We found HFRT to be effective; the median OS was 18.7 months (with 1- and 2-year OS rates of 65.9% and 33.9%, respectively) while the median LPFS was 7.2 months (with 1- and 2- year LPFS rates of 27.9% and 9.4%, respectively). The adverse effects were tolerated given that no grade ≥ 3 toxicities occurred; this was also the case in the study by Amini et al.[15].
Studies at the MD Anderson Cancer Center used HFRT (45 Gy/15 fractions) to treat patients with unresectable NSCLC who could not tolerate the CFRT; no significant differences in local recurrence and OS were observed between the 2 regimens. The 1- and 2-year OS rates of patients who received HFRT were 53% and 12%, respectively [10, 15, 16]. In a study by Abratt et al., the median OS of patients with stage III NSCLC who received palliative RT (45 Gy/15 fractions) was 8.5 months[17]. The patients in our study had better survival than did those in previous studies, which might be due in part to the innovations in cancer therapeutics (including targeted therapy, antiangiogenic therapy, immunotherapy, combination therapy, and technological improvements in other modalities).
A previous analysis demonstrated that an absolute OS benefit was observed that ranged from 0.36–0.7% for every 1 Gy increase in BED [16]. Machtay et al. also found that an increase of 1 Gy BED could improve survival by approximately 4%, along with greater acute toxicity [18]. A meta-analysis by Fairchild et al. found that patients received higher dose schedules (BED ≥ 35 Gy, α/β = 10) achieved a significantly better survival than those received lower dose schedules, with 2-year OS rates of 26.5% vs. 21.7% for well-performing patients, albeit at the cost of greater esophageal toxicity. While there was no advantage in administering high dose schedules for poorly performing patients [19]. However, a higher total dose appeared not to benefit palliative patients with lung cancer (50 Gy/20 fractions vs. 25 Gy/5 fractions) [20].
The traditional approach to increase BED is to increase the number of fractions. CFRT is usually not well-tolerated among patients with poor performance or advanced disease. Hypofractionation, on the other hand, enables the delivery of higher BED, as HFRT involves significantly fewer fractions with higher doses per fraction compared to standard modalities. Large fractions are an effective way of for ablating tumors, likely owing in part to the reduced rate of tumor cell repopulation; and may be more convenient and cheaper than conventional fractionation[21, 22]. Compared with other studies of palliative RT regimens with lower BED, patients in our study achieved higher survival benefits by increasing the dose per fraction to obtain higher a BED (58.5 Gy, α/β = 10) while adverse events remained tolerable.
Many studies comparing the efficacy of HFRT and stereotactic body radiation therapy (SBRT) for the palliative treatment of patients with advanced lung cancer showed that HFRT appeared to provide a greater survival benefit. Lewis et al. investigated the effects of fraction schedules (30 Gy/10 fractions, 20 Gy/5 fractions, and 10 Gy/1 fraction) on the survival of lung cancers treated with palliative RT and found that increasing the total dose was associated with better survival regardless of performance status [23]. Moreover, SBRT is generally not suitable for tumors that are central (i.e., close to the trachea or heart), those that are accompanied by necrosis or mediastinal lymph node metastases, or those that are large in size.
In the past decade, the use of molecularly targeted therapy has led to significantly longer survival in patients with EGFR or ALK sensitizing mutations [24]. However, previous studies focused mainly on concurrent administration of these therapies with RT as first-line treatment for patients with advanced disease, which maybe place them at a higher risk of adverse effects. In our study, 9 patients who were treated with TKIs after RT achieved significantly longer LPFS and OS with no obvious adverse effects observed. Okamoto et al. found that 2 of 9 patients with unresectable stage II NSCLC exhibiting EGFR mutations who were treated with gefitinib and concurrent RT survived for more than 5 years, although the study was stopped owing to a high incidence of adverse events [25]. In the RECEL trial that compared erlotinib versus etoposide/cisplatin with concurrent RT for patients with unresectable stage III NSCLC carrying EGFR mutations, the erlotinib/RT arm had significantly improved PFS compared to the CRT with the same incidence of adverse effects [26]. The SINDAS study showed that first-line TKI with upfront SBRT to all sites significantly improved both PFS and OS compared with TKI alone in previously untreated patients with oligometastatic NSCLC (≤ 5 lesions) carrying EGFR mutations [27].
Many studies have shown that antiangiogenic agents could produce significant survival benefits for patients with advanced NSCLC. However, previous efforts have focused more on concurrent antiangiogenic agents with RT, and few investigators have used such agents as maintenance therapy post-RT. The ECOG 4599 study showed that the addition of bevacizumab to paclitaxel/carboplatin for treating recurrent or advanced NSCLC produced a significant survival benefit [28]. The ALTER0303 trial showed that anlotinib administered as the third-or-greater-line treatment prolonged PFS and OS in patients with advanced NSCLC [29]. Moreover, patients in the HELPER study who received continuous infusion of endostar combined with CCRT for unresectable stage III NSCLC achieved favorable PFS and OS with tolerable toxicities [30]. In our current study, no survival benefit was found among 13 patients (17.6%) who were treated with antiangiogenetic therapy after RT; this may partly be due to the most of these patients (10, or 80%) having stage IV disease while 5 patients (38%) were still alive as of the last follow-up.
The recent development of immune checkpoint inhibitors (ICIs) has essentially changed the treatment profiles of patients with advanced NSCLC [31]. A network meta-analysis by Almutairi et al. that compared the efficacy and safety of PD-1/PD-L1 inhibitors in patients who were previously treated for advanced NSCLC found significant benefits of pembrolizumab and nivolumab in terms of PFS, OS, and in pairwise comparisons to docetaxel [32]. Another meta-analysis by Schulz et al. found that PD-L1/PD-1 inhibitors as second-or-later-line treatments for advanced NSCLC demonstrated greater survival benefits, producing the highest expected 5-year OS rates compared to other treatments [33]. PACIFIC study showed that, compared to placebo, durvalumab demonstrated significant PFS improvements for patients with unresectable stage III NSCLC without progression after CRT, the 3-year OS was 66.3% versus 43.5% [34, 35]. In our study, 5 patients (17.6%) received immunotherapy after RT among whom 1 was lost to follow-up and 1 was still alive after 10 months (with 5.1 months of LPFS) as of the last follow-up; the LPFS times for the other 3 patients were 6.1, 21.1, and 6.7 months, respectively, while their OS times were 23.1, 29.6 and 12.8 months, respectively. Although the sample size was small, these data preliminarily suggested that ICIs after HFRT can provide a promising survival benefit.
Previous studies have shown that the combination of RT and either TKIs, antiangiogenetic therapy, or ICIs could improve survival in patients with locally or systemically advanced NSCLC, usually at the cost of a high incidence of toxicity, although the optimal RT dose remains uncertain. In contrast, we found that patients who received TKIs, antiangiogenetic therapy, or ICIs as maintenance therapy after HFRT achieved improved survival with no obvious adverse effects.
Recent studies also found that the NLR, well-known as a marker of host inflammation, may be a useful predictor of poor prognosis in patients with NSCLC. Scilla et al. found that baseline NLR was a significant prognostic indicator in patients with locally advanced NSCLC who received definitive CRT with or without surgery [36]. A retrospective multicenter study indicated that patients with NSCLC who have high pretreatment NLR (i.e., > 5) may experience inferior PFS and OS treated with nivolumab [37]. A meta-analysis by Zhang et al. also showed that a high NLR was associated with poor PFS and OS in patients with NSCLC treated with ICIs [38]. Similar results were obtained in our study, in which patients with low NLRs had better prognoses.
Our study’s finding that patients with larger tumor sizes and greater tumor-to-lung volume ratios had poorer prognoses were similar to the conclusions of Werner-Wasik et al. [39] and Bradley et al. [40]. Strøm et al. found that patients with NSCLC tumors > 7 cm appeared to benefit notably from palliative CRT, but with an increased risk of radiation-induced esophagitis and pneumonia[41]. As such, it is possible that a larger tumor volume might not be a limitation for RT, as the incidence of adverse effects could be reduced by administering HFRT alone or sequential CRT.
Moreover, we found that patients who underwent ≥ 2 previous chemotherapy lines may experience inferior survival; as such, we posit that administering RT earlier may improve the survival of these patients.
In conclusion, our findings suggest that HFRT is safe and effective for treating patients with unresectable locally or systemically advanced who have poor prognostic factors. However, this study was limited by its retrospective design as well as its relatively short follow-up time. Further investigations using novel hypofractionated regimens combined with TKIs, antiangiogenic therapy, or immunotherapy are warranted.