Differentiated thyroid cancer is a surgical diagnosis, with most cases being effectively approached by thyroidectomy and RAI ablation. Management of the approximately 10% of patients presenting with locally advanced disease remains controversial. Indications for adjuvant radiotherapy generally include high risk presentations involving local invasion or encasement of surrounding structures (e.g. trachea, esophagus, larynx, mediastinum, and/or great vessels) with evidence of residual microscopic or gross disease, especially if this disease is iodine non-avid.
Support for adjuvant radiotherapy for microscopic residual disease is lent from retrospective reports which, taken together, suggest that curative doses of radiotherapy can reduce the 25–50% locoregional recurrence rates reported for surgery alone 1–14
. Patient selection and use of RAI varied widely across these studies, with many study subjects not receiving the full complement of treatment used in modern therapy. Two of these reports evaluated high-risk patients with an aggressive multimodality approach akin to what our institution currently uses, including total thyroidectomy, RAI, and TSH suppression. Farhati, et. al. 3
reviewed 169 cases of pathologic T4 cases without evidence for distant metastasis. Ninety-nine of these patients received 50–60 Gy; these patients had improved locoregional and distant disease control. However, multivariate analysis demonstrated that locoregional disease control benefit was isolated to patients over 40 years-old with node positive papillary disease. Phlips, et. al. 5
reviewed 94 patients with microscopic residual differentiated disease or extranodal extension, of whom 38 received EBRT. Local regional failure was 3% in the irradiated cohort, compared with 21% in unirradiated patients. Our current series is in keeping with previously published results, with an estimated LRFS at 4 years of 85% for patients presenting with proven or suspected microscopic residual disease. These, in fact, represent encouraging results in a very high-risk patient population; 96% of our study subjects had extraglandular disease spread and almost 60% had recurrent disease.
Gross, unresectable residual disease is a relatively straightforward indication for adjuvant radiotherapy18, 19
, but predicts for poor locoregional control and overall disease outcome regardless of adjuvant radiation 20, 21
. This was confirmed in our current series. Actuarial locoregional disease control at one year was 33% for these patients, with only 4/15 cases demonstrating a complete response to treatment. Gross residual disease was predictive for inferior LRFS, DSS, and OS on univariate and multivariate analysis. This emphasizes the primacy of surgical management for high-risk disease. The ability to resect disease, no matter how involved the required surgery may be, outweighed all other clinical risk factors in our study other than adverse histologic features (Hurthle cell, tall cell, poorly differentiated disease, etc.) and distant metastasis. No surrogate measure of surgical complexity (e.g. cervical neck dissection, mediastinal exploration, great vessel dissection, tracheal resection, etc.) impacted outcome.
Locoregionally recurrent disease is typically managed similarly to locally advanced disease at initial presentation. One can expect local disease control, especially for isolated cervical nodal recurrences22, 23
. In our current series, patients with recurrent disease did not appear to fare worse relative to patients treated at initial presentation, as long as all gross disease could be resected. This suggests that deferring EBRT in favor of RAI and TSH suppression alone at the time of initial disease presentation may not sacrifice ultimate local disease control or survival. However, subsequent recurrence necessitates reoperation, with significant attendant morbidity and costs. And not all recurrences can be successfully salvaged. Our institution has previously demonstrated that recurrences located in the thyroid bed and/or with soft tissue infiltration are less likely to be iodine avid and are controlled less frequently 23
. Non-avid, centrally-located recurrences should be carefully considered for adjuvant EBRT. As for earlier treatment, EBRT provides a potential local control benefit at the time of initial presentation of high-risk disease. Nonetheless, an improved toxicity profile will be necessary for EBRT to gain wider acceptance among clinicians for this and other clinical indications.
Improvement of therapeutic index serves as a strong rationale for using advanced conformal radiotherapy techniques for thyroid cancer. The concave geometry and close proximity of the thyroid bed to critical normal structures such as esophagus, trachea, larynx, lungs, spinal cord, and (in cases with high cervical disease) parotid glands make delivery of high doses challenging and contribute to the considerable toxicity seen with conventional radiotherapy. Radiation side effects can compound healing and functional problems in reconstructed regions of esophageal and trachea, and can exacerbate the salivary and pulmonary sequelae of RAI administration. Morbidity outcomes for our current series suggest an improved therapeutic index with IMRT relative to 3DRT. IMRT was associated with less frequent severe late radiation morbidity than 3DRT (2% vs. 12%, respectively). Our methodology was purposely stringent to minimize the biases of retrospective chart review, which can be particularly significant for this diagnosis given the confounding contribution of post-operative and post-RAI morbidity. We focused on severe late toxicity temporally related to radiation treatment which necessitated medical or surgical intervention. This strategy afforded clearer assessment of late toxicity, but precluded formal assessment of acute toxicity and minor chronic treatment sequelae.
Published results for thyroid IMRT remain very limited. A pilot study from Memorial Sloan-Kettering 24
examined outcomes in 20 patients treated with IMRT for differentiated or medullary thyroid cancer. Median follow-up was limited to 13 months. There were 2 local failures, yielding a 2-year local progression free survival rate of 85%. Six patients died, yielding a 2-year overall survival rate of 60%. Reported acute toxicity was mostly self-limited, with the most severe presentations consisting of Grade 3 mucositis, pharyngitis, laryngitis, and skin toxicity. This is in keeping with our experience. No severe chronic toxicity was reported, although cases of mild-moderate radiation pneumonitis, Lhermitte syndrome, dysphagia, and xerostomia were seen. More recently, a small prospective thyroid IMRT experience was published by Urbano, et. al. 25
, demonstrating encouraging results with mild, self-limited acute toxicity. Median follow-up was too short (37 weeks) for analysis of chronic toxicity.
Currently, we use IMRT for all curative treatment delivered at the UT M.D. Anderson Cancer Center for differentiated thyroid cancer. Treatment planning CT imaging extends caudally past the diaphragm to facilitate formal dose avoidance to the whole lungs. We manage locally advanced disease, especially recurrent disease, in an individualized fashion with multi-disciplinary input. In light of encouraging recent data 26
, we are using FDG-PET/CT imaging more frequently to select patients for salvage surgical resection and to restage patients post-operatively to rule out occult residual locoregional gross disease or metastases. Our current practice is to recommend adjuvant irradiation for patients with recurrent and/or gross/microscopic residual disease, especially disease infiltrating into surrounding structures which would potentially preclude safe reoperation. Clinical features such as age > 45 years or high risk histologies (e.g. high grade or tall cell papillary variants, Hurtle cell, etc.) are relative indications for adjuvant irradiation. All operative beds are treated to adjuvant doses of 57–60 Gy. Immediately-adjacent nodal basins and uninvolved bystander structures can be treated to a reduced prophylactic dose of 54 Gy. Superior coverage typically extends no higher than level II to limit doses to oral cavity and parotid glands, unless the high neck is directly involved. Portions of the operative bed affected by positive surgical margins can be boosted to doses of approximately 63 Gy, while residual gross disease is typically treated to definitive doses of 66–70 Gy as dictated by neighboring normal tissue dose-limiting constraints.