Abstract
Background
Anaplastic thyroid carcinoma (ATC) is a rare cancer and has a poor prognosis. Several radiation protocols have been reported, but the results were not satisfactory.
Objective
The aim of this study was to determine the effect of hypofractionated radiotherapy.
Methods
Thirty-three patients who received radiotherapy for ATC between January 2000 and December 2014 were retrospectively included. We defined hypofractionated radiotherapy as a single dose ≥5 Gy.
Results
Nineteen patients were treated with hypofractionated radiotherapy. Twenty-eight patients died, and 27 of those patients died from ATC. Sixteen patients died from distant metastasis and 6 from local recurrence. In the hypofractionated radiotherapy group, local recurrence occurred in 5 patients and 1 of them died from active bleeding from a local tumor. There was local recurrence in 7 patients who received the other protocol, and 5 of them died from asphyxiation, active bleeding, or uncontrollable growth of a local tumor on the neck. The median overall survival (OS) was 5 months. In multivariate analysis, patients who received an equivalent dose in 2-Gy fractions (EQD2) ≥50 Gy had significantly better OS (p = 0.016). In univariate analysis, patients who received hypofractionated radiotherapy did not have significantly better OS (p = 0.872) or local control (p = 0.090). The χ2 test showed that significantly fewer patients died from local recurrence in the hypofractionated radiotherapy group (p = 0.025).
Conclusions
Multivariate analysis showed that an EQD2 ≥50 Gy resulted in better OS, and hypofractionated radiotherapy decreased the rate of mortality from local recurrence.
Key Words: Anaplastic thyroid carcinoma, Hypofractionated radiotherapy, Radiotherapy, Radiation therapy
Introduction
Anaplastic thyroid carcinoma (ATC) is a rare cancer and has a poor prognosis. Thyroid carcinoma accounts for only 1% of all malignant neoplasms, and ATC accounts for only 1.7% of all thyroid cancers [1]. All ATC patients are diagnosed as stage IV. About half of the patients have distant metastasis at presentation, and the lung is the most common site [2]. The median survival and the 1-year overall survival (OS) rate have been reported to be 5 months and 20%, respectively [3]. The most common causes of death have been reported to be primary tumor growth, asphyxiation, or active bleeding from the neck [4, 5]. Sugitani et al. [6] showed by multivariate analysis that surgery and external beam radiotherapy ≥40 Gy were predictors of significantly better OS for patients with any stage of ATC and that chemotherapy was a predictor of significantly better OS for patients with stage IVB or IVC. Dumke et al. [7] reported that a radiation dose ≥50 Gy was a predictor of improved OS. Dandekar et al. [8] reported that 31 patients received a protocol in which the total planned dose was 60.8 Gy in twice-daily fractions of 1.8 and 2 Gy and that local control (LC) was achieved in 27 patients, but the median OS was only 70 days. Stavas et al. [9] used a dose of 54 Gy in 18 fractions, and LC was maintained in 14 of 17 patients. The median OS in their study was 9.3 months. Glaser et al. [10] and Pezzi et al. [11] reported that radiotherapy with a high total dose improved the OS of ATC patients.
Several radiation protocols have been tried, but the results have not been satisfactory. Since ATC has characteristics of rapid growth and poor radiosensitivity, we thought that hypofractionated radiotherapy would be better and treated ATC patients with 50 Gy in 10 fractions 3 times a week. The aim of this study was to determine the treatment results and side effects of hypofractionated radiotherapy for ATC.
Patients and Methods
Patients
We retrospectively reviewed a clinical database of ATC patients who received radiotherapy in our institution between January 2000 and December 2014.
Treatment
Twelve patients received total or partial thyroidectomy. Eleven patients received surgery before radiotherapy, and 1 patient received total thyroidectomy after radiotherapy due to local recurrence.
The radiation plan was created with a 2D planning system in 2000 (XIMATRON, Varian Medical Systems) and with a 3D planning system from 2001 on (CAD Plan/Eclips, Varian Medical Systems). The patients who received R0 or R1 resection were treated with 2 Gy per fraction (Gy/fr), and the other patients (R2 resection, recurrence after surgery, and inoperable) were treated with 50 Gy in 10 fractions 3 times a week. However, the attending radiation oncologist modulated the radiation strategy in accordance with the condition of the patient.
Seventeen patients received chemotherapy and 15 of those patients received concurrent chemoradiotherapy. Six patients received carboplatin and paclitaxel, 3 patients received nedaplatin and 5-fluorouracil, 2 patients received nedaplatin and etoposide, 2 patients received paclitaxel, and the other patients received several protocols as concurrent chemoradiotherapy. Two patients received chemotherapy only before radiotherapy. One patient received carboplatin and paclitaxel and the other patient received paclitaxel.
Endpoints and Follow-Up
The primary endpoint was OS. The secondary endpoints were LC and avoidance of death from local recurrence (asphyxiation, active bleeding, or uncontrollable growth of a local tumor on the neck). OS was calculated from the first day of initial treatment to death. LC was calculated from the first day of radiation to the day of local recurrence. Local recurrence was defined as enlargement of the neck mass by physical findings or image inspection, additional surgery for resection or tracheotomy, and death from asphyxiation or active bleeding from the neck.
Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Statistical Analysis
JMP® pro v.12.2.0 (SAS Institute) was used. OS and LC were calculated using the Kaplan-Meier method and compared between subgroups using the log-rank test. Predictors for OS and LC were investigated by the Cox proportional hazards model. Factors with a p value < 0.1 were included in multivariate analysis. We did not try multivariate analysis for LC because there was not a sufficient number of patients with local recurrence. Frequencies were compared using the χ2 test. A p value < 0.05 was defined as significant.
Equivalent dose in 2-Gy fractions (EQD2) was calculated by the following formula: EQD2 = D × (d + α/β)/(2 + α/β), where D is total dose, d is dose per fraction, and α/β is 10.
Results
Patient characteristics are summarized in Table 1.
Table 1.
Patient characteristics
| Age, years | |
| Median | 68 |
| Range | 41–87 |
| Gender | |
| Male | 21 (64%) |
| Female | 12 (36%) |
| Performance status | |
| 0–1 | 14 (42%) |
| 2–3 | 19 (58%) |
| Stage | |
| IVA | 4 (12%) |
| IVB | 13 (39%) |
| IVC | 13 (39%) |
| Other1 | 3 (9%) |
| Total or partial thyroidectomy | |
| Yes | 13 (39%) |
| No | 20 (61%) |
| Chemotherapy | |
| Yes | 17 (52%) |
| No | 16 (48%) |
| Concurrent chemoradiotherapy | |
| Yes | 15 (45%) |
| No | 18 (55%) |
| Total radiation dose, Gy | |
| Median | 50 |
| Range | 5–74 |
| Total EQD2, Gy | |
| Median | 62.5 |
| Range | 6.2–86.5 |
| Single radiation dose | |
| <5 Gy | 14 (42%) |
| ≥5 Gy | 19 (58%) |
| Radiation field of regional cervical lymph nodes | |
| Yes | 11 (33%) |
| No | 22 (67%) |
EQD2, equivalent dose in 2-Gy fractions.
Anaplastic change in the neck after surgery for differentiated thyroid cancer.
Radiotherapy
Nineteen patients received ≥5 Gy/fr, and we defined this group as the hypofractionated radiotherapy group. One patient received 6 Gy/fr, but she could receive only 1 fraction because her general condition became worse. One patient received 44 Gy in 22 fractions for 5 days a week at regional cervical lymph nodes and 30 Gy in 10 fractions at the primary lesion for 3 days a week as a concomitant boost. Seventeen patients received 5 Gy/fr for 3 days a week with a median total dose of 50 Gy (range 5–60 Gy).
Thirteen patients received < 5 Gy/fr. Six patients received 2 Gy/fr for 5 days a week with a median total dose of 60 Gy (range 38–70 Gy). Six patients received 3 Gy/fr for 5 days a week with a median total dose of 55.5 Gy (range 3–61 Gy). One patient received 52 Gy in 13 fractions for 3 days a week. One patient received 51 Gy in twice-daily fractions of 1.5 Gy for 5 days a week.
Twenty-two patients received radiotherapy for primary and lymph node metastasis lesions, and 11 patients received radiotherapy for primary lesions, lymph node metastasis, and regional cervical lymph nodes (Table 2).
Table 2.
Differences in treatments and results between the two radiation dose groups
| Single dose of radiotherapy | <5 Gy (14 patients) |
≥5 Gy (19 patients) |
p value |
|---|---|---|---|
| Total or partial thyroidectomy | 7 (50%) | 5 (26%) | 0.162 |
| Concurrent chemoradiotherapy | 7 (50%) | 8 (42%) | 0.653 |
| Radiation field of regional cervical lymph nodes | 8 (57%) | 3 (16%) | 0.012 |
| Local recurrence | 7 (50%) | 5 (26%) | 0.162 |
| Died from local recurrence | 5 (36%) | 1 (5%) | 0.025 |
The χ 2 test showed that there was a significant difference between the group of patients who received radiotherapy that included regional cervical lymph nodes and the group of patients who received radiotherapy for only the primary and lymph node metastasis lesions. There were significantly fewer patients who died from local recurrence in the ≥5 Gy/fr group (hypofractionated radiotherapy group).
Treatment Results
The median follow-up period was 3.2 months (range 0.4–17 months). The median OS was 5 months and the 1-year OS rate was 3.5%. The median LC period was 6.9 months and the 1-year LC rate was 12.5% (Fig. 1). Twenty-seven patients died from ATC and 1 patient died from an unknown cause. Six patients died from local recurrence: 3 from asphyxiation, 2 from active bleeding from a recurrence tumor, and 1 from growth of local recurrence. Sixteen patients died from distant metastasis: 9 from lung metastasis, 4 from brain metastasis, 2 from abdominal metastasis, and 1 from mediastinal recurrence. One patient died from an adverse event. Four patients died in another hospital: 3 showed appearance of or exacerbation of lung metastasis and 1 appearance of metastasis in the mediastinum on the last follow-up day at our institution.
Fig. 1.
Kaplan-Meier curves for overall survival (OS) and local control (LC) in ATC patients.
Twelve patients suffered from local recurrence after radiotherapy: 5 (26%) of the 19 patients in the hypofractionated radiotherapy group and 7 (50%) of the 14 patients in the < 5 Gy/fr group (p = 0.16). Moreover, 1 patient (5%) in the hypofractionated radiotherapy group and 5 patients (36%) in the < 5 Gy/fr group died from local recurrence (p = 0.025) (Table 2).
Detailed patient data are shown in the online supplementary material (for online suppl. material, see www.karger.com/doi/10.1159/000493315).
Univariate and Multivariate Analyses
In univariate analysis, patients who received a EQD2 ≥50 Gy had better OS than patients who received < 50 Gy (p = 0.018, hazard ratio [HR] = 0.27), patients with T4a had better LC than patients with T4b (p = 0.014, HR = 1.1699 × 10–9), patients with M0 had better LC than patients with M1 (p = 0.032, HR = 0.26), and patients who received a total dose ≥50 Gy had better LC than patients who received < 50 Gy (p = 0.049, HR = 0.18). Concurrent chemotherapy was no significant predictor for OS (p = 0.417, HR = 0.73) or LC (p = 0.909, HR = 1.07) (Table 3). In multivariate analysis, patients who received EQD2 ≥50 Gy had better OS than patients who received < 50 Gy (p = 0.016, HR = 0.26) (Table 4).
Table 3.
Univariate analyses for OS and LC
| OS |
LC |
|||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p value | HR | 95% CI | p value | |
| Age (≥ median vs. < median) | 1.22 | 0.57–2.60 | 0.605 | 0.58 | 0.15–1.84 | 0.357 |
| Male vs. female | 2.09 | 0.93–5.01 | 0.073 | 1.72 | 0.50–6.82 | 0.393 |
| PS 0–1 vs. 2–3 | 1.06 | 0.49–2.40 | 0.884 | 0.80 | 0.25–2.76 | 0.717 |
| T stage (T4a vs. T4b) | 0.51 | 0.12–1.48 | 0.236 | 0* | 0.59–0.59 | 0.014 |
| N stage (N0 vs. N1) | 0.82 | 0.32–1.86 | 0.649 | 0.43 | 0.06–1.81 | 0.267 |
| M stage (M0 vs. M1) | 0.71 | 0.33–1.53 | 0.276 | 0.26 | 0.07–0.89 | 0.032 |
| Thyroidectomy vs. none | 0.77 | 0.35–1.66 | 0.510 | 0.63 | 0.18–2.07 | 0.445 |
| Chemotherapy vs. none | 0.83 | 0.39–1.82 | 0.638 | 0.95 | 0.30–3.24 | 0.933 |
| CRT vs. RT | 0.73 | 0.34–1.57 | 0.417 | 1.07 | 0.34–3.66 | 0.909 |
| Total dose (≥50 Gy vs. <50 Gy) | 0.44 | 0.18–1.24 | 0.113 | 0.18 | 0.03–0.99 | 0.049 |
| EQD2 (≥50 Gy vs. <50 Gy) | 0.27 | 0.10–0.78 | 0.018 | 0.20 | 0.04–1.03 | 0.053 |
| Hypofractionation vs. <5 Gy/fr | 1.06 | 0.50–2.28 | 0.872 | 0.32 | 0.07–1.19 | 0.09 |
CI, confidence interval; CRT, chemoradiotherapy; EQD2, equivalent dose in 2-Gy fractions; HR, hazard ratio; LC, local control; OS, overall survival; PS, performance status; RT, radiotherapy. * 1.1699 × 10–9.
Table 4.
Multivariate analysis for OS
| HR | 95% CI | p value | |
|---|---|---|---|
| Male vs. female | 2.14 | 0.96–5.13 | 0.064 |
| EQD2 (≥50 Gy vs. <50 Gy) | 0.26 | 0.097–0.76 | 0.016 |
Factors with a p value <0.01 in univariate analysis were included in multivariate analysis. CI, confidence interval; EQD2, equivalent dose in 2-Gy fractions; HR, hazard ratio; OS, overall survival.
Kaplan-Meier curves for EQD2 and hypofractionated radiotherapy are shown in Figure 2.
Fig. 2.
Results of the log-rank test for Kaplan-Meier curves for an equivalent dose in 2-Gy fractions (EQD2) ≥50 Gy and hypofractionated radiotherapy. LC, local control; OS, overall survival.
Side Effects
Twelve patients suffered from grade 3 or higher adverse effects. One patient in the ≥5 Gy group suffered from grade 4 trachea necrosis, and that patient suffered from grade 5 injury to the carotid artery after salvage thyroidectomy (Table 5).
Table 5.
Side effects grade 3 or higher
| <5 Gy/fr | ≥5 Gy/fr | p value | |
|---|---|---|---|
| Pharyngeal mucositis grade 3 | 2 | 1 | 0.375 |
| Dysphagia grade 3 | 5 | 5 | 0.563 |
| Dermatitis grade 3 | 1 | 1 | 0.824 |
| Trachea necrosis grade 4 | 0 | 1 | 0.288 |
| Injury to the carotid artery grade 5 | 0 | 1 | 0.288 |
There was no significant difference between the ≥5 Gy/fr group (hypofractionated radiotherapy group) and the <5 Gy/fr group.
Discussion
To the best of our knowledge, there has been no report of ATC patients treated with hypofractionated radiotherapy with more than 5 Gy/fr. A protocol of 50 Gy in 10 fractions for 3 days a week was used in our institution for most cases. An EQD2 ≥50 Gy was an independent predictor for OS. There were significantly fewer patients who died from local recurrence in the hypofractionated radiotherapy group (p = 0.025).
Hypofractionated radiotherapy was not necessarily good for OS and LC in the Cox proportional hazards model. Patients who received hypofractionated radiotherapy tended to have better LC, but the difference was not statistically significant (p = 0.090) (Fig. 2). Stavas et al. [9] reported results for patients who received ≥2.5 Gy/fr (range 2.5–4 Gy), and the most frequently used radiotherapy dose was 54 Gy in 18 fractions (range 40–62.5 Gy). For those patients, the median OS was 9.3 months, which was better than the median OS in the present study. Fourteen (82.4%) of 17 patients in that study received total or partial thyroidectomy. The percentage of patients in that study who received surgery was higher than that in our study, and that was a reason why the median OS was better than that in our study. Several studies have shown that thyroidectomy was one of the predictors for OS in patients with ATC [6, 12, 13]. However, surgery was not a significant predictor for OS in our study (Table 3). As shown in Table 2, the number of patients who received surgery was smaller in the hypofractionated radiotherapy group than in the < 5 Gy group. Nevertheless, there was little difference between the Kaplan-Meier curves for OS in the hypofractionated radiotherapy group and the < 5 Gy group (Fig. 2). It is possible that treatment with hypofractionated radiotherapy improves the OS of patients who have not received surgery. However, there were many patients who died from distant metastasis. Therefore, it is possible that hypofractionated radiotherapy tended to improve LC, but did not improve OS.
An EQD2 ≥50 Gy was an independent predictor for OS (Table 4). Sugitani et al. [6] reported that a total radiation dose ≥40 Gy was an independent predictor for OS, and Dumke et al. [7] reported that a total radiation dose ≥50 Gy was a significant predictor for OS in univariate analysis. Glaser et al. [10] compared three to tal radiation dose groups, ≤36 Gy, 36.1–59.3 Gy, and ≥59.4 Gy, and reported that a total radiation dose ≥59.4 Gy was an independent predictor for OS in 3,552 patients. Pezzi et al. [11] similarly compared three total dose groups, < 45 Gy, 45–59.9 Gy, and 60–75 Gy, in patients with unresected ATC, and reported that a total dose of 60–75 Gy was an independent predictor for OS in 2,987 patients. Based on the results of those studies and ours, a higher dose of radiation is important for the OS of ATC patients. Twice-daily fractionated radiotherapy was used in several studies. Tennvall et al. [14] used 46 Gy in 29 fractions with a twice-daily protocol followed by surgery, and the median OS was 2 months. Wang et al. [15] used 60 Gy in 40 fractions with a twice-daily protocol in 9 patients, and the median OS was 13.6 months. Jacobsen et al. [13] used 64 Gy in 40 fractions with a twice-daily protocol in 31 patients, and the median OS was 9 months.
Several studies showed that many ATC patients died from asphyxiation or active bleeding from the neck. Tallroth et al. [4] reported that 41 (60%) of 68 patients during the period from 1930 to 1970 died from asphyxiation, and Lowe et al. [5] reported that 8 (40%) of 20 patients died from asphyxiation. A total of 113 (21%) of 547 patients in the study by Sugitani et al. [6] and 6 (18%) of the 33 patients in our study died from local recurrence. Despite the fact that there were fewer patients who received surgery, only 1 (5%) of the 19 patients in the hypofractionated radiotherapy group died from bleeding, and there were significantly fewer patients who died from local recurrence (Table 2). Jacobsen et al. [13] reported that none of their 33 patients died from asphyxiation. Their protocol was 64 Gy in 20 fractions with a twice-daily protocol and concurrent chemotherapy with doxorubicin with or without surgery. Based on the results of their study and ours, strong radiotherapy may reduce death from local tumor.
Sixteen patients died from distant metastasis, and death due to lung metastasis was more frequent in this study. Therefore, systematic drug therapy is also important. Kasmann et al. [16] reported that concurrent chemoradiotherapy was a significant predictor for OS in univariate analysis, and Foote et al. [17] reported that radiotherapy with radiosensitizing chemotherapy followed by chemotherapy was important for OS. Molecular targeted drugs have been studied. Ha et al. [18] reported that partial response and stable disease were seen in 2 and 4 of 11 patients who received imatinib, respectively, and that the 6-month and 1-year OS rates were 45.5 and 36.4%, respectively. Savvides et al. [19] reported that response and stable disease were seen in 2 and 5 of 20 patients who received sorafenib, respectively, and that the median OS and the 1-year OS rate were 3.9 months and 20%, respectively. There was no difference between those studies and our results for median OS survival, but the 1-year OS rates in those studies were higher than that in our study. Chemotherapy was not associated with OS or LC in univariate analysis in our study (Table 3). It is possible that molecular targeted drugs are associated with long survival in ATC patients. Kollipara et al. [20] reported results of immunotherapy for lymph nodes with anaplastic change in a patient with lung metastasis after thyroidectomy for well-differentiated papillary carcinoma. The patient maintained clinical remission for 20 months after the start of treatment with nivolumab.
Multimodality therapy is important to improve the outcome of ATC patients. Further research is needed to improve treatment results for ATC patients.
In conclusion, an EQD2 ≥50 Gy is an independent predictor for OS. It is possible that hypofractionated radiotherapy can reduce the rate of mortality due to local recurrence.
Statement of Ethics
This study had institutional review board approval.
Disclosure Statement
The authors declare no conflicts of interest.
Supplementary Material
Supplementary data
References
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