Few patients are offered EBRT for the adjuvant treatment of MTC. While this approach may be valid, it is not based upon prospective, randomized data. Retrospective studies have been somewhat conflicting. Samaan and colleagues published a retrospective analysis from the MD Anderson Cancer Center that primarily sought to differentiate survival rates between sporadic and familial forms of medullary thyroid cancer.[19
] As a secondary goal of the study, the researchers examined the effect of EBRT on survival. They concluded that patients receiving EBRT demonstrated significantly poorer survival, even after controlling for age, extent of disease, and surgery. The patients in this study were treated over a time period (1943 to 1987) that may not be reflective of modern radiotherapy techniques however, and subsequent studies have suggested a greater role for EBRT in improving local/regional control.
Schwartz and colleagues reported on a group of 34 MTC patients with advanced disease treated with EBRT between 1995 and 2004 and demonstrated excellent 5-year relapse-free survival, disease-free survival and overall survival rates of 87%, 62%, and 56%, respectively.[15
] Brierly and colleagues retrospectively examined 73 patients with MTC treated between 1954 and 1992 with an end-point of disease-specific survival.[4
] Forty-six of these patients received EBRT. Although use of EBRT did not influence disease-specific survival in the population as a whole, a subgroup at higher risk for local/regional recurrence due to microscopic residual disease, nodal positivity, or extrathyroidal invasion did receive a significant improvement in the rate of local/regional recurrence at 10 years (86% versus 52%, p<0.05). Similar results have been reported elsewhere.[17
In addition to the unknown benefit of EBRT, many treating physicians are reluctant to irradiate the thyroid and its draining lymphatics due to concern for toxicity. Using conventional radiotherapy techniques, it would be difficult to administer appropriate radiation doses to this area without causing significant toxicity to surrounding vital structures, such as the spinal cord, trachea, larynx, esophagus, pharynx, and parotid glands. However, with the advent of intensity–modulated radiation therapy (IMRT), higher doses of radiation can be administered while sparing normal tissues. Rosenbluth and colleagues [20
], reviewed outcomes and toxicity in a series of 20 thyroid cancer patients treated with IMRT. Although most patients developed acute toxicities, these effects were manageable with routine proactive clinical care, with no evidence of Grade IV toxicities.[20
] In a phase I trial of 13 patients, Urbano et al [21
] showed that IMRT could be administered with an acceptable level of acute toxicity, although long term results were lacking.
In an attempt to circumvent some of the biases associated with past retrospective institutional studies on the role of EBRT in the treatment of MTC, we utilized the SEER database of the National Cancer Institute. We feel that these data better capture national trends in treatment and outcomes and can provide a rational basis for the development of future randomized clinical trials. These data may still reflect a selection bias, whereby patients with more advanced disease, and therefore worse prognoses, may be offered EBRT more readily than patients with earlier, more localized disease, but we tried to ameliorate this by controlling for those factors identified as significant differences between patients who received EBRT and those who did not.
Although no improvement in overall survival was detected in patients receiving EBRT on multivariate analysis, the wide CI (0.57–3.37) reflects the sparse use of EBRT in our patient population as a whole (n=66, 12.4%). Further study utilizing a larger sample of patients receiving EBRT may be necessary to document a benefit similar to that noted in our univariate analysis of node-positive patients. After stratification for node-positivity, univariate analysis suggested a significant improvement in overall survival in patients receiving EBRT. Those receiving EBRT demonstrated an estimated 10-year survival of 87% compared to 70% in the group not receiving radiation. We were unable to perform a multivariate analysis among node-negative patients, as only 3 of these patients received EBRT.
The survival rates we documented were better than noted in other series and may reflect our method of patient selection, which eliminated patients with distant metastases, those undergoing less than total thyroidectomy, and those without any lymph nodes analyzed. Despite our promising results, our multivariate analysis found only two independent predictors of overall survival: increasing age and tumor size. Although statistically significant, the survival effect is small and may have limited clinical significance.
Several limitations of the SEER data utilized for our study make demonstrating a beneficial survival effect of radiation difficult. First, we are unable to determine, to some degree, the adequacy of surgery performed. We have attempted to diminish this concern by including only those patients who received “standard” surgical treatment for their MTC. At minimum, we considered this to be a total thyroidectomy and lymphadenectomy. Patients were considered to have had a lymphadenectomy if they had ≥ 1 lymph node resected at the time of surgery. Due to database constraints, we have no reliable way of knowing whether the lymphadenectomy was part of the planned procedure or occurred incidentally. Furthermore, we are unable to distinguish those patients with palpable nodal disease who underwent more extensive lymphadenectomy. These patients would be expected to have more lymph nodes removed at the time of surgery, but would also be expected to have an overall worse prognosis due to the more extensive burden of disease and increased likelihood of occult distant metastases that would be unaffected by local/regional radiation therapy. Several researchers have utilized serum levels of calcitonin and, more recently, CEA as important determinants of local/regional control and surrogates of disease outcomes such as recurrence and overall survival.[22
] We did not have access to serum calcitonin or CEA levels for this analysis, but these are prone to similar limitations. Persistently elevated levels of calcitonin or CEA following surgery could indicate residual local/regional disease that could potentially benefit from EBRT or could represent clinically occult distant metastases that would not be expected to respond to EBRT.
The chosen endpoint of our analysis was overall survival. We concede that, for a local/regional treatment such as EBRT, disease-free survival may be a more appropriate endpoint. Our ability to reliably determine disease recurrence using SEER data is limited, however, as has been reported by other researchers.[24
] We believe it is reasonable, in the case of MTC, to hypothesize that improved local/regional control of disease may influence overall survival given the often indolent nature of the disease. Indeed, this is the rationale for performing a total thyroidectomy rather than a lobectomy and a thyroidectomy with nodal dissection rather than a thyroidectomy alone.