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EXTERNAL RADIATION THERAPY IN THE TREATMENT OF THYROID MALIGNANCY
THYROID CANCER I1
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EXTERNAL RADIATION THERAPY IN THE TREATMENT OF THYROID MALIGNANCY James D. Brierley, BSc, MBBS, MRCP(UK), FRCR, FRCPC, and Richard W. Tsang, MD, FRCPC
This article reviews the role of external beam radiation therapy (XRT) in thyroid malignancies. It is divided into sections dealing with differentiated thyroid cancer, anaplastic thyroid cancer, medullary thyroid cancer (MTC) and thyroid lymphomas. Although the discussion is mainly confined to local or locoregional radiation, that is, to the thyroid bed or the thyroid bed and regional lymph nodes given as part of initial postoperative management or at recurrence, XRT also has an important role in the palliation of metastatic disease. DIFFERENTIATED THYROID CANCER The surgical treatment of differentiated thyroid cancer and the use of I 3 l I are discussed elsewhere. This section concentrates on the role of XRT in advanced locoregional thyroid cancer, namely, in tumors that are extending through the capsule of the thyroid into the extrathyroidal tissue and where surgical excision has either been histologically complete (i.e., the XRT is adjuvant therapy to prevent local recurrence) or incomplete (i.e., there is microscopic or macroscopic residual cancer). In patients in whom operation has not been attempted due to the advanced nature of the disease, XRT also can be considered as a cytoreductive therapy before reassessment for surgical resectability afterwards.
From the Department of Radiaticn Oncology, University of Toronto, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA ~~
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One of the earliest reports of the use of XRT in thyroid cancer was by Sheline et aPOwho in 1966 reported their experience with XRT in 58 patients with various histologies treated between 1935 and 1964. The doses used ranged from 30 to 50 Gy given in 15 to 50 days, doses that, in some cases, would be considered to be inadequate today, I3*I was not given. Fourteen patients had no attempted surgical excision due to the extent of disease. Nineteen patients had gross evidence of disease following resection, and, in 25, there was presumed residual microscopic persistent disease, tumor having been shaved off adjacent structures. Of 15 patients with papillary tumors with gross residual disease, 8 were alive and well and free from disease over the 2- to 14-year follow-up. Of the four patients with gross follicular carcinoma, three were alive and well with no evidence of recurrence. Twelve patients with papillary thyroid cancer had presumed microscopic residual disease following surgery and were given XRT; one died of metastatic disease, and 11 remained alive and well with no evidence of recurrent disease. Although the number of patients was small and the follow-up short, these results suggest that XRT even at suboptimal doses may have a role not only in controlling gross disease in well-differentiated thyroid cancer but may also contribute to local control in patients who have microscopic residual disease in the neck following resection. More recently, O’Connell et alZ3have reported the Royal Marsden Hospital experience in treating patients with differentiated thyroid carcinoma with radical XRT, giving a minimum of 60 Gy in 30 fractions. One hundred and thirteen patients received XRT; all had thyroid hormone suppression therapy, and 74 had 1311 therapy. Patients were defined by three subgroups: those with probable microscopic residual disease (tumor found at excision margin or within 2 mm of it), those with definite microscopic disease (if a blunt dissection had been carried out to remove disease from adjacent organs), and those with gross residual disease. For the 32 patients with gross residual disease, complete regression occurred in 37% following XRT. Of 25 patients with probable microscopic disease, two had an in-field recurrence (8%).Of 18 patients with definite microscopic residual disease, five had in-field recurrences (29%). We have recently reviewed the data from Princess Margaret Hospital and have found that for 33 patients with gross residual disease following attempted resection who were treated with a radical course of XRT, the actuarial local control rate was 62% at 5 years. At Princess Margaret Hospital, it is currently our policy to advise XRT for all patients with differentiated thyroid cancer who have gross residual disease following attempted resection or who are inoperable. A radical course of radiation, usually 50 Gy in 20 fractions over 4 weeks, is prescribed to a volume encompassing the thyroid bed and the gross disease. No attempt is made to include all regional lymph nodes. Patients who have undergone thyroidectomy are also given 1311 (usually, 150 to 200 mCi). All patients receive thyroxine to suppress thyroidstimulating hormone (TSH) to undetectable levels, if possible. Data from both Sheline et aPOand O’Connell et alZ3suggest that
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there may be a role for adjuvant XRT in differentiated thyroid cancer in addition to l3II therapy, but this remains controversial. Reports on the use of XRT have been retrospective, resulting in contradictory conclusions. For instance, Mazzaferri and Youngznin their report on the role of XRT in papillary thyroid cancer stated that, ”external radiation used as initial adjunctive therapy adversely influenced outcome,” whereas Simpson et a135concluded after a multi-institutional analysis of 1578 patients that they, ”provide convincing data concerning the effectiveness of external radiation and of radioiodine in the adjuvant treatment of papillary and follicular cancer patients. . . . If there is a role for adjuvant XRT therapy in differentiated thyroid cancer, the observed benefit would be improved local control in patients at risk for local relapse, and, upon longer follow-up, an improvement in survival may follow. An improvement in treatment results would not be expected in patients who already have good prognostic features and who are at low risk for local relapse, such as those at young age, with small tumours, and with tumors confined to the thyroid, but, rather, in patients who have adverse features for local recurrence, such as older age, larger tumor size, and, in particular, evidence of tumor extension through the thyroid capsule into the soft tissues of the neck.5,6, 8, Iy, 3H, 40 Many of the retrospective reports on the role of XRT included patients who may not have been expected to benefit from XRT. Especially in the earlier reports, patients may not have had what would now be considered standard therapy with 1311and TSH suppression. Mazzaferri and Youngznin 1981 described a study of 576 patients with papillary thyroid cancer. Only 28 had XRT in addition to thyroxine, but it would appear that none of the 28 had 1311.Only five tumors were greater than 1.5 cm in size, but 78% of the patients had lymph node involvement in contrast to 45% of the whole group; none had extrathyroid invasion. The dose of radiation given ranged from 10 to 70 Gy. Only five patients had 50 to 70 Gy, and the fraction size, number of fractions, and overall treatment time were not specified. With the good prognostic features of young age, small size, and lack of invasion through the thyroid capsule, it is perhaps not surprising that no evidence was found for an improvement in local control with XRT but the opposite was found, with the treated patients having a higher local relapse rate (16.7% versus 2.3% for the group as a whole). This difference may, however, be explained by the higher incidence of initial lymph node involvement and the absence of I3lI therapy in the irradiated patients. More recently, Benker et a13 have retrospectively reviewed the records of 932 patients with differentiated thyroid cancer. A total of 346 had been given XRT before their referral for consideration of 13’1therapy. The total dose of XRT given ranged from 40 to 70 Gy. Again, there is no comment on the dose per fraction or overall treatment time. Benker and co-workers concluded that they failed to prove that survival is prolonged in patients with differentiated thyroid carcinoma following postoperative XRT. A total of 205 of the 346 who received XRT had T1 or T2 tumors, and it is to be expected that they found no difference in I,
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survival between those who received XRT and those who did not in these patients with early stage disease. Neither was there an improvement in survival in patients with tumor spread beyond the thyroid gland. A subgroup analysis of patients older than 40 years revealed a 10-year survival rate of 48% for those treated without XRT and 58% for those treated with XRT; this difference was not statistically significant ( P = 0.09). No data on the local control rates following treatment with XRT were presented. Because of the referral pattern, l3II was administered following XRT, and this may not be the preferred order of treatment. It is possible that XRT could interfere with the uptake of 1311 in the neck and reduce its effectiveness by reducing the tumor cell uptake of 1311, and it is our preference to give 1311 before XRT. Benker et a13 also refer to an earlier retrospective review published in the German literature in 1983 by Leisner who reported an 88% 5-year survival rate with radiotherapy versus a 68% 5-year survival without radiotherapy, this difference was statistically significant. Samaan et a12*in a review of 1599 patients with well-differentiated thyroid cancer treated at MD Anderson Hospital noted that 113 patients were given XRT. These patients tended to be older and were more likely to be male, both poor prognostic indicators when compared with the group as a whole. They were more likely to have more extensive disease and less surgical intervention than those who did not receive XRT. When an analysis was performed on those patients with nodal and softtissue disease in the neck, there was no advantage in the use of external radiation with respect to local recurrence rate or survival. There were, however, insufficient numbers to analyze soft-tissue and lymph node involvement separately. Samaan et a12”28 concluded that there was no benefit in the use of XRT. This retrospective study provides some interesting data on the risk of local recurrence and survival in various subgroups of patients over the follow-up period of 1to 43 years (median, 11 years). The risk of local recurrence increased with more extensive local tumor from 19% for intrathyroid tumors to 22% for those with nodal involvement to 36% if there was infiltration of the soft tissues. Similarly, the survival rate fell from 93% for intrathyroid tumors and 94% for those with lymph node involvement to 82% in patients with soft-tissue involvement. If there was soft-tissue involvement at the time of surgery, 36% of patients recurred locally and 18% died, showing that it is extrathyroidal extension rather than lymph node involvement that has an adverse effect on outcome. If we could improve local control with XRT in patients with extrathyroidal extension, survival may also improve; although, of course, it may not if undetected metastasis has already occurred. Two large retrospective reviews have suggested a role for XRT in differentiated thyroid cancer, one from France by Tubiana et a142and the other from Canada by Simpson et al?3 In Tubiana’s study, 530 patients had disease confined to the neck. Sixty-six received prophylactic radiation postoperatively for extensive regional lymph node involvement, tumor invasion of the neighboring muscles, or difficult surgical excision
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of recurrence after a previous operation. The relapse-free survival rate and the overall survival rate for this group of patients given prophylactic postoperative XRT with or without iodine were lower than that for the group treated by surgery alone; however, XRT was given to a group of patients with a less favorable prognosis. Ninety-seven patients received postoperative radiotherapy after incomplete excision, and, when these were pooled with those given prophylactic XRT, the number of local recurrences was 25 (14%). This was compared with 70 local recurrences (21%) in 336 patients who did not receive XRT (61 received radioiodine therapy). This difference between the two groups is statistically significant (P< 0.05). When the dose of radiation was examined, those patients who received less than a dose of 50 Gy had a 15% in-field recurrence rate compared with a rate of 10% for those who received 50 Gy or more. This suggests the importance of giving an adequate dose of XRT. Simpson et a133reported on the treatment of papillary (1074 patients) and follicular thyroid cancer (504 patients) in 13 radiotherapy centers in Canada. A total of 201 patients had XRT, 214 patients had radioiodine, and 107 patients had both. Following resection, the patients were categorized as having no residual disease; microscopic residual disease, which meant that the tumor was at or within 2 mm of the resection margin; or gross residual disease when the surgeon reported that some visible tumor had not been removed. For those patients with no residual disease, there was no statistical difference between the treatment modalities; however, for those with microscopic residual disease and papillary pathology, there was a significant improvement in local control following the addition of l3II or XRT or both over no additional treatment at all. Although there was a difference in local control depending on treatment in patients with follicular tumors, this did not reach statistical significance. Phlips et a124have recently reported another retrospective review of patients with differentiated thyroid cancer treated between 1974 and 1989. Although smaller than the studies of Tubiana and Simpson, it is important because all of the patients received radioiodine after surgical resection, and, in addition, 38 had XRT. The overall survival was identical for the two groups, but the local relapse rate was 21% for those who received radioiodine only and 3% for those who received XRT. All of the patients who received XRT were considered to have either microscopic or minimal residual disease or positive lymph node involvement with extracapsular extension. This was not true for those patients treated with radioiodine alone who would therefore be expected to have a lower relapse rate. Of the patients who had residual tumor after an incomplete resection, two of three treated with radioiodine alone went on to have a local recurrence, whereas none of the 12 patients in the subgroup who received XRT recurred locally. In the presence of an extracapsular lymph node extension, local failure was seen in four of six patients treated with radioiodine alone and in one of six patients after XRT. Although the numbers are small and the study retrospective, it does suggest a role for
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XRT in addition to high-risk patients.
1311
in improving local control in a selected group of
Conclusions The evidence for and against a role for adjuvant XRT in differentiated thyroid cancer is exclusively retrospective in nature. If there is a role for XRT, it would not be in patients with good prognostic features who have complete surgical excision. If adjuvant treatment is required in these patients, it should be 1311 therapy. For patients with bulky residual disease, I3lI is unlikely to eradicate such disease unless a very high absorbed dose is achieved. O’Connell et alZ3note that, at least, an absorbed dose of 100 Gy is required to destroy small remnants of nodal disease and that anything less is ineffectual. Similarly, Maxon et all8 have shown that a single radioiodine administration resulting in an absorbed dose of greater than 80 Gy achieved destruction of neck nodes in 74% of patients with small volume disease defined as less than 2 g. Therefore, in the presence of gross residual disease following excision, XRT should be given to improve local control, as the reports from Sheline, Tubiana, and O’Connell show that local control can be achieved with XRT alone in this situation. Whether there is a role for XRT in the presence of either presumed or definite microscopic disease is less certain. This would be supported by retrospective reviews of Tubiana, Simpson, and Phlips but not by the retrospective data from Samaan and Benker. To compare results of different modalities of treatment by retrospective review is always fraught with difficulty. It is never made clear in some studies why some patients had XRT and others did not. The only way to define a role for XRT would be from a prospective randomized controlled trial of XRT versus no XRT in patients with presumed or definite microscopic residual disease following surgical resection. A long follow-up period for such a study would be necessary, because Tubiana et a142reported an average time to local relapse of 8.5 years, and Phlips et alZ4reported a mean time to local relapse of 49 months. Until such a study is performed and the results available, we recommend XRT in addition to 1311therapy for all patients with papillary or follicular thyroid cancer who, after a total or near-total thyroidectomy, have either probable microscopic residual disease (with positive excision margin or within 2 mm of excision) or definite microscopic disease, if a blunt dissection had been carried out to remove disease from adjacent organs. Those with probable residual disease receive 40 Gy in 15 fractions over 3 weeks in 2.57-Gy daily fractions; those with definite residual disease receive 50 Gy in 2.5-Gy daily fractions over 4 weeks. Treatment is directed to tne thyroid bed, and, usually, an anterior electron field of high energy (13 to 17 MeV) is used such that the maximum dose to the spinal cord is no more than 80% of the prescribed dose (Fig. 1). We do not give XRT for lymph node involvement unless there is invasion by disease outside the capsule of
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Figure 1. A, Simulation radiograph of typical radiation field to the thyroid bed. B, Typical isodose distribution to the thyroid bed using an anterior electron field, in this case of mixed energies, 13 MeV and 17 MeV.
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the node with extension into the soft tissues. In selected young patients with good prognostic features but minimal microscopic residual disease postoperatively that is identified clearly in the neck, and in whom there is good I3II uptake at that site, we would consider using 1311alone and withhold the use of XRT. ANAPLASTIC THYROID CANCER
After the diagnosis of anaplastic thyroid cancer, complete surgical extirpation can only be performed with curative intent in a minority of patients, and, even then, there is a high local failure ratez1 so that the use of other modalities of therapy must be considered in an attempt to obtain local control. Following surgical resection of the tumor, or biopsy only, XRT therapy alone or in combination with chemotherapy has been given in an attempt to improve local control. Anaplastic thyroid cancer does not concentrate l3II, and, therefore, there is no role for l3lI therapy in this disease. Any radiation given is usually in the form of XRT. However, even after the addition of XRT or chemotherapy, survival is still poor because of both the poor local control rate and the high incidence of metastatic disease. Junor et all2 reported on the use of radiation following surgery in 91 patients. Thirtythree had attempted curative surgery, and 58 had a biopsy only, reflecting the poor rate of resectability in this disease. Eighty-six had XRT, 18 with the addition of chemotherapy. The overall survival rate was 11% at 3 years, with a median survival of 21 months. Junor and coworkers were unable to demonstrate a dose response effect, with no improvement in survival with higher doses. Of 70 patients with detailed data on the site of recurrence, 25 had local relapse, local and distant in 25 and distant only in 20. This demonstrates that even after XRT, local control is a major problem, but, if local control is achieved, death occurs from distant metastatic disease. Despite distant dissemination, if local control can be achieved, a distressing death may be avoided from the local effects of advanced anaplastic thyroid cancer in the neck, such as esophageal or tracheal obstruction or tumor breakdown through the skin. In attempts to improve local control, several novel approaches have been tried in altering standard radiation fractionation, adding chemotherapy, and administering sequential therapy with surgical resection following initial cytoreduction. One of the first such approaches was described in 1980 by S i m p ~ o nBetween .~~ 1975 and 1982,32 patients with unresectable anaplastic thyroid cancer underwent hyperfractionated radiation at Princess Margaret Hospital. Most were given a single dose of 5 Gy followed by hyperfractionated radiation, 1 Gy given four times a day with an interfraction period of 3 hours, which now would be considered to be too short, with a high risk of subsequent damage to the spinal cord. A total dose of 35 to 45 Gy was given. Fourteen patients received additional doxorubicin. At 1 year, the local control rate was
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22%, and the median survival was 6 months, with a 3-year survival rate of 18%.Six patients failed to complete treatment due to rapidly progressive disease, and three died of treatment complication^.^^ This protocol has subsequently been abandoned. 29, 39, 46 have described combined modality therapy, Other reports13* usually using nonstandard fractionated regimes such as hyperfractionation (i.e., increased number of fractions, with a reduced size of dose of fraction), often with the addition of doxorubicin (Table 1). Kim et all3 reported a complete remission rate of 84% and an ultimate local control rate of 68% in 19 patients treated with hyperfractionated radiation and weekly doxorubicin; however, despite the lack of apparent metastatic disease at the time of initial treatment, the median survival was only 6 months, with a 3-year survival rate of 20%. Schlumberger et al,29using a low-dose hyperfractionation regimen of radiation with the addition of chemotherapy, reported a complete response rate in 5 of 20 patients; however, only three patients survived more than 20 months. Venkatesh et a1+' reported that of 121 patients treated at MD Anderson Hospital, 12 survived longer than 24 months; 10 of these long-term survivors received combined radiation and chemotherapy. Tennvall et a139have used combined hyperfractionated radiation and chemotherapy which was given before and after surgery. Thirty-three patients were treated with this regimen, and debulking surgery was possible in 23 (70%). Local control was achieved in 48%, with death being attributed to local disease in eight patients only; however, only four patients lived for 2 years or more. As there is a high risk of metastatic dissemination in anaplastic thyroid cancer, chemotherapy has been given in a adjuvant setting in addition to combining it with radiation, but there is little evidence to suggest that anaplastic thyroid cancer is a chemosensitive disease.9,29, 31.47
Conclusions In view of the poor resectability of anaplastic thyroid cancer, XRT may be given in an attempt to achieve local control. Chemotherapy has Table 1. THE RESULTS OF COMBINED HYPERFRACTIONATED RADIATION AND CHEMOTHERAPY IN ANAPLASTIC THYROID CANCER Study
No. of Patients
Local Control
Percent Survival at 2 Years
Junor et all2 Wong et aIne Werner et a146 Kim and Leeperi3 Schlumberger et aIz9 Tennvall et aP9
91* 32 19 19 20 19
39% 22% NIS 68% NIS 48%
11* 18 1st
N/S = not specified. 'All had conventional radiation; 18 patients had chemotherapy +Three patients alive at the time of analysis.
20 15 12
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been added in combination with radiation with a suggestion of improved local control in some series, but comparisons are historical, and a randomized controlled trial would be needed to confirm the benefit of additional chemotherapy. It is important to be aware that, particularly in older series, prior to the regular use of immunohistochemistry some of the long-term survivors may actually have had lymphomas. Currently at Princess Margaret Hospital, in patients with good performance status, we are evaluating a hyperfractionated radiation regimen different from that described by Simpson. For other patients, our practice is to deliver 20 Gy in five 4-Gy fractions over a week to known sites of disease. This is repeated 4 weeks later if a symptomatic response has occurred, with protection of the spinal cord to within tolerance. Consideration is also given to a policy of expectant therapy once histology has been confirmed, particularly in elderly patients with poor performance status, or in the presence of metastatic disease where there is no evidence of airway compromise. Anaplastic thyroid cancer remains an extremely lethal disease, and innovative approaches are urgently required because presently available therapies are almost invariably ineffective. MEDULLARY THYROID CANCER The incidence of lymph node involvement at the time of diagnosis of MTC is high, as it readily spreads to cervical and upper mediastinal lymph nodes. Bergholm et a14reported that even in patients with tumors as small as 1 cm, there was an 11%incidence of lymph node involvement. Saad et alZ6in a review of 161 patients reported that 44% had lymph node involvement at presentation. The mainstay of therapy in MTC is surgery, including a careful lymph node dissection if there is evidence of lymph node involvement. Whether there is a role for adjuvant XRT in MTC is controversial. As is true in differentiated thyroid malignancy, all series reviewing the role of XRT are retrospective in nature but are smaller and result in contradictory conclusions. Samaan et aP7 found that, ”radiotherapy has little effect on medullary thyroid cancer,” in contrast to Jensen et all’ who, “determined . . . the clear need for combined therapy (surgery and radiotherapy) in regional medullary cancer.” Early retrospective reviews of small series of patients suggested that MTC did respond to XRT7,34, 37; however, in a report of 202 patients treated at M D Anderson Hospital, Samaan et aP7 found a significantly lower survival in a small group of patients (15) who received XRT when compared with 29 patients matched for age, extent of disease, and surgery who did not receive radiation. In contrast, in 37 patients with regional MTC (defined as extrathyroidal extension with or without cervical lymph node involvement), Jensen et all1 reported a 97% 5-year survival rate for patients who received XRT, compared with a 62% rate for those treated by surgery alone.
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Recently, Mak et all6 have reported an improved local control rate following XRT in patients with regional disease but no improvement in survival. The actuarial locoregional control rate at 15 years was only 13% in those patients treated by surgery alone compared with 84% if postoperative XRT was administered. The possibility that radiation may improve local control but not survival was also suggested by Nguyen et a1.22We have reviewed the records of 73 patients with MTC who were referred to Princess Margaret Hospital on initial diagnosis. Again, there was no demonstrable improvement in survival, but of 40 patients with either definite microscopic residual or presumed microscopic residual disease or lymph node involvement, 25 were irradiated with a 10-year regional control rate of 86% in contrast to a rate of 52% for 15 patients who did not receive radiation. The difference just reached statistical significance (P = 0.049).
Conclusions We believe that although XRT does not appear to improve survival, most likely because in the event of extrathyroidal invasion or widespread lymph node involvement, the tumor has already metastasized beyond the neck and upper mediastinum, locoregional control is still important as cervical relapse can have a deleterious impact on the patient’s quality of life even if it does not affect survival. Following surgical excision and a careful lymph node dissection, if there is extrathyroidal involvement or significant lymph node metastases, postoperative assessment includes stimulated calcitonin measurement and CT or MR imaging scanning of the whole body. If there is no evidence of gross metastatic disease, locoregional XRT is advised. It is usually given in two phases, first, 40 Gy in 20 fractions to encompass the cervical, supraclavicular, and upper mediastinal lymph nodes over 4 weeks, and, in the fifth week, an electron boost of 10 Gy in five fractions given to the thyroid bed. THYROID LYMPHOMAS
Unlike in differentiated thyroid cancer and MTC, the role of XRT in localized thyroid lymphoma is well-established. However, thyroid lymphomas are rare, accounting for only 4% of all extralymphatic lymphoma^,'^ and they are exclusively non-Hodgkin’s lymphomas. Hodgkin’s disease in the thyroid is an extremely rare finding. The main difficulty in the histologic diagnosis of lymphoma has been the possible confusion with anaplastic carcinoma or medullary carcinoma of thyroid. Immunocytochemical techniques are now used routinely and should differentiate these conditions with certainty in adequate biopsy speci43 there is no mens. Although surgical debulking has been advocated,25, reason to suppose that thyroid lymphomas should be managed differ-
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ently from lymphomas at other extralymphatic sites that are adequately treated without surgical excision, and the main role of surgery in this disease is to obtain tissue for histologic diagnosis. Once a tissue diagnosis of thyroid lymphoma has been obtained, the patient should be staged as for any other lymphoma. For stage 111 or IV lymphoma (Ann Arbor classification), that is, disease on both sides of the diaphragm or involvement of other extralymphatic organs, systemic therapy with chemotherapy is required. If the disease remains local, stage I or limited stage I1 (i.e., confined to the neck), the choice is between radiation alone or combined modality treatment with XRT and chemotherapy. Radiation therapy alone is a potentially curative treatment for localized thyroid lymphoma of intermediate histology. The local regional tumor control rate with radiation therapy is excellent with total doses of 35 to 40 Gy given as a fractionated course over 4 weeks.41The success of a localized form of treatment such as radiation therapy is predicated on selecting patients that have a low risk of harboring occult distant disease, hence, eradicating local regional disease will translate to a high chance of cure. The most important prognostic factor for localized thyroid lymphoma is the size of the tumor mass (bulk). Large tumor bulk, particularly for tumors measuring greater than 10 cm in maximum dimension, predicts local failure and distant relapse and short survival.4l It is likely that other clinical factors that are documented to be predictors of relapse and survival are important because they are surrogates of tumor bulk, for example, resectability, the presence of airway obstruction, and extrathyroidal invasion. Because the predominate pattern of relapse is distant, with a predilection for the gastrointestinal tract, initial combined modality therapy is a logical choice for patients with unfavorable features. Chemotherapy is usually delivered before radiation and generally results in rapid tumor regression, often within a few days of drug delivery. The standard regimen consists of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), delivered every 3 to 4 weeks for three to six cycles. For aggressive lymphomas in general, other clinical features that indicate a higher risk of distant relapse and poorer survival include older age (> 60 years), high serum lactate dehydrogenase, and poor performance status.’ These features reflect a higher likelihood of distant occult disease and poorer tolerance to cytotoxic therapy. We have reviewed the results of treating 39 patients with stage I and I1 lymphomas; the overall 5-year actuarial and cause-specific survival rates were 64% and 73%, respectively, which is similar to the findings in other studies2,14, 15, 36, 41, 43, 45 (Table 2). The cause-specific survival at 5 years was 82% for those treated by combined modality therapy compared with 63% for those treated by XRT alone, despite the fact that patients treated by combined modality therapy had less favorable disease. A univariate analysis showed that tumor bulk and age were the only significant prognostic factors for cause-specific survival; treatment modality did not reach statistical ~ignificance.~~ A close association of Hashimoto’s thyroiditis and B-cell lymphomas
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Table 2. SURVIVAL OF PATIENTS WITH STAGE I AND I I THYROID LYMPHOMAS ~~~~~
~
~
Study
No. of Patients
Percent 5-Year Survival
Anscombe and Wright2* Vigliotti et a145* Tupchong et a143t Skarsgard et als6* Logue et allst Tsang et al4I* Laing et all4*
63 38 46 27 70 39 45
54 72 40 70 42 64
-
Percent 5-Year Cause-Specific Survival
64
-
70 49 73 79
'50% or more had combined modality therapy. +The majority of patients in these series had XRT alone.
has been shown by Hyjek and Isaacson.loThey suggest that lymphomas of the thyroid may be derived from mucosa-associated lymphoid tissue (MALT), which could explain the association between thyroid lymphomas and lymphomas of the gastrointestinal tract, lung, and salivary glands (4 of 11 relapses in our series occurred in the gastrointestinal tract). Laing et all4 described the presence of an irregular B-cell population (centrocytelike cells), numerous mature plasma cells, and lymphoepithelial lesions that led to the classification of MALT lymphomas. A review of the histology of 45 patients with stage I or I1 lymphomas of the thyroid treated by radiation alone in 87% of cases found that the cause-specific survival at 5 years was 90% for patients with evidence of origin from MALT but only 55% if there was no such evidence. It was concluded that, for MALT lymphomas of the thyroid, radiation alone may be sufficient.
Conclusion Despite the findings of Laing et al,14 it is currently our practice to advise combined modality therapy in all patients with intermediate grade lymphoma, except those with small bulk disease (< 3 cm) confined to the thyroid, who receive radiation alone. The chemotherapy given is usually three courses of CHOP followed 4 weeks later by radiation. Because of a high probability of microscopic involvement by drainage lymph nodes, the radiation portals should encompass bilateral neck nodes and superior mediastinal nodes in addition to the thyroid bed. A dose of 35 Gy in 20 1.75-Gy fractions over 4 weeks is usually prescribed (Fig. 2). MANAGEMENT OF METASTATIC DISEASE Because patients with metastatic thyroid cancer not infrequently live with the disease for a few years, there is a need to administer
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Figure 2. A, CT scan of a 67-year-old woman with stage 2AE immunoblastic lymphoma of the thyroid. Six courses of chemotherapy (CHOP) were given and complete clinical remission was obtained. B, Simulation radiograph of radiation fields of the same patient. 35 Gy in 20 fractions were given over 4 weeks by parallel opposed fields, 6 weeks after completion of chemotherapy.
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radiation therapy for palliation of symptoms. Common sites presenting for radiation treatment include the osseous skeleton, lymph node metastases not amenable to surgical resection or radioiodine, and, occasionally, the brain. In general, if there is an efficacious way of delivering radiation with radioiodine (i.e., in iodine-concentrating metastases), this should be given before a decision regarding the use of external radiation. However, because radioiodine alone rarely offers long-term control for bone metastases, if the goal is to achieve maximum disease control in a critical site (e.g., vertebral metastasis threatening the spinal cord), we advocate adding radiotherapy to moderately high doses (total dose of 40 to 50 Gy in 2-Gy fractions in addition to l3II, if appropriate). Because of the limited radiation tolerance of the lung, external radiation is used rarely for pulmonary metastases. COMPLICATIONS OF EXTERNAL RADIATION THERAPY
Acute complications of radiation to the thyroid bed include skin erythema, which is usually only moderate. If high-dose radiation is prescribed for macroscopic disease, dry desquamation or, rarely, moist desquamation may follow. Esophageal, tracheal, or laryngeal mucositis can occur toward the end of radiation and commonly subside 2 to 4 weeks after completion. A soft diet and analgesics may be required. Late toxicity is infrequent. Slight skin atrophy, pigmentation, and telangiectasis can occur over the thyroid bed but usually only if a fullskin dose is used. More severe changes are rare, with fibrosis and edema occurring after extensive prior surgical resection. Radiation myelopathy is preventable by careful treatment planning. Tracheal, esophageal, or laryngeal dysfunction following radiation is exceptionally rare. References 1. The International non-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329987-994, 1993 2. Anscombe A, Wright D Primary malignant lymphoma of the thyroid-a tumour of mucosa-associated lymphoid tissue: Review of seventy-six cases. Histopathology 9%-97, 1985 3. Benker G, Olbricht T, Reinwein D, et al: Survival rates in patients with differentiated thyroid carcinoma: Influence of postoperative external radiotherapy. Cancer 65:15171520, 1990 4. Bergholm U, Adami H, Auer G, et al: Clinical characteristics in sporadic and familial medullary thyroid carcinoma. Cancer 63:1196-1204, 1989 5. Cady B, Rossi R: An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 104:947-953, 1988 6. Cunningham M, Duda R, Recant W, et al: Survival discriminants for differentiated thyroid cancer. Surg 160:344-347, 1990 7. Halnan K: The non-surgical treatment of thyroid cancer. Br J Surg 62769, 1975 8. Hay I: Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 19:545-576, 1990
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9. Hoskin P, Harmer C: Chemotherapy for thyroid cancer. Radiother Oncol 10187-194, 1987 10. Hyjek E, Isaacson P: Primary B-cell lymphoma of the thyroid and its relationship to Hashimoto’s thyroiditis. Hum Pathol 19:1315-1326, 1988 11. Jensen MH, Davis RK, Derrick L: Thyroid cancer: A computer-assisted review of 5287 cases. Otolaryngol Head Neck Surg 10251-65, 1990 12. Junor E, Paul J, Reed N: Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy. Eur J Surg 18:83-88, 1992 13. Kim J, Leeper R Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 60:2372-2375, 1987 14. Laing R, Hoskin P, Vaughan Hudson B, et al: The significance of MALT histology in thyroid lymphoma: A review of patients from the BNLI and Royal Marsden Hospital. Clin Oncol 6:300-304, 1994 15. Logue J, Hale R, Stewart A, et a1 Primary malignant lymphoma of the thyroid: A clinicopathological analysis. Int J Radiat Oncol Biol Phys 22:929-933, 1992 16. Mak A, Morrison W, Garden A, et al: The value of postoperative radiotherapy for regional medullary carcinoma of the thyroid. Int J Radiat Oncol Biol Phys 30:234, 1994 17. Makepeace A, Fermont D, Bennett M: Non-Hodgkin’s lymphoma of the thyroid. Clin Radio1 38:277-281, 1987 18. Maxon HR, Englaro EE, Thomas SR Radi0’~’1therapy for well-differentiated thyroid cancer-a quantitative radiation dosimetric approach: Outcome and validation in 85 patients. J Nucl Med 33:1132-1136, 1992 19. Mazzaferri E: Radiodine and Other Treatments and Outcomes. Philadelphia, JB Lippincott, 1991, pp 1138-1165 20. Mazzaferri EL, Young RL Papillary thyroid carcinoma: A 10-year follow-up report of the impact of therapy in 576 patients. Am J Med 70:511-517, 1981 21. Nel C, van Heerden J, Goellner J, et a1 Anaplastic carcinoma of the thyroid: A clinicopathologic study of 82 cases. Mayo Clin Proc 51-58, 1985 22. Nguyen T, Chassord J, Lagarede P: Results of postoperative radiation therapy in medullary carcinoma of the thyroid. Radiother Oncol23:l-5, 1992 23. OConnell MEA, A’Hern RP, Harmer CL: Results of external beam radiotherapy in differentiated thyroid carcinoma: A retrospective study from the Royal Marsden Hospital. Eur J Cancer 30A:733-739, 1994 24. Phlips P, Hanzen C, Andry G, et al: Postoperative irradiation for thyroid cancer. Eur J Surg Oncol 19:399404,1993 25. Rosen I, Sutcliffe S, Gospodarowicz M, et a 1 The role of surgery in the management of thyroid lymphoma. Surgery 104:1095-1099, 1988 26. Saad M, Ordonez N, Rashid R, et al: Medullary carcinoma of the thyroid: A study of the clinical features and prognostic factors in 161 patients. Medicine 63:319-342, 1984 27. Samaan N, Schultz P, Hickey R Medullary thyroid carcinoma: Prognosis of familial versus sporadic disease and the role of radiotherapy. Medicine 672301-805, 1988 28. Samaan NA, Schultz PN, Hickey RC, et al: The results of various modalities of treatment of well-differentiated thyroid carcinoma: A retrospective review of 1599 patients. J Clin Endocrinol Metab 75714-720, 1992 29. Schlumberger M, Parmentier C, Delis1 M: Combination therapy for anaplastic giant cell thyroid carcinoma. Cancer 67564-566, 1991 30. Sheline GE, Galante M, Lindsay S: Radiation therapy in the control of persistent thyroid cancer. Am J Roentgen01 Rad Ther Nucl Med 97:923-930, 1966 31. Shimaoka K, Schoenfeld D, DeWys W. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 562155-2160, 1985 32. Simpson W Anaplastic thyroid carcinoma: A new approach. Can J Surg 23:25-27,1980 33. Simpson W, McKinney S, Carruthers J, et a1 Papillary and follicular thyroid cancer: Prognostic factors in 1578 patients. Am J Med 83:479488, 1987 34. Simpson W, Plamer J, Rosen I, et al: Management of medullary carcinoma of the thyroid. Am J Surg 144:420-422, 1982 35. Simpson WJ, Panzarella T, S CJ, et al: Papillary and follicular thyroid cancer: Impact of treatment in 1578 patients. Int J Radiat Oncol Biol Phys 14:1063-1075, 1988
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36. Skarsgard E, Connors J, Robins R A current analysis of primary lymphoma of the thyroid. Arch Surg 126:1199-1204, 1991 37. Steinfeld A: The role of radiation therapy in medullary carcinoma. Radiology 123:745, 1977 38. Tennvall J, Biorklund A, Moller T, et a1 Prognostic factors of papillary, follicular and medullary carcinomas of the thyroid gland: Retrospective multivariate analysis of 216 patients with a median follow-up of 11 years. Acta Radio1 Oncol 24:17-24, 1985 39. Tennvall J, Lundell G: Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic thyroid carcinoma. Cancer 74:1348-1354, 1994 40. Thoresen S, Akslen L, Glattre E, et al: Survival and prognostic factors in differentiated thyroid cancer-a multivariate analysis of 1055 cases. Br J Med 59:231-235, 1989 41. Tsang R, Gospodarowicz M, Sutcliffe S, et al: Non-Hodgkin’s lymphoma of the thyroid gland: Prognostic factors and treatment outcome. Int J Radiat Oncol Biol Phys 27599604, 1993 42. Tubiana M, Haddad E, Schlumberger M, et al: External radiotherapy in thyroid cancers. Cancer 55:2062-2071, 1985 43. Tupchong L, Hughes F, Harmer C: Primary lymphoma of the thyroid: Clinical features, prognostic factors, and results of treatment. Int J Radiat Oncol Biol Phys 12:18131821, 1986 44. Venkatesh Y, Ordonez N, Schultz P, et a1 Anaplastic carcinoma of the thyroid: A clinicopathologic study of 121 cases. Cancer 66:321-330, 1990 45. Vigliotti A, Kong J, Fuller L, et al: Thyroid lymphomas stages IE and IIE: Comparative results for radiotherapy only, combination chemotherapy only, and multimodality treatment. Int J Radiat Oncol Biol Phys 121807-1812, 1986 46. Werner B, Abele J, Alveryd A: Multimodal therapy in anaplastic giant cell thyroid carcinoma. World J Surg 8:64-70, 1984 47. Williams S, Birch R, Einhorn L Phase I1 evaluation of doxorubicin plus cisplatin in advanced thyroid cancer: A southeastern Cancer Study Group Trial. Cancer Treat Rep 70:405-407, 1986 48. Wong C, Van Dyk J, Simpson W: Myelopathy following hyperfractionated accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol 20:3-9, 1991
Address reprint requests to James D. Brierley, BSc, MBBS, MRCP(UK), FRCR, FRCPC Department of Radiation Oncology Princess Margaret Hospital 500 Sherbourne Street Toronto, Ontario M4X 1K9 Canada
0889-8529/96 $0.00
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EXTERNAL RADIATION THERAPY IN THE TREATMENT OF THYROID MALIGNANCY James D. Brierley, BSc, MBBS, MRCP(UK), FRCR, FRCPC, and Richard W. Tsang, MD, FRCPC
This article reviews the role of external beam radiation therapy (XRT) in thyroid malignancies. It is divided into sections dealing with differentiated thyroid cancer, anaplastic thyroid cancer, medullary thyroid cancer (MTC) and thyroid lymphomas. Although the discussion is mainly confined to local or locoregional radiation, that is, to the thyroid bed or the thyroid bed and regional lymph nodes given as part of initial postoperative management or at recurrence, XRT also has an important role in the palliation of metastatic disease. DIFFERENTIATED THYROID CANCER The surgical treatment of differentiated thyroid cancer and the use of I 3 l I are discussed elsewhere. This section concentrates on the role of XRT in advanced locoregional thyroid cancer, namely, in tumors that are extending through the capsule of the thyroid into the extrathyroidal tissue and where surgical excision has either been histologically complete (i.e., the XRT is adjuvant therapy to prevent local recurrence) or incomplete (i.e., there is microscopic or macroscopic residual cancer). In patients in whom operation has not been attempted due to the advanced nature of the disease, XRT also can be considered as a cytoreductive therapy before reassessment for surgical resectability afterwards.
From the Department of Radiaticn Oncology, University of Toronto, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada
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One of the earliest reports of the use of XRT in thyroid cancer was by Sheline et aPOwho in 1966 reported their experience with XRT in 58 patients with various histologies treated between 1935 and 1964. The doses used ranged from 30 to 50 Gy given in 15 to 50 days, doses that, in some cases, would be considered to be inadequate today, I3*I was not given. Fourteen patients had no attempted surgical excision due to the extent of disease. Nineteen patients had gross evidence of disease following resection, and, in 25, there was presumed residual microscopic persistent disease, tumor having been shaved off adjacent structures. Of 15 patients with papillary tumors with gross residual disease, 8 were alive and well and free from disease over the 2- to 14-year follow-up. Of the four patients with gross follicular carcinoma, three were alive and well with no evidence of recurrence. Twelve patients with papillary thyroid cancer had presumed microscopic residual disease following surgery and were given XRT; one died of metastatic disease, and 11 remained alive and well with no evidence of recurrent disease. Although the number of patients was small and the follow-up short, these results suggest that XRT even at suboptimal doses may have a role not only in controlling gross disease in well-differentiated thyroid cancer but may also contribute to local control in patients who have microscopic residual disease in the neck following resection. More recently, O’Connell et alZ3have reported the Royal Marsden Hospital experience in treating patients with differentiated thyroid carcinoma with radical XRT, giving a minimum of 60 Gy in 30 fractions. One hundred and thirteen patients received XRT; all had thyroid hormone suppression therapy, and 74 had 1311 therapy. Patients were defined by three subgroups: those with probable microscopic residual disease (tumor found at excision margin or within 2 mm of it), those with definite microscopic disease (if a blunt dissection had been carried out to remove disease from adjacent organs), and those with gross residual disease. For the 32 patients with gross residual disease, complete regression occurred in 37% following XRT. Of 25 patients with probable microscopic disease, two had an in-field recurrence (8%).Of 18 patients with definite microscopic residual disease, five had in-field recurrences (29%). We have recently reviewed the data from Princess Margaret Hospital and have found that for 33 patients with gross residual disease following attempted resection who were treated with a radical course of XRT, the actuarial local control rate was 62% at 5 years. At Princess Margaret Hospital, it is currently our policy to advise XRT for all patients with differentiated thyroid cancer who have gross residual disease following attempted resection or who are inoperable. A radical course of radiation, usually 50 Gy in 20 fractions over 4 weeks, is prescribed to a volume encompassing the thyroid bed and the gross disease. No attempt is made to include all regional lymph nodes. Patients who have undergone thyroidectomy are also given 1311 (usually, 150 to 200 mCi). All patients receive thyroxine to suppress thyroidstimulating hormone (TSH) to undetectable levels, if possible. Data from both Sheline et aPOand O’Connell et alZ3suggest that
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there may be a role for adjuvant XRT in differentiated thyroid cancer in addition to l3II therapy, but this remains controversial. Reports on the use of XRT have been retrospective, resulting in contradictory conclusions. For instance, Mazzaferri and Youngznin their report on the role of XRT in papillary thyroid cancer stated that, ”external radiation used as initial adjunctive therapy adversely influenced outcome,” whereas Simpson et a135concluded after a multi-institutional analysis of 1578 patients that they, ”provide convincing data concerning the effectiveness of external radiation and of radioiodine in the adjuvant treatment of papillary and follicular cancer patients. . . . If there is a role for adjuvant XRT therapy in differentiated thyroid cancer, the observed benefit would be improved local control in patients at risk for local relapse, and, upon longer follow-up, an improvement in survival may follow. An improvement in treatment results would not be expected in patients who already have good prognostic features and who are at low risk for local relapse, such as those at young age, with small tumours, and with tumors confined to the thyroid, but, rather, in patients who have adverse features for local recurrence, such as older age, larger tumor size, and, in particular, evidence of tumor extension through the thyroid capsule into the soft tissues of the neck.5,6, 8, Iy, 3H, 40 Many of the retrospective reports on the role of XRT included patients who may not have been expected to benefit from XRT. Especially in the earlier reports, patients may not have had what would now be considered standard therapy with 1311and TSH suppression. Mazzaferri and Youngznin 1981 described a study of 576 patients with papillary thyroid cancer. Only 28 had XRT in addition to thyroxine, but it would appear that none of the 28 had 1311.Only five tumors were greater than 1.5 cm in size, but 78% of the patients had lymph node involvement in contrast to 45% of the whole group; none had extrathyroid invasion. The dose of radiation given ranged from 10 to 70 Gy. Only five patients had 50 to 70 Gy, and the fraction size, number of fractions, and overall treatment time were not specified. With the good prognostic features of young age, small size, and lack of invasion through the thyroid capsule, it is perhaps not surprising that no evidence was found for an improvement in local control with XRT but the opposite was found, with the treated patients having a higher local relapse rate (16.7% versus 2.3% for the group as a whole). This difference may, however, be explained by the higher incidence of initial lymph node involvement and the absence of I3lI therapy in the irradiated patients. More recently, Benker et a13 have retrospectively reviewed the records of 932 patients with differentiated thyroid cancer. A total of 346 had been given XRT before their referral for consideration of 13’1therapy. The total dose of XRT given ranged from 40 to 70 Gy. Again, there is no comment on the dose per fraction or overall treatment time. Benker and co-workers concluded that they failed to prove that survival is prolonged in patients with differentiated thyroid carcinoma following postoperative XRT. A total of 205 of the 346 who received XRT had T1 or T2 tumors, and it is to be expected that they found no difference in I,
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survival between those who received XRT and those who did not in these patients with early stage disease. Neither was there an improvement in survival in patients with tumor spread beyond the thyroid gland. A subgroup analysis of patients older than 40 years revealed a 10-year survival rate of 48% for those treated without XRT and 58% for those treated with XRT; this difference was not statistically significant ( P = 0.09). No data on the local control rates following treatment with XRT were presented. Because of the referral pattern, l3II was administered following XRT, and this may not be the preferred order of treatment. It is possible that XRT could interfere with the uptake of 1311 in the neck and reduce its effectiveness by reducing the tumor cell uptake of 1311, and it is our preference to give 1311 before XRT. Benker et a13 also refer to an earlier retrospective review published in the German literature in 1983 by Leisner who reported an 88% 5-year survival rate with radiotherapy versus a 68% 5-year survival without radiotherapy, this difference was statistically significant. Samaan et a12*in a review of 1599 patients with well-differentiated thyroid cancer treated at MD Anderson Hospital noted that 113 patients were given XRT. These patients tended to be older and were more likely to be male, both poor prognostic indicators when compared with the group as a whole. They were more likely to have more extensive disease and less surgical intervention than those who did not receive XRT. When an analysis was performed on those patients with nodal and softtissue disease in the neck, there was no advantage in the use of external radiation with respect to local recurrence rate or survival. There were, however, insufficient numbers to analyze soft-tissue and lymph node involvement separately. Samaan et a12”28 concluded that there was no benefit in the use of XRT. This retrospective study provides some interesting data on the risk of local recurrence and survival in various subgroups of patients over the follow-up period of 1to 43 years (median, 11 years). The risk of local recurrence increased with more extensive local tumor from 19% for intrathyroid tumors to 22% for those with nodal involvement to 36% if there was infiltration of the soft tissues. Similarly, the survival rate fell from 93% for intrathyroid tumors and 94% for those with lymph node involvement to 82% in patients with soft-tissue involvement. If there was soft-tissue involvement at the time of surgery, 36% of patients recurred locally and 18% died, showing that it is extrathyroidal extension rather than lymph node involvement that has an adverse effect on outcome. If we could improve local control with XRT in patients with extrathyroidal extension, survival may also improve; although, of course, it may not if undetected metastasis has already occurred. Two large retrospective reviews have suggested a role for XRT in differentiated thyroid cancer, one from France by Tubiana et a142and the other from Canada by Simpson et al?3 In Tubiana’s study, 530 patients had disease confined to the neck. Sixty-six received prophylactic radiation postoperatively for extensive regional lymph node involvement, tumor invasion of the neighboring muscles, or difficult surgical excision
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of recurrence after a previous operation. The relapse-free survival rate and the overall survival rate for this group of patients given prophylactic postoperative XRT with or without iodine were lower than that for the group treated by surgery alone; however, XRT was given to a group of patients with a less favorable prognosis. Ninety-seven patients received postoperative radiotherapy after incomplete excision, and, when these were pooled with those given prophylactic XRT, the number of local recurrences was 25 (14%). This was compared with 70 local recurrences (21%) in 336 patients who did not receive XRT (61 received radioiodine therapy). This difference between the two groups is statistically significant (P< 0.05). When the dose of radiation was examined, those patients who received less than a dose of 50 Gy had a 15% in-field recurrence rate compared with a rate of 10% for those who received 50 Gy or more. This suggests the importance of giving an adequate dose of XRT. Simpson et a133reported on the treatment of papillary (1074 patients) and follicular thyroid cancer (504 patients) in 13 radiotherapy centers in Canada. A total of 201 patients had XRT, 214 patients had radioiodine, and 107 patients had both. Following resection, the patients were categorized as having no residual disease; microscopic residual disease, which meant that the tumor was at or within 2 mm of the resection margin; or gross residual disease when the surgeon reported that some visible tumor had not been removed. For those patients with no residual disease, there was no statistical difference between the treatment modalities; however, for those with microscopic residual disease and papillary pathology, there was a significant improvement in local control following the addition of l3II or XRT or both over no additional treatment at all. Although there was a difference in local control depending on treatment in patients with follicular tumors, this did not reach statistical significance. Phlips et a124have recently reported another retrospective review of patients with differentiated thyroid cancer treated between 1974 and 1989. Although smaller than the studies of Tubiana and Simpson, it is important because all of the patients received radioiodine after surgical resection, and, in addition, 38 had XRT. The overall survival was identical for the two groups, but the local relapse rate was 21% for those who received radioiodine only and 3% for those who received XRT. All of the patients who received XRT were considered to have either microscopic or minimal residual disease or positive lymph node involvement with extracapsular extension. This was not true for those patients treated with radioiodine alone who would therefore be expected to have a lower relapse rate. Of the patients who had residual tumor after an incomplete resection, two of three treated with radioiodine alone went on to have a local recurrence, whereas none of the 12 patients in the subgroup who received XRT recurred locally. In the presence of an extracapsular lymph node extension, local failure was seen in four of six patients treated with radioiodine alone and in one of six patients after XRT. Although the numbers are small and the study retrospective, it does suggest a role for
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XRT in addition to high-risk patients.
1311
in improving local control in a selected group of
Conclusions The evidence for and against a role for adjuvant XRT in differentiated thyroid cancer is exclusively retrospective in nature. If there is a role for XRT, it would not be in patients with good prognostic features who have complete surgical excision. If adjuvant treatment is required in these patients, it should be 1311 therapy. For patients with bulky residual disease, I3lI is unlikely to eradicate such disease unless a very high absorbed dose is achieved. O’Connell et alZ3note that, at least, an absorbed dose of 100 Gy is required to destroy small remnants of nodal disease and that anything less is ineffectual. Similarly, Maxon et all8 have shown that a single radioiodine administration resulting in an absorbed dose of greater than 80 Gy achieved destruction of neck nodes in 74% of patients with small volume disease defined as less than 2 g. Therefore, in the presence of gross residual disease following excision, XRT should be given to improve local control, as the reports from Sheline, Tubiana, and O’Connell show that local control can be achieved with XRT alone in this situation. Whether there is a role for XRT in the presence of either presumed or definite microscopic disease is less certain. This would be supported by retrospective reviews of Tubiana, Simpson, and Phlips but not by the retrospective data from Samaan and Benker. To compare results of different modalities of treatment by retrospective review is always fraught with difficulty. It is never made clear in some studies why some patients had XRT and others did not. The only way to define a role for XRT would be from a prospective randomized controlled trial of XRT versus no XRT in patients with presumed or definite microscopic residual disease following surgical resection. A long follow-up period for such a study would be necessary, because Tubiana et a142reported an average time to local relapse of 8.5 years, and Phlips et alZ4reported a mean time to local relapse of 49 months. Until such a study is performed and the results available, we recommend XRT in addition to 1311therapy for all patients with papillary or follicular thyroid cancer who, after a total or near-total thyroidectomy, have either probable microscopic residual disease (with positive excision margin or within 2 mm of excision) or definite microscopic disease, if a blunt dissection had been carried out to remove disease from adjacent organs. Those with probable residual disease receive 40 Gy in 15 fractions over 3 weeks in 2.57-Gy daily fractions; those with definite residual disease receive 50 Gy in 2.5-Gy daily fractions over 4 weeks. Treatment is directed to tne thyroid bed, and, usually, an anterior electron field of high energy (13 to 17 MeV) is used such that the maximum dose to the spinal cord is no more than 80% of the prescribed dose (Fig. 1). We do not give XRT for lymph node involvement unless there is invasion by disease outside the capsule of
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Figure 1. A, Simulation radiograph of typical radiation field to the thyroid bed. B, Typical isodose distribution to the thyroid bed using an anterior electron field, in this case of mixed energies, 13 MeV and 17 MeV.
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the node with extension into the soft tissues. In selected young patients with good prognostic features but minimal microscopic residual disease postoperatively that is identified clearly in the neck, and in whom there is good I3II uptake at that site, we would consider using 1311alone and withhold the use of XRT. ANAPLASTIC THYROID CANCER
After the diagnosis of anaplastic thyroid cancer, complete surgical extirpation can only be performed with curative intent in a minority of patients, and, even then, there is a high local failure ratez1 so that the use of other modalities of therapy must be considered in an attempt to obtain local control. Following surgical resection of the tumor, or biopsy only, XRT therapy alone or in combination with chemotherapy has been given in an attempt to improve local control. Anaplastic thyroid cancer does not concentrate l3II, and, therefore, there is no role for l3lI therapy in this disease. Any radiation given is usually in the form of XRT. However, even after the addition of XRT or chemotherapy, survival is still poor because of both the poor local control rate and the high incidence of metastatic disease. Junor et all2 reported on the use of radiation following surgery in 91 patients. Thirtythree had attempted curative surgery, and 58 had a biopsy only, reflecting the poor rate of resectability in this disease. Eighty-six had XRT, 18 with the addition of chemotherapy. The overall survival rate was 11% at 3 years, with a median survival of 21 months. Junor and coworkers were unable to demonstrate a dose response effect, with no improvement in survival with higher doses. Of 70 patients with detailed data on the site of recurrence, 25 had local relapse, local and distant in 25 and distant only in 20. This demonstrates that even after XRT, local control is a major problem, but, if local control is achieved, death occurs from distant metastatic disease. Despite distant dissemination, if local control can be achieved, a distressing death may be avoided from the local effects of advanced anaplastic thyroid cancer in the neck, such as esophageal or tracheal obstruction or tumor breakdown through the skin. In attempts to improve local control, several novel approaches have been tried in altering standard radiation fractionation, adding chemotherapy, and administering sequential therapy with surgical resection following initial cytoreduction. One of the first such approaches was described in 1980 by S i m p ~ o nBetween .~~ 1975 and 1982,32 patients with unresectable anaplastic thyroid cancer underwent hyperfractionated radiation at Princess Margaret Hospital. Most were given a single dose of 5 Gy followed by hyperfractionated radiation, 1 Gy given four times a day with an interfraction period of 3 hours, which now would be considered to be too short, with a high risk of subsequent damage to the spinal cord. A total dose of 35 to 45 Gy was given. Fourteen patients received additional doxorubicin. At 1 year, the local control rate was
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22%, and the median survival was 6 months, with a 3-year survival rate of 18%.Six patients failed to complete treatment due to rapidly progressive disease, and three died of treatment complication^.^^ This protocol has subsequently been abandoned. 29, 39, 46 have described combined modality therapy, Other reports13* usually using nonstandard fractionated regimes such as hyperfractionation (i.e., increased number of fractions, with a reduced size of dose of fraction), often with the addition of doxorubicin (Table 1). Kim et all3 reported a complete remission rate of 84% and an ultimate local control rate of 68% in 19 patients treated with hyperfractionated radiation and weekly doxorubicin; however, despite the lack of apparent metastatic disease at the time of initial treatment, the median survival was only 6 months, with a 3-year survival rate of 20%. Schlumberger et al,29using a low-dose hyperfractionation regimen of radiation with the addition of chemotherapy, reported a complete response rate in 5 of 20 patients; however, only three patients survived more than 20 months. Venkatesh et a1+' reported that of 121 patients treated at MD Anderson Hospital, 12 survived longer than 24 months; 10 of these long-term survivors received combined radiation and chemotherapy. Tennvall et a139have used combined hyperfractionated radiation and chemotherapy which was given before and after surgery. Thirty-three patients were treated with this regimen, and debulking surgery was possible in 23 (70%). Local control was achieved in 48%, with death being attributed to local disease in eight patients only; however, only four patients lived for 2 years or more. As there is a high risk of metastatic dissemination in anaplastic thyroid cancer, chemotherapy has been given in a adjuvant setting in addition to combining it with radiation, but there is little evidence to suggest that anaplastic thyroid cancer is a chemosensitive disease.9,29, 31.47
Conclusions In view of the poor resectability of anaplastic thyroid cancer, XRT may be given in an attempt to achieve local control. Chemotherapy has Table 1. THE RESULTS OF COMBINED HYPERFRACTIONATED RADIATION AND CHEMOTHERAPY IN ANAPLASTIC THYROID CANCER Study
No. of Patients
Local Control
Percent Survival at 2 Years
Junor et all2 Wong et aIne Werner et a146 Kim and Leeperi3 Schlumberger et aIz9 Tennvall et aP9
91* 32 19 19 20 19
39% 22% NIS 68% NIS 48%
11* 18 1st
N/S = not specified. 'All had conventional radiation; 18 patients had chemotherapy +Three patients alive at the time of analysis.
20 15 12
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been added in combination with radiation with a suggestion of improved local control in some series, but comparisons are historical, and a randomized controlled trial would be needed to confirm the benefit of additional chemotherapy. It is important to be aware that, particularly in older series, prior to the regular use of immunohistochemistry some of the long-term survivors may actually have had lymphomas. Currently at Princess Margaret Hospital, in patients with good performance status, we are evaluating a hyperfractionated radiation regimen different from that described by Simpson. For other patients, our practice is to deliver 20 Gy in five 4-Gy fractions over a week to known sites of disease. This is repeated 4 weeks later if a symptomatic response has occurred, with protection of the spinal cord to within tolerance. Consideration is also given to a policy of expectant therapy once histology has been confirmed, particularly in elderly patients with poor performance status, or in the presence of metastatic disease where there is no evidence of airway compromise. Anaplastic thyroid cancer remains an extremely lethal disease, and innovative approaches are urgently required because presently available therapies are almost invariably ineffective. MEDULLARY THYROID CANCER The incidence of lymph node involvement at the time of diagnosis of MTC is high, as it readily spreads to cervical and upper mediastinal lymph nodes. Bergholm et a14reported that even in patients with tumors as small as 1 cm, there was an 11%incidence of lymph node involvement. Saad et alZ6in a review of 161 patients reported that 44% had lymph node involvement at presentation. The mainstay of therapy in MTC is surgery, including a careful lymph node dissection if there is evidence of lymph node involvement. Whether there is a role for adjuvant XRT in MTC is controversial. As is true in differentiated thyroid malignancy, all series reviewing the role of XRT are retrospective in nature but are smaller and result in contradictory conclusions. Samaan et aP7 found that, ”radiotherapy has little effect on medullary thyroid cancer,” in contrast to Jensen et all’ who, “determined . . . the clear need for combined therapy (surgery and radiotherapy) in regional medullary cancer.” Early retrospective reviews of small series of patients suggested that MTC did respond to XRT7,34, 37; however, in a report of 202 patients treated at M D Anderson Hospital, Samaan et aP7 found a significantly lower survival in a small group of patients (15) who received XRT when compared with 29 patients matched for age, extent of disease, and surgery who did not receive radiation. In contrast, in 37 patients with regional MTC (defined as extrathyroidal extension with or without cervical lymph node involvement), Jensen et all1 reported a 97% 5-year survival rate for patients who received XRT, compared with a 62% rate for those treated by surgery alone.
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Recently, Mak et all6 have reported an improved local control rate following XRT in patients with regional disease but no improvement in survival. The actuarial locoregional control rate at 15 years was only 13% in those patients treated by surgery alone compared with 84% if postoperative XRT was administered. The possibility that radiation may improve local control but not survival was also suggested by Nguyen et a1.22We have reviewed the records of 73 patients with MTC who were referred to Princess Margaret Hospital on initial diagnosis. Again, there was no demonstrable improvement in survival, but of 40 patients with either definite microscopic residual or presumed microscopic residual disease or lymph node involvement, 25 were irradiated with a 10-year regional control rate of 86% in contrast to a rate of 52% for 15 patients who did not receive radiation. The difference just reached statistical significance (P = 0.049).
Conclusions We believe that although XRT does not appear to improve survival, most likely because in the event of extrathyroidal invasion or widespread lymph node involvement, the tumor has already metastasized beyond the neck and upper mediastinum, locoregional control is still important as cervical relapse can have a deleterious impact on the patient’s quality of life even if it does not affect survival. Following surgical excision and a careful lymph node dissection, if there is extrathyroidal involvement or significant lymph node metastases, postoperative assessment includes stimulated calcitonin measurement and CT or MR imaging scanning of the whole body. If there is no evidence of gross metastatic disease, locoregional XRT is advised. It is usually given in two phases, first, 40 Gy in 20 fractions to encompass the cervical, supraclavicular, and upper mediastinal lymph nodes over 4 weeks, and, in the fifth week, an electron boost of 10 Gy in five fractions given to the thyroid bed. THYROID LYMPHOMAS
Unlike in differentiated thyroid cancer and MTC, the role of XRT in localized thyroid lymphoma is well-established. However, thyroid lymphomas are rare, accounting for only 4% of all extralymphatic lymphoma^,'^ and they are exclusively non-Hodgkin’s lymphomas. Hodgkin’s disease in the thyroid is an extremely rare finding. The main difficulty in the histologic diagnosis of lymphoma has been the possible confusion with anaplastic carcinoma or medullary carcinoma of thyroid. Immunocytochemical techniques are now used routinely and should differentiate these conditions with certainty in adequate biopsy speci43 there is no mens. Although surgical debulking has been advocated,25, reason to suppose that thyroid lymphomas should be managed differ-
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ently from lymphomas at other extralymphatic sites that are adequately treated without surgical excision, and the main role of surgery in this disease is to obtain tissue for histologic diagnosis. Once a tissue diagnosis of thyroid lymphoma has been obtained, the patient should be staged as for any other lymphoma. For stage 111 or IV lymphoma (Ann Arbor classification), that is, disease on both sides of the diaphragm or involvement of other extralymphatic organs, systemic therapy with chemotherapy is required. If the disease remains local, stage I or limited stage I1 (i.e., confined to the neck), the choice is between radiation alone or combined modality treatment with XRT and chemotherapy. Radiation therapy alone is a potentially curative treatment for localized thyroid lymphoma of intermediate histology. The local regional tumor control rate with radiation therapy is excellent with total doses of 35 to 40 Gy given as a fractionated course over 4 weeks.41The success of a localized form of treatment such as radiation therapy is predicated on selecting patients that have a low risk of harboring occult distant disease, hence, eradicating local regional disease will translate to a high chance of cure. The most important prognostic factor for localized thyroid lymphoma is the size of the tumor mass (bulk). Large tumor bulk, particularly for tumors measuring greater than 10 cm in maximum dimension, predicts local failure and distant relapse and short survival.4l It is likely that other clinical factors that are documented to be predictors of relapse and survival are important because they are surrogates of tumor bulk, for example, resectability, the presence of airway obstruction, and extrathyroidal invasion. Because the predominate pattern of relapse is distant, with a predilection for the gastrointestinal tract, initial combined modality therapy is a logical choice for patients with unfavorable features. Chemotherapy is usually delivered before radiation and generally results in rapid tumor regression, often within a few days of drug delivery. The standard regimen consists of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), delivered every 3 to 4 weeks for three to six cycles. For aggressive lymphomas in general, other clinical features that indicate a higher risk of distant relapse and poorer survival include older age (> 60 years), high serum lactate dehydrogenase, and poor performance status.’ These features reflect a higher likelihood of distant occult disease and poorer tolerance to cytotoxic therapy. We have reviewed the results of treating 39 patients with stage I and I1 lymphomas; the overall 5-year actuarial and cause-specific survival rates were 64% and 73%, respectively, which is similar to the findings in other studies2,14, 15, 36, 41, 43, 45 (Table 2). The cause-specific survival at 5 years was 82% for those treated by combined modality therapy compared with 63% for those treated by XRT alone, despite the fact that patients treated by combined modality therapy had less favorable disease. A univariate analysis showed that tumor bulk and age were the only significant prognostic factors for cause-specific survival; treatment modality did not reach statistical ~ignificance.~~ A close association of Hashimoto’s thyroiditis and B-cell lymphomas
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Table 2. SURVIVAL OF PATIENTS WITH STAGE I AND I I THYROID LYMPHOMAS ~~~~~
~
~
Study
No. of Patients
Percent 5-Year Survival
Anscombe and Wright2* Vigliotti et a145* Tupchong et a143t Skarsgard et als6* Logue et allst Tsang et al4I* Laing et all4*
63 38 46 27 70 39 45
54 72 40 70 42 64
-
Percent 5-Year Cause-Specific Survival
64
-
70 49 73 79
'50% or more had combined modality therapy. +The majority of patients in these series had XRT alone.
has been shown by Hyjek and Isaacson.loThey suggest that lymphomas of the thyroid may be derived from mucosa-associated lymphoid tissue (MALT), which could explain the association between thyroid lymphomas and lymphomas of the gastrointestinal tract, lung, and salivary glands (4 of 11 relapses in our series occurred in the gastrointestinal tract). Laing et all4 described the presence of an irregular B-cell population (centrocytelike cells), numerous mature plasma cells, and lymphoepithelial lesions that led to the classification of MALT lymphomas. A review of the histology of 45 patients with stage I or I1 lymphomas of the thyroid treated by radiation alone in 87% of cases found that the cause-specific survival at 5 years was 90% for patients with evidence of origin from MALT but only 55% if there was no such evidence. It was concluded that, for MALT lymphomas of the thyroid, radiation alone may be sufficient.
Conclusion Despite the findings of Laing et al,14 it is currently our practice to advise combined modality therapy in all patients with intermediate grade lymphoma, except those with small bulk disease (< 3 cm) confined to the thyroid, who receive radiation alone. The chemotherapy given is usually three courses of CHOP followed 4 weeks later by radiation. Because of a high probability of microscopic involvement by drainage lymph nodes, the radiation portals should encompass bilateral neck nodes and superior mediastinal nodes in addition to the thyroid bed. A dose of 35 Gy in 20 1.75-Gy fractions over 4 weeks is usually prescribed (Fig. 2). MANAGEMENT OF METASTATIC DISEASE Because patients with metastatic thyroid cancer not infrequently live with the disease for a few years, there is a need to administer
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Figure 2. A, CT scan of a 67-year-old woman with stage 2AE immunoblastic lymphoma of the thyroid. Six courses of chemotherapy (CHOP) were given and complete clinical remission was obtained. B, Simulation radiograph of radiation fields of the same patient. 35 Gy in 20 fractions were given over 4 weeks by parallel opposed fields, 6 weeks after completion of chemotherapy.
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radiation therapy for palliation of symptoms. Common sites presenting for radiation treatment include the osseous skeleton, lymph node metastases not amenable to surgical resection or radioiodine, and, occasionally, the brain. In general, if there is an efficacious way of delivering radiation with radioiodine (i.e., in iodine-concentrating metastases), this should be given before a decision regarding the use of external radiation. However, because radioiodine alone rarely offers long-term control for bone metastases, if the goal is to achieve maximum disease control in a critical site (e.g., vertebral metastasis threatening the spinal cord), we advocate adding radiotherapy to moderately high doses (total dose of 40 to 50 Gy in 2-Gy fractions in addition to l3II, if appropriate). Because of the limited radiation tolerance of the lung, external radiation is used rarely for pulmonary metastases. COMPLICATIONS OF EXTERNAL RADIATION THERAPY
Acute complications of radiation to the thyroid bed include skin erythema, which is usually only moderate. If high-dose radiation is prescribed for macroscopic disease, dry desquamation or, rarely, moist desquamation may follow. Esophageal, tracheal, or laryngeal mucositis can occur toward the end of radiation and commonly subside 2 to 4 weeks after completion. A soft diet and analgesics may be required. Late toxicity is infrequent. Slight skin atrophy, pigmentation, and telangiectasis can occur over the thyroid bed but usually only if a fullskin dose is used. More severe changes are rare, with fibrosis and edema occurring after extensive prior surgical resection. Radiation myelopathy is preventable by careful treatment planning. Tracheal, esophageal, or laryngeal dysfunction following radiation is exceptionally rare. References 1. The International non-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329987-994, 1993 2. Anscombe A, Wright D Primary malignant lymphoma of the thyroid-a tumour of mucosa-associated lymphoid tissue: Review of seventy-six cases. Histopathology 9%-97, 1985 3. Benker G, Olbricht T, Reinwein D, et al: Survival rates in patients with differentiated thyroid carcinoma: Influence of postoperative external radiotherapy. Cancer 65:15171520, 1990 4. Bergholm U, Adami H, Auer G, et al: Clinical characteristics in sporadic and familial medullary thyroid carcinoma. Cancer 63:1196-1204, 1989 5. Cady B, Rossi R: An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 104:947-953, 1988 6. Cunningham M, Duda R, Recant W, et al: Survival discriminants for differentiated thyroid cancer. Surg 160:344-347, 1990 7. Halnan K: The non-surgical treatment of thyroid cancer. Br J Surg 62769, 1975 8. Hay I: Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 19:545-576, 1990
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9. Hoskin P, Harmer C: Chemotherapy for thyroid cancer. Radiother Oncol 10187-194, 1987 10. Hyjek E, Isaacson P: Primary B-cell lymphoma of the thyroid and its relationship to Hashimoto’s thyroiditis. Hum Pathol 19:1315-1326, 1988 11. Jensen MH, Davis RK, Derrick L: Thyroid cancer: A computer-assisted review of 5287 cases. Otolaryngol Head Neck Surg 10251-65, 1990 12. Junor E, Paul J, Reed N: Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy. Eur J Surg 18:83-88, 1992 13. Kim J, Leeper R Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 60:2372-2375, 1987 14. Laing R, Hoskin P, Vaughan Hudson B, et al: The significance of MALT histology in thyroid lymphoma: A review of patients from the BNLI and Royal Marsden Hospital. Clin Oncol 6:300-304, 1994 15. Logue J, Hale R, Stewart A, et a1 Primary malignant lymphoma of the thyroid: A clinicopathological analysis. Int J Radiat Oncol Biol Phys 22:929-933, 1992 16. Mak A, Morrison W, Garden A, et al: The value of postoperative radiotherapy for regional medullary carcinoma of the thyroid. Int J Radiat Oncol Biol Phys 30:234, 1994 17. Makepeace A, Fermont D, Bennett M: Non-Hodgkin’s lymphoma of the thyroid. Clin Radio1 38:277-281, 1987 18. Maxon HR, Englaro EE, Thomas SR Radi0’~’1therapy for well-differentiated thyroid cancer-a quantitative radiation dosimetric approach: Outcome and validation in 85 patients. J Nucl Med 33:1132-1136, 1992 19. Mazzaferri E: Radiodine and Other Treatments and Outcomes. Philadelphia, JB Lippincott, 1991, pp 1138-1165 20. Mazzaferri EL, Young RL Papillary thyroid carcinoma: A 10-year follow-up report of the impact of therapy in 576 patients. Am J Med 70:511-517, 1981 21. Nel C, van Heerden J, Goellner J, et a1 Anaplastic carcinoma of the thyroid: A clinicopathologic study of 82 cases. Mayo Clin Proc 51-58, 1985 22. Nguyen T, Chassord J, Lagarede P: Results of postoperative radiation therapy in medullary carcinoma of the thyroid. Radiother Oncol23:l-5, 1992 23. OConnell MEA, A’Hern RP, Harmer CL: Results of external beam radiotherapy in differentiated thyroid carcinoma: A retrospective study from the Royal Marsden Hospital. Eur J Cancer 30A:733-739, 1994 24. Phlips P, Hanzen C, Andry G, et al: Postoperative irradiation for thyroid cancer. Eur J Surg Oncol 19:399404,1993 25. Rosen I, Sutcliffe S, Gospodarowicz M, et a 1 The role of surgery in the management of thyroid lymphoma. Surgery 104:1095-1099, 1988 26. Saad M, Ordonez N, Rashid R, et al: Medullary carcinoma of the thyroid: A study of the clinical features and prognostic factors in 161 patients. Medicine 63:319-342, 1984 27. Samaan N, Schultz P, Hickey R Medullary thyroid carcinoma: Prognosis of familial versus sporadic disease and the role of radiotherapy. Medicine 672301-805, 1988 28. Samaan NA, Schultz PN, Hickey RC, et al: The results of various modalities of treatment of well-differentiated thyroid carcinoma: A retrospective review of 1599 patients. J Clin Endocrinol Metab 75714-720, 1992 29. Schlumberger M, Parmentier C, Delis1 M: Combination therapy for anaplastic giant cell thyroid carcinoma. Cancer 67564-566, 1991 30. Sheline GE, Galante M, Lindsay S: Radiation therapy in the control of persistent thyroid cancer. Am J Roentgen01 Rad Ther Nucl Med 97:923-930, 1966 31. Shimaoka K, Schoenfeld D, DeWys W. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 562155-2160, 1985 32. Simpson W Anaplastic thyroid carcinoma: A new approach. Can J Surg 23:25-27,1980 33. Simpson W, McKinney S, Carruthers J, et a1 Papillary and follicular thyroid cancer: Prognostic factors in 1578 patients. Am J Med 83:479488, 1987 34. Simpson W, Plamer J, Rosen I, et al: Management of medullary carcinoma of the thyroid. Am J Surg 144:420-422, 1982 35. Simpson WJ, Panzarella T, S CJ, et al: Papillary and follicular thyroid cancer: Impact of treatment in 1578 patients. Int J Radiat Oncol Biol Phys 14:1063-1075, 1988
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Address reprint requests to James D. Brierley, BSc, MBBS, MRCP(UK), FRCR, FRCPC Department of Radiation Oncology Princess Margaret Hospital 500 Sherbourne Street Toronto, Ontario M4X 1K9 Canada