kinase inhibitor as a salvage treatment.
In the present study, we used a median dose of 48 Gy with four fractions, which is the most frequently used schedule of SBRT in Japan for primary lung cancer (23). This dose is smaller than the doses used in the U.S.A. (24). The efficacy and safety of re-irradiation after higher doses should be evaluated.
In the present study, the median LPFS was 11.7 months, and long-term local control was obtained in a few patients. The adverse events are considered acceptable. Therefore, when other treatment methods are difficult to perform, fractionated re-irradiation may be an alternative. To improve the treatment results of re-irradiation for local recurrence after SBRT, dose escalation of fractionated re-irradiation, combinations of chemotherapy, and re-irradiation using an SBRT technique may be effective. To decide the optimal treatment strategy for local recurrence after SBRT, a greater number of patients and prospective randomized trials are necessary.
Conclusion
Definitive fractionated re-irradiation is thought to be a safe alternative therapy for local recurrence following SBRT, although its efficacy may be not entirely satisfactory.
Acknowledgements
This work was supported in part by JSPS KAKENHI grant numbers 23390302, 23659589.
- Received July 20, 2013.
- Revision received October 24, 2013.
- Accepted October 28, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
