External radiotherapy in the treatment of thyroid cancer

External beam radiotherapy has been used in patients with all types of thyroid epithelial cancer, medullary thyroid cancer, and thyroid lymphoma. It can be given as primary therapy to treat unresectable cancer, as adjuvant therapy after surgical resection, and as palliative therapy for recurrent cancer. It can be given alone or in combination with surgery or chemotherapy.

WELL-DIFFERENTIATED THYROID CANCER — Surgical resection is the primary treatment of patients with differentiated thyroid cancer, followed by radioiodine and then thyroxine (T4) therapy. However, not all patients have resectable disease. For those with residual tumor after surgery, radioiodine therapy is unlikely to eradicate the tumor unless the absorbed dose of radiation is high, eg, at least 100 Gy. In one study, for example, a single dose of radioiodine producing an absorbed dose over 80 Gy resulted in destruction of tumor in cervical lymph nodes in only 74 percent of patients with small-volume disease (less than 2 grams). Further radiation in the form of external beam radiation can improve local control.

That external radiotherapy is effective in controlling residual disease after surgery has been known for some time, and it has been confirmed in a large study from Hong Kong. The complete remission rate in patients with palpable disease may be as high as 78 percent with an actuarial five-year relapse free rate of 62 percent. In a series of 88 patients with well-differentiated thyroid cancer that has been incompletely resected, the five-year survival was 77 percent with radiotherapy compared with 38 percent after surgery alone (p<0.05). We recommend that patients who have macroscopic residual disease after thyroidectomy be treated with radioiodine followed by radiotherapy to the thyroid bed and known sites of disease. If thyroidectomy is not possible, radiotherapy alone is given.

 

Adjuvant therapy — Most patients with well-differentiated thyroid cancer have resectable tumors, and the results of surgery, radioiodine therapy, and T4 therapy are excellent. However, there is a subgroup of patients whose outcome is poor, namely older patients with recurrent extrathyroidal cancer that does not concentrate radioiodine. In one series of 65 patients in whom the disease recurred after surgical and radioiodine therapy, 62 percent had no tumor uptake of radioiodine.

The role of adjuvant (postoperative) external radiotherapy in patients with well-differentiated thyroid cancer has been studied only retrospectively, and many of the studies included patients at low risk of recurrence who were unlikely to benefit from the therapy. Those who are most likely to benefit are probably patients with evidence of extrathyroidal extension at the time of surgery.

Several reports have described either no benefit or even a deleterious effect of adjuvant radiotherapy. In one study, for example, the local recurrence rate was higher in patients given adjuvant radiotherapy than in those not treated (16.7 versus 2.3 percent). Other series have noted no significant improvement in survival with adjuvant radiotherapy.

In contrast, other studies have suggested an improvement in local control with radiotherapy. In a review of patients with well-differentiated thyroid cancer treated at Princess Margaret Hospital, we identified 155 patients over the age of 45 years who had microscopic residual papillary cancer after surgery. In addition to T4 therapy, 27 patients received radiotherapy, 30 radioiodine therapy, 63 both treatments, and 35 neither treatment. The 10-year cause-specific survival (100 versus 95 percent, P = 0.04) and the local recurrence-free rate (93 versus 78 percent, P = 0.01) were higher in patients given radiotherapy.  Neither the extent of surgery nor radioiodine therapy had any effect on cause-specific survival or local recurrence rate. There was no demonstrable benefit from radiation therapy in the 52 patients with follicular cancer who had microscopic residual disease after surgery.

Other reports have made the following observations:

  bullet In a group of 92 patients with locally advanced papillary or follicular thyroid cancer with extrathyroidal extension, radiotherapy resulted in improved locoregional control only in patients 38 years of age or older (89 percent versus 60 percent).
  bullet Among 114 patients in whom all gross local disease was resected, local recurrence-free survival was higher in those patients who received an adequate dose of adjuvant radiotherapy (45 Gy of cobalt or 40 Gy of orthovoltage therapy) compared with those who received an inadequate dose or were not radiated. Cause-specific survival was improved in patients with papillary, not follicular, cancer (P<0.001 for all outcomes). An update from the same group found that, among patients with papillary cancer, the dose of radiotherapy was a significant independent prognostic factor in a multivariate analysis for cause specific-survival, along with age, distant metastases at presentation, extent of surgery, size of primary tumor, extrathyroidal extension, and degree of thyrotropin (TSH) suppression. However, only 17 percent of patients were treated with radioiodine, which would be considered standard in North America.

In none of these studies was the treatment uniform with respect to surgery, radioiodine therapy, T4 therapy, or radiotherapy. In contrast, in two other studies of high-risk patients who received radioiodine and T4 therapy, in addition to radiotherapy, the following findings were noted:

  bullet In a series of 113 patients, the local recurrence rate was 3 percent among those who received radiotherapy but only 21 percent among those who did not, even though there were fewer poor-prognosis patients in the latter group.

  bullet In a study of 137 patients over 40 years of age with extrathyroidal extension of their cancers, all of whom had total thyroidectomy and radioiodine and T4 therapy, 85 patients received radiotherapy (50 to 60 Gy) to the thyroid bed and cervical and upper mediastinal lymph nodes. The patients in the radiotherapy group had fewer local and regional recurrences (P = 0.004).

These results suggest that for patients at high risk of recurrence, which we define as age greater than 45 years and gross extrathyroid extension, that is resectable, radiotherapy may reduce the likelihood of local recurrence. However, this remains controversial; thus, due to concern about the potential side effects of external radiotherapy and the relatively low morbidity from local recurrences, many centers prefer to use radiotherapy only after repeat surgery in patients who have had one or more local recurrences in the thyroid bed.

Radiation protocol — For patients with well-differentiated thyroid cancer, we usually treat the thyroid bed alone, from the hyoid to just below the suprasternal notch. However, the field is adjusted accordingly depending upon the operative and pathologic findings. Care must be taken not to deliver high doses to the spinal cord. We treat patients with gross residual or microscopic residual disease with 50 Gy, given in 20 fractions of 2.5 Gy over four weeks. For adjuvant radiotherapy after complete resection, we recommend 40 Gy in 15 fractions given over three weeks. We do not recommend radiotherapy in patients less than 45 years of age, or in older patients with only pathological extrathyroid extension, ie, not noted by the surgeon.

Well planned external beam radiotherapy treatment regimens rarely have serious long-term complications. However, acute toxicity occurs and may include the following:

  bullet Moderate skin erythema
  bullet Dry desquamation, and rarely moist desquamation
  bullet Mucositis of the esophagus, trachea and larynx, which may require a soft diet and analgesics, may develop towards the end of radiation therapy; this will subside within two to four weeks after the end of treatment.

The most common manifestations of late toxicity are skin telangiectasias and skin pigmentation. The development of esophageal and tracheal stenosis is extremely rare.

External beam radiation does not preclude future surgical intervention if required.

Bone metastases — The best therapy for patients with metastatic well-differentiated thyroid cancer, radioiodine, is less effective in patients with bone metastases. In one series, for example, the ten-year survival rate was 54 percent for patients with lung metastases, but there were no survivors among patients with bone metastases. In another report of 214 patients with distant metastases, the metastases took up radioiodine in 60 percent of those with bone involvement, but only 3 percent of these patients achieved complete remission after radioiodine therapy. A third study of 30 patients with bone metastases reported some long-term survival: 18 percent at 10 years.

Given these disappointing results of radioiodine therapy in patients with bone metastases, an aggressive surgical approach has been recommended. However, not all bone metastases are amenable to surgical resection. We therefore recommend radiotherapy in addition to radioiodine therapy for patients with unresectable bone metastases or multiple bone metastases. For solitary metastases, we usually give 50 Gy in 25 fractions, but we lower the dose to 40 Gy in 20 fractions in patients with spinal bone metastases to ensure that the dose to the spinal cord is safe

ANAPLASTIC THYROID CANCER — Anaplastic thyroid cancer is one of the most lethal of all cancers, and therapy has little effect on outcome.  Although complete surgical resection gives the best chance of cure, this is rarely possible. Anaplastic cancers do not concentrate radioiodine; as a result, radiotherapy is given with the aim of local control.

However, the prognosis remains poor. In a group of 134 patients with anaplastic cancer 98 percent had extrathyroidal extension at the time of presentation, with a survival of only three months. Neither the completeness of resection nor the use of concurrent chemoradiation had an effect on survival. There was, however, a modest improvement in survival (three months versus five months) in patients given XRT compared with those who did not receive XRT In contrast, in a smaller study of 33 patients (with a median survival of 3.8 months), a subgroup of eight patients had either no or minimal macroscopic disease after surgery and subsequent chemoradiation. Thus, it appears that there is a small group of patients who have limited or no extrathyroid extension who benefit from an aggressive approach of surgery followed by postoperative therapy.

Recommendations — The main goal of local therapy in patients with anaplastic thyroid cancer is to prevent death from uncontrolled disease in the neck. We rarely see patients who are surgical candidates. We treat patients with good performance status who have local disease in the neck (before or after resection) with accelerated hyperfractionated radiotherapy without chemotherapy. For patients with poor performance status or known metastatic disease, we give palliative radiation only.

  Radiation protocol — The radiation fields in patients with anaplastic thyroid cancer are usually tailored to include the thyroid bed and the adjacent lymph nodes. No attempt is made to treat the entire neck or mediastinum unless disease is documented in these sites. In patients with good-performance status, we give 60 Gy in 40 fractions, two fractions a day for four weeks. In patients with poor performance status or known metastatic disease, we give palliative radiation only, 20 Gy in five fractions, with the option of a second course four weeks later for patients who respond.

MEDULLARY THYROID CANCER — The best treatment for patients with medullary cancer is thyroidectomy and lymphadenectomy. Radiotherapy may be useful both for primary therapy if resection is incomplete and adjuvant therapy.

Primary therapy — If complete surgical resection is not possible, we recommend radiotherapy because local control can be achieved in some patients. In a report of 21 patients with macroscopic residual disease after surgery who were treated with radiotherapy, the local relapse-free rate was 20 percent.

Adjuvant therapy — Studies of the benefit of adjuvant radiotherapy in patients with medullary cancer are conflicting. A significantly lower survival was reported in a series of 15 patients who received radiotherapy, as compared with 29 patients matched for age, extent of disease, and surgery who did not receive radiotherapy. However, other studies suggested a benefit from radiotherapy in terms of local control. In one report, for example, local control was achieved in 59 percent of patients with persistently elevated calcitonin and no evidence of distant disease treated with radiotherapy, compared with 29 percent without radiotherapy.

However, this benefit is not accompanied by an improvement in survival, presumably because of microscopic disease beyond the neck. Nevertheless, local and regional control is still important because of the morbidity of locally recurrent disease. Radiotherapy seems to be beneficial in minimizing local recurrences, and is probably indicated for this purpose.

Radiation protocol — For patients with medullary cancer, radiotherapy is usually given in two phases. First, 40 Gy is given in 20 fractions over four weeks to encompass the cervical, supraclavicular and upper mediastinal lymph nodes. In the fifth week, a boost of 10 Gy in five fractions is given to the thyroid bed.

THYROID LYMPHOMA — Thyroid lymphomas are rare, accounting for less than 1 percent of all malignant thyroid tumors; the majority have aggressive histology, most commonly diffuse large B-cell lymphoma. Although surgical debulking has been advocated, the main role for surgery in this disease is to obtain tissue for histological diagnosis

Patients with thyroid lymphomas should be staged like any other patient with lymphoma. In those with stage I or limited stage II disease (ie, disease confined to the neck), the choice is between radiotherapy alone or combined radiotherapy and chemotherapy. The rate of local control with 35 to 40 Gy given in four weeks is excellent. In one series of 39 patients, almost all of whom were treated with radiotherapy alone or in combination with chemotherapy, five-year actuarial survival and cause-specific survival rates were 64 and 73 percent, respectively. Although the patients treated by combined radiotherapy and chemotherapy had less favorable disease, the cause-specific survival rate at five years was 82 percent for those treated with combined therapy as compared with 63 percent for those treated with radiotherapy alone, a difference that did not achieve statistical significance. Radiation therapy alone is adequate treatment for localized indolent lymphomas such as mucosa-associated lymphoid tissue lymphoma, or follicular lymphoma.

Recommendations — We recommend combined therapy for all patients with aggressive histology lymphoma. Chemotherapy, when given before radiotherapy, usually results in rapid tumor regression. The standard regimen consists of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), given every three to four weeks for three to six cycles. We usually give three courses of CHOP followed four weeks later by radiotherapy.

Radiation protocol — The radiation protocol for thyroid lymphoma is usually similar to the large phase 1 treatment for medullary cancer: 35 Gy is given in 20 fractions over four weeks to encompass the thyroid, neck nodes bilaterally, and superior mediastinal nodes.