Indications of external beam radiation therapy in non-anaplastic thyroid cancer and impact of innovative radiation techniques

Critical Reviews in Oncology/Hematology 86 (2013) 52–68

Indications of external beam radiation therapy in non-anaplastic thyroid cancer and impact of innovative radiation techniques夽 X.S. Sun a,b , S.R. Sun c , N. Guevara d , P.Y. Marcy e , I. Peyrottes f , S. Lassalle g , A. Lacout h , J.L. Sadoul i , J. Santini j , D. Benisvy k , A. Lepinoy a , J. Thariat l,∗ a Department of Radiation Oncology, Jean Minjoz University Teaching Hospital, Boulevard Flemming, Besan¸ con, F-25000, France Department of Radiation Oncology, Centre Hospitalier Belfort-Montbéliard, Site du Mittan, 56 rue du Maréchal Juin, 25200 Montbéliard, France c Department of Pathology, Centre Hospitalier Belfort-Montbéliard, 25200 Montbéliard, France d Department of Head and Neck Surgery and Otology, Institut Universitaire de la Face et du Cou – Université Nice Sophia Antipolis, 33 av Valombrose, 06189 Nice, France e Department of Radiology, Centre Antoine Lacassagne, Institut Universitaire de la Face et du Cou – Université Nice Sophia Antipolis, 33 av Valombrose, 06189 Nice, France f Department of Pathology, CAL – Institut Universitaire de la Face et du Cou – Université Nice Sophia Antipolis, 33 av Valombrose, 06189 Nice, France g Department of Pathology, Centre Hospitalier Universitaire, Voie Romaine, 06000 Nice, France h Imaging Centre, 47 rue du Pont Rouge, 15000 Aurillac, France i Department of Endocrinology, Centre Hospitalier Universitaire Archet, 06000 Nice, France Department of Head and Neck Surgery, Institut Universitaire de la Face et du Cou – Université Nice Sophia Antipolis, 33 av Valombrose, 06189 Nice, France k Nuclear Medicine, Centre Lacassagne, Nice, France l Department of Radiation Oncology, Centre Antoine Lacassagne, Institut Universitaire de la Face et du Cou – Université Nice Sophia Antipolis, 33 av Valombrose, 06189 Nice, France b

j

Accepted 25 September 2012

Contents 1. 2. 3.

4.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Differentiated thyroid carcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Surgical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Postoperative radioiodine scanning and ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Postoperative EBRT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Insular carcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Medullary thyroid carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Irradiation technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Target volumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. Dose–effect correlations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.4. IMRT studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations: ATC, anaplastic thyroid carcinoma; BID, bis in die (twice daily-fractionation); DTC, differentiated thyroid carcinoma; PTC, poorly differentiated carcinomas; EBRT, external beam radiation therapy; IHC, immunohistochemistry; IMRT, intensity modulated radiation therapy; MRI, magnetic resonance imaging; MTC, medullary thyroid carcinoma; RAI, radioactive iodine; SEER, surveillance, epidemiology, and end results; WDTC, well differentiated thyroid carcinoma; WHO, World Health Organization. 夽 This work was done during the French diploma of innovative techniques in radiation therapy http://www.diu-radiotherapie.com. ∗ Corresponding author. Tel.: +33 492031269; fax: +33 492031570. E-mail address: [email protected] (J. Thariat). 1040-8428/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2012.09.007

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X.S. Sun et al. / Critical Reviews in Oncology/Hematology 86 (2013) 52–68

53

Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Annex 1. TNM staging for thyroid cancer (7th ed., 2009) [21] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Papillary or follicular (differentiated) thyroid cancer in patients younger than 45 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Papillary or follicular (differentiated) thyroid cancer in patients 45 years and older . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medullary thyroid cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

64 65 65 65 65 66 68

Abstract Background: The mainstay of treatment for differentiated thyroid carcinomas is surgery. There is hardly any room for radiation therapy in differentiated thyroid carcinomas. We aimed to update recommendations for RT in the context of histological variants, increased use of radioiodine and new irradiations techniques. Materials and methods: A search of the French and English literature was performed using thyroid carcinoma, radiation therapy, surgery, variants and radioiodine. Results: Papillary, follicular, Hürthle and medullary carcinomas represent about 80%, 11%, 3% and 4% of all thyroid carcinomas, respectively. Ten-year survival rates for patients with papillary, follicular and Hürthle cell carcinomas are 93%, 85%, and 76%, respectively. The occurrence of criteria such as older age (45 or 60 years-old), massive primary disease, extensive extracapsular spread and macroscopic iodine-negative components inconsistently indicate external beam irradiation (EBRT). The impact of EBRT on poorer-prognosis histological variants is an emerging issue. Noteworthy, the incidence of laryngeal and wound healing complications has been an important limitation to EBRT. However, intensity modulated radiation therapy (IMRT) offers clear dosimetric advantages on tumor coverage and organ sparing such as the larynx, thus reducing late toxicities to less than 5%. Iodine contrast agents should be avoided during 4–6 weeks before radioiodine. PET CT is increasingly used in iodine-negative tumors. Conclusion: There are elective indications for EBRT and IMRT has the potential to improve local control. © 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Differentiated thyroid carcinoma; Radioiodine; Prognostic factors; Histological variants; Papillary; Follicular and Hürthle; Insular; Medullary; Radiation therapy; IMRT

1. Introduction Thyroid cancers represent approximately 1% of all new cancers each year corresponding to 3500 new yearly cases in France responsible for 300 deaths and 80,000 persons undergoing surveillance for that cancer [1]. Thyroid carcinomas arise from either endodermally derived follicular cell to give rise to differentiated thyroid carcinoma (DTC) (including papillary and follicular), and anaplastic carcinomas (ATC) or neuroendocrine-derived calcitonin-producing C cells, which give rise to medullary thyroid carcinomas (MTC). Insular carcinomas are poorly differentiated carcinomas (PTC) of intermediate prognosis between DTC and ATC. Oncocytic (or Hurthle cell-) carcinomas are considered a variant of follicular carcinomas when oncocytic cells make ≥75% of oncocytic cells, or papillary carcinomas when exclusively made of oncocytic cells with typical papillarycarcinoma nuclei (WHO 2004 classification) (Fig. 1). Other exceptional primary thyroid cancers include thyroid lymphomas, sarcomas, and squamous cell or mucoepidermoid carcinomas. Papillary, follicular, medullary carcinomas and ATC represent 80%, 11%, 4% and 1–2% of all thyroid carcinomas, respectively [2,3]. We aimed at updating the recommendations for external beam radiation therapy (EBRT) in non-anaplastic thyroid carcinomas (including DTC, PTC and MTC) based on classical histoclinical characteristics, histological variants/subtypes [4] (Fig. 5a–f) and new imaging and treatment strategies (Fig. 6), including intensity modulated

radiation therapy. The overall management strategy of locoregional disease and the treatment of metastases were beyond the scope of this critical review. The incidence of thyroid malignancies is three times higher in women than in men. It peaks in the third and fourth decades of life. Thyroid carcinomas are staged according to the 7th edition of the AJCC classification (annex 1). Patients with thyroid cancers generally have a favorable prognosis compared with that of patients with many other solid tumors. The 10-year survival rates for patients with papillary, follicular and Hürthle cell carcinomas are 93%, 85%, and 76%, respectively [5]. The contemporary treatment of patients with thyroid malignancy requires a multidisciplinary approach involving an endocrinologist, a surgeon, a pathologist, a radiologist, a nuclear medicine specialist and, on occasion, medical and radiation oncologists. The main stay of treatment is surgery. The management of differentiated thyroid carcinomas involves a combination of surgery, thyroid stimulating hormone suppression, and radioactive iodine (RAI). The role of external beam radiotherapy (EBRT) in the management of differentiated thyroid cancer (DTC) is limited and remains controversial, partly due to a lack of randomized controlled trials. Furthermore, this area of study is hampered by the relatively small number of patients and the long natural history of the disease. Treatment is mostly surgical for the subset of patients with medullary carcinoma. The aim of this review was on one hand, to update data on EBRT use in differentiated thyroid carcinomas, MTC, and

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X.S. Sun et al. / Critical Reviews in Oncology/Hematology 86 (2013) 52–68

Fig. 1. Histological variants and subtypes. Adapted from the WHO Classification 2004 [4,6].

PTC and on the other hand to envision EBRT use in the era of highly conformal irradiation techniques such as intensity modulated radiation therapy (IMRT). 2. Materials and methods A search of the French and English literature from 2000 to 2012 was performed using the following MESH terms: thyroid, carcinoma, follicular, insular, Hürthle, medullary, papillary, surgery, radiation therapy, chemoradiation, radioiodine. 3. Results and discussion 3.1. Differentiated thyroid carcinomas Papillary and follicular carcinomas make up the welldifferentiated thyroid carcinomas. They occur three times more frequently in women than in men. These slow-growing tumors arise from thyroid hormone- and thyroglobulinproducing follicular cells of the thyroid. These cells take up iodine and produce thyroglobulin in response to TSH stimulation. This feature has both diagnostic and therapeutic value for managing residual disease and recurrences after surgical excision. Papillary carcinoma represents approximately 80% of all thyroid carcinomas. Mean age at presentation is 34–40 years.

Cases can occur either alone or in association with some rare diseases like (Gardner syndrome, Cowden disease, etc.). Radiation-induced cancers are identified in subjects irradiated during childhood; this lifelong risk peaks around 20 years after radiation exposure. Association with Hashimoto chronic lymphocytic thyroiditis and Graves–Basedow disease is controversial. On gross pathologic examination, papillary carcinomas are whitish invasive neoplasms with ill-defined margins. Papillary carcinoma may be multicentric, with foci present in both the ipsilateral and contralateral lobes. Tumors can grow directly through the thyroid capsule to invade surrounding structures. Clinically evident lymph node metastases are frequent at presentation. Microscopic metastases are present in one half [1]. The most common site of lymph node involvement is the central compartment (level 6) located medial to the carotid sheaths on both sides, with extension from the hyoid bone superiorly to the sternal notch inferiorly. The jugular lymph node chains (levels II–IV) are the next most common sites of cervical node involvement. Lymph nodes in the posterior triangle of the neck (level 5) may also develop metastases. Papillary carcinoma has several variants, including follicular, macrofollicular, cribriform, diffuse sclerosing or solid – trabecular/solid forms and cytologic variants such as tall cell, columnar, oncocytic (oxyphil cells or Hürthle cells or eosinophilic cells), clear cells, fusiform cells, giant cells, hobnail cells, fasciitis-like stroma, and Warthin-like variants [6]. The diffuse sclerosing and tall cell variants are

X.S. Sun et al. / Critical Reviews in Oncology/Hematology 86 (2013) 52–68

considered aggressive subtypes of papillary thyroid cancer [7] as is the columnar variant in the elderly. A SEER database (1988–2008) revealed a 61% increase in classic papillary carcinoma incidence, compared to 126% and 158% in diffuse sclerosing and tall cell variants, respectively [7]. These two aggressive variants were associated with higher rates of extrathyroidal extension, multifocality, and nodal and distant metastasis. Nodal metastasis was more likely with diffuse sclerosing (72% vs. 67% tall cell vs. 56% papillary thyroid cancer); distant metastasis was most common with tall cell variants (11% vs. 7% diffuse sclerosing vs. 4% of papillary thyroid carcinomas). These variants were associated with significantly reduced survival (5-year overall: 88% diffuse sclerosing, 81% tall cell vs. 94% classic papillary carcinoma) [7]. Follicular carcinoma represents about 10% of thyroid cancers. It is associated with low dietary intake or retention of iodine. Mean age at diagnosis is between the fourth to sixth decades. On gross pathology, the tumors appear as round, encapsulated, light brown neoplasms with fibrosis, hemorrhage and cystic changes. Under microscopy, neoplastic follicular cells have a solid, trabecular, or follicular growth pattern. The tumors are divided into minimally and widely invasive lesions depending on capsule and vascular invasion. Local thyroid capsule invasion can occur. Unlike papillary carcinoma, cervical metastases from follicular carcinomas are uncommon. However, the rate of distant metastasis (lung, bone) is significantly increased (20%). Follicular carcinoma has two variants, namely the oncocytic cell or clear cell types. The long-term disease-free survival with aggressive management is 90% overall. Prognostic factors include age (recurrences are more common <20 and >60 years, worse >60), gender, size (>4 cm) and extra-thyroidal invasion of surrounding tissues. Overall, papillary and follicular carcinoma is associated with a 30-year cancer-related death rate of 6% and 15%, respectively. Poorer outcomes have been associated with age [8–10], gender [11], tumor size, grade, extrathyroidal extension (from minimal invasion of peri-thyroidal fat to invasion of the prevertebral fascia; T3 or T4) [12–19], lymph node metastases and type of surgery, tumor size, extent of postsurgical residual disease (R1/2), local recurrence, which might indicate irradiation. BRAF V600E mutation, identified in up to 50% of papillary thyroid carcinoma, has been shown to define subsets of patients carrying higher rates of recurrence and tumorrelated mortality. RET rearrangements and BRAF mutations are mutually exclusive in papillary carcinogenesis, although they may cooperate during tumorigenesis in medullary carcinomas. 3.1.1. Surgical treatment The mainstay of treatment for DTC is surgery [20] (if the disease is resectable according to TNM classification, annex 1 [21]). The extent of surgical therapy (extent of thyroidectomy and neck dissection) for well-differentiated neoplasms is controversial [22] but is out of the scope of this review.

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Briefly, over the years, modifications to total thyroidectomy have been proposed in an effort to reduce recurrent laryngeal nerve injury and hypoparathyroidism associated with total thyroidectomy [22]. However, a SEER study of over 20,000 subjects showed that the 10-year overall and cause-specific survivals were improved with total thyroidectomy over other techniques (local excision, lobectomy, near-total thyroidectomy). Patients with diffuse sclerosing (72% vs. 56%) and tall cell variants may benefit from more aggressive treatment including thyroidectomy and radioiodine, regardless of tumor size [7]. 3.1.2. Postoperative radioiodine scanning and ablation After thyroidectomy, radioiodine scanning and ablation has become a standard for diagnosing and treating residual thyroid tissue, or regional and distant metastases from well-differentiated thyroid carcinomas. It is increasingly prescribed for lesions ≥1 cm [23,24]. FDG-PET/CT may be useful in post-thyroidectomy patients who present with increasing thyroglobulin levels and a negative 131 I whole-body scan [24]. It is also useful in the initial (post thyroidectomy) staging of high-risk patients with less differentiated (and thus less iodine-avid and clinically more aggressive) subtypes, such as tall cell and Hürthle cell variants, and in poorly differentiated carcinomas [24]. 3.1.3. Postoperative EBRT The role of irradiation has been studied in many retrospective studies [25–35] (Table 1 ) and remains controversial [36–40]. A subset of patients at high risk for local recurrence may curatively benefit from adjuvant EBRT [41]. The difficulty in determining the optimal management is the lack of randomized control trials and the reliance on single institution prospective databases and retrospective reviews, complicated by changes in pathology assessment, surgical and radiation therapy techniques over time. However, a topic of controversy remains on the extent of extrathyroidal extension. A retrospective study from Princess Margaret Hospital in Canada showed that patients >60 years with extrathyroidal extension and no gross residual disease after surgery had improved 10-year cause-specific survival (81.0% vs. 64.6%) and local relapse-free rates (86.4% vs. 65.7%) with adjuvant EBRT [9]. Patients under 60 years had improved local control only. Also, some authors suggest that patients with minimal extrathyroidal extension (T3) benefit from irradiation with regards to locoregional failure in patients over 60 years [39] but such criteria are not clearly mentioned in international recommendations (Fig. 2). In Sia’s study [39] there was a significant benefit on local control in patients over 45 years with T3 disease treated with irradiation at 5 years (96.8% vs. 90%, p = 0.03) although, in this subgroup, there was a trend toward more use of RAI in patients who also had EBRT. There was also a benefit in those over 60 years (96% vs. 87.5%, p = 0.02), with no difference in the use of RAI. There was no benefit with irradiation in T3 patients less than 45 years [39]. The other factors associated

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Table 1 Review of the literature for the role of radiation therapy in differentiated thyroid carcinomas. Year

Median follow up (year)

N Pts

Period

131 I

Tubiana [25]

1985

8

539

1943–1976

+/−

Simpson [70]

1988

4–24

1578

NA

131 I:

Tsang [14]

1998

10.8

382

1958–1985

Chow [71]

2002

9.2

842®

Kim [31]

2003

4.6

Brierley [9]

2005

11.3

(Pts)

Radiation therapy (Pts)

EBRT modalities

Median dose (Gy); dose (Gy)/F

Benefit from EBRT

Survical %

336: woRT (including 61 131 I-) 180 w/RT (66 R0 or N1 and Ro, 97 R2, 17 non operable) NA

Conv.

25–30 (<1956); 50 (≥1956) + boost 5–10 if R2

Local relapse: w/o RT (70/336) = 21% RT (25/180) = 14% p < 0.05

5-year R0 = 94% 5-year R2 = 78%

Conv.

NA

131 I:

215 RT: 185

w/RT: 185 w/o RT: 197 pap. and R1: 155

Conv.

45 (5–65) 2.25/F ≥50 (if R2)

1960–1997

620 repeat 131 I until no uptake following surgery

w/RT: 105 w/o RT: 737 w/R2: 124 (RT: 69, woRT: 55)

Conv.

54.6 ± 9.7 (mean dose)

91

1981–1997

+/−

91 pap. T4 or N1 23 (R1/R2 or N1) w/RT, 68 131 I alone

Conv.

61.2 (50–70) 1.8–2/F

729

1958–1998

+/−

w/RT: 318, w/o RT: 411 (including 70/729: >60 y w/T4 w/o R2)

NA

NA

Control for large tumors by RT or 131 I: CR = 15/42 (36%) PR = 18/42 (43%) 10-year CSS and LRFR: RT vs. w/o RT = 93% and 91% vs. 90% (p = 0.38), and 82% (p = 0.14) Among 155 pap. and R1 10-year CSS and LRFR: RT vs. w/o RT = 100% and 93% vs. 95% (p = 0.04) and 78% (p = 0.01) 124 w/R2: (LRR and 10-year LRC) RT vs. wo RT = 36.2% and 56.2% vs. 70.9% and 24% (p = 0.002) 7-year OS: RT vs. w/o RT: 90% vs. 98%, p = 0.5 LRCR 5-year: 95% vs. 68% (p = 0.04) 70 Pts (47 w/RT vs. 23 w/o RT): >60 y w/T4 w/o R2: 10-year CSS, LRFR = 81%, 86% vs. 65% (p = 0.04), 66% (p = 0.01)

214 RT: 201 131 I and RT: 107

10-year CSS and OS Pap: 93% and 85% Foll.: 69% and 56% RT No survival benefit for follicular tumors

10-year CSS: stage I, 99.8% stage II, 91.8% stage III, 77.4% stage IV, 37.1%

10-year CSS, and LRFR: 87%, and 85%

X.S. Sun et al. / Critical Reviews in Oncology/Hematology 86 (2013) 52–68

Author

Table 1 (Continued) Year

Median follow up (year)

Meadows [33]

2006

4.1

Keum [32]

2006

NA

Schwartz [10]

2009

3.2

Period

131 I

(Pts)

Radiation therapy (Pts)

EBRT modalities

Median dose (Gy); dose (Gy)/F

Benefit from EBRT

Survical %

42

1962–2003

Surg + RT: 22 Surg + 131 I: 14 RT alone: 5 RT + 131 I: 1

Conv. or IMRT

64.9 1.8–2/F

5-year LRC: R2 vs. R1 = 70% vs. 100% (p = 0.0177)

5-year LRC, CSS and OS: 88%, 80% and 54%

68®

1986–1997

25 w/RT (24 no uptake 131 I, 1 prior 131 I) 43 w/o RT (13 w/131 I)

Stage IVa = 12, Stage IVb = 10 Recurrence = 20 (R1 = 22, R2 = 20, M1 = 9) 68 (12 R0, 43 R1, 13 R2) (a) 25 w/RT (24 T4a, 1 T4b) (b) 43 w/o RT (43 T4a) Stage III = 2, Stage IVa–c = 128 NA = 1 ETDS = 126 (R1 = 62, R2 = 15)

NA

50–63

LRR and 10-year LPFS: w/RT vs. w/o RT = 8% and 89% vs. 51% (p < 0.01) and 38% (p < 0.01)

10-year OS: (a) 63% vs. (b) 79% p = 0.98

3D or IMRT

74 Pts (3D): 60 (38–72) or 57 Pts (IMRT): 60 (56–66)

4-year LRFS, DSS, OS = 79%, 76%, 73% SLM: IMRT vs. 3D: 2% vs. 12% Survival: IMRT = 3D 5-year CSS and LRCR: 76% and 81% 5-year LRCR: R0-1 vs. R2 and non operable: 89% vs. 69% (p = 0.03) 5-year RFS: w/RT vs. w/o RT: 100% vs. 94% (3% relapse w/o RT) R2 w/RT: 10-year CSS and LRFR = 48% and 90% R0-1 w/RT: 10-year CSS and LRFR = 92% and 93% Pts > 60y w/T3 w/o R2: 5 year LRFR: w/RT vs. w/o RT = 96% vs. 87.5% (p = 0.02) 5-year LCR: LF vs. EF= 40% vs. 89% (p = 0.04), no difference on toxicity

N Pts

131

1996–2005

107 (82%) prior to RT, 12 (9%) 131 I after RT 131 I

Azrif [65]

2008

5.4

49

1990–2000

8 weeks after Prior 131 I

29 = R0-1, 19 = R2 (8 only biopsy) 1 NA margins

Conv.

40–50/16 F (2.5–3.125/F)

Biermann [72]

2009

2.6

351

2000–2003

351 Pts: 131 I until no uptake: RT

47 w/pT4 ± N1 w/RT: 26/351 w/o RT: 325/351

3D

Sia [39]

2010

10.8

323

1958–1999

w/131 I: 258 w/o 131 I: 65

T3: 169 T4a: 91, T4b: 58 w/RT: 208 w/o RT: 115 w/R2: 40

NA

R0: 59.4, 1.8/F R1: 66.6, 1.8/F pN0: 50.4, 1.8/F pN1: 54, 1.8/F NA

Kim [64]

2010

3.3

23

2004–2008

NA

23 w/T4 or N1 (11 RT w/LF or 12 EF)

3D

LF: 62.5 (62.5–67.7) EF: 62.5: 50 + 12.5 boost (60–69)

10-year CSS and LRFR: 85.4% and 92% Pts > 45 y w/T3 5-year LRFR: w/RT vs. w/o RT = 96.8% vs. 90% (p = 0.03)

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Author

19 Pts (83%) alive 5-year OS, DFS, LCR = 75%, 57%, 61% 57

+/− 1970–1986 932 1990 Benker [74]

NA

+/− 1977–1994 699 1997 Lin [73]

NA

NA NA 6 NA 2001 Nutting [68]

EBRT = RT, external beam radiation therapy; LCR, local control rate; LRR, locoregional recurrence rate; LRFR, locoregional relapse-free rate; LRFS, locoregional relapse free survival; LPFS, local progression free survival; OS, overall survival; DSS, disease specific survival; CSS, cause-specific survival; LRC(R), locoregional control (rate); LPFR, local progression-free rate; SLM, severe late morbidity; ETDS, extra-thyroidal disease spread; RFS, recurrence-free survival; Surg., surgery; NA, not accessible; CR, complete response; PR, partial response, ® Pap., papillary; Foll., follicular; R0, microscopic no residual disease; R1, microscopic residual disease; R2, gross residual disease; LF, limited field; EF, elective field; RRT, radical radiotherapy; PRT, palliative radiotherapy; Conv., conventional radiation therapy; 3D, tridimensional radiation therapy; IMRT, intensity modulated radiotherapy; F, fraction; w/, with; w/o, without; y, year; vs., versus; gy, gray.

No survival benefit (a benefit limited to older Pts >40 y w/T3/T4, p < 0.09) Mostly 40–60 Conv.

w/RT: 72 (stages 2–3: 32) w/o RT: (stages 2–3: 172) w/RT: 346 (T1: 18; T2: 187; T3/T4: 141) w/o RT: 586

Conv.

Mostly 60 2/f

IMRT improves PTV coverage and decreases spinal cord dose No survival benefit 46–60 2/f IMRT Conv. vs. 3D vs. IMRT

Benefit from EBRT Median dose (Gy); dose (Gy)/F EBRT modalities Year Author

Table 1 (Continued)

Median follow up (year)

N Pts

Period

131 I

(Pts)

Radiation therapy (Pts)

Dosimetric study

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Survical %

58

Differentiated thyroid carcinoma (papillary, follicular)

T4 (massive extrathyroidal disease)

Extensive extranodal spread (N+ECNS+) If age > 60 yo*

R1/2

R2 or unresectable

Radioiodine negative

Radioiodine positive and age > 45 yo

EBRT (IMRT recommended)

Fig. 2. Consensual indications of radiotherapy among all International Recommendations. NB, non consensual strategies not shown on figure. Noteworthy, variants are taken into account although then NCCN suggest that Hürthle cell carcinoma may benefit from EBRT in case of R2 and/or T4 disease even if radioiodine positive. See proposal for a scoring system to be validated (Table 3). R1, microscopic residual disease; R2, gross residual disease; N, lymph node; ECNS, extracapsular nodal spread. *According to British recommendations.

with improved cause-specific survival were postoperative status (no residual disease) and papillary histology. Tumor size (1 cm and 1–4 cm) and postoperative status (no residual disease) were associated with improved local relapse-free rates [39]. In 40 patients with postoperative gross residual disease undergoing radiotherapy, 10-year cause-specific survivals and local relapse-free rates were 48% and 90%, respectively (vs. 85.4% and 91.7% in the whole population). Thus, even if disease is controlled in the neck, there is a high risk of death from distant metastatic disease. The American Thyroid Association guidelines recommend irradiation in patients over age of 45 with grossly visible extra-thyroidal extension (T4a and T4b) at the time of surgery and a high likelihood of microscopic residual disease [42–44]. Irradiation is also indicated for unresectable/gross residual carcinomas and/or for lesions that do not exhibit radioiodine uptake (NCCN v3.2011). Anyway, the potential benefit needs to be balanced against the generally excellent outcomes with surgery and radioactive iodine as well as the expected side-effects of radiotherapy, although these ones may be reduced with modern radiation techniques. Another key issue is whether an improvement in local control only is sufficient to indicate irradiation, given the fact that local relapses may be salvaged with surgery and radioiodine on one hand and that, on the other hand, salvage surgery in irradiated necks is associated with more morbidity. The controversy resides between residual R1 that seem to benefit from EBRT and R2 that might not benefit in several retrospective studies. Patients with previously untreated tumors and those receiving ≥64 Gy may also have better outcomes with irradiation [33]. Extra-glandular disease spread was seen in 126 patients (96%), microscopically positive

X.S. Sun et al. / Critical Reviews in Oncology/Hematology 86 (2013) 52–68

surgical margins were seen in 62 patients (47%), and gross residual disease was seen in 15 patients (11%) [10]. EBRT provided durable locoregional disease control for patients with high-risk differentiated thyroid cancer but this was more evident in patients with microscopic burden than in those with gross disease [10]. The British Thyroid Association recommends irradiation in patients over 60 years of age with “extensive extranodal spread after optimal surgery, even in the absence of evident residual disease” (http://www.british-thyroid-association. org/guidelines/). This factor (aggressive nodes) is only found in the British guidelines. It should be noted that extracapsular nodal spread does not imply the same poor prognosis as in squamous cell carcinomas of the head and neck. The ambiguity here relies on the term “extensive”, which may imply extension to adjacent muscles or trachea, which for the British should indicate irradiation although for in other guidelines, this rather indicates radical nodal surgery followed by radioiodine. When surgical excision of recurrent disease is not feasible, external-beam radiation therapy may also be useful. In such situations, chemotherapy, usually with doxorubicin, yields response rates of 35–40% and molecular therapies, especially those targeting key tyrosine kinases and/or inhibiting angiogenesis [19], are still investigational. The lack of radioiodine fixation is also associated with worse prognosis. Fewer Hürthle cell carcinomas concentrated 131 I than do papillary or follicular carcinomas. In a series of 101 patients with distant metastases, 131 I uptake by pulmonary metastases was seen in more than 50% of the follicular (64%) and papillary (60%) carcinoma but in only 36% of Hürthle cell carcinomas [45]. Tall-cell papillary variants, which have a 10-year mortality of up to 25%; columnar variant papillary carcinoma (a rapidly growing tumor with a high mortality rate); and diffuse sclerosing variants, which infiltrate the entire gland. Interestingly, another much less described prognostic factor here was the presence of high-risk histologic features (26% of patients) [10]. In particular, Hurthle carcinoma has a 5-year survival rate of 50–60% and patients are at high risk for recurrent and metastatic disease. Because tumors do not take up iodine well and are less TSH sensitive, they are not amenable to thyroid suppression and radioiodine therapy. Mills et al. suggest that, despite these characteristics, there do not seem to be a role for adjuvant irradiation in Hurthle carcinomas [46] in the absence of other classical recognized poor prognosis factors as those described above for differentiated thyroid carcinomas. Schwartz et al. suggest that tall cell, Hurthle, clear cell variants and poorly differentiated undergo irradiation [10]. Conversely, in Kazaure’s study, patients with these aggressive variants who received EBRT did not experience improved survival [7]. A summary of consensual indications of radiotherapy based on International Recommendations is provided in Fig. 2. The importance of the variants of well differentiated thyroid carcinomas might be worth being better accounted for in

59

international recommendations. We below propose a scoring system, that is currently being tested in a retrospective study (Table 2). 3.2. Insular carcinomas Insular thyroid carcinomas are synonyms of poorly differentiated thyroid carcinomas that represents about 3% of thyroid carcinomas [47]. In Lam’s and Kazaure’s studies, patients with insular carcinoma were younger and had smaller tumors (median size 5 cm) than ATC [47,48]. This poorly differentiated thyroid carcinoma is of follicular origin. It is relatively little described in the literature and its incidence is largely unknown because it is either described as poorly differentiated or more rarely insular carcinoma. Its prognosis is indeed intermediate between that of differentiated thyroid carcinomas and ATC [47]. Insular histology is associated independently with compromised survival (hazard ratio [HR], 2.1) compared with well differentiated carcinomas [48]. Its mortality rate was 7.1%, 12%, and 54.3% for patients with localized, regional, and distant stage, respectively [48]. The 5-year disease-specific survival rates are of 72.6%, 97.2%, and 9.1% for patients with insular, well differentiated carcinomas, and ATC, respectively [48]. In Lam’s 2000 study, five- and 10-year survivals were 46% and 42% for insular thyroid carcinoma vs. 15% and 3% for ATC with a median follow up of 10 years, which compared to 80% for follicular carcinomas and 92% for papillary carcinomas at 10 years [47]. Although its treatment is not standardized, it is thus usually treated like an aggressive differentiated thyroid carcinoma [47,48] (Table 3). Insular carcinoma can be screened during follow-up by thyroglobulin levels. Treatment should include total thyroidectomy and high-dose radioiodine for all patients and neck dissections for patients with lymph node disease, including those with low-burden/oligometastatic disease [48]. However, the level of radioiodine does not always correlate with radioiodine efficacy. FDG-PET scanning is increasingly indicated in RAI-negative tumors (Fig. 6). There is apparently no room for concurrent adjuvant chemoradiotherapy on the basis of histology by itself. It may be inferred from the literature that histology of poorer prognosis, such as some histological subtypes of well-differentiated carcinomas or insular thyroid carcinomas may, by themselves, justify irradiation. It is questionable whether chemotherapy should be added to irradiation in such cases (Fig. 3). Lai et al. did not observe a survival benefit from RAI or EBRT in their analysis of 82 patients with insular carcinoma [76]. On the basis of expert opinion (Category C recommendation), the American Thyroid Association encourages the use of high-dose RAI (100–200 mCi) for patients with aggressive tumor histology, including the insular subtype. 3.3. Medullary thyroid carcinoma Medullary thyroid carcinoma represents 4% of thyroid carcinomas and is responsible for 13% of thyroid cancer

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Table 2 Proposal for a scoring system (that would have to be validated) including classical prognostic factors and histologies for differentiated thyroid carcinomas (follicular and papillary).

Age (A + B) Gender Resecability Extensive extracapsular nodal spread Extrathyroidal disease R0–R1–R2 Histological variants (tall-cell, Hurthle-cell, columnar, diffuse sclerosing, solid variant?) Recurrent disease (risk of recurrent nerve damage, etc.) Tumors with radioiodine fixation

0 point

1 point

2 points

<45 years-old Female Resectable No

45–60 years-old Male

>60 years-old

4 points

Unresectablea Yes T4 R1

T3 R0 No

R2a

Yes

No

Yes

Yes

No

If the score ≥4, irradiation should be discussed, and if the score ≥6, irradiation should be recommended. This score may be used to account for minor and major prognostic criteria, it is a proposal from the authors but must be further validated. R1, microscopic residual disease; R2, gross residual disease; A, American Thyroid Association guidelines; B, British Thyroid Association guidelines. a Any one. Table 3 Insular (poorly differentiated) carcinoma of the thyroid. Author

Year

No. total Pts

Rodriguez [75]

1998

Lam [47] Lai [76]

2000 2006

Agha [77]

2007

8

Jung [78] Rufini [79] Kazaure [48]

2007 2007 2012

17 33 114

6

22 82 (meta analysis from 23 articles)

Surgery

Chemo.

EBRT

131 I

Survival (%) 5-year [10-year]

Yes (100%)

No

Yes

Yes (100%)

Yes Yes

No ?

Yes Yes

No Yes

Yes (7/8)

No

No

Yes (6/8)

Yes (94%) Yes (100%) Yes (95%)

No Yes No

Yes (18%) Yes Yes (16%)

Yes (77%) Yes (100%) Yes (57%)

2 death (12–140 months) 4 alive (42–140 months) [42%] 5-year and 10-year: 72.2% and 52% 5-year: 79.3% (131 I wo RT) 40% (131 I w/RT) 46.7% RT wo 123 I 1 AWOD 2 AWD 5 dead within 20 months [70%] 72.6% DSS

Chemo., chemotherapy; RT = EBRT, external-beam radiation therapy; DSS, disease-specific survival; w/(wo) RT, with (without) RT; AW(O)D, alive with(without) disease.

deaths [2,49]. About 75% of MTCs occur sporadically and 25% familially. Calcitonin level is used at diagnostic (along with genetic testing) and to identify residual and metastatic disease after thyroidectomy. On gross examination, MTCs are fairly well circumscribed but unencapsulated. Most

Fig. 3. Is there a continuum between WDTC and ATC? Focus on insular thyroid carcinoma.

tumors arise in the middle/upper third of the thyroid lobes. Sporadic tumors are unilateral and inherited forms are often multifocal. MicroMTCs (≤1 cm) also have poor prognostic features, including nodal involvement [50]. MTCs typically have a lobular, trabecular, insular or sheet-like growth pattern (+/− amylosis). Some tumors have a fibrotic character. Immunohistochemical stains for calcitonin and carcinoembryonic antigen are microscopically useful for differentiating MTC from other tumors. Patients whose calcitonin levels remain increased after surgery or those with rising calcitonin levels during follow-up, should benefit from chest CT-scan, bone scintigraphy and MRI in order to define their residual disease. In this setting, FDG-PET/CT is usually disappointing while FDOPA-PET/CT might be more useful [24]. MTCs are treated with total thyroidectomy and lymphatic dissection of the anterior compartment of the neck (central bilateral level VI) and homolateral levels III–IV +/− selective neck dissection (sparing non lymphatic structures

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when possible) of levels II, III, IV, and V when metastases are clinically evident. Lymph node metastases occur in 55–75% of patients [51,52] unlikely with extracapsular spread. If the vasculature of the parathyroid gland is disrupted, autotransplantation of the parathyroid gland is performed. Prognosis is dependent on the quality of initial surgical resection. Ten-year survival is 80%. MTC does not uptake iodine and is thus not treated with radioiodine [53]. External-beam radiation treatment has traditionally played a limited role in the management of MTC. However, EBRT should be considered as a treatment option for patients with locally advanced MTC to optimize locoregional control [54]. In old studies, such as Tubiana’s study on 539 patients including 115 MTC patients, 35 underwent postoperative EBRT based on the presence of gross residual disease, nodal involvement and/or positive margins. There was no difference in survival or disease-free survival between irradiated and non-irradiated patients despite the poorer prognosis of the former. In Fife’s study on 51 irradiated patients between 1960 and 1992, 5-, 10- and 20-year overall survivals were 69%, 52% and 30%, respectively. Five-year local control was 100% for patients without residual disease, 65% for patients with R1 disease and 24% for patients with gross residual disease [55]. However, there may be a benefit of irradiation on local control for stage IVa–c patients at high risk of relapse [56] as suggested by a study from MD Anderson Cancer Center on 34 consecutive patients in whom 5-year disease free survival was 87% and overall survival 56%. Similarly, in a mixed series from MSKCC [57], there were 12 MTC out of 76 thyroid cancer patients at high risk of local relapse and thus irradiated postoperatively. 80% of MTC patients had T4 disease. Four-year local control was 72%. Five patients had unresectable disease and were controlled 18 months following irradiation. Conversely, according to recent SEER analyses [40,58], main prognostic factors were age and tumor size and there was no benefit of irradiation on survival for patients with nodal metastases. Finally, recommendations suggest adjuvant EBRT for patients with massive extra-thyroidal involvement (T4a–b) and R1 disease, or following resection of bulky central and cervical nodes with extra-capsular spread (NCCN v3.2011); [44,59] (Fig. 4). In any case, it should be ascertained that optimal surgery has been performed before considering EBRT. Indeed, complementary surgery, as for lymph nodes, will carry over much more morbidity after EBRT; and this later might hamper any further surgical procedure, in case of local recurrence. Moreover, it should be emphasized that EBRT although it may control local persistent/recurrent disease, will not counteract distant metastases which eventually would carry a specific morbidity and mortality. Therefore, it may be worth setting up studies to assess the impact of adjuvant EBRT in CMT patients for whom despite the experience of the surgeon the probability of a complete resection is high (R2, R1, extensive lymph node involvement) and there is no clues for distant metastases.

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Fig. 4. The management of medullary thyroid cancer recommended by NCCN v3.2011. Irradiation should be recommended with IMRT.

3.4. Irradiation EBRT for thyroid carcinoma represents a significant technical challenge as the target volume lies close to or surrounds the spinal cord [60]. With improvements in radiation techniques, adequate dose can be effectively delivered to the region at risk while minimizing dose to surrounding critical structures [44,54,61,62]. Technological improvements may thus change the indications of (modern) EBRT for thyroid cancer in the near future but we are only at the dawn of that change and the level of evidence is still too low to propose a therapeutic switch. 3.4.1. Irradiation technique Irradiation technique and prescription dose can vary widely among centres. Tri-dimensional/conformational EBRT had supplanted conventional bi-dimensional EBRT and is being replaced by IMRT (ICRU 83). Most old series used two large opposite antero-posterior fields, including bilateral cervical and superior mediastinal nodal areas [63]. Doses were limited to 50 Gy because of the spinal cord, +/− a 10–15 Gy boost using two oblique anterior fields. 3.4.2. Target volumes Target volumes vary among physicians and institutions. An important reason for the reluctance to perform irradiation in thyroid cancer (except form anaplastic cancer) is based on its toxicities and excess morbidity of salvage surgery in irradiated tissues. With this in mind, it may be of interest to adapt radiation fields and deliver focused irradiation on areas at high risk of local relapse as defined by the surgeon. Kim et al. recently reported a series of 23 patients with locally advanced or recurrent locoregional thyroid carcinoma [64]. Two target volumes strategies were compared: limited-fields in 11

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Fig. 5. (a–f) Variants and patterns of aggressiveness. (a) Largely invasive oncocytic follicular carcinoma. HES 100×. (b) Follicular carcinoma, vascular infiltration. HES 200×. (c) Papillary carcinoma follicular variant lymph node metastasis. HES 400×. (d) Papillary carcinoma. Extracapsular infiltration. HES 100×. (e) Insular carcinoma. (f) Medullary thyroid carcinoma.

patients only included the operative bed or gross relapse and metastatic nodes or elective-fields in 12 patients including the operative bed or gross relapse and cervical and superior mediastinal nodal areas. The limited-field group received 62.5 Gy on primary and nodes vs. 50 Gy in the elective-fields group on primary bed, negative cervical and mediastinal nodes and a 12.5 Gy boost on positive nodes and gross primary tumor in 1.8–2 Gy fractions. Six patients (55%) had a locoregional relapse in the limited-field group and three (27%) with metastases vs. one patient (8%) experiencing a locoregional relapse and 1 patient (8%) metastases in the elective-field group. Five-year locoregional control was significantly improved in the elective-field group (89% vs. 40%, p = 0.041). There were no significant differences in severe acute toxicities. The

limited-field and elective-field groups were comparable in terms of techniques (3DRT or IMRT). There was no significant difference on 5-year overall and disease-free survival. Azrif reported similar observations on a series of 49 differentiated thyroid carcinoma patients with median follow-up of 5 years [48]. Four patients having mediastinal relapse had been irradiated using two non-coplanar lateral fields, with insufficient coverage of level VII. Delineation guidelines [65] are of great help for radiation oncologists. Azrif et al. recommended to target volumes that encompass the thyroid bed and regional neck nodes and the superior mediastinum level VII excluding the lymph nodes on both sides of the trachea within the anterior and posterior mediastinum extending from the brachiocephalic veins to the carina

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Fig. 6. Radioiodine-negative insular carcinoma with positive FDG PET CT in a 75 years old male.

(compartment 4) with the aim to facilitate dose escalation to improve loco-regional control and avoiding radiation induced mediastinal toxicity. Image guided radiation therapy might also help to adapt/reduce dose volumes but this remains to be validated.

3.4.3. Dose–effect correlations Tubiana published a series of 539 patients including 180 patients receiving adjuvant EBRT in 1985 [25]. Before 1956, the tumor dose was 25–30 Gy in 3 weeks. Later, dose was increased to 50 Gy with a 5–10 Gy boost. There was a

Fig. 7. 3D irradiation (left), 7-field IMRT (right), see better laryngeal and esophageal sparing with improvement of 66 Gy-neck target volume.

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significant reduction of local relapse rates in patients undergoing irradiation (25/180, 14%) vs. no irradiation (70/336, 21%). Moreover, there was a significant difference between the number of relapses in irradiation fields in patients receiving ≥50–54 Gy and in patients undergoing X-ray irradiation or radium, suggesting a role of dose in local control [66]. Finally, doses are about 50 Gy (≈56 Gy using simultaneous integrated boost (SIB)) for completely resected disease and yield 66–70 Gy for gross disease and massive extracapsular spread either using conventional fractionation or SIB. 3.4.4. IMRT studies The thyroid gland lies anteriorly in the low neck and has multiple bilateral lymphatic cervical and mediastinal drainages, which constitute potential target volumes around organs at risk namely the larynx, esophagus, salivary glands, spinal cord, trachea and lungs, limiting dose escalation when using conventional irradiation techniques [67]. IMRT improved planning target volumes (PTV) coverage and reduced the spinal cord dose [68]. A simultaneous integrated boost technique with five equispaced fields produced the best dose distribution. IMRT should reduce the risk of myelopathy or may allow dose escalation in patients with thyroid cancer. Recent advances of conformational irradiation, namely IMRT, allow better delivery of high dose irradiation in microscopic and macroscopic disease volumes while avoiding unwanted toxicity. Such advantages have previously been shown in nasopharyngeal cancers [44]. Although IMRT in thyroid carcinomas has not been formerly assessed in randomized trials, it is increasingly being used for the above-mentioned advantages and based on dosimetric studies [68]. IMRT has been used at MD Anderson Cancer Center in patients with stage 3–4 differentiated thyroid carcinomas. Patients had either 3DRT or IMRT with a median dose of 60 Gy. Although IMRT did not impact on survival outcomes in Schwartz’s retrospective study (non randomized), it was associated with less frequent severe late morbidity (12% vs. 2%). Decreased toxicities with new techniques have also been shown in several other studies; Schwartz et al. [10]. A pilot study from the Memorial Sloan-Kettering Cancer Center on 20 patients with differentiated or medullary carcinoma exposed by IMRT to 63 Gy (54–70 Gy) showed after 2 years, two local failures and a local relapse-free survival of 85% [10,61]. Six patients have died, yielding a 2-year survival rate of 60%. Acute toxicities were deemed acceptable (grade 3 mucositis: 7 patients; grade 3 pharyngitis: 3 patients; grade 3 dermatitis: 2 patients; grade 3 laryngitis: 2 patients; no grade 4 toxicity). IMRT has become a standard in thyroid carcinomas and the following recommendations may be made [10,61]: low-risk clinical target volume (CTV): 54 Gy including primary and nodal micrometastatic disease (bilateral levels II–VII), intermediate risk CTV: 59.4–63 Gy including primary tumor bed and the whole thyroid as well as level VI nodes, and a high risk CTV for microscopically (R1): 63–66 Gy or macroscopically positive margins or unresectable disease (R2): 63–70 Gy.

Very few studies have provided accurate data on toxicities. However, recent comparative studies of 3D vs. IMRT showed that IMRT reduces the risk of late toxicities: Acute grade 3+ toxicity rates are about 8–25%, 9–35%, 4%, 10–32% and 10% for cutaneous, mucosal, salivary, esophageal (dysphagia) and laryngeal (edema, hoarseness) toxicities, respectively [10,57,61,62,64,69]. Late toxicities have hardly been reported with IMRT compared to almost 10% (mostly dysphagia, esophageal stricture) with conventional irradiation [10,57,62]. Based on dosimetric advantages and lower late toxicities, IMRT should become a standard for thyroid carcinomas (Fig. 7). 4. Conclusion The mainstay of treatment of differentiated carcinomas is surgery (+/− radioiodine, with de-escalation at stake for early stages at the moment). Radiation therapy has a role in selected patients who are at high-risk for local recurrence with differentiated carcinomas, medullary carcinomas and poorly differentiated carcinomas. While irradiation of radioiodinenegative unresectable gross disease appears as a consensus, there remain important uncertainties in how to select highrisk patients for radiotherapy, given the low evidence build from small retrospective studies. A scoring system including classical prognostic factors and histologies is thus proposed with the aim to better define the role of EBRT in WDTC. This scoring system will, of course, have to be validated (Table 2). Conformational techniques such as IMRT should be selected at least with the aim to decrease toxicities. The impact of IMRT (and more generally of highly conformal irradiation techniques) on local control and survival rates needs to be investigated. Focused irradiation of areas at risk of relapse in WDTC also merits a conceptual approach and close cooperation between surgeon, pathologist and radiation oncologist. Conflict of interest The authors declare no conflict of interest or financial disclosure. Reviewers Dr. Yungan Tao, Institut Gustave-Roussy, Department of Radiotherapy, 39 Rue Camille-Desmoulins, F-94805 Villejuif, France. Professor Jacques Bernier, Clinique de Genolier, Dept of Radio Oncology, 1 route du Muids, CH-1272 Genolier, Switzerland. Acknowledgement Special thanks to Pr Francois Demard for carefully reviewing this manuscript.

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Annex 1. TNM staging for thyroid cancer (7th ed., 2009) [21] T categories for thyroid cancer (other than anaplastic thyroid cancer) TX: Primary tumor cannot be assessed. T0: No evidence of primary tumor. T1: The tumor is 2 cm (slightly less than an inch) across or smaller and has not grown out of the thyroid. T1a: The tumor is 1 cm (less than half an inch) across or smaller and has not grown outside the thyroid. T1b: The tumor is larger than 1 cm but not larger than 2 cm across and has not grown outside of the thyroid. T2: The tumor is between 2 cm and 4 cm (slightly less than 2 in.) across and has not grown out of the thyroid. T3: The tumor is larger than 4 cm or it has begun to grow a small amount into nearby tissues outside the thyroid. T4a: The tumor is any size and has grown extensively beyond the thyroid gland into nearby tissues of the neck, such as the larynx (voice box), trachea (windpipe), esophagus (tube connecting the throat to the stomach), or the nerve to the larynx. This is also called moderately advanced disease. T4b: A tumor of any size that has grown either back toward the spine or into nearby large blood vessels. This is also called very advanced disease.

65

Stage III: One of the following applies: T3, N0, M0: The tumor is larger than 4 cm or has grown slightly outside the thyroid (T3), but it has not spread to nearby lymph nodes (N0) or distant sites (M0). T1–T3, N1a, M0: The tumor is any size and may have grown slightly outside the thyroid (T1–T3). It has spread to lymph nodes around the thyroid in the neck (N1a) but not to distant sites (M0). Stage IVA: One of the following applies: T4a, any N, M0: The tumor is any size and has grown beyond the thyroid gland and into nearby tissues of the neck (T4a). It may or may not have spread to nearby lymph nodes (any N). It has not spread to distant sites (M0). T1–T3, N1b, M0: The tumor is any size and may have grown slightly outside the thyroid gland (T1–T3). It has spread to certain lymph nodes in the neck (cervical nodes) or to lymph nodes in the upper chest (superior mediastinal nodes) or behind the throat (retropharyngeal nodes) (N1b) but not to distant sites (M0). Stage IVB (T4b, any N, M0): The tumor is any size and has grown either back to the spine or into nearby large blood vessels (T4b). It may or may not have spread to nearby lymph nodes (any N), but it has not spread to distant sites (M0). Stage IVC (any T, any N, M1): The tumor is any size and may or may not have grown outside the thyroid (any T). It may or may not have spread to nearby lymph nodes (any N). It has spread to distant sites (M1).

Papillary or follicular (differentiated) thyroid cancer in patients younger than 45 Medullary thyroid cancer Younger people have a low likelihood of dying from differentiated (papillary or follicular) thyroid cancer. The TNM stage groupings for these cancers take this fact into account. So, all people younger than 45 years with these cancers are stage I if they have no distant spread and stage II if they have distant spread. Stage I (any T, any N, M0): The tumor can be any size (any T) and may or may not have spread to nearby lymph nodes (any N). It has not spread to distant sites (M0). Stage II (any T, any N, M1): The tumor can be any size (any T) and may or may not have spread to nearby lymph nodes (any N). It has spread to distant sites (M1).

Papillary or follicular (differentiated) thyroid cancer in patients 45 years and older Stage I (T1, N0, M0): The tumor is 2 cm or less across and has not grown outside the thyroid (T1). It has not spread to nearby lymph nodes (N0) or distant sites (M0). Stage II (T2, N0, M0): The tumor is more than 2 cm but not larger than 4 cm across and has not grown outside the thyroid (T2). It has not spread to nearby lymph nodes (N0) or distant sites (M0).

Age is not a factor in the stage of medullary thyroid cancer. Stage I (T1, N0, M0): The tumor is 2 cm or less across and has not grown outside the thyroid (T1). It has not spread to nearby lymph nodes (N0) or distant sites (M0). Stage II: One of the following applies: T2, N0, M0: The tumor is more than 2 cm but not larger than 4 cm across and has not grown outside the thyroid (T2). It has not spread to nearby lymph nodes (N0) or distant sites (M0). T3, N0, M0: The tumor is larger than 4 cm or has grown slightly outside the thyroid (T3), but it has not spread to nearby lymph nodes (N0) or distant sites (M0). Stage III (T1–T3, N1a, M0): The tumor is any size and may have grown slightly outside the thyroid (T1–T3). It has spread to lymph nodes around the thyroid in the neck (N1a) but not to distant sites (M0). Stage IVA: One of the following applies: T4a, any N, M0: The tumor is any size and has grown beyond the thyroid gland and into nearby tissues of the neck (T4a). It may or may not have spread to nearby lymph nodes (any N). It has not spread to distant sites (M0). T1–T3, N1b, M0: The tumor is any size and may have grown slightly outside the thyroid gland (T1–T3). It has spread to certain lymph nodes in the neck (cervical nodes)

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or to lymph nodes in the upper chest (superior mediastinal nodes) or behind the throat (retropharyngeal nodes) (N1b) but not to distant sites (M0). Stage IVB (T4b, any N, M0): The tumor is any size and has grown either back toward the spine or into nearby large blood vessels (T4b). It may or may not have spread to nearby lymph nodes (any N), but it has not spread to distant sites (M0). Stage IVC (any T, any N, M1): The tumor is any size and may or may not have grown outside the thyroid (any T). It may or may not have spread to nearby lymph nodes (any N). It has spread to distant sites (M1).

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Hospital of Besanc¸on, France and visiting professor in the Shan Dong University, the Wei Fang Medical University, and the University Hospital of Bin Zhou, China. He had his clinical fellowship at the University Hospital of Besanc¸on, France. His areas of interest include head and neck, lung cancers. He is member of the GORTEC (French working group for head and neck cancer), IFCT (French working group for chest cancer), SFRO, ESTRO.

Biographies

Dr Shan Rong Sun, MD, is a pathologist at the Department of Pathology of the Belfort-Montbéliard Hospital, France. She had her clinical fellowship at the University Hospital of Besanc¸on. Her areas of interest include head and neck, gynecologic cancers.

Dr Xu Shan Sun, MD, is an oncologist and radiotherapist at the Department of Radiation Oncology of the University

Dr Alexis Lepinoy, is a resident at the Department of Radiation Oncology of the University Hospital of Besanc¸on, France.