3. Discussion
We report on the utilization of hypofractionated RT in a pooled patient cohort of 71 patients with ATC. To our knowledge, this is one of the largest studies reported to date, evaluating hypofractionated RT that was defined as a single dose per fraction ≥2.5 Gy [
12,
13,
17].
The outcomes concerning OS and treatment-related toxicity reported in our pooled analysis are consistent with previous reports, with the majority of ATC patients presenting with symptomatic or metastatic disease. Improved OS in our cohort was observed in patients receiving multimodal treatment (p = 0.006) and male patients (p = 0.04). Administering ChT concurrent to hypofractionated RT showed a survival benefit of more than 30% at 12 months but was not an independent predictor (p = 0.327). The results of the pooled data analysis suggest that a total dose of EQD2 ≥50 Gy (p = 0.014) and multimodal treatment (p < 0.001) correlate with longer survival and, hence, are crucial for favorable OS.
When applied in ATC, conventional RT has been shown to provide symptom palliation with similar outcomes compared to conventional RT regarding local control [
6,
12,
13,
17]. In this context, Oweida et al. [
11] investigated radiosensitivity toward hypofractionated RT of human ATC cell lines in an orthotopic mouse model [
11,
18] following the in vitro characterization of the levels of radiosensitivity based on genetic profiling of the ATC cell lines. The definition of hypofractionated RT at ≥2.5 Gy per fraction is aligned with our treatment protocol. A 51.8-fold decrease in local tumor growth (
p = 0.0097) assessed by average photon radiance (
p = 0.0094) in vivo at day 36 was reported in that study compared to the control, whereas conventional RT showed a 6.7-fold decrease (
p = 0.0057), respectively. In addition, hypofractionated RT treated mice had significantly longer OS than conventionally irradiated mice (HR = 6.049, 95% CI 1.863–28.05,
p < 0.001) and a decreased rate of pulmonary metastases (
p < 0.001), resulting in a strong preclinical rationale for the utilization of hypofractionated RT concepts.
To date, however, the use of hypofractionated RT in the treatment for ATC remains highly controversial. It is still mostly administered in palliative setting with a common cumulative dose ≤30 Gy [
6]. Despite extensive research, studies comparing differently fractionated RT regimens for ATC are not available. For this purpose, we have investigated hypofractionation as an integral part of ATC treatment. Due to its rapid progression and the early onset of metastatic disease, management of ATC patients requires a multimodal approach including surgical resection of the primary tumor followed by chemoradiation [
5,
6,
7].
The most recent study on ATC of Fan et al. [
19] provided a comprehensive retrospective analysis of different outcomes in 104 ATC patients treated in a multimodal approach, which was administered to a total of 51% of patients and had a significant association (
p = 0.017) with a decreased risk of local disease progression, but no association with OS was found. Multimodal treatment approaches such as surgery followed by concurrent chemoradiotherapy have been shown to be significantly relevant for the beneficial OS as an independent predictor by Glaser et al. [
20]. Similar findings were reported by several authors [
12,
20,
21,
22,
23] and may be attributable to lower recurrence rate [
24] and a decrease in local complication rate caused by impending of trachea or damage to esophagus and carotid artery [
23,
25]. Our single center data as well as our pooled analysis supports the multimodal treatment approach (
p = 0.006,
p < 0.001).
However, normofractionated RT remains the standard care in these studies, and data evaluating other fractionation regimens such as hypofractionation are limited [
20,
21,
22,
23,
26]. Conversely, studies gathered by systematic review investigated the integration of hypofractionation into the treatment. Nachalon et al. [
14] investigated hypofractionated RT in 23 patients with ATC (surgical resection performed in 22%) and reported ChT to have a significant effect on survival (
p = 0.01; administered to 48% of all patients). Stavas et al. [
12] applied hypofractionated RT to 17 ATC patients in combination with surgery (82%) and ChT (88%-paclitaxel with or without carboplatin). Notably, Stavas et al. [
12] and Nachalon et al. [
14] do also stand out with their reported survival rates of 9.3 (range: 4.6–14) and 6 (range 2.1–9.8) months, respectively. These OS-rates are comparable to what has been reported for the entire cohort by e.g., Fan et al. [
19] (seven months: 95%; CI: 4.5–9.5 months), where hyperfractionation and conventional fractionation regimens were used instead. Therefore, integration of hypofractionated RT into multimodal treatment could be considered for patients with ATC.
Apart from multimodal approaches, one of the crucial findings concerning radiotherapy for ATC was a significant dose-response relation [
20,
26,
27]. Wendler et al. [
26] showed the dose-response relation in a multi-center study for a cohort consisting of 100 patients with a total EBRT > 40 Gy (HR = 0.34, 95% CI 0.15–0.76,
p = 0.008).
Large-scale analyses of patients from National Cancer Data Base by Glaser et al. [
20] or Pezzi et al. [
27] showed improved OS to be associated with high-dose RT in exceed of 59.3 Gy (HR = 0.67,
p < 0.005) and 59 Gy (
p = 0.008), respectively. These results are comparable to our findings in both, single center and pooled data evaluation with an EQD2 > 50 Gy being associated with longer OS. Importantly, data of Nachalon et al. [
14] on the beneficial outcome of ATC patients treated with hypofractionated RT in curative intention (
p < 0.001) possibly implies comparable dose-response relation given different irradiation dosages of the gross tumors (70 Gy vs. 50–63 Gy vs. <30 Gy). Nevertheless, decisions for specific treatments were made based on individual characteristics of patients, including performance status, disease progression and resectability. Compared to our data, Takahashi et al. [
13] similarly reported a total dose of >50 Gy (
p = 0.049) to correlate with longer OS in the univariate analysis. In order to compare normofractionated to hypofractionated RT, we performed a PSM analysis based on the same database assessment protocol with a 1:2 matching. After exclusion of palliative treatment and adjustment for performance status and gender, hypofractionated RT appears to be non-inferior to normofractionated RT concerning OS. Although, ATC is thought to be relatively radioresistant, treatment response could be achieved with sufficient cumulative radiation doses using hypofractioned regimes.
Development of distant metastases is a common part of disease progression in patients with ATC and can thus be a limiting factor for therapy related decisions. It is considered a significant risk factor for the survival [
28]. Correspondingly, Stavas et al. [
12] demonstrated a difference in the median OS for those patients with and without distant metastases (6.4 months vs. 14.2 months), respectively. This is also comparable with the results on metastatic status that were found in the studies mentioned previously [
20,
21,
26,
27]. In contrast, however, Wang et al. [
16] and our study found no impact of TNM stage on progression-free survival or OS.
In addition, Quality of life (QoL) remains one the most important therapy goals in ATC and sufficient palliation of symptoms impacts OS and PFS. Indeed, Sugitani et al. [
28] evaluated 677 patients with ATC from 38 different institutions and identified presence of acute local symptoms, such as severe dysphonia, dysphagia, dyspnea, and progressive tumor growth <1 month (
p = 0.0014), as significant risk for shorter OS in both univariate and multivariate analysis. Correspondingly, hypofractionation was reported to achieve local control in 71% of patients in an Australian study of So et al. [
17]. It was administered to a cohort of 14 patients, who had a distant metastatic disease in 50%. In total, several studies [
12,
13,
16,
17] gathered by systematic review showed that hypofractionation can sufficiently provide an acceptable local control rate of 71–82% at the time of the last follow-up or death. This is comparable to the study mentioned previously [
19] and not inferior to the results of single or combined modality treatment of Veness et al. [
29]. In our study, however, we found no local progression during RT or within follow-up (≤12 months).
Based on our data, irradiation with higher dosages per single fraction over a shorter period of time is sufficient to effectively reduce primary tumor volume. Importantly, radiotherapy-induced acute and late toxicities need to be considered using alternative fractionation regimens [
30]. We found a manageable treatment-related toxicity of hypofractionated RT in our single center cohort as well as studies included into systematic review [
12,
13,
14,
16,
17]. These results, especially of Stavas et al. [
12], are similar to our single center data and seem to have more tolerable toxicity profiles than in the previously mentioned studies. On the contrary, toxicity rates obtained in the study of Takahashi et al. [
13] excel across the studies included in the systematic review. The authors used an ultra-hypofractionated RT in ATC patients with a median dose per fraction of 5 Gy [
13]. Therefore, patients in that study developed acute grade 3 dysphagia, mucositis, and dermatitis in 26%, 5%, and 5% of cases, respectively, in the hypofractionated RT group (
n = 19), but also one case of grade 4 toxicity due to the injury of trachea and one case of grade 5 injury of carotid artery (18%) were reported. We found that hypofractionated RT (≥4Gy/fr) is not beneficial for OS compared to moderate hypofractionated RT. Importantly, RT with a single dose of 2.50 to 3.50 Gy per fraction shows a trend of more favorable survival compared with ≥4 Gy (12-month survival rate of 23 versus 6%,
p = 0.077). Currently, the extent to which ultra-hypofractionation is associated with greater toxicity rates is controversial, as it has been reported for several other cancer subtypes [
31].
Historically, hyperfractionated RT was considered as an alternative to normo- or hypofractionated RT regimen [
32]. Dandekar et al. [
10] treated 39 patients (80% with ATC) with hyperfractionated RT and were confronted with higher toxicity rates, when compared to our results: 38%, 12%, 30%, and 30% of grade 3 erythema, desquamation, dysphagia and esophagitis were reported. Respectively, grade 4 toxicity was reported in for 18%, 9%, 44%, and 47% of cases (
n = 34/39). In addition, local control (complete/partial response and stable disease) was reported in a total of 85% of patients in that research group, which is comparable to the reported results of studies from our systematic review.
With respect to the pathogenesis of radiation-induced toxicities, irradiation dosage may not be the only influence on the rate of adverse events [
30]. The actual irradiation technique impacts radiation-induced acute and late toxicities. E.g., IMRT is reported to be safer by delivering higher doses of irradiation (66 Gy vs. 60 Gy 3D-CRT,
p = 0.005) with a better homogeneity than 3D-CRT, sparing high-risk regions (e.g. salivary gland, myelon) and to have a beneficial impact on OS and progression-free survival (PFS) (OS: HR = 0.30,
p = 0.005; PFS: HR = 0.33,
p = 0.005) [
33]. Potential escalations are therefore possible because of a lower rate on severe toxicities—a total of 2 patients was reported to develop CTCAE Grade 3 dermatitis after IMRT by Park et al. [
33]. In our study, however, IMRT technique did not achieve significance for beneficial OS in the univariate analysis (
p = 0.701).
Several limitations must be considered for our study such as the retrospective nature and, therefore, a risk of including hidden selection biases. Despite the small patient numbers and long recruiting time in our single center cohort, our pooled analysis remains one of the largest studies reported to date.
Hypofractionated RT shows manageable toxicity with acceptable local control even in dose-escalated regimens. Further prospective studies need to address hypofractionated RT in the context of multimodal treatment of ATC.
