|Year : 2014 | Volume
| Issue : 3 | Page : 526-530
Comparing outcomes in poorly-differentiated versus anaplastic thyroid cancers treated with radiation: A surveillance, epidemiology, and end results analysis
Shruthi Arora1, Paul Christos2, Anthony Pham1, Prashant Desai1, A Gabriella Wernicke1, Dattatreyudu Nori1, K. S. C. Chao1, Bhupesh Parashar1
1 Department of Radiation Oncology, Stich Radiation Center, New York, NY 10065, USA
2 Department of Public Health, Division of Biostatistics and Epidemiology, Weill Cornell Medical Center, New York, NY 10065, USA
|Date of Web Publication||14-Oct-2014|
Stich Radiation Center, Weill Cornell Medical Center, New York, NY 10065
Source of Support: Dr. Paul Christos was partially supported by the following grant: Clinical Translational Science Center (CTSC) (2UL1TR000457.06), Conflict of Interest: None
Purpose: Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are considered the most aggressive cancers of the head and neck. The aim of the study was to evaluate and compare survival outcomes in PDTC and ATC in a large population-based cohort.
Materials and Methods: Patients with PDTC and ATC diagnosed from 1973 to 2008 were obtained from Surveillance, Epidemiology, and End Results database. Kaplan-Meier survival analysis and log-rank analyses were performed to evaluate (1) The effect of histology on cause-specific survival (CSS) and (2) the influence of factors such as treatment, treatment sequence, race, sex, and age on CSS. Multivariate analysis was performed to assess the independent effect of these factors on CSS.
Results: A total of 1352 patients with PDTC and ATC were identified. PDTC constituted 52.4% of patients versus 47.6% for ATC. Median CSS was similar in the two histology groups (P = 0.14). Both PDTC and ATC patients receiving radioisotopes showed a significantly better CSS compared to external beam radiation (P < 0.0001). PDTC and ATC Patients receiving radiation prior to surgery demonstrated a significantly lower CSS compared to patients receiving radiation postoperatively (P < 0.0001). Female gender and black/nonwhite race tended to improve CSS in PDTC and ATC patients (P = 0.29 and P = 0.03, for gender and race, respectively). However, multivariate analysis revealed only type of radiation treatment and age to be independently associated with CSS.
Conclusion: This is the first large population-based study evaluating PDTC and ATC outcomes in patients who received radiation treatment. Radioisotope use and timing of radiotherapy (postoperative vs. preoperative) were associated with improved CSS in both histologies.
Keywords: Outcomes, radiation, surveillance, epidemiology, and end results, thyroid
|How to cite this article:|
Arora S, Christos P, Pham A, Desai P, Wernicke A G, Nori D, Chao K, Parashar B. Comparing outcomes in poorly-differentiated versus anaplastic thyroid cancers treated with radiation: A surveillance, epidemiology, and end results analysis. J Can Res Ther 2014;10:526-30
|How to cite this URL:|
Arora S, Christos P, Pham A, Desai P, Wernicke A G, Nori D, Chao K, Parashar B. Comparing outcomes in poorly-differentiated versus anaplastic thyroid cancers treated with radiation: A surveillance, epidemiology, and end results analysis. J Can Res Ther [serial online] 2014 [cited 2019 Sep 17];10:526-30. Available from: http://www.cancerjournal.net/text.asp?2014/10/3/526/138207
| > Introduction|| |
Thyroid cancer is the ninth most common cancer in women around the world. The incidence of thyroid cancer worldwide is now estimated at 213,179 persons/year with a mortality of 35,383 persons/year.  The American Cancer Society estimates that in 2012 about 56,460 new cases (43,210 in women, and 13,250 in men) of thyroid cancer will be diagnosed in United States of America and it will contribute to more than 1780 deaths (1000 women and 780 men).  Anaplastic carcinoma of thyroid (ATC), though uncommon, is the most lethal form of thyroid cancer. Very few anaplastic thyroid cancer patients survive longer than 1 year, and reports of long-term survivors casts doubt on the validity of their diagnosis.  Compared to other histological types of thyroid malignancies, ATC is more common in the elderly over the age of 65. It constitutes 1-2% of all thyroid tumors with a mean survival of only 6 months. ,,, Poorly differentiated carcinoma of thyroid (PDTC) accounts for up to 10% of all thyroid cancers. This may be inaccurate due to inconsistent definitions of PDTC used by different authors.  The term PDTC was defined by the 2004 World Health Organization classification and a consensus was reached on its diagnostic features in 2006 at the Turin, Italy consensus meeting.  A clinically aggressive thyroid carcinoma of follicular cell origin, PDTC falls between ATC and well-differentiated thyroid carcinoma, morphologically as well as clinically. Both PDTC and ATC may arise from well-differentiated thyroid carcinoma (papillary or follicular). , Most of these cancers are treated with combination therapies including surgery, radioisotopes, chemotherapy, and external radiation.
Surveillance, Epidemiology, and End Results (SEER) Program is a premier source for cancer statistics in the United States. SEER contains data across geographic regions on incidence, prevalence, mortality, and population-based variables and currently represents approximately 28% of the US population.  It gives information on incidence, prevalence and survival from specific geographic areas and compiled reports on all of these plus cancer mortality for the entire country. It is supported by the National Cancer Institute and Centers for Disease Control and Prevention.
The aim of this study was to evaluate and compare survival outcomes in PDTC and ATC in a large population-based sample cohort from the SEER database. This analysis examines the effects of radiotherapy (RT) in patients with PDTC and ATC using this large population-based database.
| > Materials and methods|| |
Patients with ATC and PDTC diagnosed between 1973 and 2008 were selected for the study from the SEER database. Data of 17 SEER registries including the regions of Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, Utah, Los Angeles, San Jose-Monterey, Alaska, Rural Georgia, Greater California, Kentucky, Louisiana, and New Jersey were studied. All patients who received radiation either as definitive treatment or postoperatively and also patients who received postoperative radioisotope implants were included in the study. Patients diagnosed as ATC and PDTC was identified using ICD-O-3 codes.
Descriptive statistics (including mean, standard deviation, median, range, frequency, and percent) were calculated to characterize the study cohort in relation to demographic, prognostic, and treatment factors of interest. The primary endpoint was cause-specific survival (CSS). CSS was ascertained by selecting thyroid cancer as the cause of death in the SEER database search. Deaths due to causes other than thyroid cancer were censored when estimating CSS. CSS was defined as the time from diagnosis until death from thyroid cancer or until date of last follow-up or death from other cause. Kaplan-Meier survival analysis was performed to evaluate CSS and the log-rank test was employed to compare CSS between demographic, prognostic, and treatment characteristics of interest (i.e. age, gender, race, histology, type of treatment, and treatment sequence). Univariate Cox proportional hazards regression analysis was performed to assess the effect of patient age on CSS. Multivariate Cox proportional hazards regression analysis was performed to evaluate the independent effect of demographic, prognostic, and treatment factors on CSS. Competing-risks survival regression was also performed to adjust the multivariate CSS hazard ratios (HRs) for the competing event of death due to causes other than thyroid cancer (based on Fine and Gray's proportional subhazards model).  All P values are two-sided with statistical significance evaluated at the 0.05 alpha level. Ninety-five percent confidence intervals (95% CI) for HRs and subhazard ratios (SHRs) were calculated to assess the precision of the obtained estimates. All analyses were performed using SPSS version 20.0 (SPSS Inc., Chicago, IL, USA) and STATA version 12.0 (StataCorp, College Station, TX, USA).
| > Results|| |
A total of 1352 patients who received radiation as a part of their treatment were identified and selected for the study. The median age of the selected patients was 63 years (range: 7-99 years). Patient characteristics are shown in [Table 1]. Treatment characteristics are shown in [Table 2]. Patient characteristics and treatment characteristics between ATC and PDTC are shown in [Table 3] and [Table 4]. Of the 1352 patients, 708 patients (52.4%) had PDTC while 644 patients (47.6%) had ATC. Females constituted 64.6% of the study population, while 35.4% were male patients. Of the PDTC and ATC patients, 65.1% and 64.0% were female, respectively. Whites constituted 83.4% of the patients while blacks and other races constituted 5.7% and 10.9% of the study population, respectively. 70 patients (5.2%) had Stage I disease, 23 (1.7%) had Stage II disease, 57 (4.2%) had Stage III disease, and 288 (21.3%) had Stage IV disease. However, stage classification was missing for 914 patients (67.6%), and therefore, stage could not be further evaluated in the analysis. RT in the form of external beam RT, radioactive implants etc., was a part of treatment in 58.9% of patients and radioisotopes were utilized in 41.1% of patients. A majority of the patients (94.6%) received postoperative radiation (external or radioisotopes).
Of the entire cohort of which the survival information was available, 547 (40.5%) were alive at the time of study and 805 (59.5%) had died. Regarding CSS, of the entire cohort for which CSS information was available, 638 (47.2%) were alive at the last follow-up or had died from causes other than thyroid cancer, and 666 patients (49.3%) had died from thyroid cancer.
Median follow-up time, based on survivors, for the entire cohort was 4.8 years (range = 0.0, 34.5 years). Kaplan-Meier CSS, compared between the two histological groups of patients treated with radiation, is presented in [Figure 1]. Median CSS was 49 months (95% CI = 22.6 months, 75.4 months) for patients with PDTC when compared to 32 months (95% CI = 14.9 months, 49.1 months) for patients diagnosed with ATC (P = 0.14). Patients receiving radioisotopes showed a significantly better CSS compared to patients who received external beam radiation (100 months CSS of 73.4% vs. 17.7%, respectively, P < 0.0001), and this finding was consistent when stratified by histology. Patients receiving radiation prior to surgery demonstrated a significantly lower CSS compared to patients receiving radiation postoperatively (median CSS = 9 months [95% CI = 4.8 months, 13.2 months] vs. 51.0 months [95% CI = 30.7 months, 71.3 months], respectively, P < 0.0001), and this finding was also consistent when stratified by histology. Median CSS tended to be slightly better for female patients compared to male patients (53.0 months [95% CI = 23.5 months, 82.5 months] vs. 37.0 months [95% CI = 23.9 months, 50.1 months], respectively, P = 0.29) and median CSS differed by ethnicity (white: Median CSS = 36.0 months [95% CI = 23.3 months, 48.7 months]; black/other: Median CSS = 108.0 months [95% CI = not estimated]; P = 0.03). The univariate HR (for thyroid cancer death) for each 1 year increase in age in the study cohort was 1.04 (95% CI = 1.03, 1.04; P < 0.0001).
Multivariate analysis revealed the following independent associations with thyroid cancer death (i.e. CSS): Histology (ATC vs. PDTC [referent], HR = 0.99, 95% CI = 0.85-1.16, P = 0.93), type of radiation (external beam vs. other [referent], HR = 4.28, 95% CI = 3.56-5.15, P < 0.0001), gender (female vs. male [referent], HR = 0.94, 95% CI = 0.80-1.10, P = 0.45), race (black/other vs. white [referent], HR = 0.97, 95% CI = 0.78-1.22, P = 0.81), and age (1 year increase in age, HR = 1.03, 95% CI = 1.020-1.031, P < 0.0001). Adjusting the above multivariate HRs for the competing event of death due to causes other than thyroid cancer only minimally altered the HRs (histology, SHR = 0.99, 95% CI = 0.84-1.16, P = 0.87; type of radiation, SHR = 3.99, 95% CI = 3.34-4.77, P < 0.0001; gender, SHR = 0.94, 95% CI = 0.80-1.11, P = 0.47; race, SHR = 0.94, 95% CI = 0.74-1.19, P = 0.61; age, SHR = 1.02, 95% CI = 1.017-1.028, P < 0.0001).
| > Discussion|| |
Our study is the first large population-based study comparing outcomes in PDTC versus ATC in patients treated with RT. Patients with PTDC showed a better CSS compared with ATC although it was not statistically significant.
In our study, the median age at diagnosis was 61.5 years and 64.5 years for patients diagnosed with PDTC and ATC, respectively. This is similar to multiple studies that have reported a median age of diagnosis in the sixth and seventh decade. ,,,, Both ATC and PDTC were predominantly seen in females, that closely corresponds to the results of the study conducted in Tokyo that reported a female: Male ratio of 1.9:1.0 for PDTC and 0.7:1.0 for anaplastic carcinoma. 
There are no randomized control studies on the use of external beam radiation in the treatment of thyroid cancers, but radiation still plays an important role as an adjuvant treatment following surgery and in unresectable tumors to improve local control. ATC is relatively radio resistant, but radiation is still essential for local control and for palliation. Retrospective evaluation of the use of external radiation in PDTC show that it is essential for preventing local relapse, but improved survival is not seen. 
Surgical respectability remains the most important factor for CSS and this explains the improved CSS of patients who received postoperative radiation in our study. Presumably, patients who received preoperative radiation did so due to poor respectability. We compared the median CSS between patients with PDTC and ATC. The median CSS was 49 months in PDTC as compared to 32 months in ATC (P = 0.14). A number of studies have reported on the survival outcomes in patients diagnosed with these histological subtypes. Siironen et al.,  studied the therapeutic outcomes of 52 patients with ATC and PDTC between 1990 and 2008 and reported a median survival of only 3.1 months for ATC, and 38 months for PDTC. Multimodal therapy was successful for 9 (20%) of ATC patients and their median survival was the longest (11.6 months) among the treatment groups. Patients with ATC treated with a combination of surgery and RT had a median survival of 7.7 months compared to patients receiving RT alone, who had a median survival of 1.7 months. The 5 years overall survival was 7% and 50%, respectively for ATC and PDTC.
Sakamoto et al.  studied the relationship between histological type and survival in 258 patients with thyroid malignancy between 1965 and 1980 and reported a 5 years cumulative survival rate for poorly differentiated carcinoma of 65%, while none of the 25 patients with ATC survived for 5 years. Patel and Shaha  analyzed 42 patients of well-differentiated, PDTC, and ATCs with a median follow-up of 43 months. PDTC and ATC were reported in 12 and 15 patients, respectively. The authors compared the clinical characteristics and reported a 5 years disease-free survival, 5 years CSS, and overall survival of 51%, 70%, and 70%, respectively for PDTC while it was 0% for patients with ATC (P < 0.0001). We have similar findings in our study where radioisotope use was associated with improved CSS. This is expected since radioisotope use can be considered a surrogate marker for the degree of differentiation and is therefore associated with increased CSS.
McIver et al.  evaluated the outcomes in 134 cases of ATC and reported a Female: Male ratio of 1.5:1.0 and a mean age of 67 years, with patients receiving postoperative RT having a slightly longer median survival (5 vs. 3 months), which was not significant (P < 0.08). Multimodal therapy, including operation, chemotherapy, and RT, did not improve survival in their study.
Chen et al.  have evaluated the survival in patients with ATC treated with a combination of surgery and RT and reported an overall survival at 2 and 5 years of 12.9% and 7.5%, respectively, with a median survival of 4 months. Patients with disease confined to the thyroid with no extension beyond the capsule have 2 and 5 years overall survival rates of 32.7% and 22.9% and a median survival of 9 months. With disease extension into adjacent tissue, the median survival was 6 months, and overall survival was 16.2% and 10.1% at 2 and 5 years, respectively. Median survival for patients with further extension or distant metastatic disease was 3 months with a 2 years overall survival of 2.1%.
In a retrospective analysis, Levendag et al.  have reported a series of 51 patients who received radiation with or without chemotherapy. Patients who received >30 Gy had a median survival of 3.3 months, as opposed to the 0.6 month survival of those receiving <30 Gy. The authors concluded that although radiation is indispensible for achieving a higher short-term survival, death occurs due to distant metastases. Junor et al.  have reported no survival benefit with radiation therapy, despite an 80% initial response in patients and 39% initial complete response. One of the limitations of our study is the lack of chemotherapy data. However, chemotherapy is not known to be extremely effective in PDTC or ATC.
| > Conclusion|| |
This is the first large population-based study evaluating PDTC and ATC outcomes in patients who received radiation treatment. Radioisotope use and timing of RT were associated with improved CSS in both histologies. Although some retrospective studies have shown a significantly increased survival in patients with PDTC versus ATC, our study showed a nonsignificant increase in CSS for the former. This data is useful in making management decisions in this challenging set of patients as well as in designing novel clinical trials.
| > Acknowledgments|| |
Dr. Paul Christos was partially supported by the following grant: Clinical Translational Science Center (2UL1TR000457-06).
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[Table 1], [Table 2], [Table 3], [Table 4]