S P E C I A L

F E A T U R E U p d a t e

Update on External Beam Radiation Therapy in Thyroid Cancer

James D. Brierley
Department of Radiation Oncology, University of Toronto, Princess Margaret Hospital, Toronto, Ontario, Canada M5G 2M9

Surgery is the mainstay of treatment for thyroid cancer. The role for external beam radiotherapy (EBRT) as an adjuvant to surgery or as the primary therapy is established in anaplastic thyroid cancer but is controversial in differentiated thyroid cancer and uncertain in medullary thyroid cancer. This update reviews the recent reported success of combining EBRT with taxanes in anaplastic thyroid cancer. Also discussed are the recent reports from large single institutions that support the recommendations of the American and British Thyroid Associations on the use of EBRT in high-risk differentiated thyroid cancer. Further evidence on the role of EBRT in MTC is discussed. The important advances in the delivery of EBRT using intensity-modulated radiation and image-guided radiation that result in more accurate and potentially more effective radiation therapy with less toxicity are also discussed. (J Clin Endocrinol Metab 96: 2289 2295, 2011)

ver the last 2 yr, papers published on the topic of external beam radiotherapy (EBRT) in thyroid oncology that have been the most promising have been in the least likely of thyroid pathologies, anaplastic thyroid cancer (ATC), with reports suggesting that the combination of EBRT and taxanes may be effective in controlling the disease, admittedly in only a small number of cases that are highly selected. In addition, there has been a major advance in radiation techniques with the increasing availability of intensity-modulated radiotherapy (IMRT). In differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC), there have been further single institutional retrospective reports evaluating the effectiveness of EBRT in reducing the local relapse rate in high-risk patients. These four areas will be discussed.

Anaplastic Thyroid Cancer

Given the universally poor results of treatment of ATC over the years, there have been many novel attempts to improve outcome. The most promising, in terms of local control of the otherwise devastating effect of rapidly progressing cervical disease, have been with trimodality therISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright 2011 by The Endocrine Society doi: 10.1210/jc.2011-1109 Received March 29, 2011. Accepted May 16, 2011.

apy combining surgery with radiation and chemotherapy. Tennvall et al. (1) reported on three successive protocols in 55 patients of hyperfractionated radiotherapy and a variety of chemotherapy agents and surgery. The local control rate was 60%, but the 2-yr survival was only 9%. In only 24% was death attributable to local failure, reflecting the high rate of distant metastatic disease that is unresponsive to chemotherapy. At Princess Margaret Hospital, after initial high toxicity rates with concurrent chemotherapy and hyperfractionated radiation and the lack of chemosensitivity of ATC, we chose to give hyperfractionated radiation alone (2, 3). The theoretical advantage of hyperfractionated radiation (multiple small radiation doses that allow more than one radiation treatment a day) is that with small fractions, toxicity is reduced and the treatment can be accelerated so that a radical course of radiation can be given over a shorter than usual time period, which is theoretically important in tumors such as ATC that grow rapidly and potentially grow during a 6- to 7-wk course of EBRT. Using hyperfractionated accelerated radiation (60 Gy in 40 twice daily fractions of 1.5 Gy over 4 wk), we reported a 6-month local progression-free rate of 94% in patients receiving high-dose radiotherapy.
Abbreviations: ATC, Anaplastic thyroid cancer; CSS, cause-specific survival; DTC, differentiated thyroid cancer; EBRT, external beam radiotherapy; ETE, extrathyroidal extension; IGRT, image-guided radiotherapy; IMRT, intensity-modulated radiotherapy; LRFR, locoregional relapse-free rate; MTC, medullary thyroid cancer.

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There was an improved median survival after this regime (13.6 months) compared with conventional fractionation (10.3 months); the difference was not significant, although the number of patients was small. This was in a selected group of patients with good performance status and no evidence of metastatic disease. Patients treated with palliative EBRT had a median survival of only 3 months. The 2-yr survival of patients treated with high-dose EBRT was 9.2%, again demonstrating the problem of uncontrolled distant metastatic disease. In contrast, in a report of a similar twice a day fractionation scheme, but with larger fractions (2 or 1.8 Gy in contrast to 1.5 Gy) and larger volumes from the mastoid to the carina, the group from the Royal Marsden Hospital reported a median survival of only 70 d and an unacceptable toxicity (4). There is increasing evidence that taxanes, which are radio-sensitizing agents, may be more effective chemotherapeutic agents than those traditionally used in ATC. Ain et al. (5) initially reported encouraging response rates to paclitaxel. More recently, in a series of nine stage IVB (locoregional disease extending beyond the thyroid) and four stage IVC (metastatic disease) patients given induction paclitaxel, there was a 33% response rate in the stage IVB group, including one complete response, and a 25% (one of four) response rate in the stage IVC group when given before EBRT. The authors reported a 44% 1-yr survival in nine patients with stage IVB ATC treated with induction paclitaxel in comparison to 5.9% in a historical control group and concluded that induction chemotherapy with paclitaxel was of value in stage IVB patients. Bhatia et al. (6) have reported, as part of a larger cohort of 53 patients, on six treated with continuous-infusion paclitaxel and twice-daily radiation in three separate weeklong cycles. Of the 53 in their study, there were five longterm survivors; only one, however, was treated with radiation and paclitaxel; the other four were treated with cisplatin or carboplatin. More encouraging are the results of two recent studies on the use of concurrent taxanes and radiation. In the first, a short report of six patients treated with EBRT to a standard dose of 60 Gy in 30 fractions along with docetaxel 100 mg every 3 wk for six cycles, the chemotherapy was started with the first week of radiation and continued thereafter (7). Two patients had a partial remission, and four had a complete response. Three of the complete responses were reported to have had microscopic residual disease, so it is uncertain how response could be measured in these three patients, except that they remain free from recurrence. One of these three had metastatic lung disease and had a complete response to the measurable disease. That being said, achieving a complete response in a patient with a 658-cm mass is still an impressive result. The

treatment was not without toxicity with mucositis/stomatitis, esophagitis, and dermatitis. All patients required hospitalization for nutritional support. The median survival was 15.6 months. In a somewhat larger series with regionally confined ATC seen at the Mayo Clinic, 10 patients with IVA or IVB disease had IMRT and four cycles of chemotherapy after surgery when it was possible (8). Four of the patients had no residual disease (R0 resection), and three had microscopic residual disease (R1 resection). Three had gross residual disease, and two of these patients had debulking procedures (R2 resection). All but one had radiation to a biologically equivalent dose higher than 60 Gy in 30 fractions; all had concurrent chemotherapy, docetaxel and doxorubicin being the commonest chemotherapy agents used. The median survival was 44 months, and the 2-yr survival was 60%. The combination was better tolerated than described by Troch et al. (7) in that only two required hospitalization. Foote et al. (8) concluded that in patients with regionally confined ATC, an aggressive approach with IMRT and radio-sensitizing and adjuvant chemotherapy appears warranted. It is, however, salient to note that of 25 patients initially seen, 10 (40%) had metastatic disease, and five (20%) chose not to proceed with the aggressive approach at the Mayo Clinic, showing that such an approach is only appropriate in a selected group of patients. The reason for the differences in rates of hospitalization in the two series is uncertain. It could be due to differences in chemotherapy given and its administration, or the radiotherapy dose, or even the use of IMRT as described below, but it is probably multifactorial. There is increasing evidence of a possible role for targeted therapies in DTC; however, most of this comes from DTC and MTC (9), with few reports in ATC (10, 11). In other tumor sites, EBRT has been combined with newer biological agents such as sorafenib with some suggestion of success (12). To explore such combinations, the Radiation Therapy Oncology Group (RTOG) has recently opened a multicenter randomized phase II study of IMRT, paclitaxel, and pazopanib (a second-generation, multitargeted tyrosine kinase inhibitor), compared with IMRT and paclitaxel alone in ATC. This study will not only show whether there is a potential benefit from adding pazopanib, but will also give valuable data on the efficacy of IMRT and taxanes in a prospective multicenter setting. Summary Although the outcome of patients with ATC remains extremely poor, with the possible exception of patients with incidental ATC confined to the thyroid gland, there may be improved local control with concurrent EBRT and taxanes. Further studies such as the RTOG phase II study

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need to be done to confirm the improved outcome on a multinstitutional basis and to study whether there is any benefit from adding newer biological agents.

Radiotherapy Technique
The aim of EBRT in general is to reduce the risk of local recurrence in patients considered to be at high risk of recurrence in the volume treated after surgery and radioactive iodine. In the case of DTC, this is typically the thyroid bed, in particular the tracheoesophageal groove. The aim of a good radiotherapy treatment plan is to obtain an even distribution of radiation dose throughout the volume at risk of recurrence while at the same time sparing the organs at risk of developing significant radiation toxicity. The curvature of the neck, the change in density across the volume produced by the air gap of the trachea and the bone of the vertebrae and the horseshoe shape of the neck, and the desired high-dose radiation volume makes this a volume that is very difficult, if not impossible, to treat adequately without some degree of compromise when using conventional radiation therapy treatment planning. IMRT uses computers and linear accelerators to sculpt a three-dimensional radiation dose map, ensure better distribution of radiation dose to the required treatment volume, and generate dose gradients with narrower margins than those allowed using traditional methods (Fig. 1). This makes IMRT especially suitable for treating complex treatment volumes and avoiding organs at risk that may be dose limiting. As a consequence, IMRT may provide benefits in radiation to the thyroid bed in that we can now ensure that the appropriate dose is given to the volume at risk of recurrence without the compromises that were previously required that almost invariably resulted in a degree of underdosing, and this should result in a greater therapeutic gain from EBRT. The ability to avoid more normal tissue and/or enable possible dose escalation is also facilitated by image-guided radiotherapy (IGRT), whereby images are taken during the radiation treatment and ensure accurate day-to-day set-up that allows the radiation oncologist to treat a smaller volume of normal tissue. In the past, volumes were increased to allow for uncertainties caused by patient movement during and between treatments. IGRT should thereby further reduce potential toxicity. Figure 2 is an example of a cone beam computed tomography scan taken halfway through a course of radiotherapy. The image shows two overlapping scans, one taken at the time of treatment planning and one immediately before treatment, in which the bones are aligned. It can be seen that the tumor mass has shrunk and that the tracheostomy tube is now 1.4 cm closer to the vertebral

FIG. 1. An IMRT plan for a 63-yr-old man who presented with recurrent papillary thyroid cancer. At the time of surgery, there was local invasion of the soft tissues around the trachea, with involvement of the lower pharynx and upper esophagus close to the insertion of the recurrent laryngeal nerve. Tumor was resected, but residual gross disease was left. A, Anterior/posterior view. B, Lateral view. The area shaded in orange is the volume considered at moderate risk of relapse and is prescribed 56 Gy. The yellow line is the 56 Gy isodose line; all the tissue within this line receives a minimum of 56 Gy. The area shaded in mauve is at high risk and is prescribed 66 Gy. The green line is the 66 Gy isodose; all the tissue within this line receives a minimum dose of 66 Gy. Other isodose lines are also included.

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of IMRT and IGRT over conventional radiation will never been shown; however, the benefits in reducing toxicity and improving local control have been proven in other complex head and neck volumes, and it is not unreasonable to assume that the same is true for EBRT to the thyroid bed, especially if cervical lymph nodes are to be included in the radiation volume. Advance radiation techniques including IMRT and IGRT should ideally be employed when treating thyroid cancer with EBRT.

Differentiated Thyroid Cancer

FIG. 2. Computed tomography scan taken on the treatment unit using IGRT, halfway through a course of radiotherapy for ATC. The image shows two overlapping scans, one taken at the time of treatment planning (purple) and one immediately before treatment (green) in which the bones are aligned (white). The red line indicates the position of the gross tumor at the start of treatment, and the white line indicates the clinical target volume. It can be seen that the tumor mass has shrunk and that the tracheostomy tube is now 1.4 cm closer to the vertebral body than it was at the time of treatment planning.

body. This image can be used to adjust the radiation treatment plan if required. In a comparison of EBRT techniques, Nutting et al. (13) found that IMRT improved the planning target volume coverage and reduced the spinal cord dose, and they concluded that IMRT should reduce the risk of myelopathy and may allow dose escalation in patients with thyroid cancer. In a series from the MD Anderson Cancer Center comparing patients treated with IMRT with those treated with conformal radiotherapy, the authors reported less late toxicity with IMRT, but this was not statistically significant (14). The Cancer Care Ontario has a well-developed program of treatment practice guidelines; the program has recently reviewed the evidence in support of IMRT in a wide variety of tumor sites. They have concluded that, although insufficient evidence was obtained in a systematic review to propose evidence-based recommendations for thyroid cancer, because IMRT can improve target coverage in such a difficult volume to treat, which may translate into an increase in local control with or without the ability to safely increase the maximum tumor dose, there are compelling reasons why IMRT should be offered to patients with thyroid cancer as an alternative to conventional treatment planning (see http:// www.cancercare.on.ca/common/pages/UserFile.aspx?fileId 87007). Summary The combination of IMRT and IGRT is a major advance in radiation therapy. Given the small numbers of patients undergoing EBRT to the thyroid bed, the benefit

Up to now, the evidence in support of EBRT in DTC has come from retrospective reviews, all of which have the inherent biases of such studies, and although the earlier studies were conflicting, later reports were sufficient for both the American Thyroid Association (ATA) and the British Thyroid Association (BTA) guidelines to recommend EBRT in certain high-risk patients (Table 1). Attempts in North America to perform a randomized trial have not been successful. However, one was started in Europe (16). Unfortunately, it closed because of poor accrual, and only 8% of 311 accrued patients received EBRT. All patients were treated with thyroidectomy, 131I therapy, and TSH suppression and were randomized to receive additional EBRT. Only 45 of a potential 311 patients consented to randomization, and therefore the study changed to a prospective cohort study. Twenty-six of the 47 patients randomized received EBRT. Of these 26, there were no recurrences, compared with 3% in the non-EBRT trial. This was obviously not a significant difference. There TABLE 1. American Thyroid Association Guideline and British Thyroid Association Guideline on the use of EBRT in DTC
American Thyroid Association Guideline (25) The use of external beam irradiation to treat the primary tumor should be considered in patients over age 45 with grossly visible extrathyroidal extension at the time of surgery and a high likelihood of microscopic residual disease, and for those patients with gross residual tumor in whom further surgery or RAI would likely be ineffective. The sequence of external beam irradiation and RAI therapy depends on the volume of gross residual disease and the likelihood of the tumor being RAI responsive. British Thyroid Association Guideline (15) Gross evidence of local tumor invasion at surgery, presumed to have significant macro- or microscopic residual disease, particularly if the residual tumor fails to concentrate sufficient amounts of radioiodine. Extensive pT4 disease in patients over 60 yr of age with extensive extranodal spread after optimal surgery, even in the absence of evident residual disease.
RAI, Radioactive iodine.

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was one serious complication from EBRT, and therefore the study concluded that routine EBRT in locally invasive DTC can no longer be recommended. The inclusion criteria were DTC with local extension beyond the thyroid capsule (pT3 and pT4), freedom from distant metastases, and age between 18 and 70 yr at the time of initial surgery. Of the 26 who received EBRT, the mean age was only 47, and 15 had tumors less than 1 cm in size; the mean size was 1.9 cm, with a SD of 0.9 cm. Although it is not clear how many had T4a disease, it would seem that many patients who received EBRT may not have been at high risk of locoregional recurrence and that it is unlikely that the majority of patients would meet the ATA or BTA criteria for EBRT. The study does not provide any convincing evidence to refute the potential benefit of EBRT in high-risk patients. Over the last 2 yr in North America, two large cancer centers have published retrospective reviews that show a high local relapse-free rate after EBRT in patients considered to be at high risk of relapse, supporting the use of EBRT in these patients; however, because EBRT was standard practice in these centers, there is no control group. The Memorial Sloane Kettering group reported a 4-yr locoregional control of 72% in 76 patients considered to be at high risk of cervical relapse (64 had DTC, 12 had MTC, and 84% had T4 disease) (17). The 2- and 4-yr overall locoregional control rates for all histological types were 86 and 72%, respectively, and the 2- and 4-yr overall survival rates for all patients were 74 and 55%, respectively. Of the non-MTC patients, 16 (25%) had a local failure, with more local failures in the tall cell group (four of 12, or 33%) than other histologies. Grade 3 acute mucositis and dysphagia occurred in 14 (18%) and 24 (32%) patients, respectively. Four patients (5%) experienced significant late toxicity requiring a percutaneous endoscopic gastrostomy tube. The authors concluded that EBRT had acceptable toxicity and was effective in controlling locally advanced disease. The MD Anderson group has reported on 131 patients with DTC; 126 (96%) had extrathyroidal extension (ETE) (14). Seventy-six patients (58%) had recurrent disease, 62 (47%) had microscopically positive surgical margins, 15 (11%) had gross residual disease, and 57 (44%) had IMRT. The locoregional relapse-free rate (LRFR) was 79% at 4 yr, and IMRT was associated with less frequent late toxicity. The MD Anderson group concluded that in patients with high-risk DTC, EBRT provided durable locoregional disease control. Another retrospective review from a major radiation center (the Christie Hospital, Manchester, UK) also supports the use of EBRT in high-risk patients (18). Nineteen patients had unresectable or gross residual disease, and 24 patients had microscopic residual disease. The 5-yr locoregional con-

trol rate was 89.1% for those with clear or microscopic positive margins and 69.2% for patients with macroscopic residual or inoperable disease. The 5-yr LRFR was 69.2%, and 5-yr cause-specific survival (CSS) was 58.3%; LRFR was 89.1% and CSS was 91.4% with negative or microscopic residual disease. We recently reported on an analysis of our database in an attempt to identify variables that affected outcome in patients with DTC and ETE (19). Previously in our institution, EBRT was considered in all patients with ETE, but now radiotherapy is not advised for patients with T3 tumors (minimal ETE) or in young patients. Because age is such a significant factor in DTC, we speculated that if we accept that ETE benefits older patients with T4a disease, there may be a benefit for ETE in younger patients with T4b disease and conversely in older patients with minimal ETE T3 disease. Not surprisingly, prognostic factors were similar to those found in studies of all patients with DTC irrespective of ETE. In patients with postoperative gross residual disease treated with radiotherapy, 10-yr CSS and LRFR were 48% and 90%, respectively, showing that although EBRT can achieve local control, distant metastatic disease remains a major problem and is the cause of death in the majority of patients with ETE. For patients without gross residual disease after surgery, the 10-yr CSS and LRFR were 92% and 93%, respectively. In patients older than 60 yr with T3 ETE but no gross residual disease postoperatively, there was an improved LRFR at 5 yr of 96%, compared with 87.5% without EBRT (P 0.02). We were unable to show a benefit in young patients with T4b disease, but the numbers were small. We concluded that patients with gross ETE benefit from EBRT and there may be a potential benefit in reducing locoregional failure in patients over 60 yr with minimal ETE (T3), but the benefit is small and must be weighed against the risk of toxicity from EBRT. Currently at our institution, we reserve EBRT for patients over the age of 50 yr with T4a or T4b tumors and not for T3 patients because the risk of recurrence is small and the improvement in local failure is also small. The volume to be treated is controversial. It is our practice to routinely treat the thyroid bed and adjacent lymph node areas. The clinical target volume is defined to cover thyroid bed, jugular, and posterior cervical lymph nodes from the level of the hyoid to the aortic arch, including levels III, IV, VI, and partial level V nodal regions, and this volume is adjusted according to the surgical and pathology findings. We reserve EBRT to the whole cervical region in patients we consider to be at high risk of relapse in that area, namely patients with extranodal capsule extension or multiple nodal recurrences. This volume is smaller than that described by both the Memorial Sloane Kettering and

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MD Anderson groups. Two recent reports from Korea and the United Kingdom support the use of extended volumes. Kim et al. (20) reported in a small study of 23 patients that there was a 55% risk of locoregional relapse (six of 11 patients) treated with limited volume EBRT (to the primary or recurrent tumor and involved nodes), compared with only 8% (one of 12) if an extended volume was treated (including the cervical and upper mediastinum). In the study described above from the Christie Hospital, Azrif et al. (18) reported a high risk of failure if the upper mediastinum is not treated. The larger volumes come at the cost of higher toxicity, so it is important that the volume at risk of relapse is carefully considered. Despite the more limited volume that we frequently use, the locoregional relapse rate in our series of patients with ETE and no gross residual disease was only 7%. More information is required to ascertain which patients require extended field EBRT as well as the risk of higher acute and late toxicities. Summary There is further single institutional data supporting the use of adjuvant EBRT in highly selected patients with DTC, usually patients with extensive ETE (or repeated cervical nodal recurrence) in whom local recurrence would require extensive ablative surgery. Despite the advances in delivery of EBRT described above, careful selection of high-risk patients is required to ensure that the benefits of reducing the risk of recurrence outweigh the cost of toxicity.

given EBRT for locally advanced disease had MTC with a locoregional failure rate of 33%. In a larger series from MD Anderson, 34 patients assessed as being at high risk of locoregional relapse (gross or microscopic residual disease, soft tissue extension, nodal disease, or mediastinal involvement) had a 5-yr relapse-free rate of 87% and a 5-yr survival rate of 56%. Confirming the earlier studies showing that EBRT can result in locoregional control but distant relapse is a major issue in these patients. Summary Further single institutional data supports the use of EBRT in improving local control in highly selected patients with MTC. However, given the natural history of the disease, survival is not improved; therefore, EBRT should be reserved only in patients at high risk of devastating cervical recurrence requiring extensive ablative surgery.

Conclusion
In recent years, advances in EBRT have come in the combination with taxanes in the management of ATC, which may be advanced further with combination with newer biological agents and in the advances in radiation delivery. In both DTC and MTC, there is further evidence supporting the role of EBRT in patients with gross residual or unresectable disease and more evidence supporting the use in selected patients at high risk of locoregional failure after surgery and for DTC. Unfortunately, the German example has confirmed that a randomized trial to support the use of EBRT in selected cases is not feasible. We need to more clearly define both the patients without gross residual disease who benefit from EBRT and the volumes that need to be irradiated. Advances in radiation techniques continue to help accurately deliver radiation therapy, thereby increasing the effectiveness of EBRT and reducing toxicity.

Medullary Thyroid Cancer

In MTC, an analysis of SEER (the Surveillance Epidemiology and Results Program of the National Cancer Institute) data showed no survival benefit to EBRT when given in node-positive patients on univariate analysis, but on multivariate analysis only increasing age and tumor size significantly influenced overall survival (21). This lack of benefit from EBRT in improving survival for MTC is not surprising, given that previous retrospective studies had only shown an improvement in locoregional control in high-risk patients and no survival benefit presumably because of the high risk of microscopic metastatic disease in patients considered to be at high risk of locoregional failure (ETE and/or multiple nodal involvement). The findings of previous retrospective reports (22, 23) on the potential benefit of EBRT in high-risk patients has been supported by data from MD Anderson and Memorial Sloane Kettering (17, 24). In the report from Terezakis et al. (17) on EBRT discussed above, 12 of the 76 patients

Acknowledgments
Address all correspondence and requests for reprints to: James D. Brierley, Department of Radiation Oncology, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. E-mail: James.brierley@rmp.uhn.on.ca. Disclosure Summary: The author has nothing to disclose.

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