Version May 2024
INTRODUCTION — Surgical resection is the primary treatment for patients with differentiated (ie, papillary and follicular) thyroid cancer, followed by radioiodine, and then thyroxine therapy. Most patients with well-differentiated thyroid cancer have resectable tumors, and the results from surgery, radioiodine, and thyroxine therapy are excellent.
External beam radiotherapy (EBRT) is used infrequently in the management of differentiated thyroid cancer. It is predominantly indicated for palliation of locally advanced unresectable or recurrent/metastatic disease in patients whose tumors do not concentrate radioiodine. We also consider EBRT in older patients with microscopic residual radioactive iodine refractory thyroid cancer following resection of all clinically evident gross disease.
The use of EBRT in the treatment of differentiated thyroid cancer will be reviewed here. Other aspects of the management of differentiated thyroid cancer are discussed separately, as is the role of EBRT in other thyroid malignancies, such as anaplastic and medullary thyroid cancer.
●(See "Differentiated thyroid cancer: Overview of management".)
●(See "Differentiated thyroid cancer: Surgical treatment".)
●(See "Anaplastic thyroid cancer", section on 'Our approach to treatment'.)
INDICATIONS FOR EBRT — For patients with differentiated thyroid cancer, the main indications for external beam radiotherapy (EBRT) to the thyroid bed and known sites of disease include:
●Palliation for locally advanced unresectable disease or symptomatic recurrent/metastatic disease that is refractory to radioiodine.
●Residual macroscopic disease following resection of all clinically evident disease, with absent or inadequate radioiodine avidity.
●Older patients (age 55 years or older) who have gross extrathyroid extension (T4 disease) (table 1) at the time of surgery and selected younger patients with T4b or extensive T4a disease and poor histologic features (ie, insular or poorly differentiated histology) whose disease is resected, but in whom there is a high likelihood of residual microscopic disease that is known or strongly suspected to be non-radioiodine avid and in whom additional surgical intervention at the time of recurrence would be ineffective or associated with unacceptable morbidity.
For patients undergoing complete resection, lymph node involvement by itself is not an indication for EBRT, because regional control is usually achieved with surgery and radioiodine. However, EBRT could also be considered for older patients with unresectable lymph node involvement (eg, nodal involvement that intimately involves the carotid artery).
In patients with local or regional recurrence, when feasible, repeat surgery and, if the tumor is iodine avid, additional radioiodine, is the preferred approach. However, patients with multiple recurrences in the thyroid bed or cervical nodes, especially if the interval between recurrences is short, may achieve control with EBRT. The risk of multiple operations versus the risks of EBRT should be reviewed for each such patient. EBRT also represents a reasonable approach to the rare patient with locally recurrent disease with loss of radioiodine avidity, such as may occur with multiple local recurrences in the thyroid bed or cervical nodes.
There are no randomized trials that address specific indications for EBRT in patients with differentiated thyroid cancer, and practice is variable [1-3]. In general, indications for EBRT in patients with differentiated thyroid cancer are based upon clinical experience and retrospective studies, which are described below.
Localized disease
Macroscopic — For patients with macroscopic unresectable disease in the neck that does not concentrate radioiodine, we suggest EBRT. Some thyroid cancer experts also administer EBRT to patients with unresectable disease in the neck despite radioiodine uptake, if the degree of iodine uptake compared with the size of the residual disease suggests that the radioiodine alone will be insufficient to control disease, or if the unresectable disease is markedly avid (standardized uptake value [SUV] >10) on fluorodeoxyglucose positron emission tomography (FDG PET) scanning.
Many retrospective studies have shown a benefit of EBRT in patients with macroscopic residual disease [3-12]. Radioiodine therapy alone is unlikely to eradicate residual tumor unless the absorbed dose of radiation is high, ie, at least 100 Gy [13]. In one study, as an example, a single dose of radioiodine producing an absorbed dose over 80 Gy resulted in destruction of tumor in cervical lymph nodes in only 74 percent of patients with small-volume disease (less than 2 grams) [14]. Further radiation in the form of EBRT can improve local control.
The efficacy of EBRT in controlling macroscopic residual disease is illustrated by the following observations:
●In a study from Hong Kong of 842 patients, 124 of whom had gross residual disease, the 69 patients who had EBRT had better local regional control at 10 years compared with those who did not have EBRT (56 versus 24 percent) [6].
●In a series of 88 patients with well-differentiated thyroid cancer that had been incompletely resected, the five-year survival was 77 percent with EBRT compared with 38 percent after surgery alone [8].
●In another study, the five-year locoregional control was 69.2 percent for 19 patients with macroscopic residual or inoperable disease, and the five-year cause-specific survival was 58.3 percent [15].
Even better results have been seen in more contemporary series, many of which utilized advanced radiation therapy approaches such as intensity-modulated radiotherapy (IMRT) alone or with concurrent chemotherapy. As examples:
●Memorial Sloan Kettering Cancer Center reported on 66 patients with gross residual/unresectable non-anaplastic, non-medullary thyroid cancer who received EBRT (77 percent with IMRT) over a 22-year period [11]. The median overall survival was 42 months, and the three-year locoregional progression-free survival rate was 77.3 percent. In a subsequent report on 27 patients who received IMRT (8 patients) or IMRT plus concurrent chemotherapy with weekly intravenous doxorubicin (CC-IMRT, 19 patients) for gross residual/unresectable non-anaplastic, non-medullary thyroid cancer, the two-year cumulative incidence of locoregional progression-free survival was 79.7 percent for all patients, and 50 and 78.3 percent for the IMRT and CC-IMRT groups, respectively [16]. Two-year overall survival was 77.3 percent with no difference between IMRT and CC-IMRT.
●The MD Anderson group reported on 131 patients with high-risk or recurrent disease [10]. For the 15 patients with gross residual or unresectable disease treated with IMRT (43.5 percent) or conventional EBRT, four had a complete response. The locoregional control rate was 22 percent.
Microscopic residual and completely resected high-risk disease — We suggest EBRT for the following subsets of patients with microscopic residual and completely resected high-risk disease:
●Older patients age 55 years or older who have T4 disease (ie, gross widespread/multifocal extrathyroid extension, tracheal perichondrium, or esophageal muscularis involvement) (table 1) at the time of surgery in whom additional surgical intervention at the time of recurrence would be ineffective or associated with unacceptable morbidity unless the surgical resection has achieved an R0 resection (complete surgical removal of all involved structures).
●Very selected younger patients with poor histologic features (ie, insular or poorly differentiated histology) and resected T4b or extensive T4a disease, as these patients have a high likelihood of residual microscopic disease that is known or strongly suspected to be non-radioiodine avid. While the majority of younger patients with aggressive histologies will not require EBRT, there are a very select few with locally invasive disease into major neck structures that may benefit from the locoregional control offered by EBRT. We seldom recommend EBRT in younger patients with more aggressive histologies on the basis of involvement of cervical lymph nodes.
The role of EBRT in patients with suspected microscopic persistent disease or a completely resected but high-risk tumor is poorly defined. EBRT may be beneficial for patients with complete resection who are at high risk of recurrence after radioiodine, but defining which patients are at risk and determining the population for whom EBRT should be offered remains controversial. Multidisciplinary discussion prior to EBRT is advised.
Modern-day studies of EBRT in patients receiving standard management suggest benefit in some patient groups. However, the role of EBRT in this setting has not been successfully studied in randomized trials. As an example, in one trial, patients with locally invasive completely resected differentiated thyroid cancer with extrathyroid extension or microscopically positive resection margins, treated with radioiodine and thyroid hormone suppression, were randomly assigned to receive additional EBRT or not [4]. There was inadequate recruitment, and the trial became a prospective cohort study. Of the 47 patients participating in the study, 26 received EBRT. After a mean follow-up of 930 days, recurrences occurred in 0 versus 3 percent, and the difference was not statistically significant. One limitation of this study was the inclusion of patients at low risk of recurrence who were unlikely to benefit from the EBRT. Another was that the follow-up in this study is much too short to properly assess the effectiveness of EBRT, given that differentiated thyroid cancer has a decades-long natural history.
Retrospective studies suggest a benefit of EBRT in high-risk groups, particularly older patients with evidence of extrathyroidal extension at the time of surgery [1,5,9,10,15,17-19]. Most of the literature combines patients with completely resected high-risk disease, those with microscopically positive margins, and patients with locally recurrent tumors. As examples:
●In a pooled quantitative analysis of eight studies (2388 patients) evaluating the role of EBRT in differentiated thyroid cancer, the mean recurrence rate in patients receiving EBRT regardless of stage or residual disease status was 8 percent, and in those who did not receive EBRT, it was 25 percent [20]. There appeared to be an improvement in local regional control following EBRT in patients over age 45 at high risk for locoregional recurrence.
●In a subgroup analysis of 70 patients from a single institution who were over 60 years of age, had extrathyroidal extension (T4 disease), and no gross residual disease after surgery, 47 received radiotherapy and 23 did not [5]. The 10-year cause-specific survival (81 versus 65 percent) and locoregional relapse-free rate (86 versus 66 percent) were significantly higher in patients who received radiotherapy than in those who did not.
●In another study of 169 patients with extrathyroidal extension who were free of disease after thyroidectomy, radioiodine, and thyroxine therapy, there were significantly fewer local and regional recurrences in patients who had received EBRT (7 versus 21 patients) [18].
●In a retrospective study of 88 patients with T4a disease treated with radioiodine with or without EBRT, locoregional control was worse with radioiodine alone compared with radioiodine and EBRT (five-year disease-free survival 43 versus 57 percent) [21]. In patients with only recurrent laryngeal nerve invasion, radioiodine alone appeared to give good disease control. However, radioiodine alone was insufficient if there was widespread multifocal, extrathyroidal extension, tracheal perichondrium, or esophageal muscularis involvement. These patients appeared to benefit from EBRT.
While the results of these studies are generally favorable, the absence of a randomized control group makes it difficult to conclude that there is a definite benefit from EBRT. This approach may be offered to patients with resected disease and with high-risk features on postoperative pathology (eg, widespread/multifocal extrathyroidal extension, tracheal perichondrium, or esophageal muscularis involvement). The decision to pursue EBRT must not be made lightly, as EBRT can have lasting late toxicity, including feeding tube dependence and xerostomia. The risk of potential late toxicity must be weighed against the risk of unresectable recurrent disease. Therefore, limiting the field of radiation is critical to minimize radiation late effects. (See 'Adverse effects' below.)
Palliative — For patients with locally advanced unresectable disease, when radioiodine fails to control local growth and spread of disease, we suggest EBRT for palliation. EBRT can be given alone or in combination with chemotherapy. The role of chemotherapy for such patients is reviewed separately. (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy", section on 'Patient selection for systemic therapy'.)
Distant disease — EBRT may be useful for patients with differentiated thyroid cancer who have progressive or symptomatic metastatic disease (soft tissue, bone, or central nervous system [CNS]) that is refractory to radioiodine and not amenable to surgery [22]. The role of chemotherapy for such patients is reviewed separately. (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy", section on 'Patient selection for systemic therapy'.)
For patients with symptomatic and/or progressive unresectable lung metastases not amenable to radioiodine, we suggest EBRT. This may be stereotactic body radiotherapy (SBRT), if appropriate. For patients with asymptomatic indolent soft tissue metastases, monitoring without therapy may be acceptable. Stereotactic radiotherapy approaches, as opposed to EBRT, are preferred for unresectable CNS oligometastases. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques' and "Stereotactic cranial radiosurgery".)
We suggest EBRT (or SBRT for vertebral metastases) for patients with unresectable bone metastases or multiple bone metastases that are refractory to radioiodine therapy. All patients with painful bone metastases should be referred for EBRT/SBRT to aid pain control. EBRT is also used to control asymptomatic bone metastases if they are in weightbearing sites. Although many patients now receive a single dose of EBRT for palliation of a painful bone metastasis, we prefer multiple fractions because of the frequent association of a soft tissue mass and the fact that survival in these patients is often prolonged. For patients with multiple bone metastases or a very limited life expectance (less than three months), single-fraction EBRT is appropriate (image 1). (See "Radiation therapy for the management of painful bone metastases", section on 'Single-dose versus fractionated treatment' and "Radiation therapy for the management of painful bone metastases", section on 'Stereotactic radiation therapy'.)
Radioiodine is often less effective in patients with bone metastases. As an example, in one report of 214 patients with distant metastases, the metastases took up radioiodine in 60 percent of those with bone involvement, but only 3 percent of these patients achieved complete remission after radioiodine therapy [23]. Given these disappointing results of radioiodine therapy in patients with bone metastases, an aggressive surgical approach has been recommended [24]. However, not all bone metastases are amenable to surgical resection. Therefore, EBRT or SBRT (for vertebral metastasis) is usually administered to patients with solitary or oligometastatic, iodine-refractory, unresectable bone metastases.
Patients with bone metastases should also be considered for treatment with an osteoclast inhibitor to reduce the rate of skeletal-related events (including fracture). This subject is addressed elsewhere. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)
Guidelines from expert groups — Guidelines from several groups are variable in their recommendations regarding the role of EBRT in differentiated thyroid cancer:
●The 2015 guidelines from the American Thyroid Association (ATA) recommend EBRT (in combination with surgery and radioiodine) for patients with aerodigestive invasive disease [25]. They recommend against routine adjuvant EBRT in patients who have had initial complete surgical resection. However, the use of EBRT in this latter setting is controversial. Selective use of EBRT may be considered in patients with initial complete surgical resection who have locally advanced disease and in patients >60 years with extrathyroidal extension. It is unknown whether EBRT reduces the risk of recurrence in patients with aggressive histologic subtypes who have adequate initial surgery and/or radioiodine.
EBRT may also be considered in patients undergoing multiple and frequent neck reoperations for palliation of locoregional recurrent disease.
●The National Comprehensive Cancer Network (NCCN) recommends consideration of EBRT for patients with gross or recurrent locoregional or distant metastatic disease that is not amenable to radioiodine (ie, radioiodine imaging shows inadequate uptake) [22].
●A 2015 statement from the American Head and Neck Society recommends EBRT for patients with gross residual or unresectable locoregional disease, except for patients <45 years with limited gross disease that is radioiodine avid [26]. Adjuvant EBRT may be considered in selected patients >45 years old with high likelihood of microscopic residual disease and low likelihood of responding to radioiodine. This statement preceded the release of the American Joint Committee on Cancer (AJCC) eighth edition (table 1) that uses 55 years as the cutoff age for poor prognosis, and 55 years may be a more appropriate age cut-off.
●In updated 2014 guidelines from the British Thyroid Association, the indications for primary management with EBRT are rare and fall into the palliative setting where a specific symptom is to be addressed with no intent to cure [27]. Adjuvant EBRT is recommended for patients with a high risk of recurrence/progression who have gross evidence of local tumor invasion at surgery with significant macroscopic residual disease, or residual or recurrent tumor that fails to concentrate radioiodine (ie, locoregional disease where further surgery or radioiodine is ineffective or impractical).
●Guidelines from the European Society of Medical Oncology (ESMO) state that EBRT may be indicated when complete surgical excision is not possible or when there is no significant radioiodine uptake in the tumor [28].
RADIATION PROTOCOL
General approach (IMRT) — For patients with well-differentiated thyroid cancer, the clinical target volume is defined to treat the thyroid bed, including the tracheoesophageal groove, level VI lymph nodes (from the hyoid to just below the suprasternal notch), and level VII lymph nodes (the upper mediastinal area) (figure 1). This reduces the risk of toxicity. The volume can be adjusted based on surgical and pathology findings. We prefer not to radiate the lateral necks initially, unless the surgeon feels that future surgical resection of a subsequent lateral neck lymph node recurrence is not possible. If surgical resection of a subsequent lateral neck lymph node recurrence is considered to be safe and effective, the preference is to omit the lateral necks from the radiation field to further minimize toxicity.
Typically, we prescribe 70 Gray (Gy) in 35 fractions to the site of gross residual disease. We administer 60 to 66 Gy (2 Gy per fraction) to the tracheoesophageal groove (the area at high risk for microscopic residual disease), and we concurrently give 54 Gy (1.8 Gy per fraction) to the upper mediastinum. This is followed by a boost of 10 Gy (2 Gy per fraction) to the gross disease.
External beam radiotherapy (EBRT) should ideally be delivered using advanced techniques such as intensity-modulated radiotherapy (IMRT). IMRT should be the standard of care for treating cancers of the head and neck, including the thyroid [1,9,10,29]. IMRT allows for more precise delivery of EBRT, sparing more normal tissue and potentially reducing acute and late toxicity (image 2). These advantages are due to the fact that IMRT utilizes variable, computer-controlled intensities within each radiation therapy beam. This allows the volume of tissue receiving full-dose radiation to more closely conform to the shape of the region that is intended to be treated than can be achieved using uniform doses that are delivered with conventionally planned two-dimensional EBRT or three-dimensional conformal radiation therapy (3D-CRT) techniques. The advantages of IMRT are particularly evident when the target volumes have complex shapes, concave regions, or are adjacent to many critical normal structures. (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)
The benefits of IMRT were shown in a series from MD Anderson in which IMRT was associated with less frequent late morbidity (eg, esophageal stricture, chronic dysphagia, laryngeal edema) than conventionally planned two-dimensional EBRT [10].
Proton beam therapy — Intensity-modulated proton beam therapy is a newer technology for the treatment of differentiated thyroid cancer, and there are small reported series demonstrating further benefits to reduce toxicity [30]. Other newer technologies such as magnetic resonance linear accelerator can be considered when there is a need to real-time adapt the treatment volume.
ADVERSE EFFECTS — External beam radiotherapy (EBRT) is associated with acute and long-term adverse effects. Minimizing the dose and volume of tissue exposed reduces adverse effects but must not compromise disease control [1,11,31]. (See "Radiation therapy techniques in cancer treatment", section on 'Radiation side effects'.)
●Acute effects – Acute toxicity occurs during radiotherapy and may include the following:
•Moderate skin erythema
•Dry desquamation and, rarely, moist desquamation
•Mucositis of the esophagus, trachea, and larynx (which may require a soft diet, analgesics, and possibly enteral feeding) may develop towards the end of radiation therapy; this will subside within two to four weeks after the end of treatment
•Dysphagia
●Long-term effects – Well-planned radiotherapy treatment regimens rarely have serious long-term complications. The most common manifestations of late toxicity are skin telangiectasias and skin pigmentation. A survey of 34 patients treated for advanced thyroid cancer showed that compared with thyroidectomy or thyroidectomy with postoperative radioiodine, there were significant decreases in chewing, swallowing, and appetite and significant increases in pain in patients who received EBRT [32].
The development of esophageal stenosis is rare, and tracheal stenosis is extremely rare. Dry mouth, esophageal stricture requiring dilation, and chronic dysphagia requiring a feeding tube have been reported [10]. In one retrospective report, 5 percent of patients were dependent on feeding tubes because of significant late toxicity following EBRT [9]; feeding tube dependence was not reported in other studies likely due to EBRT technique, dosing, and fields [7,18]. A prospective phase II trial published by Memorial Sloan Kettering Cancer Center showed very encouraging results with the use of IMRT for patients who required EBRT after careful discussion at the head and neck tumor board. The toxicity profile was minimal with excellent patient-reported outcomes [16].
Patients with thyroid cancer who receive EBRT may be at risk of a second cancer, at a rate similar to those with head and neck cancer who are also treated with radiation therapy (approximately 1 to 5 percent). (See "Second primary malignancies in patients with head and neck cancers", section on 'Risk factors'.)
Therefore, attention must be paid to decrease the amount of tissue radiated to reduce this risk. Long-term toxicity to normal tissues depends in part upon the size of each treatment fraction as well as the total radiation dose. Late effects can be minimized by delivering the lowest effective dose to the smallest area. Decreasing the size of each radiation fraction should permit higher total doses without increasing late morbidity. For younger patients, there may be an advantage of using proton beam therapy to minimize the risk of second malignancies. (See "Overview of approach to long-term survivors of head and neck cancer".)
While EBRT does not preclude future surgical intervention, surgery (if required) may be more challenging, and many surgeons are uncomfortable operating on a previously irradiated site.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thyroid nodules and cancer".)
SUMMARY AND RECOMMENDATIONS
●Primary therapy: Surgery – Surgical resection is the primary treatment of patients with differentiated thyroid cancer. External beam radiotherapy (EBRT) is used infrequently in the management of differentiated thyroid cancer. (See 'Introduction' above and "Differentiated thyroid cancer: Overview of management".)
●Indications for EBRT
•Macroscopic unresectable – For patients who have inoperable macroscopic residual disease after thyroidectomy, with absent or inadequate radioiodine avidity, we suggest EBRT to the thyroid bed and known sites of disease (Grade 2C). (See 'Macroscopic' above.)
Some thyroid cancer experts also administer EBRT to patients with unresectable disease in the neck despite radioiodine uptake, if the degree of iodine uptake compared with the size of the residual disease suggests that the radioiodine alone will be insufficient to control disease, or if the unresectable disease is markedly avid (standardized uptake value [SUV] >10) on fluorodeoxyglucose positron emission tomography (FDG PET) scanning.
•Microscopic residual – For patients age 55 years or older with T4 disease (ie, gross widespread/multifocal extrathyroid extension, tracheal perichondrium, or esophageal muscularis involvement) with microscopically positive resection margins and non-radioiodine-avid disease in whom additional surgical intervention at the time of recurrence would be ineffective or associated with unacceptable morbidity, we suggest EBRT (Grade 2C). (See 'Microscopic residual and completely resected high-risk disease' above.)
For very selected younger patients with poor histologic features and either resected T4b or extensive T4a disease (table 1), we suggest EBRT (Grade 2C), as these patients have a high likelihood of having residual non-radioiodine avid disease. Poor histologic features include insular or poorly differentiated histology. (See 'Microscopic residual and completely resected high-risk disease' above.)
•Palliative care and/or distant disease – EBRT is indicated for palliation in patients with differentiated thyroid cancer who have unresectable locally advanced or symptomatic metastatic disease that is refractory to radioiodine. (See 'Palliative' above.)
For patients with symptomatic and/or progressive unresectable lung metastases not amenable to radioiodine, EBRT is used for palliation. For patients with asymptomatic indolent soft tissue metastases, monitoring without therapy may be acceptable. Stereotactic radiosurgery is preferred over EBRT for unresectable central nervous system (CNS) metastases. (See 'Distant disease' above.)
Patients with unresectable, painful bone metastases or multiple bone metastases that are refractory to radioiodine therapy should be referred for EBRT or stereotactic body radiotherapy (SBRT) to aid pain control. EBRT is also used to control asymptomatic bone metastases if they are in weightbearing sites. Patients with bone metastases should also be considered for osteoclast inhibitor therapy to reduce the frequency of skeletal-related events, including fracture. (See 'Distant disease' above.)
●Radiation protocol – When it is indicated, EBRT to the neck should ideally be delivered using advanced techniques such as intensity-modulated radiation therapy (IMRT). (See 'Radiation protocol' above.)
●Adverse effects – EBRT is associated with acute (skin erythema, mucositis, dysphagia) and long-term (skin pigmentation, dry mouth, esophageal stricture) adverse effects. Minimizing the dose and volume of tissue exposed reduces adverse effects but must not compromise disease control. (See 'Adverse effects' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James D Brierley, MB, BS, FRCP, FRCR, FRCPC, who contributed to an earlier version of this topic review.
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