The successful treatment of thyroid cancer depends on the histology of the cancer, its size, presence of metastasis. The external beam radiation therapy (EBRT) can be given locally to the neck or to isolated metastases where there has been insufficient 131I uptake for an adequate therapeutic effect [13.1]. EBRT is effective for locoregional control and certain metastatic foci in thyroid carcinoma. It can be used alone or in combination with 131I. Definitive EBRT requires careful treatment planning because doses as high as 70 Gy are required and administered over a 7.5 week period. By comparison, thyroid lymphoma requires only about 45 Gy over 4.5 to 5 weeks [13.2].
Although EBRT can be performed using either a linear accelerator or cobalt teletherapy machines, the sharper beam and the larger field sizes, along with the better availability of photons and electrons favour the use of the linear accelerator over cobalt-60 in treating thyroid cancers.
Indications for EBRT of thyroid cancer are shown in Table 13.1, but more generally include:
• Bulky tumour (e.g. mediastinal disease) large enough that it is uncontrollable by 131I alone.
• Residual bulky tumour in the central neck, trachea, and oesophageal area or cervical nodal regions after thyroid surgery and removal of malignant cervical adenopathy that may not be controlled by 131I alone.
• Skeletal metastasis
⎯ uptake of 131I is insufficient
⎯ impending pathologic fracture, regardless of the degree of 131I uptake
• Brain metastases.
• Metastases (lung) if symptomatic or when other treatment methods have been unsuccessful.
• Relief of pressure symptoms occurring in vital areas caused by soft tissue masses.
• Superior vena cava syndrome.
• Continually recurring thyroid cancer regardless of 131I uptake.
• Recurrent or metastatic thyroid cancer occurring after maximal 131I therapy.
• In sequence or conjunction with chemotherapy, particularly in anaplastic cancer.
• Inoperable locally advance thyroid cancer: EBRT as palliation.
General indications of EBRT according to histological classification (3-4) are given in Table 13.1.
TABLE 13.1. GENERAL INDICATIONS FOR EBRT ACCORDING TO HISTOLOGICAL CLASSIFICATION
Tumour Stage Treatment
Papillary or Follicular Invasive, <45 years age Invasive, or possible residual
>45 years age
Recurrent, any age, first 131I repeatedly
Lymphoma All External irradiation to
thyroid bed.
Anaplastic All External irradiation to
thyroid bed.
Persistent and Recurrent Disease
1. Local recurrence 2. Bone metastases
External irradiation if 131I is ineffective.
External irradiation to symptomatic areas.
13.2. Differentiated thyroid cancer
The role of external beam radiation therapy (EBRT) in differentiated thyroid cancer has been reviewed in the presence of gross residual disease after attempted surgical excision.
Retrospective series have reported local control is possible with EBRT. If used in addition to
131I, there is a role for adjuvant EBRT in differentiated thyroid cancer, it is only in patients in whom there is a high risk of relapse in the thyroid bed. There is evidence to suggest that EBRT can improve the local relapse-free rate in selected patients, such as those over the age of 45 years, those with microscopic residual disease, or extensive extra-thyroidal invasion [13.5].
The previous widespread belief that these cancers are ‘radio-resistant’ is now less evident as more reports on the beneficial result of EBRT in papillary and follicular cancer are published [13.6]. Several authors have retrospectively reviewed their experience with EBRT and suggested an improved local control and/or survival benefit [13.7]. Simpson and Carruthers showed that patients with surgically narrow or microscopically positive margins may benefit from the addition of EBRT in moderate doses [13.8]. This study combined 13 Canadian institutions using EBRT in patients with high-risk fractures, including those with extra-thyroidal invasion, high grade malignancy and older age group. Local control significantly improved both papillary and follicular cancer. Overall survival in papillary thyroid cancer significantly improved with and without use of 131I therapy. Tubiana and co-workers retrospectively reviewed 539 patients with thyroid cancer, where 97 received post-operative EBRT and some received 131I also [13.9]. EBRT was given for prophylactic treatment and for macroscopic residual disease. Overall, the risk of local recurrence was significantly reduced with the addition of EBRT.
Benker and associates showed no survival benefit with addition of EBRT in 932 patients of differentiated thyroid cancer [13.10]. On subset analysis, patients of age more than 40 years, and those with T-3 and T-4 disease experienced improved survival which was statistical significance.
A Belgian study of 94 patients with microscopic and macroscopic residual disease or nodal involvement with extracapsular extension showed that despite poorer prognostic factors in the EBRT group (38 of whom had EBRT) [13.11], only one local failure was reported compared with 14 in those patients who only received 131I therapy. In this study, toxicity due to EBRT was low, with doses at 55 Gy to the treatment volume.
A study of 1599 patients from the MD Anderson Cancer Hospital in the USA showed that 113 patients who received EBRT failed to report any advantage [13.12]. However, a selection bias where the EBRT group had poorer prognostic factors, more advanced disease, less surgery than the rest of the population influenced the findings.
The overall data published from these studies indicates that although the definitive role of EBRT for differentiated thyroid cancer remains controversial, there appears to be a select population of patients having microscopic or presumed microscopic residual cancer, who may benefit from the addition of local EBRT. These cancers slowly regress after radiation therapy often requiring more than a year to obtain the maximum response, analogous to the situation when 131I is used to treat gross disease. Radiation therapy is particularly useful for treating the thyroid bed when residual microscopic disease is suspected. When gross disease is present, either local, regional or as a solitary distant metastasis, EBRT should be administered in addition to the functioning tumour, since 131I alone may not eradicate gross tumour masses completely or permanently. Under ideal clinical circumstances, however, this will be a rare requirement, as patients should have adequate surgical removal of gross thyroid tissue followed by radioiodine treatment. Palliative EBRT is also useful in alleviating bone pain, and preventing pathologic fractures or superior vena cava compression in some patients [13.6].
13.3. Medullary thyroid cancer
At present, surgery is the most important treatment for medullary thyroid cancer (MTC).
Radiotherapy and chemotherapy play a marginal role in advanced MTC [13.13, 13.14]. As with papillary and follicular cancers, MTC responds slowly following radiotherapy. There is no place for small volume irradiation in the primary treatment of this tumour. Radiotherapy should always consist of modified mantle technique [13.6]. In MTC and undifferentiated thyroid cancer, once the cancer spreads to distant organs, there is virtually no efficacious therapy. However, growing knowledge of the specific genes involved in thyroidal oncogenesis may contribute to the future development of more effective treatment modalities [13.9].
13.4. Anaplastic thyroid cancer
Since EBRT is a localized form of treatment, the impact of radiation must be assessed in terms of local control within the irradiated volume. However, local control and cure rate are not synonymous, and despite local control, the majority of patients die of disseminated disease [13.6].
13.5. Lymphoma
Combined chemotherapy and irradiation are effective in thyroid lymphoma [13.6].
Consequently, total thyroidectomy should no longer be considered the first-line treatment.
Furthermore, there is evidence to suggest that the most efficacious therapy is systemic chemotherapy in combination with EBRT for local control. Debulking surgery has a role to provide relief from acute airway obstruction [13.15]. Radiotherapeutic management of clinical stages I and II primary thyroid lymphoma should include treatment of the neck, axillae and mediastinum to a dose of approximately 4000 cGy using a continuous course technique [13.16].
13.6. Miscellaneous malignancy
For rare variants such as squamous cell cancer, post-surgical EBRT may also have a role.
Other histologic varieties, including Hurtle cell carcinoma are characterized by advanced disease at the time of diagnosis and by may be unresponsive to treatment. Except where there is a clear-cut palliative benefit often, these malignancies go untreated because the acute complications may exceed any benefit produced by surgery, irradiation or chemotherapy.
13.7. Squeal of radiotherapy
Acute reactions in treating very large volume include:
• Mucositis requiring supportive treatment including intravenous fluid, soft diet and analgesic;
• Monilial superinfection — requiring antifungal antibiotics.;
• Fatigue and lassitude — usually subsiding within 1-4 weeks after completion of EBRT;
• Haematopoietic depression — rarely prevents completion of EBRT but the patient’s blood count should be monitored regularly.
Late reactions are infrequent and include:
• Lhermitte’s syndrome — consists of sensation felt like an electric shock down the back and into the legs on flexing the head briskly. This appears 2-3 months after EBRT, and most often subsides over 9-12 months, but may persist for up to 24-30 months.
• Transverse radiation myelopathy — manifests within 9-15 months if spinal cord tolerance doses are exceeded.
• Radiation skin atrophy — minimal with high energy radiation.
• Dryness of the mucous membranes within treatment volume.
• Secondary malignancies (mainly skin lesions) are rarely seen.
13.8. Other radiotherapy modalities
• Intra-operative radiation therapy (IORT) has been used for poorly differentiated non-anaplastic thyroid carcinoma. IORT is administered after tumour surgery (4-10 Gy) and combined with post-operative percutaneous irradiation [13.16].
• A similar potential role exists for brachytherapy.
REFERENCES TO SECTION 13
[13.1] TUBIANA, M., LACOUR, J., MENNIER, J.P., BERGIRON, C., et al., External radiotherapy and radioiodine in the treatment of 359 thyroid cancers, Br J Radio 48 (1975) 894-907.
[13.2] PEREZ, C.A., BRADY, L.W., Principles and Practice of Radiation Oncology, 3rd edn, Lippincott-Raven Publishers, Philadephia (1998) 1171-1192.
[13.3] DE GROOT, L.J., LARSEN, P.R., REFETOFF, S., STANBURY, J.B., The thyroid and its diseases, Thyroid Neoplasia, 5th edn (1984) 815-816.
[13.4] NUQUI, E.A., The Philippine Handbook of Clinical Oncology, 2nd edn, Raintree Trading and Publishing, Philippines (2002) 197-198.
[13.5] BRIERLEY, J.D., TSANG, R.W., External-beam radiation therapy in the treatment of differentiated thyroid cancer, Semin Surg Oncol 16 (1999) 42-49.
[13.6] DECOX, J., Moss Radiation Oncology: Rationale, Technique and Result, 7th edn, Mosby Publisher, Philadelphia (1994) 280-302.
[13.7] GUNDERSON, L.L., TEPPER, J.E., Clinical Radiation Oncology, 1st edn, Livingstone (2000) 534-546.
[13.8] SIMPSON, W.J., CARRUTHERS, J.S., The role of external radiation in the management of papillary and follicular thyroid cancer, Am J Surg 136 (1978) 457-460.
[13.9] TUBIANA, M., HADDAD, E., SCHLUMBERGER, M., HILL, C., ROUGIER, P., SARRAZIN, D., External radiotherapy in thyroid cancers, Cancer 55 (1985) 2062-2071.
[13.10] BENKER, G., OLBRICHT, T., REINWEIN, D., et al., Survival rates in patients with differentiated thyroid CA: Influence of postoperative external radiotherapy, Cancer 65 (1990) 1517-1520.
[13.11] PHLIPS, P., HANZEN, C., ANDRY, G., VAN HOUTTE, P., FRUULING, J., Postoperative irradiation for thyroid cancer, Eur J Surg Oncol 19 (1993) 399-404.
[13.12] SAMAAN, N.A., SCHULTZ, R.N., HICKLY, R.C., The result of various modalities of treatment of well-differentiated thyroid carcinomas: A retrospective review of 1599 patients, J Clin Endocrinol Metab 75 (1992) 714-720.
[13.13] VITALE, G., CARAGLIN, M., CICCARELLI, A., LUPOLI, G., ABBRUZZESE, A., TAGLIAFERRI, P., Current approaches and perspective in the therapy of medullary thyroid carcinoma, Cancer 91 (2001) 1797-1808.
[13.14] GIMM, O., Thyroid Cancer, Cancer Lett 163 (2001) 143-156.
[13.15] WITZFIELD, D.A., WINSTON, J.S., HICKS, W.L., LOREE, T.R., Clinical presentation and treatment of non-Hodgkin’s lymphoma of the thyroid gland, Ann Surg Oncol 8 (2001) 338-341.
[13.16] WOLF, G., GEYER, E., LAGSTEGER, W., RAMSCHAK, S., ROSANELLI, G., Intraoperative radiation therapy in advanced thyroid cancer, Eur J Surg Oncol 21 (1995) 357-359.
14. ROLE OF CHEMOTHERAPY