Abstract
Background/Aim: To identify predictors of survival after multimodal treatment including surgery plus postoperative radio(chemo)therapy) for anaplastic thyroid cancer. Patients and Methods: Nine potential factors were evaluated in nine patients regarding survival after 6, 12 and 24 months. These factors were age, gender, Karnofsky performance score, tumour stage, nodal stage, resection margin status, radiation dose, concurrent chemotherapy administered with irradiation and symptom control at the end of radiotherapy. Results: Survival rates were 67% at 6 months, 56% at 12 months and 22% at 24 months. On univariate survival analysis, concurrent radiochemotherapy (p=0.018) and controlled symptoms at the end of radiotherapy (p=0.03) were associated with improved survival. A trend for better survival was seen in patients with microscopically (R1) versus macroscopically (R2) residual disease (p=0.058). Conclusion: Prognostic factors for survival after multimodal treatment for anaplastic thyroid cancer were identified. Concurrent radio-chemotherapy resulted in significantly better survival and should be recommended.
Anaplastic thyroid cancer (ATC) is a rare but very aggressive type of cancer associated with a dismal prognosis (1-7). It represents only 1-5% of all thyroid tumours. Survival is generally limited to 3-6 months as a consequence of an aggressive tumour biology promoting invasion and metastasis (1-3, 5, 8). Effective treatment options are warranted, and multimodal therapy offers opportunities to prolong survival and improve quality of life (5-7). Curative surgery is a major therapeutic option in the treatment of ATC and the few available data indicate that resection followed by postoperative radiotherapy (PORT) may offer a further survival benefit due to improved local control compared to surgery alone (2, 4).
However, there is no standard therapeutic regimen for the treatment of ATC due to lack of evidence. Furthermore, the majority of patients are still treated with palliative intention (2, 6). Postoperative PORT combined with concurrent chemotherapy represents an intensive treatment option. It may be associated with high acute toxicity including fatigue, myelopathy, dysphagia or pancytopenia. Consequently, potential candidates for this treatment option should be well selected taking into account the patient's prognosis. However, prognostic factors in the multimodal treatment of ATC remain largely unclear. This study contributes to the treatment allocation and optimization of post-operative radiochemotherapy programs to achieve the best possible treatment outcome. We analyzed nine potential prognostic factors for survival after 6, 12 and 24 months.
Patients and Methods
In this retrospective study, we included nine patients diagnosed with ATC at our hospital from 2006 to 2014 and who underwent multimodal treatment consisting of surgery followed by postoperative radio(chemo)therapy. According to the American Joint Committee on Cancer (AJCC), three patients had stage IVa disease, four patients had stage IVb disease and two patients stage IVc disease, respectively (9). A hemi-thyroidectomy was performed in five patients. In four patients, total thyroidectomy was planned, but only achieved in two patients. Irradiation was performed at median one month after diagnosis of ATC (range: 0-5 months).
Four patients received combined chemotherapy with carboplatin and paclitaxel. Three patients received single-agent chemotherapy with doxorubicin and one patient with gemcitabine. One patient refused the planned concurrent chemotherapy.
The radiation dose was given as equivalent dose in 2 Gy fractions (EQD2). The median EQD2 was 58 Gy (range: 32.5-60 Gy). Two EQD2 levels (≤58 Gy vs. >58 Gy) plus eight additional patient characteristics were analysed for potential associations with survival. These characteristics were age (≤64 vs. ≥65 years), gender, Karnofsky performance score (≤80 vs. >80), AJCC stage (IVa vs. IVb/IVc), N stage (1a vs. other), resection margin status (microscopically incomplete=R1 vs. macroscopically incomplete=R2), concurrent chemotherapy (yes vs. no), symptom control at the end of radiotherapy (worse vs. controlled symptoms).
Patient characteristics and survival analysis (Kaplan–Meier method and the log-rank test).
The univariate analyses of these factors with respect to survival were performed using the Kaplan–Meier method and the log-rank test (10). Patient characteristics showing a significant association with survival (p<0.05) or at least a trend (p<0.06) were additionally included in a multivariate (Cox regression) analysis.
Results
Patients were followed until death or for a minimum of 24 months (range=24-45 months). Median survival was 12 months (range=2-45 months). The results of the survival analysis are summarized in Table I. Survival rates were 67% at 6 months, 56% at 12 months and 22% at 24 months, respectively. An improved survival at 24 months was found on univariate analysis for concurrent chemotherapy in addition to irradiation (p=0.018) and controlled symptoms at the end of radiotherapy (p=0.030). A trend for better survival was seen in patients after R1-resection vs. macroscopic R2-resection (p=0.058). None of the investigated factors reached significance on multivariate analysis.
Discussion
ATC is a highly aggressive tumour with a survival prognosis of only a few months (1-3, 5-8, 11). For these patients more effective treatment concepts and a set of prognostic factors are needed to optimize outcome and improve treatment allocation. Effective treatment options for patients with ATC are limited. In recent literature, surgery was recommended whenever possible to improve survival and local control. In a retrospective study of 67 patients even incomplete resection led to an improvement in survival (4). The first meta-analysis assessing the impact of PORT showed a prolonged survival in patients undergoing surgery followed by PORT when compared to \patients treated with surgery alone (2). However, new radiotherapy techniques and radio-sensitizing agents plus adjuvant chemotherapy have been suggested to further improve local control and impact survival (8). The use of several anticancer drugs was investigated with more favourable results; however, the patient prognosis remains poor (11).
In a study of Onoda et al. radiochemotherapy with docetaxel improved loco-regional control of patients with ATC and was associated with acceptable toxicity (11). Swaak-Kragten et al. reported an improvement by 23% in 12-month-survival in patients receiving doxorubicin concurrently with radiotherapy and additionally following radiotherapy (7). However, prognostic factors of survival in this setting still need to be defined. Consequently, the aim of our study was to identify such prognostic factors for patients receiving multimodal treatment in order to optimize treatment allocation and improve individualized patient care. The analysis of the registry of the ATC Research Consortium of Japan showed that the absence of acute symptoms was associated with better survival (12). In our study, symptom control was also a factor significantly associated with improved survival resulting in a 2-year survival rate of 40%. In comparison, recent data from the literature suggested a 2-year survival rate of 10-20% (2), whereas Foote et al. reported a 2-year survival rate of 60% in patients with ATC and favourable patient characteristics such as more favourable tumour stage, namely stage IVa compared to stages IVb and IVc (8). In the study of Foote et al., 70% of the patients with ATC had stage IVa compared to only 33% in our present study. This difference may explain the more favourable 2-year survival rate in the study of Foote et al. when compared to the 2-year-survival rate in our study (8). Aggressive treatment strategies including surgery, chemotherapy and radiotherapy have been suggested to improve survival in patients with ATC (13). This finding agreed well with the result of our study that the use of concurrent chemotherapy in addition to radiotherapy improved survival. Swaak-Kragten et al. reported a better local control with concurrent radio-chemotherapy than with radiotherapy alone but no survival benefit (7). In order to validate our findings and to improve the evidence of prognostic factors for patients with ATC, a prospective multicentre study would be required. Furthermore, the optimal chemotherapy program for ATC needs to be defined in prospective studies. However, since patients with ATC are relatively rare, such prospective trials including a cohort of patients large enough to achieve an adequate statistical power cannot be expected soon. Therefore, retrospective studies are the best data currently available. However, with respect to the presents study, its retrospective nature, the relatively small number of patients and the heterogeneous distribution of chemotherapy regimens included should be taken in account.
In conclusion, prognostic factors for survival in patients treated with multimodal therapy for ATC were identified in this study. Concurrent radiochemotherapy resulted in improved survival compared to radiotherapy alone and should, therefore, be recommended, in particular for patients with good performance status.
Footnotes
This article is freely accessible online.
Conflicts of Interest
On behalf of all Authors, the corresponding Author states that there is no conflict of interest related to this study.
- Received July 20, 2016.
- Revision received August 5, 2016.
- Accepted August 18, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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