This study reports the outcome of patients previously treated with CFRT for stage III NSCLC, and reirradiated with SABR because of lung recurrence.
At last follow-up, 32 patients had relapsed (16 local, 13 regional and 21 metastatic relapse), and 29 patients died, leading to a 2 and 4-year PFS and OS of 26.1%/10.8 and 48.9%/30.8%, respectively (Kaplan-Meier). Thus, approximately one-third of patients were alive 4 years after SABR but only 10.8% free of relapse, emphasizing that in addition to local control, distant control is concerning for this population. Although adjuvant chemotherapy was not prognostic in the present study (Tables 3 and 4), it was likely underpowered to address this question. The latest National Comprehensive Cancer Network guidelines (NCCN version 3.2019) regarding local recurrence in NSCLC advises reresection or SABR with no clear recommendation on the treatment thereafter (observation or systemic therapy). To our knowledge, there is no study which analysed the impact of adjuvant chemotherapy after the treatment of local recurrence in stage III NSCLC. However, regarding the high rate of relapse following SABR reirradiation, adjuvant systemic treatment (chemotherapy, immunotherapy) may be recommended. Newer strategies could combine SABR and immunotherapy, as the SABR may improve immunotherapy efficacy, as described in the recent randomized phase II trial for advanced NSCLC [22].
In our study, age was the only variable associated with OS. Otherwise, there were no factors significantly correlated with MFS, PFS or OS, and interestingly central tumors treated with SABR for an in-field relapse had no significant difference in OS, when compared to the remaining cohort. In this subgroup there was also a significant increase of grade 2–5 toxicities (42.9% versus 4.5%, p = 0.007). This consequently suggests that patients with central and in-field relapse are also good candidate for SABR reirradiation. Of note central tumors (n = 24) presented with a higher risk of local relapse suggesting that the absence of LC difference between central tumors treated for an in-field relapse (n = 21) with others, may be due to a lack of statistical power.
In the present cohort the cause of death was not only cancer related but also to treatment related toxicities (n = 2), lung infection (n = 3) and unknown cause (n = 4). A recent study found that cause of death in locally advanced NSCLC was mainly cancer related, but 3 years after diagnosis, the proportion of death related to cardiovascular disease, other cancer, chronic obstructive pulmonary disease, increases up to 25–40% [23]. Managing non-cancer related morbidity is still important in this frail population.
Previous studies analyzing SABR reirradiation on the thorax did find similar results as our study, with good survival and acceptable toxicity profile, but included a heterogeneous patient population, including patients of all stages, with locoregional or metastatic relapse, and patients previously treated by CFRT or SABR.
By limiting our scope to stage III NSCLC, our study is one of the first to analyze the outcome of SABR reirradiation in patients with stage III at first diagnosis, with the largest follow-up (47 months) and largest population (n = 46) to date. A smaller series that is similar to our current study, reported 17 patients reirradiated for in-field relapse and noted a 1-year OS of 59% and a 1-year LC of 86%, but with a 12% fatal toxicity rate (median follow-up = 18 months) [10]. Kelly et al described the treatment of 37 patients (initial NSCLC stage: I to IV) with a median follow-up of 15 months: there were 19% grade 3 alveolitis and 8% grade 3 esophagitis [24]. Liu et al reported pulmonary toxicities of 72 patients treated with reirradiation (median follow-up = 16 months), however the prior thoracic irradiation included NSCLC, small-cell lung cancer and esophageal cancer [14]. Other reirradiation series describe a 1-year LC rate ranging between 65 and 77%, none of which analyzed a homogeneous population of stage III NSCLC patients [9, 12, 15, 25]. Prognostic factors for better outcome in the context of locally relapse stage III NSCLC are unknown, In patients with re-irradiated for NSCLC, Kelly et al found that out-of-field recurrences had a better PFS [24], but the patient’s initial NSCLC stage ranged from I-IV. In the present study, good candidates for SABR reirradiation in locally relapsed stage III NSCLC patients includes: peripheral tumors, tumor size < 33 mm (or 13 mL), and an interval between irradiation and in-field relapse ≥12 months. Larger cohorts are required to further delineate the prognostic factors in this population. Toxicity after thoracic reirradiation continues to be a concern. A pooled analysis of 14 studies evaluating toxicity after high-dose reirradiation of NSCLC found mean rates of 7% for pulmonary toxicity grades ≥3. Grade 5 lethal bleeding was observed in 12 of 408 patients (3%) [7]. Therefore, it is important to mitigate these toxicities by reducing prescription dose, tumor coverage (to protect proximal bronchial vascular tree (PBV) and lung) or increasing the number fractions. Dose constraints in this setting are difficult to establish when combining a conventional and hypofractionated radiotherapy regimen. Hepel et al identified that 1 cc and 4 cc of PBV should not receive more than a mean dose of 20 Gy and 15 Gy, respectively [26].
Of note, the patient with fatal hemoptysis in our cohort presented with an elevated mean dose to the PBV (mean dose to 1 and 4 cc were of 53 and 50 Gy, respectively). Other dose constraints used by previous authors during thoracic reirradiation were reviewed by De Bari et al and corresponded with the normal tissue constraint guidelines from RTOG 0813 [12].
Another solution to decrease toxicities could be to increase the number of fractions during SABR, such as 8 fractions instead of 3 or 5, as already performed by Temming et al [27]. In the context of thoracic reirradiation, Liu et al encourages caution to be taken if patients are PS 2–3, have a forced expiratory volume in 1 s (FEV1) < 65%, previous PTV spanning bilateral mediastinum or V20 ≥ 30% on the composite plan (SABR + CFRT) [14].
One of the limitations of this present study is its retrospective nature and there was no prospective follow-up of the toxicities. We collected the toxicities reported in the records which can underreport low grades toxicities. To minimize this, a phone call was made to all living patients (n = 27) to collect missing toxicities. We could not reach 7 patients, which may lead to a recall bias. Due to the retrospective nature of the study (longstanding irradiation or previous irradiation performed in another center) we also could not perform cumulative dosimetry to better appreciate the risk of toxicity. Another limitation of this study is the absence of margin between GTV and CTV: this policy was used in order to decrease the risk of toxicities but this could have led to decreased tumor coverage.
Lastly, although our series includes the largest population of stage III patients reirradiated with SABR, the statistical power may not have been sufficient to detect all putative prognostic factors.