Abstract
Aim: For local recurrence of non-small cell lung cancer (NSCLC), stereotactic body radiation therapy (SBRT) has become increasingly popular. Many patients with recurrent NSCLC are unable to receive high-dose SBRT [biologically effective dose (BED) >100 Gy] due to poor performance status and potential normal tissue damage. Patients and Methods: Thirty-one patients receiving lower-dose SBRT with a BED of 57.6 to 96.0 Gy, were analyzed for local control, freedom from distant progression and survival. Results: In the entire series, local control rates were 96% at 1, 2 and 3 years. Freedom from distant progression rates were 74%, 65% and 65%, respectively, and survival rates were 87%, 65% and 65%, respectively. On multivariate analysis, freedom from distant progression was significantly associated with absence of distant metastases (p=0.009), and survival with BED >75 Gy (p=0.039). Conclusion: SBRT with BED <100 Gy provided very promising outcomes when administered for recurrent NSCLC. A BED >75 Gy is recommended, which was superior to lower doses.
- Non-small cell lung cancer
- local recurrence
- stereotactic body radiation therapy
- biologically effective dose
Of all patients with lung cancer those with non-small cell lung cancer (NSCLC) account for about 80% (1). Primary treatment of locally advanced NSCLC follows standard approaches and usually includes three-dimensional (3D) conformal radiotherapy supplemented by chemotherapy and, if complete resection can be achieved, thoracic surgery. When a local recurrence occurs, treatment approaches are far less standardized. A second course of 3D conformal radiotherapy with sufficiently high doses is mostly not possible due to the potential damage to the surrounding organs at risk. Therefore, for a local recurrence of NSCLC of a limited size, high-precision radiotherapy in the form of stereotactic body radiation therapy (SBRT) has become more popular during recent years (2). The appropriate dose of SBRT for recurrent NSCLC needs further clarification. For the primary treatment of stage I/II NSCLC, a biologically effective dose (BED) of >100 Gy is recommended (3-5).
However, in the situation of recurrent NSCLC, many patients have a worse performance status and may not be able to tolerate such high doses. Furthermore, one may not be able to safely administer such high doses because the cumulative dose of both irradiation to the primary tumor and SBRT of the recurrent disease is relevant for the potential damage to the organs at risk. In the present study, SBRT with a BED of less than 100 Gy was investigated with respect to local control, freedom from distant progression and survival.
Patients and Methods
Thirty-one patients treated with fractionated SBRT for a local recurrence of NSCLC were retrospectively evaluated in this study. The SBRT dose was prescribed to the outer margins of the recurrent tumor. The BED was calculated with the following equation:
where TD is the total dose, DFx is the dose per fraction, and α/β=10 Gy for tumor cell kill (6). The BED used here ranged between 57.6 Gy and 96.0 Gy.
The most commonly used fractionation regimen was 8×6 Gy (BED=76.8 Gy) in 21 patients (68%), followed by 6×6 Gy (BED=57.6 Gy) in three patients (10%) and 3×12.5 Gy (BED=84.4 Gy) in three patients (10%), respectively. Two patients received 8×6 Gy (BED=86.4 Gy), one patient 10×6 Gy (BED=96.0 Gy) and one patient 15×3.3 Gy (BED=65.8 Gy). The patients were analyzed for local control of the irradiated recurrent tumor, freedom from distant progression (i.e. at sites other than those treated with SBRT) and survival. In addition, nine factors were investigated for associations with the three endpoints. These factors were gender, age (≤66 vs. ≥67 years, median age=66 years), Eastern Cooperative Oncology Group (ECOG) performance score (0-1 vs. 2), interval between first diagnosis of NSCLC and SBRT of recurrent disease (≤30 vs. ≤31 months, median=31 months), distant metastasis (no vs. yes), site of recurrence (upper lobe vs. lower lobe vs. both), histology (adenocarcinoma vs. squamous cell carcinoma vs. large cell anaplastic carcinoma), irradiated volume (≤20 vs. >20 ml, median=20 ml) and BED (<70 vs. >75 Gy). The univariate analyses were performed with the Kaplan–Meier method and the log-rank test (7). Since only one local recurrence occurred during the entire period of follow-up, no comparative analyses were performed for local control. In addition to the univariate analyses, the significant factors were included in a Cox regression model for multivariate analyses.
Rates of freedom from distant progression at 1, 2 and 3 years following sterotactic body radiation therapy (SBRT) for a local recurrence of non-small cell lung cancer (NSCLC).
Rates of survival at 1, 2 and 3 years following sterotactic body radiation therapy (SBRT) for a local recurrence of non-small cell lung cancer (NSCLC).
Results
In the entire series, the local control rates were 96% at 1 year, as well as at 2 and 3 years. The rates of freedom from distant progression were 74%, 65% and 65%, respectively, and the survival rates were 87%, 65% and 65%, respectively. On univariate analysis, freedom from distant progression was significantly positively associated with absence of distant metastases (p=0.002) and a BED of >75 Gy (p=0.002). The data of the entire analysis of freedom from distant progression are shown in Table I. In the subsequent Cox regression analysis, absence of distant metastases remained significant [exponent (B)=0.15, 95% confidence interval=0.04-0.52, p=0.009], whereas a BED >75 Gy was not significant [exponent (B)=3.68, 95% confidence interval=0.57-23.96, p=0.17].
According to the univariate analyses of survival, favorable histology (p=0.004) and a BED >75 Gy (p=0.014) had a positive impact on treatment outcome. The results of the complete analyses of survival are given in Table II. In the subsequent Cox regression analysis, a BED >75 Gy remained significant [exponent (B)=8.04, 95% confidence interval=1.12-58.03, p=0.039], whereas histology did not [exponent (B)=0.14, 95% confidence interval=0.01–3.58, p=0.23].
SBRT with lower doses (BED <100 Gy) was well tolerated. No patient developed radiation pneumonitis.
Discussion
The treatment of patients with NSCLC is continuously improving, mainly due to the use of novel systemic agents and more personalized treatment approaches, which are facilitated by the implementation of new clinical and pre-clinical prognostic factors (8-13). As a consequence of these improvements, patients with metastatic NSCLC live considerably longer. Since the risk of developing a local recurrence of NSCLC increases with a patient's lifetime, the number of patients who require treatment of such a recurrence is growing. In many cases of local or locoregional recurrence of NSCLC, adequate surgery is technically not possible or indicated. For these patients, radiotherapy is requested. However, radiotherapeutic options may be limited due to the patient's poor performance status or previous irradiation (14). Therefore, high-precision radiotherapy with SBRT is often used for recurrent NSCLC. However, there is a lack of data regarding SBRT of recurrent NSCLC. High SBRT doses (BED >100 Gy) as recommended for the primary treatment of stage I NSCLC are often not possible for recurrent NSCLC, taking into account the patient's often poor performance status and the expected radiation toxicity, including pneumonitis (15, 16). In the present study, we investigated the administration of lower doses of SBRT (BED <100 Gy) for this situation.
In this study, the local control rate at 3 years was 96%, which was very similar to the 3-year local control rates observed after SBRT with a BED >100 Gy for the primary treatment of stage I/II NSCLC. The 3-year local control rates of three previous studies that investigated SBRT with a BED of >100 Gy for stage I/II NSCLC ranged between 91% and 95% (3-5). In the study of Lagerwaard et al., the 2-year survival rate was 64% for patients treated with SBRT with a BED of 105-180 Gy for stage I disease (5). The 3-year survival rate in the study of Xia et al. was 64% for patients with stage II NSCLC receiving SBRT with a BED of >100 Gy (4). The survival rates are very similar to the 2-year and 3-year survival rates of 65% and 65% in the present study of SBRT for recurrent NSCLC. These similarities demonstrate that SBRT with a BED <100 Gy is quite effective for recurrent NSCLC. In addition, it is well tolerated, since in contrast to other studies using higher doses of SBRT, no patient in the present study developed radiation pneumonitis (15, 16). However, the SBRT dose should not be too low. This study suggests better results for a BED >75 Gy when compared to lower doses. Given the limitations of a retrospective study, an SBRT schedule of 8×6 Gy (BED=76.8 Gy), which was used for the majority of the patients included in this study, may be recommended for treating recurrence of NSCLC.
In conclusion, this study suggests that SBRT with a BED <100 Gy can lead to very promising local control and survival rates when used for a local recurrence of NSCLC. A BED >75 Gy was superior to lower doses and, therefore, appears recommendable for unresectable recurrent NSCLC.
Footnotes
Conflicts of Interest
On behalf of all Authors, the corresponding Author states that there is no conflict of interest related to this study.
- Received November 23, 2015.
- Revision received December 17, 2015.
- Accepted December 23, 2015.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
