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The management of advanced thyroid cancer
Clinical Oncology (2004) 16: 561–568 doi:10.1016/j.clon.2004.08.009
Overview The Management of Advanced Thyroid Cancer P. C. Wilson*, B. M. Millary, J. D. Brierleyy *Department of Clinical Oncology, Bristol Haematology and Oncology Centre, Bristol, UK; yDepartment of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada ABSTRACT: Although the prognosis of the majority of patients with thyroid cancer is excellent there are some patients with advanced thyroid cancer in whom the prognosis is poor. Such patients include: patients with locally invasive or recurrent differentiated thyroid cancer and medullary thyroid cancer, and all patients with anaplastic cancer. The management of patients with advanced thyroid cancer is reviewed with emphasis on the role of external beam radiotherapy. Wilson, P. C. et al. (2004). Clinical Oncology 16, 561–568 Ó 2004 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Thyroid neoplasms, radiotherapy, drug therapy Received: 8 March 2004 Revised: 2 August 2004 Accepted: 9 August 2004
Introduction
The thyroid gland contains two main cell types, follicular epithelial cells and C cells. Follicular epithelial cells give rise to most thyroid cancers, usually grouped into differentiated carcinomas (papillary and follicular) and undifferentiated carcinoma (anaplastic). Within the spectrum from differentiated to undifferentiated, there are also Hu¨rthle-cell tumours and insular carcinoma. Insular carcinoma is a poorly differentiated tumour, probably part of a continuum from differentiated to anaplastic thyroid cancer [1]. Differentiated thyroid cancer has a high cure rate compared with anaplastic thyroid cancer, which has an invariably poor prognosis. Medullary thyroid carcinoma originates from the C cells, and these cancers are, therefore, aetiologically, pathologically and clinically distinct from those arising from the follicular cells. The management of thyroid cancer is primarily influenced by histological type, and for differentiated cancer, age and extent of disease. There is a paucity of randomised phase III studies in thyroid oncology; therefore, the following discussion is based on reports of historically treated, uncontrolled patient populations. Differentiated Thyroid Cancer Definition of Advanced Differentiated Thyroid Cancer
For the purpose of this report, advanced disease is defined as the presence of extrathyroidal extension (T4a and T4b by UICC 6th edition [2]), recurrent disease in the thyroid bed, Author for correspondence: Dr. James Brierley, Department of Radiation Oncology, Princess Margaret Hospital, 610 University Avenue, 5th Floor, Toronto, Ontario, M5G 2M9, Canada. Tel: C1 416 946 2124; Fax: C1 416 946 6566; E-mail: [email protected] (J. D. Brierley). 0936-6555/04/080561C08 $35.00/0
metastatic disease in the lung that does not take up iodine, and bone and other metastases. The current treatment policy of surgical excision followed by radioactive iodine and thyroid stimulating hormone (TSH) suppression, as recommended by the British Thyroid Association and the Royal College of Physicians [3] and described by Vini and Harmer [4], results in cure for most patients with differentiated thyroid cancer. However, there is still a small subgroup of patients whose outcome is poor, and these patients usually have advanced disease at initial diagnosis or at relapse. Although recurrence rates are highest at extremes of age, survival with treatment may be excellent in younger patients [5,6]. Treatment of Advanced Differentiated Thyroid Cancer Locoregional Disease
Ideally, treatment should be a thyroidectomy and the removal of all gross disease followed by adjuvant 131Iodine (131I) therapy. Complete surgical resection is important because survival is adversely affected by gross residual disease (R2 resection) compared with no (R0), or microscopic (R1) residual disease [7,8]. Using the 6th edition of UICC staging classification, all tumours with extrathyroidal extension are no longer classified purely as T4 disease. A distinction is made on the basis of the extent and site of extrathyroid extension. If the tumour has minimal extension to the sternothyroid muscle or perithyroid tissues, it is classified as T3. Tumours that invade the subcutaneous soft tissues, the larynx, trachea, oesophagus or recurrent laryngeal nerve are classified as category T4a (Fig. 1), but, if there is invasion of prevertebral fascia, mediastinal vessels or encasement of the carotid artery, then the tumour is classified as T4b. A T4a tumour may be resected and
Ó 2004 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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Fig. 1 – (A) Computed tomography scan and (B) anatomic diagram of locally advanced thyroid cancer with extrathyroidal extension.
successfully shaved or dissected off the involved structures, but with the assumption of residual microscopic disease. Invasion of the cartilage or intraluminal involvement may require more extensive resection, although ideally, the extent of surgery should be balanced with preservation of function. Gross residual disease after resection of T4b tumours is inevitable. 131I therapy is unlikely to eradicate gross residual tumour unless a high absorbed dose of radiation is achieved. Further radiation in the form of radical external beam radiotherapy (EBRT) may improve local control. Many retrospective series have reported local control of gross disease with EBRT [9–15]. O’Connell et al. [16] reported the Royal Marsden Hospital experience of treating patients with differentiated thyroid cancer with EBRT (60 Gy in 30 daily fractions over 6 weeks). Fortynine patients had gross residual disease: complete response was attained in 37% and partial regression in an additional 25%. In a review of patients at Princess Margaret Hospital between 1958 and 1985, of 33 patients with gross residual
disease, the local relapse-free rate at 5 years was 62%, and the cause-specific survival rate was 65% [8]. In a study from Hong Kong [17], 124 patients with gross locoregional disease after surgery treated with EBRT showed a reduction in the risk of local failure. The use of EBRT is controversial for those patients with microscopic residual disease. All reports on the use of EBRT have been retrospective, with varying criteria for patient selection, resulting in contradictory conclusions. Several studies [18–20] have described either no or a deleterious effect for EBRT, but many others have described benefit [8,10,13,21–26]. One study from Toronto found superior local control and improved survival in patients who received EBRT for microscopic residual disease [8]. This benefit was confirmed in a recent update with longer follow-up (10-year local relapse-free rate 93% compared with 83% for patients not receiving EBRT, P Z 0.01; and cause-specific survival 99% compared with 93%; P Z 0.04) [27]. However, in this and in other studies, not all patients had a total thyroidectomy, adjuvant 131I or TSH suppression, which would now be considered standard therapy. More recent studies [24,25] using ‘standard therapy’ have shown a benefit from additional EBRT in high-risk patients. In one report [24] of 137 patients overall who had undergone a total thyroidectomy, radioactive iodine ablation and TSH suppression, there was an increase in the freedom from locoregional and distant failure in patients over the age of 40 years with extrathyroidal extension and lymph-node involvement in the 85 patients who received EBRT compared with those who did not. EBRT was also a predictive factor for improvement in time to locoregional recurrence (P Z 0.004) and locoregional and distant failure (P Z 0.0003). In the absence of randomised data, we believe there is sufficient evidence from this study and the other retrospective studies (Table 1) to recommend EBRT in addition to standard therapy in high-risk patients. However, the definition of high-risk remains uncertain. The British Thyroid Association and the Royal College of Table 1 – Results of adjuvant external radiotherapy in high-risk disease from retrospective studies: 10-year local recurrence
Tubiana et al. [12] Simpson et al.* [11] Esik et al. [23] Ford et al. [26] Phlips et al. [25] Farahati et al.x [24] Tsang et al.* [8] Kim et al.k[91]
Surgery with and without 131 Iodine (%)
Surgery and radiotherapy with and without 131 Iodine
21 18 52y 63y 21 50z 22 37.5
14 14 11y 18y 3 1%z 7 4.8
*Surgery alone group had local recurrence rate of 74%. yCompares low dose vs higher dose. zLocal and distant failures. xPapillary only. k5-year locoregional relapse rate.
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THE MANAGEMENT OF ADVANCED THYROID CANCER
Physicians guidelines recommend EBRT in patients with gross evidence of local invasion at surgery and significant macro or microscopic residual disease, particularly if there is residual tumour that fails to concentrate 131I and is apparent only by raised thyroglobulin. However, after radioactive iodine, even if there is demonstrated uptake in the neck, it is uncertain whether this uptake is by residual normal thyroid tissue or residual disease. Consequently, at Princess Margaret Hospital, we recommend EBRT, to the thyroid bed alone, after 131I therapy in high-risk patients defined as older (O45–50 years) with potential microscopic residual disease after resection of gross extrathyroid extension (i.e. UICC 6th edition category T4a or T4b but not T3). We will consider EBRT in younger patients if the extrathyroid extension is extensive or if there is gross residual disease after resection (R2 resection). Patients with gross residual disease receive 50 Gy in 20 fractions or its equivalent. The dose may be reduced to 40 Gy in 15 fractions or its equivalent in the presence of microscopic residual disease. If the decision is made to treat a large volume, including the cervical nodes for instance, or if there is extracapsular extension and local invasion of cervical nodes, fractionation is changed to 2 Gy fractions. The radiation techniques are described below. Locoregional Relapse
Little has been published on the management of local regional relapse; however, it should probably be treated in the same way as locally advanced primary disease. The main treatment modality should be surgery, if possible, followed by 131I therapy and TSH suppression. Relapses tend to be in the cervical lymph nodes (regional relapse) rather than in the thyroid bed (local recurrence) [8,28]. Patients with nodal recurrence should have a neck dissection followed by 131I, with a high expectation of tumour control [28]. However, if the tumour burden is low (i.e. nodes ! 2 cm) then radioactive iodine without surgery may be adequate. If there is extracapsular lymph-node involvement with infiltration of the soft tissues of the neck or persistent or recurrent nodal disease despite full neck dissection and 131I, then additional EBRT may be given to maximise the chance of local control [22]. Locally recurrent disease in the thyroid bed is usually more ominous than lymph-node recurrence. This generally occurs in older patients with T4 lesions at initial diagnosis. The probability of the disease at this point concentrating radioiodine may be lower than with cervical nodal recurrence [29]. Despite this, the management at the time of recurrence remains the same: a combination of surgical resection, if possible, followed by routine postoperative 131I and consideration of EBRT.
Distant Metastatic Disease 131
Iodine Uptake
The mainstay of therapy for metastatic disease is radioiodine, but this will only be effective if a total or near total
thyroidectomy has been carried out. Failure to achieve a complete remission from metastatic disease is predicted by the following factors: failure to concentrate 131I, age above 40 years and the presence of bone metastases [30,31]. Brown et al. [32] reported no 10-year survivors in a group of patients with bone metastases treated by 131I, but a 54% 10-year survival in patients with lung metastases. People with bone metastases in general do not respond well to 131I [31,33], and therefore, surgical resection of a solitary lesion may be appropriate [33]. In patients with a solitary metastasis in whom a prolonged survival is expected and surgical excision is not possible, a high dose of EBRT may be a given to maximise the duration of local control. Even patients who present with distant metastatic disease may have a prolonged survival. In one series of 44 such patients, the 20-year survival was 43% [34]. Ideally, treatment should still consist of a total thyroidectomy to resect the primary lesion and also to facilitate the use of 131I therapy. Failure to Take up
131
Iodine Therapy
Little effective therapy is available for patients who have not responded to the above treatments [35]. Single-agent doxorubicin, with a response rate of 25–40%, is the most effective chemotherapeutic agent [36,37]. There is little evidence to suggest that combination chemotherapy is more effective. In a small randomised study (84 evaluable patients), which included all thyroid cancer histologies, no difference was observed in overall response rate when doxorubicin was compared with doxorubicin and cisplatinum [37], although the complete remission rate was higher with the combination. For patients unresponsive to radioiodine, re-differentiation of their tumours with retinoid therapy or combination chemotherapy has been reported to increase uptake of 131I [38], but the therapeutic results have been disappointing [39], as have those reports on the use of lithium carbonate to increase uptake of 131I [40]. Raised Thyroglobulin and Negative 131Iodine Upake Scan
The finding of an elevated thyroglobulin level with a negative radioiodine scan presents a difficult clinical situation. This can represent de-differentiation of the tumour, with reduction or loss of its ability to accumulate iodine. Therefore, detection of residual tumour foci is important to allow for further surgical resection or external beam radiotherapy if appropriate. Further investigation with imaging modalities, such as ultrasound, computed tomography or magnetic resonance imaging, may be helpful but can be difficult to interpret on the background of post-surgical changes. The use of dynamic imaging for this scenario is under investigation. Use of 2-[18F]fluoro-2deoxy-D-glucose positron emission tomography has demonstrated a sensitivity of 70–90% in identifying the source of elevated thyroglobulin [41], increasing sensitivity correlated with thyroglobulin levels [42,43]. The diagnostic value of somatostatin receptor scintigraphy with 111Indiumoctreotide has also been evaluated [44,45]. Further
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investigation and refinement of these non-invasive functional techniques will hopefully allow increased ability to identify residual tumour that may be amenable to surgical resection.
Medullary Thyroid Cancer Definition of Advanced Medullary Thyroid Cancer
Nodal involvement in the neck and superior mediastinum is relatively common at presentation (about 50%), and there may be infiltrative local disease into the soft tissues of the neck. Extensive locoregional disease is not always completely resectable, resulting in postoperative microscopic or macroscopic disease. In some cases, after what was thought to be complete surgical resection and lymph-node dissection, there may be residual disease shown only by high serum calcitonin and carcinoembryonic antigen levels [46,47].
Distant Metastatic Disease
The most frequent sites of metastatic disease are liver, lung and bone. Treatment intent is palliative and includes supportive measures, analgesic drugs and consideration of the potential benefits of chemotherapy, hormonal therapy and local radiation. Chemotherapy is documented to have a response rate of 15–30%. Regimens may include doxorubicin, either as single agent or with cisplatin [37], 5-fluorouracil containing combinations [54–57] and others [15,36]. Hormonal therapy consists of somatostatin analogues (e.g. octreotide), which have been reported to lessen symptoms, reduce calcitonin levels, but generally do not induce tumour shrinkage [58–61]. A higher response rate has been reported with a combination of octreotide and interferon alpha [58,62]. Local radiation can be used for symptomatic bone metastases. Experimental therapies with targeted radiation and monoclonal antibodies conjugated to radionucleotides (e.g. anti-carcinoembryonic antigen, or 111Indium-octreotide, 131I-MIBG) are being studied [63–65] as are gene therapeutic approaches [66].
Treatment of Advanced Medullary Thyroid Cancer Locoregional Disease
The standard management is surgery, comprising a total thyroidectomy and central node dissection if the lymph nodes are thought to be involved. In addition, selective lymph-node dissection might be required if further lymph nodes are thought to be involved [48]. Radioactive iodine has no role in the management of medullary thyroid cancer; however, after surgery for high-risk disease (gross or microscopic residual disease, or extensive regional lymphnode involvement), adjuvant EBRT to the thyroid bed and regional nodal tissue may be considered, in the absence of known distant metastatic disease, to try to reduce the local recurrence rate. Without further treatment, about half of these high-risk patients will experience recurrences in the neck [49]. Radiation doses of 40 Gy in 2 Gy fractions to the neck and upper mediastinum, followed by a 10 Gy boost to the thyroid bed, have been associated with a locoregional control rate of 86% at 10 years [49]. Adjuvant EBRT does not affect overall survival, but locoregional control is important because cervical relapse can have a deleterious effect on the patient’s quality of life. Other investigators have reported similar results [50–52]. Fersht et al. [53] have also reported a trend toward improved local relapsefree rate in high-risk patients (29% local relapse after EBRT but 59% relapse without EBRT; P Z 0.29). Therefore, for patients with high-risk disease, extrathyroid extension or multiple-nodal involvement, with hypercalcitoninemia and no evidence of metastatic disease, radiation should be considered to improve local relapsefree rate. For patients with gross residual disease after surgery, the local control rate after EBRT is as low as 20% [49]; therefore, every attempt should be made to completely extirpate disease surgically. When this is not possible, external radiation may result in long-term local control in a few patients. There is no role for adjuvant chemotherapy.
Anaplastic Thyroid Cancer Definition of Advanced Anaplastic Thyroid Cancer
All patients with anaplastic thyroid cancer (ATC) are considered to have advanced cancer (6th edition UICC T4a or T4b disease [2]), because the prognosis is invariably poor. Some ATC have been found to co-exist with areas of differentiated thyroid carcinoma in the gland, suggesting that the anaplastic component arose from pre-existing differentiated disease (de-differentiation) [67–69]. In the analysis of the EORTC thyroid cancer study group [70], the prognosis of patients with any element of anaplasia within a differentiated thyroid cancer was no different from patients with anaplastic tumour throughout, with a 1-year survival of 10%.
Treatment of Anaplastic Thyroid Cancer Locoregional Disease
Complete surgical resection gives the best chance of cure; however, this is only possible in a few patients [71–74]. Those most amenable to this approach are patients with predominantly differentiated thyroid carcinoma and only a small focus of ATC [74,75], in whom the surgery can be carried out without undue morbidity. Some data suggest occasional long-term survival in patients who have undergone complete resection; however, in many of these patients, the anaplasia is found incidentally as a small focus [72,73]. Radical surgery is not warranted in patients with more extensive invasion of adjacent structures, as it has a significantly negative effect on quality of life and no survival benefit [73]. Unfortunately, most patients with ATC are unresectable at the time of diagnosis. A surgical biopsy may be necessary to confirm the diagnosis, and
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THE MANAGEMENT OF ADVANCED THYROID CANCER
a tracheostomy can alleviate critical upper airway obstruction. ATC does not concentrate 131I, and so radiotherapy is the mainstay treatment for local control and palliation of symptoms to try to maintain quality of life. The ineffectiveness of radiation alone in this disease has led to the development of both novel fractionation schedules and concurrent chemotherapy regimens. Because anaplastic thyroid cancer grows quickly, hyperfractionated and accelerated radiation have been used, sometimes in combination with chemotherapy and surgical resection. The most successful regimen in obtaining local control is that described by the Swedish group [76–78], which involves combined preoperative hyperfractionated radiation and chemotherapy followed by surgical resection. After resection, further radiation and chemotherapy are given. Although only 24% of patients died because of uncontrolled local disease, the 2-year survival was only 9%. Other approaches to intensify radiotherapy have met with limited success owing to increased morbidity of normal tissues [79,80]. Invariably, the median survival is between 3 and 6 months. Patients with good performance status with no evidence of distant metastatic disease may benefit from an aggressive approach with high-dose radiotherapy with or without concurrent chemotherapy or altered fractionation, such as accelerated hyperfractionated radiotherapy, otherwise a palliative approach is warranted [81] (Table 2). Haigh et al. [82] have reported an estimated 5-year survival of 50% in a small highly selected subgroup: eight patients underwent surgical resection with either no residual disease or only microscopic residual disease, and subsequently had combined chemotherapy and radiotherapy. However, the median survival of the group as a whole (33 patients) was only 3.8 months. In contrast, in the large Mayo series of 135 patients [83], multi-modality therapy did not improve survival, although there was a small non-significant improvement in median survival in patients who received radiation compared with those who did not (3 vs 5 months; P Z 0.08). Even if local control is achieved with EBRT, death still occurs from distant metastatic disease [67,71,73–76,80, 84,85]. Chemotherapy for metastatic disease has not been effective [86]. The expected 5-year survival is about 5% with any of the currently available treatment approaches
[71,73–76,84,85]. Although doxorubicin and cisplatin have been the most common drugs used, there have been recent reports of activity of other drugs. Ain et al. [87] reported a response rate of 53% to paclitaxel; however, there remains little evidence that anaplastic carcinoma of the thyroid is chemosensitive. Distant Metastatic Disease
The main goal of treatment is to palliate symptoms, with the expectation of a short survival. Chemotherapy is frequently ineffective [36,37,86,87], and local radiation may be used for pain control. Anaplastic thyroid cancer remains an extremely lethal disease, and innovative approaches are needed, as presently available therapies are seldom effective. External Beam Radiation Therapy
Below is a description of the typical dose and fractionation used at Princess Margaret Hospital and a variety of techniques that have been used to attempt to overcome the difficulties of treating this volume. The thyroid bed volume curves around the vertebral body and includes the air column in the trachea. As it adopts a U-shaped volume, it is challenging to produce a technique that adequately treats the thyroid bed and spares the spinal cord to a dose within tolerance. If the lymph nodes are considered at risk, at least two phases of treatment are required to stay within spinal cord tolerance. A variety of techniques such as direct electrons, and two antero-lateral oblique wedged fields, have been described to overcome the difficulties [8,88,89]. To treat the thyroid bed, a clinical target volume from the hyoid to suprasternal notch is determined. This includes the prevertebral fascia to the anterior aspects of the transverse processes, laterally to mid sternocleidomastoid, encompassing the carotid artery and jugular vein, ensuring adequate coverage of the tracheosophageal groove (Fig. 1). Adjustments of the encompassed volume are made relative to presurgical diagnostic imaging and operative reports. Ideally, presurgical diagnostic imaging would be used as a baseline for definition of the thyroid bed; however, because of concerns of iodine load, with iodinated contrast affecting subsequent management with
Table 2 – Local control and survival after fractionated radiation and concurrent chemotherapy in anaplastic thyroid cancer
Kim and Leeper [92] Schlumberger et al. [86] Tennvall et al. [78] Wong et al. [80] Mitchell et al. [79] Haigh et al. [82] *At 20 months. yNot stated.
Patients
Local control (%)
Median survival (months)
2-year survival (%)
Fractionation
Concurrent chemotherapy
19 20 55 32 17 33
68 NSy 60 22 76 NSy
6 NSy 2–4.5 6 2.5 3.8
20 15* 9 18 NSy 20
Hyperfractionated Hypofractionated Hyperfractionated Accelerated/hyperfractionated Accelerated Not stated
Yes Yes Yes Yes No Yes
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I, these are not routinely performed. The simplest technique that is commonly used at Princess Margaret Hospital takes advantage of the characteristic rapid fall off of direct electron beams and the effect of the neck contour that can produce an acceptable treatment volume with a direct electron field. A planning computed tomography (CT) is essential to ensure appropriate coverage of the planing target volume and to ensure the cord dose remains in tolerance. This is particularly important given the effect of the trachea and column of air on the dose distribution. Mixed energies of 12 MeV and 16 MeV or 16 MeV alone are common energies used. In the absence of gross disease, at Princess Margaret Hospital, 40 Gy in 15 fractions over 3 weeks is prescribed. If gross disease is present, then a higher dose of 50 Gy in 20 fractions over 4 weeks is given [8,81]. An alternative technique is to use two antero-lateral oblique wedged fields, as in larynx cancer [89]. The posterior border is placed to exclude the spinal cord. If it is determined that the clinical target volume should include the cervical and superior mediastinal lymph nodes, as well as the thyroid bed, a two-phase technique is commonly used. The initial volume (phase I) includes the regional lymph nodes from the mastoid tip to the carina, including the thyroid bed. The phase I volume may consist of parallel opposing antero-posterior/postero-anterior fields to 40–46 Gy. The patient is supine with neck extended to avoid the parotid glands and the oral cavity. Shielding for the mandible and lung tissue should be routinely used. It is also important to obtain a sagittal isodose distribution to obtain an accurate spinal cord dose. The aim of phase I is to deliver a dose of 40–46 Gy before starting the off-cord treatment, the dose depending on the phase II technique and the spinal cord dose with phase II. The phase II volume should include the tissues considered at highest risk of relapse, aiming to boost the high-risk area to a total dose of 14 Gy (cumulative total dose of 60 Gy). For the boost to the thyroid bed alone, the technique used can be a direct anterior electron beam as described above, or antero-lateral oblique wedge fields. Another alternative is a lateral pair of angled-down oblique fields, achieved with a couch rotation of 10–20 degrees, aiming inferiorly to avoid the shoulders, off the spinal cord. The main disadvantage of this technique is possible exposure of the parotid glands, due to the higher entrance point of the lateral beams. Since the thyroid bed target volume is U-shaped and it is often necessary to include regional lymph nodes, treatment planning of this difficult volume is ideal for conformal radiotherapy, or intensity-modulated radiation therapy [90]. Currently at Princess Margaret Hospital, a conformal plan is used either to treat the thyroid bed alone or to include the cervical nodes. Typically, this involves five fields, with an anterior field and four post-oblique fields, often with segmentation of these beams. Well-planned EBRT has acceptable acute toxicity, rarely produces serious complications and does not preclude future surgical intervention if required. During the radiation, moderate skin erythema will develop, and with the higher doses of radiation, dry or rarely moist desquamation occurs.
Mucositis of the oesophagus, trachea and larynx can occur towards the end of radiation. Depending on the superior extent of the fields, change of taste and xerostomia may occur, which may be exacerbated in differentiated thyroid cancer by previous radioactive iodine. Late toxicity is infrequent; the most common is skin telangiectasia, increased skin pigmentation, soft tissue fibrosis and mild lymphoedema predominantly in the submental area. Oesophageal and tracheal stenosis is extremely rare. Neither Tsang et al. [8] nor Farahati et al. [24] reported any RTOG grade IV late toxicity.
Conclusion
Most patients with thyroid cancer have an excellent prognosis; however, as we have discussed within this review, there are a small but significant number with advanced disease in whom prognosis may be very poor. Radiotherapy continues to have a role in the improvement of local control and palliation. There are, however, no effective chemotherapeutic agents for any of the histologies of advanced thyroid cancer; therefore, the development of novel therapies, such as biological modifiers or new chemotherapy agents, are needed. These patients could be incorporated into phase I and II studies. Acknowledgements. The authors wish to thank Laura Nash for her assistance in the preparation of this manuscript and Bruna Ariganello for artwork production. References 1 van den Brekel MW, Hekkenberg RJ, Asa SL, Tomlinson G, Rosen IB, Freeman JL. Prognostic features in tall cell papillary carcinoma and insular thyroid carcinoma. Laryngoscope 1997;107:254–259. 2 Sobin LH, Wittekind C, eds. TNM classification of malignant tumours. 6th edn. John Wiley and Sons, New York, 2002. 3 British Thyroid Association. Guidelines for the management of thyroid cancer in adults. London, UK: Royal College of Physicians, 2002: 1–70. 4 Vini L, Harmer C. Radioiodine treatment for differentiated thyroid cancer [comment]. Clin Oncol 2000;12:365–372. 5 Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:418–428. 6 Vassilopoulou-Sellin R, Goepfert H, Raney B, Schultz PN. Differentiated thyroid cancer in children and adolescents: clinical outcome and mortality after long-term follow-up. Head Neck 1998;20:549–555. 7 Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993;114: 1050–1057; discussion 1057–1058. 8 Tsang RW, Brierley JD, Simpson WJ, Panzarella T, Gospodarowicz MK, Sutcliffe SB. The effects of surgery, radioiodine and external radiation therapy on the clinical outcome of patients with differentiated thyroid cancer. Cancer 1998;82:375–388. 9 Sheline GE, A’Hern RP, Galante M, Lindsay S. Radiation therapy in the control of persistent thyroid cancer. Am J Roentgenol Radium Ther Nucl Med 1966;97:923–930. 10 Simpson WJ, McKinney SE, Carruthers JS, Gospodarowicz MK, Sutcliffe SB, Panzarella T. Papillary and follicular thyroid cancer. Am J Med 1987;83:479–488. 11 Simpson WJ, Panzarella T, Carruthers JS, Gospodarowicz MK, Sutcliffe SB. Papillary and follicular thyroid cancer: impact of
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56 Orlandi F, Caraci P, Berruti A, et al. Chemotherapy with dacarbazine and 5-fluorouracil in advanced medullary thyroid cancer. Ann Oncol 1994;5:763–765. 57 Schlumberger M, Abdelmoumene N, Delisle MJ, Couette JE. Treatment of advanced medullary thyroid cancer with an alternating combination of 5 FU-streptozocin and 5 FU-dacarbazine. The Groupe d’Etude des Tumeurs a Calcitonine (GETC). Br J Cancer 1995;71: 363–365. 58 di Bartolomeo M, Bajetta E, Buzzoni R, et al. Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group Cancer 1996;77: 402–408. 59 Frank-Raue K, Ziegler R, Raue F. The use of octreotide in the treatment of medullary thyroid carcinoma. Horm Metab Res Suppl 1993;27:44–47. 60 Mahler C, Verhelst J, de Longueville M, Harris A. Long-term treatment of metastatic medullary thyroid carcinoma with the somatostatin analogue octreotide. Clin Endocrinol (Oxf) 1990;33:261–269. 61 Modigliani E, Cohen R, Joannidis S, et al. Results of long-term continuous subcutaneous octreotide administration in 14 patients with medullary thyroid carcinoma. Clin Endocrinol (Oxf) 1992;36:183–186. 62 Lupoli G, Cascone E, Arlotta F, et al. Treatment of advanced medullary thyroid carcinoma with a combination of recombinant interferon alpha2b and octreotide. Cancer 1996;78:1114–1118. 63 Behr TM, Sharkey RM, Juweid ME, et al. Phase I/II clinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgG. J Nucl Med 1997;38:858–870. 64 Juweid ME, Hajjar G, Stein R, et al. Initial experience with high-dose radioimmunotherapy of metastatic medullary thyroid cancer using 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen MAb and AHSCR. J Nucl Med 2000;41:93–103. 65 Stein R, Juweid M, Zhang CH, Goldenberg DM. Assessment of combined radioimmunotherapy and chemotherapy for treatment of medullary thyroid cancer. Clin Cancer Res 1999;5:3199s–3206s. 66 Drosten M, Putzer BM. Gene therapeutic approaches for medullary thyroid carcinoma treatment. J Mol Med 2003;81:411–419. 67 Ain KB. Anaplastic thyroid carcinoma: behavior, biology, and therapeutic approaches. Thyroid 1998;8:715–726. 68 Ain KB. Anaplastic thyroid carcinoma: a therapeutic challenge. Semin Surg Oncol 1999;16:64–69. 69 van der Laan BF, Freeman JL, Tsang RW, Asa SL. The association of well-differentiated thyroid carcinoma with insular or anaplastic thyroid carcinoma: evidence for dedifferentiation in tumor progression. Endocr Pathol 1993;4:215–221. 70 Byar DP, Green SB, Dor P, et al. A prognostic index for thyroid carcinoma. A study of the E.O.R.T.C. Thyroid Cancer Cooperative Group Eur J Cancer 1979;15:1033–1041. 71 Junor EJ, Paul J, Reed NS. Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy. Eur J Surg Oncol 1992;18:83–88. 72 Nel CJ, van Heerden JA, Goellner JR, et al. Anaplastic carcinoma of the thyroid: a clinicopathologic study of 82 cases. Mayo Clin Proc 1985;60:51–58. 73 Passler C, Scheuba C, Prager G, et al. Anaplastic (undifferentiated) thyroid carcinoma (ATC). A retrospective analysis Langenbecks Arch Surg 1999;384:284–293. 74 Voutilainen PE, Multanen M, Haapiainen RK, Leppaniemi AK, Sivula AH. Anaplastic thyroid carcinoma survival. World J Surg 1999;23: 975–978; discussion 978–979.
75 Demeter JG, De Jong SA, Lawrence AM, Paloyan E. Anaplastic thyroid carcinoma: risk factors and outcome. Surgery 1991;110: 956–961; discussion 961–953. 76 Nilsson O, Lindeberg J, Zedenius J, et al. Anaplastic giant cell carcinoma of the thyroid gland: treatment and survival over a 25-year period. World J Surg 1998;22:725–730. 77 Tennvall J, Lundell G, Hallquist A, Wahlberg P, Wallin G, Tibblin S. Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic thyroid carcinoma. Report on two protocols. The Swedish Anaplastic Thyroid Cancer Group. Cancer 1994;74: 1348–1354. 78 Tennvall J, Lundell G, Wahlberg P, et al. Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery. Br J Cancer 2002;86:1848–1853. 79 Mitchell G, Huddart R, Harmer C. Phase II evaluation of high dose accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol 1999;50:33–38. 80 Wong CS, Van Dyk J, Simpson WJ. Myelopathy following hyperfractionated accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol 1991;20:3–9. 81 Brierley JD, Tsang RW. External radiation therapy in the treatment of thyroid malignancy. Endocrinol Metab Clin North Am 1996;25: 141–157. 82 Haigh PI, Ituarte PH, Wu HS, et al. Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival. Cancer 2001;91:2335–2342. 83 McIver B, Hay ID, Giuffrida DF, et al. Anaplastic thyroid carcinoma: a 50-year experience at a single institution. Surgery 2001;130: 1028–1034. 84 Lo CY, Lam KY, Wan KY. Anaplastic carcinoma of the thyroid. Am J Surg 1999;177:337–339. 85 Tan RK, Finley 3rd, RK, Driscoll D, Bakamjian V, Hicks Jr., WL, Shedd DP. Anaplastic carcinoma of the thyroid: a 24-year experience. Head Neck 1995;17:41–47; discussion 47–48. 86 Schlumberger M, Parmentier C, Delisle MJ, Couette JE, Droz JP, Sarrazin D. Combination therapy for anaplastic giant cell thyroid carcinoma. Cancer 1991;67:564–566. 87 Ain KB, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. Thyroid 2000;10:587–594. 88 Brierley JD, Tsang RW. External radiation therapy in the treatment of thyroid cancer [review]. Endocrinol Metab Clin North Am 1996;25: 141–157. 89 Harmer C, Bidmead M, Shepherd S, Sharpe A, Vini L. Radiotherapy planning techniques for thyroid cancer. Br J Radiol 1998;71:1069– 1075. 90 Nutting CM, Convery DJ, Cosgrove VP, et al. Improvements in target coverage and reduced spinal cord irradiation using intensity-modulated radiotherapy (IMRT) in patients with carcinoma of the thyroid gland. Radiother Oncol 2001;60:173–180. 91 Kim TH, Yang DS, Jung KY, Kim CY, Choi MS. Value of external irradiation for locally advanced papillary thyroid cancer. Int J Radiat Oncol Biol Phys 2003;55:1006–1012. 92 Kim JH, Leeper RD. Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 1987;60: 2372–2375.
Overview The Management of Advanced Thyroid Cancer P. C. Wilson*, B. M. Millary, J. D. Brierleyy *Department of Clinical Oncology, Bristol Haematology and Oncology Centre, Bristol, UK; yDepartment of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada ABSTRACT: Although the prognosis of the majority of patients with thyroid cancer is excellent there are some patients with advanced thyroid cancer in whom the prognosis is poor. Such patients include: patients with locally invasive or recurrent differentiated thyroid cancer and medullary thyroid cancer, and all patients with anaplastic cancer. The management of patients with advanced thyroid cancer is reviewed with emphasis on the role of external beam radiotherapy. Wilson, P. C. et al. (2004). Clinical Oncology 16, 561–568 Ó 2004 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Thyroid neoplasms, radiotherapy, drug therapy Received: 8 March 2004 Revised: 2 August 2004 Accepted: 9 August 2004
Introduction
The thyroid gland contains two main cell types, follicular epithelial cells and C cells. Follicular epithelial cells give rise to most thyroid cancers, usually grouped into differentiated carcinomas (papillary and follicular) and undifferentiated carcinoma (anaplastic). Within the spectrum from differentiated to undifferentiated, there are also Hu¨rthle-cell tumours and insular carcinoma. Insular carcinoma is a poorly differentiated tumour, probably part of a continuum from differentiated to anaplastic thyroid cancer [1]. Differentiated thyroid cancer has a high cure rate compared with anaplastic thyroid cancer, which has an invariably poor prognosis. Medullary thyroid carcinoma originates from the C cells, and these cancers are, therefore, aetiologically, pathologically and clinically distinct from those arising from the follicular cells. The management of thyroid cancer is primarily influenced by histological type, and for differentiated cancer, age and extent of disease. There is a paucity of randomised phase III studies in thyroid oncology; therefore, the following discussion is based on reports of historically treated, uncontrolled patient populations. Differentiated Thyroid Cancer Definition of Advanced Differentiated Thyroid Cancer
For the purpose of this report, advanced disease is defined as the presence of extrathyroidal extension (T4a and T4b by UICC 6th edition [2]), recurrent disease in the thyroid bed, Author for correspondence: Dr. James Brierley, Department of Radiation Oncology, Princess Margaret Hospital, 610 University Avenue, 5th Floor, Toronto, Ontario, M5G 2M9, Canada. Tel: C1 416 946 2124; Fax: C1 416 946 6566; E-mail: [email protected] (J. D. Brierley). 0936-6555/04/080561C08 $35.00/0
metastatic disease in the lung that does not take up iodine, and bone and other metastases. The current treatment policy of surgical excision followed by radioactive iodine and thyroid stimulating hormone (TSH) suppression, as recommended by the British Thyroid Association and the Royal College of Physicians [3] and described by Vini and Harmer [4], results in cure for most patients with differentiated thyroid cancer. However, there is still a small subgroup of patients whose outcome is poor, and these patients usually have advanced disease at initial diagnosis or at relapse. Although recurrence rates are highest at extremes of age, survival with treatment may be excellent in younger patients [5,6]. Treatment of Advanced Differentiated Thyroid Cancer Locoregional Disease
Ideally, treatment should be a thyroidectomy and the removal of all gross disease followed by adjuvant 131Iodine (131I) therapy. Complete surgical resection is important because survival is adversely affected by gross residual disease (R2 resection) compared with no (R0), or microscopic (R1) residual disease [7,8]. Using the 6th edition of UICC staging classification, all tumours with extrathyroidal extension are no longer classified purely as T4 disease. A distinction is made on the basis of the extent and site of extrathyroid extension. If the tumour has minimal extension to the sternothyroid muscle or perithyroid tissues, it is classified as T3. Tumours that invade the subcutaneous soft tissues, the larynx, trachea, oesophagus or recurrent laryngeal nerve are classified as category T4a (Fig. 1), but, if there is invasion of prevertebral fascia, mediastinal vessels or encasement of the carotid artery, then the tumour is classified as T4b. A T4a tumour may be resected and
Ó 2004 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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Fig. 1 – (A) Computed tomography scan and (B) anatomic diagram of locally advanced thyroid cancer with extrathyroidal extension.
successfully shaved or dissected off the involved structures, but with the assumption of residual microscopic disease. Invasion of the cartilage or intraluminal involvement may require more extensive resection, although ideally, the extent of surgery should be balanced with preservation of function. Gross residual disease after resection of T4b tumours is inevitable. 131I therapy is unlikely to eradicate gross residual tumour unless a high absorbed dose of radiation is achieved. Further radiation in the form of radical external beam radiotherapy (EBRT) may improve local control. Many retrospective series have reported local control of gross disease with EBRT [9–15]. O’Connell et al. [16] reported the Royal Marsden Hospital experience of treating patients with differentiated thyroid cancer with EBRT (60 Gy in 30 daily fractions over 6 weeks). Fortynine patients had gross residual disease: complete response was attained in 37% and partial regression in an additional 25%. In a review of patients at Princess Margaret Hospital between 1958 and 1985, of 33 patients with gross residual
disease, the local relapse-free rate at 5 years was 62%, and the cause-specific survival rate was 65% [8]. In a study from Hong Kong [17], 124 patients with gross locoregional disease after surgery treated with EBRT showed a reduction in the risk of local failure. The use of EBRT is controversial for those patients with microscopic residual disease. All reports on the use of EBRT have been retrospective, with varying criteria for patient selection, resulting in contradictory conclusions. Several studies [18–20] have described either no or a deleterious effect for EBRT, but many others have described benefit [8,10,13,21–26]. One study from Toronto found superior local control and improved survival in patients who received EBRT for microscopic residual disease [8]. This benefit was confirmed in a recent update with longer follow-up (10-year local relapse-free rate 93% compared with 83% for patients not receiving EBRT, P Z 0.01; and cause-specific survival 99% compared with 93%; P Z 0.04) [27]. However, in this and in other studies, not all patients had a total thyroidectomy, adjuvant 131I or TSH suppression, which would now be considered standard therapy. More recent studies [24,25] using ‘standard therapy’ have shown a benefit from additional EBRT in high-risk patients. In one report [24] of 137 patients overall who had undergone a total thyroidectomy, radioactive iodine ablation and TSH suppression, there was an increase in the freedom from locoregional and distant failure in patients over the age of 40 years with extrathyroidal extension and lymph-node involvement in the 85 patients who received EBRT compared with those who did not. EBRT was also a predictive factor for improvement in time to locoregional recurrence (P Z 0.004) and locoregional and distant failure (P Z 0.0003). In the absence of randomised data, we believe there is sufficient evidence from this study and the other retrospective studies (Table 1) to recommend EBRT in addition to standard therapy in high-risk patients. However, the definition of high-risk remains uncertain. The British Thyroid Association and the Royal College of Table 1 – Results of adjuvant external radiotherapy in high-risk disease from retrospective studies: 10-year local recurrence
Tubiana et al. [12] Simpson et al.* [11] Esik et al. [23] Ford et al. [26] Phlips et al. [25] Farahati et al.x [24] Tsang et al.* [8] Kim et al.k[91]
Surgery with and without 131 Iodine (%)
Surgery and radiotherapy with and without 131 Iodine
21 18 52y 63y 21 50z 22 37.5
14 14 11y 18y 3 1%z 7 4.8
*Surgery alone group had local recurrence rate of 74%. yCompares low dose vs higher dose. zLocal and distant failures. xPapillary only. k5-year locoregional relapse rate.
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THE MANAGEMENT OF ADVANCED THYROID CANCER
Physicians guidelines recommend EBRT in patients with gross evidence of local invasion at surgery and significant macro or microscopic residual disease, particularly if there is residual tumour that fails to concentrate 131I and is apparent only by raised thyroglobulin. However, after radioactive iodine, even if there is demonstrated uptake in the neck, it is uncertain whether this uptake is by residual normal thyroid tissue or residual disease. Consequently, at Princess Margaret Hospital, we recommend EBRT, to the thyroid bed alone, after 131I therapy in high-risk patients defined as older (O45–50 years) with potential microscopic residual disease after resection of gross extrathyroid extension (i.e. UICC 6th edition category T4a or T4b but not T3). We will consider EBRT in younger patients if the extrathyroid extension is extensive or if there is gross residual disease after resection (R2 resection). Patients with gross residual disease receive 50 Gy in 20 fractions or its equivalent. The dose may be reduced to 40 Gy in 15 fractions or its equivalent in the presence of microscopic residual disease. If the decision is made to treat a large volume, including the cervical nodes for instance, or if there is extracapsular extension and local invasion of cervical nodes, fractionation is changed to 2 Gy fractions. The radiation techniques are described below. Locoregional Relapse
Little has been published on the management of local regional relapse; however, it should probably be treated in the same way as locally advanced primary disease. The main treatment modality should be surgery, if possible, followed by 131I therapy and TSH suppression. Relapses tend to be in the cervical lymph nodes (regional relapse) rather than in the thyroid bed (local recurrence) [8,28]. Patients with nodal recurrence should have a neck dissection followed by 131I, with a high expectation of tumour control [28]. However, if the tumour burden is low (i.e. nodes ! 2 cm) then radioactive iodine without surgery may be adequate. If there is extracapsular lymph-node involvement with infiltration of the soft tissues of the neck or persistent or recurrent nodal disease despite full neck dissection and 131I, then additional EBRT may be given to maximise the chance of local control [22]. Locally recurrent disease in the thyroid bed is usually more ominous than lymph-node recurrence. This generally occurs in older patients with T4 lesions at initial diagnosis. The probability of the disease at this point concentrating radioiodine may be lower than with cervical nodal recurrence [29]. Despite this, the management at the time of recurrence remains the same: a combination of surgical resection, if possible, followed by routine postoperative 131I and consideration of EBRT.
Distant Metastatic Disease 131
Iodine Uptake
The mainstay of therapy for metastatic disease is radioiodine, but this will only be effective if a total or near total
thyroidectomy has been carried out. Failure to achieve a complete remission from metastatic disease is predicted by the following factors: failure to concentrate 131I, age above 40 years and the presence of bone metastases [30,31]. Brown et al. [32] reported no 10-year survivors in a group of patients with bone metastases treated by 131I, but a 54% 10-year survival in patients with lung metastases. People with bone metastases in general do not respond well to 131I [31,33], and therefore, surgical resection of a solitary lesion may be appropriate [33]. In patients with a solitary metastasis in whom a prolonged survival is expected and surgical excision is not possible, a high dose of EBRT may be a given to maximise the duration of local control. Even patients who present with distant metastatic disease may have a prolonged survival. In one series of 44 such patients, the 20-year survival was 43% [34]. Ideally, treatment should still consist of a total thyroidectomy to resect the primary lesion and also to facilitate the use of 131I therapy. Failure to Take up
131
Iodine Therapy
Little effective therapy is available for patients who have not responded to the above treatments [35]. Single-agent doxorubicin, with a response rate of 25–40%, is the most effective chemotherapeutic agent [36,37]. There is little evidence to suggest that combination chemotherapy is more effective. In a small randomised study (84 evaluable patients), which included all thyroid cancer histologies, no difference was observed in overall response rate when doxorubicin was compared with doxorubicin and cisplatinum [37], although the complete remission rate was higher with the combination. For patients unresponsive to radioiodine, re-differentiation of their tumours with retinoid therapy or combination chemotherapy has been reported to increase uptake of 131I [38], but the therapeutic results have been disappointing [39], as have those reports on the use of lithium carbonate to increase uptake of 131I [40]. Raised Thyroglobulin and Negative 131Iodine Upake Scan
The finding of an elevated thyroglobulin level with a negative radioiodine scan presents a difficult clinical situation. This can represent de-differentiation of the tumour, with reduction or loss of its ability to accumulate iodine. Therefore, detection of residual tumour foci is important to allow for further surgical resection or external beam radiotherapy if appropriate. Further investigation with imaging modalities, such as ultrasound, computed tomography or magnetic resonance imaging, may be helpful but can be difficult to interpret on the background of post-surgical changes. The use of dynamic imaging for this scenario is under investigation. Use of 2-[18F]fluoro-2deoxy-D-glucose positron emission tomography has demonstrated a sensitivity of 70–90% in identifying the source of elevated thyroglobulin [41], increasing sensitivity correlated with thyroglobulin levels [42,43]. The diagnostic value of somatostatin receptor scintigraphy with 111Indiumoctreotide has also been evaluated [44,45]. Further
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investigation and refinement of these non-invasive functional techniques will hopefully allow increased ability to identify residual tumour that may be amenable to surgical resection.
Medullary Thyroid Cancer Definition of Advanced Medullary Thyroid Cancer
Nodal involvement in the neck and superior mediastinum is relatively common at presentation (about 50%), and there may be infiltrative local disease into the soft tissues of the neck. Extensive locoregional disease is not always completely resectable, resulting in postoperative microscopic or macroscopic disease. In some cases, after what was thought to be complete surgical resection and lymph-node dissection, there may be residual disease shown only by high serum calcitonin and carcinoembryonic antigen levels [46,47].
Distant Metastatic Disease
The most frequent sites of metastatic disease are liver, lung and bone. Treatment intent is palliative and includes supportive measures, analgesic drugs and consideration of the potential benefits of chemotherapy, hormonal therapy and local radiation. Chemotherapy is documented to have a response rate of 15–30%. Regimens may include doxorubicin, either as single agent or with cisplatin [37], 5-fluorouracil containing combinations [54–57] and others [15,36]. Hormonal therapy consists of somatostatin analogues (e.g. octreotide), which have been reported to lessen symptoms, reduce calcitonin levels, but generally do not induce tumour shrinkage [58–61]. A higher response rate has been reported with a combination of octreotide and interferon alpha [58,62]. Local radiation can be used for symptomatic bone metastases. Experimental therapies with targeted radiation and monoclonal antibodies conjugated to radionucleotides (e.g. anti-carcinoembryonic antigen, or 111Indium-octreotide, 131I-MIBG) are being studied [63–65] as are gene therapeutic approaches [66].
Treatment of Advanced Medullary Thyroid Cancer Locoregional Disease
The standard management is surgery, comprising a total thyroidectomy and central node dissection if the lymph nodes are thought to be involved. In addition, selective lymph-node dissection might be required if further lymph nodes are thought to be involved [48]. Radioactive iodine has no role in the management of medullary thyroid cancer; however, after surgery for high-risk disease (gross or microscopic residual disease, or extensive regional lymphnode involvement), adjuvant EBRT to the thyroid bed and regional nodal tissue may be considered, in the absence of known distant metastatic disease, to try to reduce the local recurrence rate. Without further treatment, about half of these high-risk patients will experience recurrences in the neck [49]. Radiation doses of 40 Gy in 2 Gy fractions to the neck and upper mediastinum, followed by a 10 Gy boost to the thyroid bed, have been associated with a locoregional control rate of 86% at 10 years [49]. Adjuvant EBRT does not affect overall survival, but locoregional control is important because cervical relapse can have a deleterious effect on the patient’s quality of life. Other investigators have reported similar results [50–52]. Fersht et al. [53] have also reported a trend toward improved local relapsefree rate in high-risk patients (29% local relapse after EBRT but 59% relapse without EBRT; P Z 0.29). Therefore, for patients with high-risk disease, extrathyroid extension or multiple-nodal involvement, with hypercalcitoninemia and no evidence of metastatic disease, radiation should be considered to improve local relapsefree rate. For patients with gross residual disease after surgery, the local control rate after EBRT is as low as 20% [49]; therefore, every attempt should be made to completely extirpate disease surgically. When this is not possible, external radiation may result in long-term local control in a few patients. There is no role for adjuvant chemotherapy.
Anaplastic Thyroid Cancer Definition of Advanced Anaplastic Thyroid Cancer
All patients with anaplastic thyroid cancer (ATC) are considered to have advanced cancer (6th edition UICC T4a or T4b disease [2]), because the prognosis is invariably poor. Some ATC have been found to co-exist with areas of differentiated thyroid carcinoma in the gland, suggesting that the anaplastic component arose from pre-existing differentiated disease (de-differentiation) [67–69]. In the analysis of the EORTC thyroid cancer study group [70], the prognosis of patients with any element of anaplasia within a differentiated thyroid cancer was no different from patients with anaplastic tumour throughout, with a 1-year survival of 10%.
Treatment of Anaplastic Thyroid Cancer Locoregional Disease
Complete surgical resection gives the best chance of cure; however, this is only possible in a few patients [71–74]. Those most amenable to this approach are patients with predominantly differentiated thyroid carcinoma and only a small focus of ATC [74,75], in whom the surgery can be carried out without undue morbidity. Some data suggest occasional long-term survival in patients who have undergone complete resection; however, in many of these patients, the anaplasia is found incidentally as a small focus [72,73]. Radical surgery is not warranted in patients with more extensive invasion of adjacent structures, as it has a significantly negative effect on quality of life and no survival benefit [73]. Unfortunately, most patients with ATC are unresectable at the time of diagnosis. A surgical biopsy may be necessary to confirm the diagnosis, and
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a tracheostomy can alleviate critical upper airway obstruction. ATC does not concentrate 131I, and so radiotherapy is the mainstay treatment for local control and palliation of symptoms to try to maintain quality of life. The ineffectiveness of radiation alone in this disease has led to the development of both novel fractionation schedules and concurrent chemotherapy regimens. Because anaplastic thyroid cancer grows quickly, hyperfractionated and accelerated radiation have been used, sometimes in combination with chemotherapy and surgical resection. The most successful regimen in obtaining local control is that described by the Swedish group [76–78], which involves combined preoperative hyperfractionated radiation and chemotherapy followed by surgical resection. After resection, further radiation and chemotherapy are given. Although only 24% of patients died because of uncontrolled local disease, the 2-year survival was only 9%. Other approaches to intensify radiotherapy have met with limited success owing to increased morbidity of normal tissues [79,80]. Invariably, the median survival is between 3 and 6 months. Patients with good performance status with no evidence of distant metastatic disease may benefit from an aggressive approach with high-dose radiotherapy with or without concurrent chemotherapy or altered fractionation, such as accelerated hyperfractionated radiotherapy, otherwise a palliative approach is warranted [81] (Table 2). Haigh et al. [82] have reported an estimated 5-year survival of 50% in a small highly selected subgroup: eight patients underwent surgical resection with either no residual disease or only microscopic residual disease, and subsequently had combined chemotherapy and radiotherapy. However, the median survival of the group as a whole (33 patients) was only 3.8 months. In contrast, in the large Mayo series of 135 patients [83], multi-modality therapy did not improve survival, although there was a small non-significant improvement in median survival in patients who received radiation compared with those who did not (3 vs 5 months; P Z 0.08). Even if local control is achieved with EBRT, death still occurs from distant metastatic disease [67,71,73–76,80, 84,85]. Chemotherapy for metastatic disease has not been effective [86]. The expected 5-year survival is about 5% with any of the currently available treatment approaches
[71,73–76,84,85]. Although doxorubicin and cisplatin have been the most common drugs used, there have been recent reports of activity of other drugs. Ain et al. [87] reported a response rate of 53% to paclitaxel; however, there remains little evidence that anaplastic carcinoma of the thyroid is chemosensitive. Distant Metastatic Disease
The main goal of treatment is to palliate symptoms, with the expectation of a short survival. Chemotherapy is frequently ineffective [36,37,86,87], and local radiation may be used for pain control. Anaplastic thyroid cancer remains an extremely lethal disease, and innovative approaches are needed, as presently available therapies are seldom effective. External Beam Radiation Therapy
Below is a description of the typical dose and fractionation used at Princess Margaret Hospital and a variety of techniques that have been used to attempt to overcome the difficulties of treating this volume. The thyroid bed volume curves around the vertebral body and includes the air column in the trachea. As it adopts a U-shaped volume, it is challenging to produce a technique that adequately treats the thyroid bed and spares the spinal cord to a dose within tolerance. If the lymph nodes are considered at risk, at least two phases of treatment are required to stay within spinal cord tolerance. A variety of techniques such as direct electrons, and two antero-lateral oblique wedged fields, have been described to overcome the difficulties [8,88,89]. To treat the thyroid bed, a clinical target volume from the hyoid to suprasternal notch is determined. This includes the prevertebral fascia to the anterior aspects of the transverse processes, laterally to mid sternocleidomastoid, encompassing the carotid artery and jugular vein, ensuring adequate coverage of the tracheosophageal groove (Fig. 1). Adjustments of the encompassed volume are made relative to presurgical diagnostic imaging and operative reports. Ideally, presurgical diagnostic imaging would be used as a baseline for definition of the thyroid bed; however, because of concerns of iodine load, with iodinated contrast affecting subsequent management with
Table 2 – Local control and survival after fractionated radiation and concurrent chemotherapy in anaplastic thyroid cancer
Kim and Leeper [92] Schlumberger et al. [86] Tennvall et al. [78] Wong et al. [80] Mitchell et al. [79] Haigh et al. [82] *At 20 months. yNot stated.
Patients
Local control (%)
Median survival (months)
2-year survival (%)
Fractionation
Concurrent chemotherapy
19 20 55 32 17 33
68 NSy 60 22 76 NSy
6 NSy 2–4.5 6 2.5 3.8
20 15* 9 18 NSy 20
Hyperfractionated Hypofractionated Hyperfractionated Accelerated/hyperfractionated Accelerated Not stated
Yes Yes Yes Yes No Yes
566 131
CLINICAL ONCOLOGY
I, these are not routinely performed. The simplest technique that is commonly used at Princess Margaret Hospital takes advantage of the characteristic rapid fall off of direct electron beams and the effect of the neck contour that can produce an acceptable treatment volume with a direct electron field. A planning computed tomography (CT) is essential to ensure appropriate coverage of the planing target volume and to ensure the cord dose remains in tolerance. This is particularly important given the effect of the trachea and column of air on the dose distribution. Mixed energies of 12 MeV and 16 MeV or 16 MeV alone are common energies used. In the absence of gross disease, at Princess Margaret Hospital, 40 Gy in 15 fractions over 3 weeks is prescribed. If gross disease is present, then a higher dose of 50 Gy in 20 fractions over 4 weeks is given [8,81]. An alternative technique is to use two antero-lateral oblique wedged fields, as in larynx cancer [89]. The posterior border is placed to exclude the spinal cord. If it is determined that the clinical target volume should include the cervical and superior mediastinal lymph nodes, as well as the thyroid bed, a two-phase technique is commonly used. The initial volume (phase I) includes the regional lymph nodes from the mastoid tip to the carina, including the thyroid bed. The phase I volume may consist of parallel opposing antero-posterior/postero-anterior fields to 40–46 Gy. The patient is supine with neck extended to avoid the parotid glands and the oral cavity. Shielding for the mandible and lung tissue should be routinely used. It is also important to obtain a sagittal isodose distribution to obtain an accurate spinal cord dose. The aim of phase I is to deliver a dose of 40–46 Gy before starting the off-cord treatment, the dose depending on the phase II technique and the spinal cord dose with phase II. The phase II volume should include the tissues considered at highest risk of relapse, aiming to boost the high-risk area to a total dose of 14 Gy (cumulative total dose of 60 Gy). For the boost to the thyroid bed alone, the technique used can be a direct anterior electron beam as described above, or antero-lateral oblique wedge fields. Another alternative is a lateral pair of angled-down oblique fields, achieved with a couch rotation of 10–20 degrees, aiming inferiorly to avoid the shoulders, off the spinal cord. The main disadvantage of this technique is possible exposure of the parotid glands, due to the higher entrance point of the lateral beams. Since the thyroid bed target volume is U-shaped and it is often necessary to include regional lymph nodes, treatment planning of this difficult volume is ideal for conformal radiotherapy, or intensity-modulated radiation therapy [90]. Currently at Princess Margaret Hospital, a conformal plan is used either to treat the thyroid bed alone or to include the cervical nodes. Typically, this involves five fields, with an anterior field and four post-oblique fields, often with segmentation of these beams. Well-planned EBRT has acceptable acute toxicity, rarely produces serious complications and does not preclude future surgical intervention if required. During the radiation, moderate skin erythema will develop, and with the higher doses of radiation, dry or rarely moist desquamation occurs.
Mucositis of the oesophagus, trachea and larynx can occur towards the end of radiation. Depending on the superior extent of the fields, change of taste and xerostomia may occur, which may be exacerbated in differentiated thyroid cancer by previous radioactive iodine. Late toxicity is infrequent; the most common is skin telangiectasia, increased skin pigmentation, soft tissue fibrosis and mild lymphoedema predominantly in the submental area. Oesophageal and tracheal stenosis is extremely rare. Neither Tsang et al. [8] nor Farahati et al. [24] reported any RTOG grade IV late toxicity.
Conclusion
Most patients with thyroid cancer have an excellent prognosis; however, as we have discussed within this review, there are a small but significant number with advanced disease in whom prognosis may be very poor. Radiotherapy continues to have a role in the improvement of local control and palliation. There are, however, no effective chemotherapeutic agents for any of the histologies of advanced thyroid cancer; therefore, the development of novel therapies, such as biological modifiers or new chemotherapy agents, are needed. These patients could be incorporated into phase I and II studies. Acknowledgements. The authors wish to thank Laura Nash for her assistance in the preparation of this manuscript and Bruna Ariganello for artwork production. References 1 van den Brekel MW, Hekkenberg RJ, Asa SL, Tomlinson G, Rosen IB, Freeman JL. Prognostic features in tall cell papillary carcinoma and insular thyroid carcinoma. Laryngoscope 1997;107:254–259. 2 Sobin LH, Wittekind C, eds. TNM classification of malignant tumours. 6th edn. John Wiley and Sons, New York, 2002. 3 British Thyroid Association. Guidelines for the management of thyroid cancer in adults. London, UK: Royal College of Physicians, 2002: 1–70. 4 Vini L, Harmer C. Radioiodine treatment for differentiated thyroid cancer [comment]. Clin Oncol 2000;12:365–372. 5 Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:418–428. 6 Vassilopoulou-Sellin R, Goepfert H, Raney B, Schultz PN. Differentiated thyroid cancer in children and adolescents: clinical outcome and mortality after long-term follow-up. Head Neck 1998;20:549–555. 7 Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993;114: 1050–1057; discussion 1057–1058. 8 Tsang RW, Brierley JD, Simpson WJ, Panzarella T, Gospodarowicz MK, Sutcliffe SB. The effects of surgery, radioiodine and external radiation therapy on the clinical outcome of patients with differentiated thyroid cancer. Cancer 1998;82:375–388. 9 Sheline GE, A’Hern RP, Galante M, Lindsay S. Radiation therapy in the control of persistent thyroid cancer. Am J Roentgenol Radium Ther Nucl Med 1966;97:923–930. 10 Simpson WJ, McKinney SE, Carruthers JS, Gospodarowicz MK, Sutcliffe SB, Panzarella T. Papillary and follicular thyroid cancer. Am J Med 1987;83:479–488. 11 Simpson WJ, Panzarella T, Carruthers JS, Gospodarowicz MK, Sutcliffe SB. Papillary and follicular thyroid cancer: impact of
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