Dosimetry, Efficacy, Safety, and Cost-Effectiveness of Proton Therapy for Non-Small Cell Lung Cancer

Simple Summary Non-small cell lung cancer (NSCLC) is the most common malignancy requiring radiotherapy (RT) as an important part of its multimodality treatment, the emergence of proton therapy may further allow for a sharper dose of build-up and drop-off com-pared to photon therapy, which has potentially improved clinical outcomes of NSCLC. Currently, there has been much emerging evidence focusing on dosimetry, efficacy, safety, and cost-effectiveness of proton therapy for non-small cell lung cancer (NSCLC) published, however, a comprehensive review comparing these therapies is, to date, lacking. This review focuses on these aspects of dosimetry, efficacy, safety, and cost-effectiveness of proton therapy for NSCLC. Abstract Non-small cell lung cancer (NSCLC) is the most common malignancy which requires radiotherapy (RT) as an important part of its multimodality treatment. With the advent of the novel irradiation technique, the clinical outcome of NSCLC patients who receive RT has been dramatically improved. The emergence of proton therapy, which allows for a sharper dose of build-up and drop-off compared to photon therapy, has potentially improved clinical outcomes of NSCLC. Dosimetry studies have indicated that proton therapy can significantly reduce the doses for normal organs, especially the lung, heart, and esophagus while maintaining similar robust target volume coverage in both early and advanced NSCLC compared with photon therapy. However, to date, most studies have been single-arm and concluded no significant changes in the efficacy for early-stage NSCLC by proton therapy over stereotactic body radiation therapy (SBRT). The results of proton therapy for advanced NSCLC in these studies were promising, with improved clinical outcomes and reduced toxicities compared with historical photon therapy data. However, these studies were also mainly single-arm and lacked a direct comparison between the two therapies. Currently, there is much emerging evidence focusing on dosimetry, efficacy, safety, and cost-effectiveness of proton therapy for NSCLC that has been published, however, a comprehensive review comparing these therapies is, to date, lacking. Thus, this review focuses on these aspects of proton therapy for NSCLC.


Introduction
Lung cancer is the most commonly diagnosed malignancy and cause of cancer-related death, and patients affected by non-small cell lung cancer (NSCLC) comprise > 80% of the patients with lung cancer [1]. Radiotherapy (RT) is an important part of the multimodality treatment for NSCLC. With the advent of novel irradiation techniques, such as

Dosimetry
Proton therapy has a completely different dose distribution compared with conventional photon beams. Unlike X-ray irradiation, the energy during proton therapy is deposited with depth and produces a maximum peak close to the end of the range [8]. The maximum peak is well known as the "Bragg peak", which may be used for dose increment for cancer therapy while reducing the radiation dose to the normal tissue [10,11]. Indeed, published dosimetry studies have indicated that proton therapy significantly reduces the dose to normal structures, especially in relation to the lung, heart, and esophagus, when maintaining similar robust target volume coverage to the clinical target volume (CTV) in both early and advanced NSCLC compared with photon therapy. Currently, passive scattered proton therapy (PSPT) and active pencil beam scanning (PBS) are the two forms of proton therapy in use [12]. The former form uses one or two levels of scatterer to widen the proton beam enough in order to cover the target, while the latter form uses magnets to deflect the proton beams directly, rather than a scatterer. The majority of comparative studies about dosimetry included patients with advanced NSCLC. Studies on the impacts of proton therapy on early-stage cancers were limited, as listed in Table 1. Those that do exist were mainly conducted in a retrospective manner, and include only two prospective studies [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27].

PSPT
Among the limited studies using proton therapy for early-stage NSCLC, PSPT has favorable CTV coverage and distributes lower mean doses to the normal tissues, compared with photon therapy. As reported by Wink et al. [15] in a retrospective study including 25 patients, CTV doses were more homogenous, and the dose directed to the spinal cord was lowest with PSPT, compared with IMRT, VMAT, and CyberKnife. Wang et al. [13] reported that in 24 patients with stage I NSCLC, the 95% isodose line of PSPT covered more CTV than that of 3D-CRT (86.4% versus 43.2%), and the mean dose to lung, heart, esophagus, and spinal cord was also lower, as well as V 5Gy and V 20Gy to the lungs. The two studies mentioned above were focused on early-stage patients undergoing a hypofractionated radiation therapy regimen (60)(61)(62)(63)(64)(65)(66) Gy in 8-10 fractions).  For locally advanced NSCLC, PSPT also reduces the dose to the critical normal tissues and prevent lower-dose target coverage. One of the only two prospective studies indicated that PSPT could keep the dose to the target at 70 Gy for patients with stage IA-IIIB NSCLC, while sparing the lung, compared with 3D-CRT/IMRT (mean lung dose, 13.5 Gy versus 18.9 Gy/16.4 Gy) [17]. The second prospective study was a phase III trial, reported by Giaddui T et al. comparing the dose parameters for 26 lung IMRT, with 26 proton PSPT plans. As a result, the dose parameters for the IMRT and PSPT plans were very close. However, the PSPT plans led to lower dose values for normal structures (including lung V 5Gy , 34.4% versus 47.2%; maximum spinal cord dose, 31.7 Gy versus 43.5 Gy; heart V 5Gy , 19% versus 47%; and heart V 30Gy , 11% versus 19%) [23]. The dosimetry comparative studies of PSPT for advanced-stage patients were mostly using conventional regimens (66-74 Gy in 33-37 fractions).
However, two respective comparative studies revealed similar or worse dose distribution to the lung or esophagus for PSPT. Wu et al. [22] reported that in 33 patients with stage III NSCLC, all of the dose parameters of proton therapy were lower than 3D-CRT, except for the esophageal dose, which was slightly higher than that of the photon plan (V 50Gy , 20.2 versus 16.6%), but the difference was not significant. Another study by Shusharina et al. [24] with 83 patients (II-IV stage NSCLC), reported that, although higher lung V 5Gy was observed for IMRT, whereas higher V 60Gy for was observed for PSPT, the mean lung dose was similar. However, these two studies were both retrospectives and may have been prone to selection bias.

PBS
PBS may have advantages compared with PSPT in terms of offering greater dose conformality [28]. The entry dose of PSPT is often unmodulated, even after using the layerstacking method [5]. Meanwhile, the movement of the target during PSPT causes dose distribution disturbances due to interplay and blurring effects, which leads to dose misses and unwanted doses to healthy organs. PBS generates more conformal high-dose volumes than PSPT, with significant sparing of nearby organs, and intensity-modulated proton therapy (IMPT) can be comprehended [29]. Gjyshi et al. [30] compared two independent cohorts with locally advanced NSCLC (86 received PSPT and 53 received IMPT) with data extracted from a prospective registry study, and found that lower mean radiation doses to the lungs (16.0 Gy versus 13.0 Gy, p < 0.001), heart (10.7 Gy versus 6.6 Gy, p = 0.004), and esophagus (27.4 Gy versus 21.8 Gy, p = 0.005) resulted in lower rates of pulmonary (28% versus 3%, p = 0.006) and cardiac (14% versus 0%, p = 0.05) toxicities for IMPT.
IMPT is also sensitive to uncertainties or target motion. Four-dimensional (4D)computed tomography (CT) ventilation imaging-guided proton therapy, based on breathing patterns, may be helpful for reducing uncertainties and dosing to the normal tissues [31][32][33]. IMPT via a deep-inspiration breath-hold, deformable image registration with daily adaptive proton therapy, and liver-ultrasound-based motion modeling may also provide additional benefits [34][35][36][37]. FLASH proton therapy which optimizes tissue-receiving dose rate distribution and dose distribution may also provide substantial improvements, compared to IMPT, for normal tissue sparing [38].
As displayed in Table 1, published dosimetry comparative studies with proton and photon therapy for IMPT were all retrospective studies with <30 cases. The only study for early-stage NSCLC (15 patients with centrally/superiorly located stage I NSCLC) was reported by Register et al., which revealed that IMPT and PSPT significantly reduced doses to the surrounding normal tissues while maintaining a high radiation dose focused on the tumor, compared with SBRT (total lung volume receiving 5 Gy, 10 Gy, and 20 Gy, respectively) [14]. The rest of the dosimetry studies included patients with stage III NSCLC, and consistent results were observed for IMPT with comparable, if not better, CTV dose homogeneity/coverage while sparing the lung, heart, spinal cord, and esophagus to a greater extent. In addition, IMPT allowed for further dose escalation, compared with photon therapy [16]. Zhang X et al. reported that IMPT might allow further dose escalation (a mean maximum tolerated dose to 83.5 Gy or 84.4 Gy) and prevent lower-dose target coverage for the treatment of stage IIIB NSCLC, while sparing more lung, heart, spinal cord, and esophagus, compared with IMRT, and with similar normal tissue sparing compared with PSPT [16]. Therefore, PBS, which is gradually replacing PSPT in the clinical practice of proton therapy, may potentially overcome the limitations of PSPT and reduce treatmentrelated toxicity.
Notably, some studies reported special characters for proton, compared with photon therapy. Palma G et al. [39] reported that in 178 patients with advanced NSCLC who were treated with PSPT/IMRT (66/74 Gy, conventional fractionation) with concurrent chemotherapy, significant dose differences of the heart and the lower lungs was found in the 40 patients who developed clinically symptomatic pneumonitis, compared with those without pneumonitis, which may substantiate potential factors in the development of pneumonitis. Harris et al. [40] retrospectively reported that in 160 (78 photons, 82 protons) patients with locally advanced NSCLC who were treated with chemoradiotherapy, among them, 40 (20 photons, 20 protons) patients exhibited grade ≥2 pneumonitis. After multivariate analysis, V 40Gy turns out to be statistically significant for proton and a potential pneumonitis predictor is V 40Gy ≤ 23%, and not V 20Gy or Dmean which are traditionally used in photon therapy. However, the dose-response of proton therapy for normal tissue complications has been validated as similar to that of photon therapy, based on a pneumonitis model [41]. Xiang et al. [42] identified 450,373 pediatric and adult patients with cancers (33.5% with 3D-CRT, 65.2% with IMRT, and 1.3% received proton therapy) from the National Cancer Database, and during a median follow-up of 5.1 years, the rate of diagnosed secondary cancer was 1.55% per year, suggesting that proton therapy was associated with lower risk of secondary cancer compared with IMRT (adjusted odds ratio 0.31, p < 0.0001). Further study with a long follow-up duration is needed.
In summary, proton therapy (both PSPT and PBS) has a dosimetry advantage compared with photon therapy both for early-stage or advanced NSCLC, both theoretically and clinically. This advantage leads to favorable or comparable CTV coverage with more homogenous dose distribution and more normal tissue sparing in most of the studies, and potentially with improved clinical outcomes involving efficacy and safety, which are then discussed below.

Efficacy and Safety
The clinical outcomes of proton therapy varied from study to study. Previously published prospective studies and nationwide retrospective studies involving proton therapy for NSCLC, with reported local control rate/failure rate/overall survival (OS)/progressionfree survival (PFS)/disease-free survival (DFS), are included and summarized in Table 2 for early-stage NSCLC [43][44][45][46][47][48] and in Table 3 for advanced-stage NSCLC [49][50][51][52][53][54][55][56]. For early-stage NSCLC, six prospective studies and one nationwide retrospective study were found. In addition, seven prospective studies and one nationwide retrospective study were found for advanced-stage NSCLC. Notably, the proton therapy was delivered via the form of PSPT or IMPT, and some studies were using both or were not indicated; for this case we only used "proton therapy" in the tables and the following context.

Early-Stage NSCLC
In a systematic literature review published for proton therapy treating early-stage lung cancer, including one phase II study, two prospective studies, and two retrospective studies published before the 2010s, the 2-year local control rate, OS, and cause-specific survival rates were 87%, 31-74%, and 58-86%, respectively [10]. In addition, the 5-year local control rate, OS, and cause-specific survival rates were 57%, 23%, and 46%, respectively [10]. As revealed by the studies listed in Table 2, including more recent studies, the 2-year local control rate was reported with 87-95%, and the 2-year OS and cause-specific survival rate were 42.9-74% and 86%, respectively. Pneumonitis was the major toxicity, while therapy-related toxicities of grade >3 were not common.    In particular, the largest prospective study was focused on hypo-fractionated proton therapy for 111 patients with stage I NSCLC, as accounted by Bush et al., where the clinical outcomes of the entire group improved as the prescription dose increased with a 4-year OS of 18% (for 51 Gy), 32% (for 60 Gy), and 51% (for 70 Gy). The rest of the prospective studies included a relatively small sample size (ranging from 21 to 43 patients). The studies by Iwata et al. (46) included 43 patients receiving proton therapy and 27 patients receiving carbon-ion therapy. For all of the 70 patients, the 4-year OS, local control, and PFS rates were 58%, 75%, and 46%, respectively, with no significant differences between the two regimens. Grade 3 pulmonary toxicity was observed in two patients [46]. The only nationwide retrospective study of PSPT was reported by Ohnishi et al. [48], which is the largest study, including 669 patients with stage I NSCLC. The median follow-up period was 38.2 months for all patients. The 3-year OS and PFS rates were 79.5% and 64.1%, respectively. The incidence of grade ≥ 3 pneumonitis and dermatitis were 1.7% and 0.4%, respectively. In addition, photon therapy may also be used in special circumstances. Kim et al. [58] retrospectively reviewed 30 patients suffering from complications, with stage I-II NSCLC and idiopathic pulmonary fibrosis (22 patients managed with X-ray and eight patients with proton therapy). During the follow-up (median 11 months), four patients who died within one month of the onset of pulmonary symptoms were all treated with X-ray. The 1-year OS was 46.4% for X-ray and 66.7% for proton therapy (p = 0.081). Nagata et al. [59] reported proton therapy (66 Gy in 10 fractions) for 48 patients with stage I ground-glass opacity (GGO)-type lung cancer, the 3-year OS, DFS, and local control were 91.7%, 85.4%, and 92.5%, respectively. Radiation pneumonitis was frequent (89.6%), followed by rib fracture and cough (both 27.1%) while all the complications were grade ≤ 2.
A direct comparative prospective study of proton therapy and photon therapy is now lacking for early-stage NSCLC. Li et al. [60] compare lung changes in patients with early-stage NSCLC after matching 23 pairs of stereotactic body radiation therapy with protons (SBPT)/SBRT, including five patients treated with both modalities. Normal lung responses following SBPT significantly increased in the early time (<6 months, median 3 months), and did not then change significantly thereafter; dose-defined lung inflammation occurred earlier compared with SBRT, while no significant difference in the maximum response was reported. These differences were the most pronounced in insensitive (response > 6 HU/Gy) patients. In a meta-analysis published in 2010 [3], which included five studies on proton therapy, the 5-year OS for proton therapy was 40%, which was significantly higher than conventional RT (20%) and similar to that for SBRT (42%) in stage I inoperable NSCLC. Proton therapy resulted in no grade 3/4 esophagitis, dyspnea, or treatment-related deaths [3]. Only four out of 336 patients had grade 3/4 pneumonitis [3]. Moreover, another meta-analysis published in 2017, which included 72 SBRT studies and nine hypo-fractionated proton studies (mostly single-arm) for the treatment of early-stage lung cancer. Proton therapy was associated with improved OS and PFS in univariate metaanalysis. However, the OS benefit did not reach statistical significance after multivariate meta-analysis, but the 3-year local control still favored proton therapy [5]. All of the studies included in the above two meta-analyses had a small sample size and were single-arm without direct comparison; the comparison being based on historical data. Therefore, the conclusion regarding the efficacy and safety of proton therapy over photon therapy should be further explored in prospective comparative studies.

Locally Advanced NSCLC
Studies with proton therapy for locally advanced NSCLC are limited. Most of these studies are single-armed, and studies presenting a direct comparison with photon therapy are also limited, as shown in Table 3. In the only randomized controlled trial (RCT) which compared IMRT (n = 92) with PSPT (n = 57), both with concurrent chemotherapy, PSPT resulted in less lung dose, of 5 to 10 Gy, while exposing more lung to ≥20 Gy. The heart was less exposed to all dose levels (5 to 80 Gy). The grade ≥ 3 radiation pneumonitis rate was 8.1% (IMRT, 6.5% versus PSPT, 10.5%) and corresponding local failure rates were 10.7% (IMRT, 10.9% versus PSPT, 10.5%) [53]. The historical data comparison in MD Anderson Cancer Center by Sejpal et al. [49], included 62 patients treated with chemotherapy and proton therapy (period 2006-2008), 74 patients with chemotherapy and 3D-CRT (period 2001-2003), and 66 patients with chemotherapy and IMRT (period 2003-2005). The median follow-up times were 15.2, 17.9, and 17.4 months, respectively. As a result, the rates of grade ≥ 3 pneumonitis and esophagitis were significantly lower (proton, 2%, and 5%; 3D-CRT, 30%, and 18%; IMRT, 9%, and 44%), despite the higher radiation dose in the proton group (74 Gy versus 63 Gy in the other groups). Kim et al. [61] retrospectively reviewed 223 patients with locally advanced NSCLC who received concurrent chemoradiotherapy (29 with PSPT and 194 with IMRT), and found that the lung V ≥5-20Gy and the mean dose were significantly lower in patients receiving PSPT than in those receiving IMRT (p < 0.001). Severe radiation-induced lymphopenia was associated with lung V 5Gy and worse 2-year OS, which still favors PSPT (odds ratio 0.13, p = 0.003). In another study by Kim et al. [62], 25 patients underwent PSPT and 194 patients underwent IMRT, and those patients undergoing PSPT exhibited less radiation exposure in the lung, heart, and spinal cord compared to IMRT. The 2-year locoregional control rates (IMRT 72.1% vs. PSPT 84.1%; p = 0.287), the rates of esophagitis (grade ≥ 3) (IMRT 8.2% vs. PSPT 20.0%; p = 0.073), and rates of radiation pneumonitis (grade ≥ 2) (IMRT 28.9% vs. PSPT 16.0%; p = 0.263) were all similar, although worse pulmonary function at the baseline was reported for patients receiving PSPT. The largest retrospective study of the National Cancer Database included patients with stage II and III NSCLC (photon 1549 and proton 309, after propensity-matched analysis), and here, proton therapy was associated with improved 5-year OS (22% versus 16%, p = 0.025) compared with photon radiotherapy [52].
Concurrent radio-chemotherapy with proton therapy is currently undergoing testing in a prospective manner for locally advanced NSCLC. The largest prospective study, by Nguyen et al. [50] included 21 patients with stages II and 113 patients with stage III NSCLC, who were treated with PSPT and chemotherapy. The median OS was 40.4 months and 30.4 months, respectively, with a corresponding 5-year DFS of 17.3% and 18.0%. One patient with esophagitis (grade 4) and 16 patients with grade 3 complications (pneumonitides in two cases, esophagitis in six cases, and dermatitides in eight cases) was noted. In an open-label, single-group phase 2 trial [55], 64 NSCLC patients (stage IIIA, 30; IIIB, 34) were enrolled and treated with concurrent chemotherapy (carboplatin-paclitaxel) and high dose PSPT (74 Gy). The median OS was 26.5 months (5-year OS, 29%) and 5-year PFS was 22%. The outcomes seem superior to previously published breakthrough results with photon RT for locally advanced NSCLC (median OS 16-17 months), but are comparable with the control arm of the recently updated PACIFIC trial [63][64][65]. The control arm in the PACIFIC trial had a median OS of 29.1 months, and a 5-year OS/PFS of 33.4%/19 %. However, patients with tumor progression or with grade 2 or higher pneumonitis were excluded from the study [65]. Distant failures (48%) were the main causes, compared with local (16%) and regional (8%) recurrence [55]. Acute toxic effects were all ≤ grade 3 (acute esophagitis in 36% and pneumonitis in 2% of patients). Late toxic effects were also recorded (including 2% grade 2 esophageal stricture, 2% grade 4 esophagitis, 28% ≤ grades 3 pneumonitis, 3% bronchial stricture, and 2% grade 4 bronchial fistula). There were no acute or late grade 5 toxic effects [55].
The prospective investigation of a radical regimen with hypo-fractionated or doseescalation for proton therapy turned out to be well tolerated. Hoppe et al. [56] reported a multicenter phase I trial that enrolled 18 patients with stage II/III NSCLC, although the study closed early because of slow accrual and competing enrollment with no maximum tolerated dose identified. Proton therapy delivered at 2.5 Gy per fraction in five patients, 3 Gy per fraction in five patients, 3.53 Gy per fraction in seven patients, and 4 Gy per fraction in 1 patient to a total dose of 60 Gy resulted in only 2 severe adverse events attributed to chemotherapy occurred among seven patients treated at 3.53 Gy per fraction. The results indicated that hypo-fractionated proton therapy, combined with concurrent chemotherapy, has an acceptable toxicity profile. Hoppe et al. [51] reported a phase II study for dose-escalated proton therapy with concurrent chemotherapy, 14 patients with 9 stage IIIA and 5 stages IIIB NSCLC were included, and the dose-escalation of 74 to 80 Gy was also well-tolerated. The median OS was 33 months with a median PFS of 14 months. The 2-year OS rate was 57% and the 2-year PFS rate was 25%. Late grade 3 gastrointestinal and pulmonary toxicity was noted in one patient, while no grade 3 acute toxicities related to proton therapy. In addition, Ohnishi et al. [66] retrospectively reported that in 45 patients with stage III NSCLC managed with PSPT (74 Gy, concurrent chemotherapy), the 3-year and 5-year OS/PFS rates were reported with 63.7%/22.2% and 38.8%/17.7%, respectively, with a median of 49.1/13.1 months. No grade 4/5 acute/late non-hematologic toxicities were observed.
In summary, photon therapy was promising for locally advanced NSCLC with improved clinical outcomes and reduced toxicity when compared with historical photon therapy data, although the direct comparison was limited. Toxicities were acceptable, and pneumonitis/esophagitis were the most common observed toxicities. Rates of severe (grade 3) toxicities of proton therapy were lower than in photon therapy in the retrospective study, but this was not the case in the only RCT [53]. Further exploration of concurrent radio-chemotherapy/hypo-fractionated or dose-escalation regimen in the setting of PBS is ongoing (such as the ongoing RCT: RTOG 13-08) [23], and direct comparison is warranted.

Cost-Effectiveness
Currently, proton therapy is being used as a treatment for various cancers [70]. However, owing to low cost-effectiveness, the necessity of proton therapy was discussed in several studies [70]. Compared with photon therapy, the initial cost was 2.4-fold higher for proton therapy, however, after adding the costs of treating adverse effects, the total cost was reduced by 2.6-fold for proton therapy [70,71]. In a recent report using an influence diagram to model for radiation delivery in lung cancer, the overall costs (radiation plus toxicity costs) and upfront proton treatment costs exceeded that of photons [72]. The relatively lower rate of pneumonitis and esophagitis rates help protons to recover some of the total cost. Peeters et al. [73] described higher costs for the combined proton and lower costs for the photon, and the cost for lung cancer between particle and photon therapies involves a relatively small difference. Grutters et al. [74] analyzed the cost-effectiveness in inoperable stage I NSCLC, costs for quality-adjusted life years (QALYs) of proton therapy, carbon-ion therapy, 3DCRT, and SBRT were 2.33, 2.67, 1.98, and 2.59, respectively, which is the lowest for carbon-ion therapy. Grutters et al. [74] recommended not adopting proton as a standard treatment for NSCLC. Though current costs favor photon therapy in most studies, the preference for proton therapy may be found with relatively small reductions in the cost of proton therapy [72]. Therefore, it is hard to draw a conclusion now, based on the present limited evidence of cost-effectiveness for proton therapy over other therapies in treating lung cancer. More evidence is needed to support evidence-based treatment decisions [74].

Perspective
In recent years, the high rate of local failure and tumor recurrence in NSCLC was still a hard-hitting issue, though immunotherapy and targeted therapies developed rapidly in the treatment of NSCLC, [12,75]. Proton therapy is expected to further decrease the local tumor recurrence and reduce the toxicities, especially in patients with pulmonary disease/dysfunction. Despite the uncertainty of the proton range of patients with NSCLC, mitigation of the temporal effects, and potential dose discrepancies, proton therapy still needs to be fully integrated. Due to the limitations of this review, which are that the review only included selected studies but not all retrospective studies and did not compare or analyze the quality/limitation of each selected study, there is currently a lack of robust evidence to indicate its clinical superiority. Meanwhile, the cost of proton therapy is higher than that of photon therapy. Therefore, it is expected that the cost-effectiveness will need to be improved before proton therapy is routinely recommended. Furthermore, specific regimens of hypo-fractionated or dose-escalation for proton therapy (especially PBS) are warranted in further studies.

Conclusions
Proton therapy is a promising treatment for NSCLC, while direct comparisons of dosimetry, efficacy, and safety, and cost-effectiveness with photon therapy in prospective studies are warranted before proton therapy can be routinely recommended.

Conflicts of Interest:
The authors declare no conflict of interest.