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Clinical outcome of anaplastic thyroid carcinoma treated with radiotherapy of once- and twice-daily fractionation regimens
Version of Record online: 11 SEP 2006
Copyright © 2006 American Cancer Society
Volume 107, Issue 8, pages 1786–1792, 15 October 2006
How to Cite
Wang, Y., Tsang, R., Asa, S., Dickson, B., Arenovich, T. and Brierley, J. (2006), Clinical outcome of anaplastic thyroid carcinoma treated with radiotherapy of once- and twice-daily fractionation regimens. Cancer, 107: 1786–1792. doi: 10.1002/cncr.22203
- Issue online: 3 OCT 2006
- Version of Record online: 11 SEP 2006
- Manuscript Accepted: 10 JUL 2006
- Manuscript Revised: 28 JUN 2006
- Manuscript Received: 2 MAY 2006
- anaplastic thyroid carcinoma;
- external beam radiotherapy;
- twice-daily fractionation;
- local control;
The purpose was to assess local control, survival, and toxicity after radiotherapy in patients with anaplastic thyroid carcinoma, and to compare clinical outcomes between once-daily and twice-daily fractionation regimens.
A retrospective review of patients with anaplastic thyroid carcinoma (n = 47) who underwent external beam radiotherapy from 1983 to 2004 was conducted. Twenty-three patients underwent radical radiotherapy with a radiation dose >40 Gy, and 24 patients underwent palliative radiotherapy with a dose ≤40 Gy. Of radical radiotherapy, radiation was given with once-daily (14 patients) or twice-daily fractionation (9 patients; 1.5 Gy per fraction) to a total dose of 45–66 Gy. Most patients (37 patients; 78.7%) were followed to death.
The 6-month local progression-free rate in patients who underwent radical radiotherapy was 94.1%, significantly higher compared with palliative radiotherapy (64.6%; P = .02). The median actuarial overall survival was greater in patients with radical radiotherapy (11.1 months) compared with palliative radiotherapy (3.2 months; P < .0001). The median overall survival in patients with twice-daily fractionation (13.6 months) was 3.3 months longer than patients treated with once-daily fractionation (10.3 months), but the difference was not statistically significant (P = .3). For patients treated with twice-daily fractionation, 3 patients had Grade 3 acute skin toxicity, and no patient had Grade 3 or higher esophageal toxicity.
Radiotherapy can result in local control of anaplastic thyroid carcinoma. A twice-daily fractionation regimen is well tolerated and has a trend to longer survival, which deserves a larger study. Cancer 2006. © 2006 American Cancer Society.
The majority of thyroid malignancies are well differentiated and have an excellent prognosis, but anaplastic thyroid carcinoma is an extremely aggressive cancer. Although it only accounts for 2% of thyroid cancer incidence, it accounts for 14% to 39% of thyroid cancer deaths.1, 2 It rapidly invades surrounding local tissues and metastasizes to distant organs. Median survival is usually less than 6 months, and death is either due to uncontrolled local invasion or distant metastasis.3, 4 In the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, there were 516 patients with anaplastic thyroid carcinoma from 1973 to 2000. Only 7.5% of patients had intrathyroidal anaplastic thyroid carcinoma, whereas 37.6% of patients had extrathyroidal invasion and/or regional lymph node involvement, and 43.0% of patients had distant metastasis. The cancer-specific mortality at 6 and 12 months was 69.4% and 80.7%, respectively.5 Because of the poor prognosis, all anaplastic thyroid carcinoma are classified as Stage IV by International Union Against Cancer (UICC-TNM staging)6 and American Joint Committee on Cancer (AJCC).7
The majority of patients with anaplastic thyroid carcinoma die from aggressive local regional disease, primarily from upper airway respiratory failure.8, 9 For this reason, aggressive local therapy is indicated in all patients who can tolerate it. Although rarely possible, complete surgical resection gives the best chance of long-term control and improved survival.10–12 Unfortunately, most patients have unresectable cancer at the time of diagnosis.8, 13 As anaplastic thyroid carcinoma does not concentrate 131iodine, external beam radiotherapy is the mainstay of treatment for local control. Because anaplastic thyroid carcinoma grows rapidly, hyperfractionated accelerated radiation therapy is a logical strategy, as it enables treatment to be given over a short time with tolerable toxicity and has been used with or without chemotherapy and surgical resection. Although paclitaxel resulted in a 53% response rate in a small Phase II study,14 in general anaplastic thyroid cancer is not a chemosensitive tumor.15–17 At Princess Margaret Hospital the policy has been to treat with radiation alone so that the dose of radiotherapy need not be adjusted to take account of the chemotherapy toxicity. Since 1997, radiotherapy with twice-daily fractionation at 1.5 Gy per fraction to a total dose of 60 Gy in 40 fractions over 4 weeks without chemotherapy has been used in patients with good performance status (generally Eastern Cooperative Oncology Group [ECOG] 2 or better). This study was conducted to assess local control, survival, and toxicity after external beam radiotherapy in patients with anaplastic thyroid carcinoma, and to compare clinical outcomes between once-daily and twice-daily fractionation regimens.
MATERIALS AND METHODS
A retrospective review of patients with anaplastic thyroid carcinoma who underwent external beam radiotherapy at Princess Margaret Hospital from January 1983 to December 2004 was conducted. The inclusion criteria were patients who had biopsy-proven anaplastic thyroid carcinoma of spindle or giant cell type and who had received external beam radiotherapy. Pathology was reviewed on referral at Princess Margaret Hospital for all patients. In those patients who survived longer than 12 months, pathology was re-reviewed (by S.A. and B.D.) to ensure the diagnosis of anaplastic thyroid carcinoma. Seven patients were excluded from this study because they did not receive radiotherapy. Forty-seven patients met the inclusion criteria and were included in this study. This study was approved by the institutional Research Ethics Board.
Staging investigations including liver function profile, neck ultrasound, and/or computed tomography (CT), and/or magnetic resonance imaging (MRI) chest and abdominal imaging were performed on initial assessment. In addition, complete blood count and electrolyte analysis were routinely done before radiotherapy. Patients were staged with TNM staging of UICC/AJCC 6th edition.6, 7
Radiotherapy was delivered with either Cobalt-60 (6 patients) or linear accelerators (4–25 MV photon or 9–17 MeV electron; 41 patients). Gross tumor volume (GTV) included the primary tumor and enlarged regional lymph nodes. Clinical target volume included GTV with 1 cm margin, thyroid bed, tracheoesophageal groove, and levels 3, 4, 6, and part of level 5 lymph nodes. The planning target volume typically encompassed the clinical tumor volume and extended from the hyoid to the suprasternal notch. To prevent excessive acute toxicity, the level 2 lymph nodes were not routinely included on the assumption that cure would be unlikely if there was extensive microscopic nodal involvement given the high probability of distant metastases. Patients could be spared undue radiation toxicity by not irradiating the entire cervical lymph nodes chain. A variety of techniques were used: 2-field anterior-posterior opposed photon fields (17 patients, 36.2%), 2-field anterior-posterior opposed photon fields with second phase cone-down of 2-field anterior-posterior opposed photon fields (14 patients, 29.8%), 2-field anterior-posterior opposed photon with second phase of 1-field anterior-posterior electron field (6 patients, 12.8%), and single field of anterior-posterior electron field (3 patients, 6.4%). More recently, 5-field photon conformal technique with 1 anterior field and 4 posterior oblique fields (7 patients, 14.9%) was used in radical radiotherapy. Patients with good performance status (ECOG 2 or better) and without distant metastases were treated with radical radiotherapy. Palliative radiotherapy was delivered to those patients with either poor performance status or distant metastases.
In those patients who underwent radical radiotherapy (23 patients; 49%), 14 patients received radiotherapy with once-daily fractionation, and 9 patients received twice-daily fractionation after 1997. Twice-daily irradiation was recommended for patients with good performance status, who were motivated, and could attend twice-daily radiotherapy. The radiation dose prescribed was greater than 40 Gy in radical radiotherapy. The median and most frequently prescribed dose was 60 Gy (52.2%) with a range of 45–66 Gy. For patients on a once-daily fractionation schedule, radiation was typically delivered 60 Gy in 30 fractions over 6 weeks. For patients treated on a twice-daily fractionation schedule, 60 Gy was delivered in 40 fractions at 1.5 Gy per fraction twice-daily over 4 weeks. There was a minimum 6-hour interval between the twice-daily fractions.
In those patients treated with palliative intent (24 patients; 51%), the radiation fields were similar to radical radiotherapy except for 5-field conformal radiation, which was only used in radical radiotherapy. Radiation total dose was 40 Gy or less in the palliative radiotherapy group. The median and most frequently prescribed dose was 20 Gy in 5 fractions over 1 week (50% patients). The schedules varied from 5 Gy in 1 fraction to 20 Gy in 5 fractions over 1 week followed by a 2–4 weeks split with a second phase of 20 Gy in 5 fractions over 1 week (7 patients). Adriamycin-based chemotherapy was used in 4 palliative patients, either before radiotherapy (2 patients) or concurrent with radiotherapy (2 patients).
Routine follow-up assessment after radiotherapy included history and physical examination. Ultrasound, CT, MRI, and other imaging were performed if clinically indicated.
The primary endpoints were local progression-free rate and overall survival. The secondary endpoint was toxicity. All events were measured from the first day of radiotherapy to the date of their occurrence or date of last contact. Adverse effects of treatment were graded according to the Radiation Therapy Oncology Group (RTOG) toxicity criteria.
SAS (Cary, NC) program v. 8.2 was used for statistical analysis. The sample size for this study was based on the available number of patients within the relevant time period. All the survival rates were expressed as actuarial data, and all toxicity percentages were crude data. Survival rates were calculated by the Kaplan-Meier method, and the log rank test was used for univariate analysis. The A chi-square test and Fisher exact test were used to compare rates. The Student t-test was applied to compare continuous variables between once-daily fractionation and twice-daily fractionation regimens. In all tests, P < 0.05 was considered statistically significant.
All 47 study patients were included in the analysis. There were 25 males and 22 females (M:F ratio, 1.1:1). The median age of patients was 68.8 (range, 39.4–89.7) years. Performance status was not prospectively collected. The demographic characteristics of the patients are summarized in Table 1. Eight patients (17%) had distant metastasis before radiotherapy and 16 patients developed distant metastasis after radiation. At the last follow-up, 10 patients (21.3%) were alive and 37 patients (78.7%) died. The median follow-up time was 4.7 months (range, 0.2–114 months) for all patients.
|Characteristics||All patients (n = 47)||Radical (n = 23)||Palliative (n = 24)|
|Age, y (range)||68.8 (39.4–89.7)||66.9 (39.4–79)||70.5 (46.1–89.7)|
|Presenting symptoms, %|
|Neck mass||87.2 (41/47)||87 (20/23)||87.5 (21/24)|
|Dysphagia||49.0 (23/47)||43.5 (10/23)||54.2 (13/24)|
|Hoarseness||40.4 (19/47)||30.4 (7/23)||50.0 (12/24)|
|Neck pain||17.0 (8/47)||13.0 (3/23)||20.8 (5/24)|
|Dyspnea||14.9 (7/47)||8.7 (2/23)||20.8 (5/24)|
|Duration of symptoms before diagnosis (mo)*||3 (0.2–24)||4.5 (0.2–24)||3 (1–12)|
|Reason for referral|
|Primary radical radiotherapy||22||13||9|
|Gross/microscopic residual after surgery||11||5||6|
|Tumor size before treatment (cm)*||8 (3–16)||6.8 (3–15)||10 (3–16)|
|Surgery prior to radiation|
Patients who had local disease progression or local recurrence were classified as experiencing an event for local progression-free rate analysis. Deaths were censored when they occurred. In patients treated with radical radiotherapy, the actuarial local progression-free rates were 94.1% (crude rate 81.8%) at 6 months and 74.1% (crude rate 75.0%) at 2 years. There were no significant prognostic factors identified for progression-free rate, including age, sex, tumor size, TNM stage (Stages IVA, IVB, IVC), and radiotherapy fractionation regimen. There was no dose/response relation observed for the group treated with doses greater than 40 Gy. When patients were divided into subgroups by extent of surgery as thyroidectomy and no gross residual tumor vs. thyroidectomy with minimal residual tumor vs. debulking surgery vs. biopsy only, there was no correlation between extent of surgery and local progression-free rate. However, it is important to note that the number of patients was small within the subgroups. Twelve patients had gross primary tumor at the start of radical radiotherapy. Complete response, partial response, and stable disease were found in 2, 8, and 2 patients, respectively, in these patients with gross disease at the start of radiotherapy. No patient had local progression during radiation. The crude local response rate was 83.3% in patients with gross local disease at the start of radiotherapy.
In patients who underwent palliative radiation, the local progression-free rates at 3 and 6 months were 83.0% and 64.6%, respectively, but all palliative patients died within 9 months (Fig. 1). The local progression-free rate was significantly greater for patients treated radically compared with those treated palliatively (P = .02). The median local progression-free rate could not be accurately calculated because of the small sample size and short follow-up time in this study. Of patients who had palliative radiation, 22 patients had gross primary tumor at the start of radiotherapy. Complete response, partial response, stable disease, and local progression were found in 0, 4, 13, and 5 patients, respectively. The crude local response rate was 18.2% in patients with gross local disease at the start of radiotherapy.
Salvage surgery was performed in 1 patient after radiotherapy had failed. This patient underwent partial excision of thyroid mass for symptom control of dysphagia. The symptom improved after surgery, but the patient died of thyroid cancer 2 months later.
Patients who died regardless of cause were classified as experiencing an event for the overall survival analysis. The median actuarial overall survival was 5.6 months and the 2-year overall survival was 4.1%. For patients treated with radical radiotherapy, the overall survival rates at 6 months, 1 year, and 2 years were 79.8%, 46.1%, and 9.2%, respectively; the median survival was 11.1 months. Age, sex, tumor size, TNM stage (Stages IVA, IVB, IVC), and extent of surgery were not identified as significant prognostic factors for overall survival. Similarly, there was no radiation dose response effect in radically treated patients. There was 1 long-term survivor in patients treated with radical radiotherapy. This patient was a 76-year-old woman who presented with a 4.5-cm mass in the neck. She underwent subtotal thyroidectomy followed by radical radiotherapy. This patient was alive and cancer-free at 9.5 years follow-up after radiotherapy.
For patients treated with palliative radiotherapy, the actuarial overall survival rates at 3 months and 6 months were 54.2% and 16.7%, respectively, and the median survival was 3.2 months. No patient survived more than 9 months (Fig. 2). The median overall survival was significantly greater in patients who underwent radical radiotherapy compared with palliative radiotherapy (11.1 vs. 3.2 months, P < .0001).
Of patients who died after radical radiotherapy, 30.8%, 38.4%, and 30.8% of patients died of local disease, distant metastases, both local and distant diseases, respectively. Of those patients who died after palliative radiotherapy, 47.4%, 21.0%, and 31.6% of patients died of local disease, distant metastases, both local and distant diseases, respectively. There was a trend toward more patients dying of distant metastases in patients who underwent radical radiotherapy (P = .16).
There were no Grade 3 or higher acute esophagitis in patients who underwent radical radiotherapy. Three patients with twice-daily fractionation and 2 patients with once-daily fractionation developed Grade 3 acute skin toxicity. All patients with acute skin toxicity recovered after treatment with topical medications. There was no Grade 3 or higher late toxicity.
In patients who underwent palliative radiotherapy, 1 patient developed Grade 3 acute esophagitis. This patient received adriamycin, cisplatin, and bleomycin combined chemotherapy 2 weeks before radiotherapy. Grade 3 or higher acute skin toxicity was not observed in patients with palliative radiation. There was also no Grade 3 or higher late toxicity in patients treated with palliative radiotherapy.
Comparison between Twice-Daily and Once-Daily Fractionation Regimens
Of all patients who underwent radical radiotherapy, 9 had twice-daily treatment and 14 had once-daily treatment. The median overall survival in patients with twice-daily fractionation (13.6 months) was 3.3 months longer than patients with once-daily fractionation (10.3 months), but the difference was not statistically significant (P = .3). The overall survival rates of these 2 groups are summarized in Table 2. There was no statistical difference in local progression-free rate between the twice-daily fractionation regimen (median, 7 months) and once-daily fractionation regimen (median, 6.5 months, P = .5). The Grade 3 or higher skin toxicity did not differ between the twice-daily fractionation regimen (3 patients) and once-daily fractionation regimen (2 patients).
|Median survival||13.6 mo||10.3 mo||.3|
The treatment outcome of anaplastic thyroid carcinoma is unsatisfactory. In the largest series of 135 patients from a single institution, the Mayo Clinic group reported their 50 years of experience in treating anaplastic thyroid carcinoma with multimodality therapy including surgery, radiotherapy, and chemotherapy. The multimodality therapy did not improve survival. Radiotherapy had a trend to improved survival. The median survival in patients with and with out radiation was 5 months and 3 months, respectively (P = .08).18
Because anaplastic thyroid carcinoma grows rapidly, hyperfractionated accelerated radiation has been used, sometimes in combination with chemotherapy. A Swedish group has used multimodality therapy including combined preoperative hyperfractionated radiation and chemotherapy, followed by surgical resection, postoperative radiation, and chemotherapy. In a total of 55 patients, surgery was possible in 40 patients. Although this aggressive approach resulted in a local recurrence-free rate of 60%, the median survival was only 3.5 months, and 2-year survival was only 9%.19–21 De Crevoisier et al.12 from France reported improved local control with a combination of surgery, chemotherapy, and hyperfractionated accelerated radiotherapy. Of 24 patients treated, local control was obtained in 19 patients (79%), but the median survival was only 10 months. Toxicities were common in patients treated with this protocol. The Grades 3 and 4 toxicities of neutropenia, pharyngoesophagitis, anemia, and thrombocytopenia were 73%, 33%, 27%, and 13%, respectively. This protocol achieved good local control at the cost of high toxicity. Death was mainly caused by distant metastasis.12 Other investigators also reported the results of hyperfractionated radiotherapy with chemotherapy, with local control rates ranging from 22% to 76%, and median survivals varied from 2.5 to 12 months.15, 22–24
In a previous study at Princess Margaret Hospital, Wong et al.25 reported 32 patients with anaplastic thyroid carcinoma treated with radiotherapy from 1975 to 1982. The radiation dose was 30–45 Gy at 1 Gy per fraction given 4 times a day at 3-hour intervals. Local control was achieved in 22% of patients and the median survival was less than 6 months. Two patients (6.3%) developed radiation myelopathy. This technique was abandoned because of the high risk of radiation myelopathy. Since 1983, radical radiotherapy with once-daily fractionation and sub sequently twice-daily fractionation regimens has been used in patients with good performance status at the Princess Margaret Hospital.
Survival in patients with anaplastic thyroid carcinoma is poor. The median survival in most series is 3 to 6 months.21, 24, 26 In view of this, quality of life is important. Radiotherapy alone in this series was well tolerated and resulted in local progression-free rate at 6 months of 94.1% in patients treated radically, and 64.6% in patients treated with palliative intent. As to be expected, patients with metastatic disease or poor performance status who were treated with palliative intent had worse outcomes than patients treated with radical radiotherapy. By selecting patients with good performance status and without distant metastases for aggressive therapy, we were able to achieve a median survival of 11.1 months without significant toxicity. Although there was a trend to improved survival with twice-daily radiotherapy, it was not statistically significant. However, the patient number is small and we continue to use hyperfractionated accelerated radiotherapy, but now with an intensity-modulated radiation therapy (IMRT) technique using volumes as described previously. Given the acceptable toxicity rate, in an attempt to further increase the biological effect and enhance local control we are currently exploring the effect of dose escalation with twice-daily radiation with IMRT. Although it may be attractive to treat all patients with twice-daily radiotherapy to try to maximize local control in the neck, we do not think it is warranted to subject patients to a month or more of twice-daily radiation who have poor performance status or metastatic disease and a life expectancy of only 3 months. We continue to reserve an aggressive radiotherapy treatment for patients with good performance status (ECOG 2 or better) and without distant metastases.
In conclusion, radiotherapy is moderately effective in the local control of anaplastic thyroid carcinoma. There is no apparent benefit from a radiation dose greater than 40 Gy, but this must be interpreted with caution due to the small number of patients treated with radical intent and other confounding factors. Twice-daily fractionation is well tolerated and has a trend to longer survival. We will continue to explore twice-daily fractionation in the treatment of anaplastic thyroid carcinoma.
- 6International Union Against Cancer. TNM classification of malignant tumours, 6th ed. New York: Wiley-Liss, 2002.
- 7American Joint Committee on Cancer. AJCC cancer staging manual, 6th ed. New York: Springer, 2002.