Introduction

Lung cancer is the leading cause of cancer-related death worldwide being responsible of one quarter of all deaths [1]. Non-small cell lung cancer (NSCLC) represents the majority of lung cancer diagnosis, and most of these are in locally advanced stage, half of which unresectable [2, 3]. Definitive concurrent chemo-radiation therapy (CRT) represents the cornerstone of curative intent treatment in unresectable patients [4]. The standard radiation scheme is 60–66 Gy delivered in 30–33 fractions [5].

Nevertheless, after standard radiation doses of CRT, the risk of local recurrence remains high and 5-year survival is poor. [6, 7]. Improving outcomes for these unfavorable patients still remains challenging. Radiation Therapy Oncology Group (RTOG) 0617 randomized phase 3 study failed to show a beneficial effect in survival when delivering higher dose of RT at 2 Gy per fraction [8]. In locally advanced NSCLC, a strong correlation between survival and overall treatment time was found [9, 10]. A strategy to increase the biological effective dose (BED) of RT could be obtained using hypofractionated regimens characterized by a reduction in the overall treatment time with dose per fraction higher than 2 Gy [11,12,13].

Considering the technological worldwide implementation in RT facilities and the issue of maintaining limited waiting list for the patients, hypofractionated was adopted in many centers and in several clinical settings, including lung cancer [14].

Aim of the current narrative review is to assess the benefit of hypofractionated RT, with or without concurrent chemotherapy (CT), in terms of effectiveness and feasibility in the treatment of locally advanced NSCLC.

Materials and methods

All studies included in the present review satisfied the following criteria: (1) patients with locally advanced NSCLC, (2) patients treated with hypofractionated RT with radical intent, (3) with a minimal dose per fraction of 2.4 Gy, (4) patients treated with hypofractionated RT with or without concomitant CT, (5) studies published from 2007 onwards, (6) English manuscripts. Studies were excluded if no detailed information (e.g., clinical outcomes, toxicity) were reported. Meta-analysis, review articles were excluded from the analysis.

A detailed literature search strategy was developed a priori. Key words and subject terms used in the search included: (“lung neoplasms”[MeSH Terms] OR (“lung”[All Fields] AND “neoplasms”[All Fields]) OR “lung neoplasms”[All Fields] OR (“lung”[All Fields] AND “cancer”[All Fields]) OR “lung cancer”[All Fields]) AND (“drug therapy”[Subheading] OR (“drug”[All Fields] AND “therapy”[All Fields]) OR “drug therapy”[All Fields] OR “chemotherapy”[All Fields] OR “drug therapy”[MeSH Terms] OR (“drug”[All Fields] AND “therapy”[All Fields]) OR “chemotherapy”[All Fields]) AND (“radiotherapy”[Subheading] OR “radiotherapy”[All Fields] OR “radiotherapy”[MeSH Terms]) AND locally[All Fields] AND advanced[All Fields]) OR “ Hypofractionated Radiotherapy” [All Fields] AND “lung neoplasm”[All Fields].

The search strategy was applied to Ovid MEDLINE (R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE (R) 1946 to present. The grey literature was searched by applying a similar strategy to Google Scholar, PubMed and the Proquest Dissertation and Theses databases. Additional references were identified by a manual review of the reference lists of included articles.

Studies that met inclusion criteria were systematically analyzed by all the authors. Disagreement was resolved by consensus; if consensus could not be achieved, the study coordinator provided an assessment of eligibility.

For data extraction, all the papers were scrutinized for the following information: study design (retrospective, prospective); number of patients; number of patients comprise in study with concomitant CT; oncological treatment strategy (RT alone and/or sequential CRT, versus concurrent CRT); total dose; dose per fraction; definition of acute and late toxicity profile clinical outcomes.

Results

Twenty-nine studies [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43] of hypofractionated RT in locally advanced NSCLC with or without concurrent CT that met the inclusion criteria were identified, for a total of 2614 patients. Among these studies, nine were retrospective, while 20 were prospective. Of these, eight were phase I trials, and ten were phase II trials.

Clinical outcomes in non-concurrent chemotherapy group

Seventeen studies [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31], for a total of 1730 patients, without concurrent CT that met the inclusion criteria were identified. Three of them predicted a comparison arm with concurrent CT [15, 16, 26]. CT was administered in 15 studies, generally with neo-adjuvant intent (Table 1). In one study, no details regarding CT were reported [29]. The most common CT agents employed were cisplatin (70.5%), predominantly in doublet with, gemcitabine or vinorelbine.

Table 1 Studies of hypofractionated radiation therapy with non-concurrent chemotherapy in locally advanced non-small cell lung cancer
Full size table

The most common RT technique was 3D-conformal radiation therapy (3D-CRT) (64.7%), whereas intensity-modulated RT (IMRT) was employed in only three studies (23.5%); in one study patients were treated with protons. The delivered dose ranged from 45 to 85.5 Gy, with a dose per fraction ranging from 2.4 to 4 Gy. The equivalent doses at 2-Gy fractions (EQD2) calculated considering an alpha/beta ratio of 10 Gy and 3 Gy, according to Fowler et al. [44], ranged from 48.8 to 95.6 Gy, and from 54 to 109.8 Gy, respectively. Actuarial 2-year progression free survival (PFS), which was reported in 12 studies, ranged from 13 to 57.8%, and 1-, 2- and 3-year overall survival (OS) ranged from 51.3 to 95%, from 22 to 68.7%, and from 7 to 32%, respectively.

In only three studies (17.6%), elective lymph nodes were irradiated. Acute esophagitis occured in 0–15% of patients, while late esophageal toxicity occurred in 0–16%. Regarding pulmonary toxicity, acute pneumonitis occured in 0–44%, whereas late pneumonitis occured in 0–47%, most commonly ≤ Grade 3.

Clinical outcomes in concurrent chemotherapy group

Sixteen studies of hypofractionated RT [15, 16, 26, 30, 31] delivered concomitantly with CT were identified, for a total of 884 treated patients (Table 2). The most common CT agents employed were cisplatin 50%, carboplatin 25% and vinorelbine 37.5%; other agents employed less frequently were, liposomal doxorubicin, docetaxel, gemcitabine, cetuximab and ALK-inhibitors. The most common RT technique was 3D-CRT (68.75%), whereas IMRT was employed in 31.25% of the studies. The delivered dose ranged from 52.5 to 75 Gy, with a dose per fraction ranging from 2.4 to 3.5 Gy. The equivalent doses at 2-Gy fractions (EQD2) calculated considering an alpha/beta ratio of 10 Gy and 3 Gy, ranged from 58.4 to 81.2 Gy, and from 63.2 to 90 Gy, respectively. Two studies included the elective nodal irradiation. Actuarial 2-year PFS, which was reported in seven articles, ranged from 19 to 57.8%. OS at 1, 2 and 3 years ranged from 28 to 95%, from 38.6 to 68.7%, and from 31 to 44%, respectively. Two studies did not report any survival results [37, 39]. Acute esophagitis occurred in 0–41.7%, while late esophageal toxicity occurred in 0–8.3%.

Table 2 Studies of hypofractionated radiation therapy concomitant chemotherapy in locally advanced non-small cell lung cancer
Full size table

The overall incidence of acute pneumonitis ranged from 0 to 23%, whereas late pneumonitis occured in 0–47%, similarly to the non-concomitant CT group.

Discussion

Most of NSCLC patients with locally advanced disease have poor prognosis [45]. A key element for lung cancer treatment is the achievement of local control. In fact, the treatment failure of the primary NSCLC has a detrimental impact in terms of PFS, metastasis-free survival and OS [46].

To date, the standard of care is represented by RT using conventional fractionation, with concurrent or sequential platinum-based CT [47]. Several studies hypothesized the potential usefulness of a dose-escalated approach to improve the oncological outcomes. In the RTOG-0617 trial, the standard dose RT was compared to high-dose conformal RT with concurrent and consolidation platinum-based CT. At a median follow-up of 22.9 months, 74 Gy given in 2 Gy per fractions with concurrent CT showed to be not better than 60 Gy for patients affected by stage III NSCLC. The authors concluded that high-dose conformal RT might be potentially harmful [8].

On the other hand, it has been demonstrated that a long duration of RT in NSCLC seems to be detrimental in terms of tumor control and survival, due to accelerated repopulation of tumor cells, with a loss of local control of 1.66% per day of lengthening over 6 weeks [9, 10]. Thus, alternative strategies to increase the effective dose by reducing the overall treatment time could be achieved with hypofractionated regimens. In the present review, we analyzed the available literature data concerning the role of hypofractionated RT in the management of locally advanced NSCLC distinguishing two main groups: (1) non-concurrent CT patients and (2) concomitant CT patients.

Looking at the first patients’ category, 1-, 2- and 3-year OS ranged between 51 and 95%, 22 and 68%, and 7 and 32%, respectively; 2-year PFS varied from 13 to 58%. These results seem promising if compared to the outcomes of conventional fractionation by historical cohorts. Specifically, in the meta-analysis by Auperin et al. [5], exploring the impact of concomitant versus sequential CT in combination with conventional RT in locally advanced NSCLC, a 3-year OS rate of 18.1% was registered in the non-concurrent arm. In the same meta-analysis [5], there was a significant benefit of CRT as compared with sequential CRT with an absolute survival benefit of 5.7% at 3 years, and an increased survival to 23.8% in the concomitant arm. The PFS analysis showed an absolute benefit of 2.9% at 3 years, increasing the PFS from 13.1 to 16.0% with concomitant CRT. Acute esophageal toxicity (Grade 3–4) was higher in concomitant CRT comparing to the sequential strategy (18% versus 4%). There was no significant difference regarding pulmonary toxicity.

Analyzing the clinical outcomes of hypofractionated RT administered concomitantly with CT, 3-year OS ranged from 31 to 44%, whereas 2-year PFS varied between 19 and 58%. Speculatively, potential higher rates of oncological outcomes compared to conventional CRT could be expected using a hypofractionation regimen in non-concurrent than in concomitant hypofractionated RT for NSCLC. This phenomenon could be related to a potential higher sensitivity of NSCLC cells to higher radiation dose per fraction. Obviously, these last assumptions need to be confirmed and a direct comparison between different fractionation schedules requires well-designed randomized studies before to draw any kind of definitive conclusion.

Radiobiological modelings suggest that shortened treatment schedules might increase the risk of late toxicity. These last concerns are heightened with hypofractionated regimens when larger doses per fraction are used, particularly in the context of concurrent CRT [48]. In the available data here reported, acute esophagitis occurred in 0–15% in the non-concurrent group comparing to 0–41.7% in the concomitant arm. Regarding pulmonary toxicity, acute pneumonitis occurred in 0–44%, whereas late pneumonitis was recorded until to 47% of cases, most commonly ≤ Grade 3. A similar pulmonary toxicity profile was noted in the non-concomitant hypofractionated group.

Conclusions

In summary, in the current review of the literature an extreme heterogeneity was noted in terms of the RT-treatment schedules, in terms of the adopted techniques as well as the administered drugs in combination with irradiation. However, several data appear to be more robust: an overall low toxicity profile was documented both in the concomitant and non-concomitant chemotherapy groups, when using RT schedule of 2.7–4.0 Gy/fraction.

Our review suggests a potential positive relationship between the overall treatment time with the PFS and the OS in NSCLC. However, the efficacy of hypofractionated RT schemas has to be proved yet in prospective trials.. These conditions associated with the rapid evolution of technologies and the hypothesis of association with new target agents and immunotherapy could constitute, in the future, a potential new frontier in the treatment of locally advanced NSCLC.