HOLLYWOOD, Florida (EGMN) – The U.S. National Comprehensive Cancer Network has updated its thyroid carcinoma guidelines to add consideration of small molecule kinase inhibitors in metastatic disease treatment, refine diagnosis and treatment strategies based on fine needle aspiration, and provide new information on thyroid-stimulating hormone suppression.

The panel of 26 physicians reviewed meeting data and published trials, and noted increasing off-label use of small molecule kinase inhibitors in patients with thyroid carcinoma. They said these agents can be considered to treat papillary, follicular, Hürthle cell, or medullary carcinoma, if a clinical trial is unavailable or inappropriate.

Although it’s a drug class recommendation, “we specifically mention sorafenib and sunitinib as options,” Dr. Steven I. Sherman said at the annual conference of the National Comprehensive Cancer Network (NCCN). Best supportive care also remains a consideration for these patients with clinically progressive or symptomatic disease.

Neither kinase inhibitor is indicated for thyroid cancer. The U.S. Food and Drug Administration has approved sorafenib in advanced renal cell carcinoma and hepatocellular carcinoma; and sunitinib in gastrointestinal stromal tumors (GIST) and metastatic renal cell carcinoma. Both are under investigation in other tumors.

The NCCN revised procedures for evaluation of thyroid nodules, especially follicular or Hürthle cell neoplasms and follicular lesions of undetermined significance that cannot be diagnosed by fine needle aspiration (FNA). For example, management of an undetermined lesion depends on whether thyroid stimulating hormone is high, normal, or low. If it is high or normal, repeat FNA and consider surgery based on clinical findings concerning growth or suspicious findings on ultrasound. If the TSH is low, perform a thyroid scan, and repeat FNA based on the same factors if the scan is cold; if it is hot, evaluate and treat for thyrotoxicosis.

A follicular lesion of undetermined significance still carries a 5%-10% risk of cancer, Dr. Sherman said.

Diagnostic categories based on FNA findings also changed in the guideline update. One category, for example, is patients who have or are suspected of having papillary, medullary, or anaplastic thyroid carcinoma. These patients have a 99% risk of cancer, and should go directly to primary treatment, said Dr. Sherman, department chair and professor of endocrine neoplasia and hormonal disorders in the division of internal medicine at the University of Texas M.D. Anderson Cancer Center, Houston.

If the FNA indicates thyroid lymphoma, refer to NCCN Non-Hodgkin’s Lymphoma Guidelines. If the FNA comes back as an insufficient biopsy or as nondiagnostic, treatment is dictated by whether it is cystic or solid. “An insufficient biopsy still carries a 1%-7% risk of cancer,” Dr. Sherman said.

For a benign nodule, the risk of cancer, at most, is 1%, he said, and observation is recommended. However, if there is nodule growth, repeat the FNA or consider surgery.

Patient age over 45 years is no longer a factor that should raise clinical suspicion with a solitary thyroid nodule greater than 1 cm in diameter in the setting of an unknown TSH level, according to the new guidelines.

In addition, for patients with a positive FNA finding, the panel provides a less stringent recommendation for a chest radiograph: “Consider chest x-ray” instead of “chest x-ray, if not recently done.” There is greater consensus now behind the panel’s recommendation to perform a lateral neck ultrasound in this group of patients.

In addition, the NCCN added Principles of Thyroid Stimulating Hormone Suppression to the guidelines, providing specific recommendations for use of levothyroxine for TSH suppression in papillary, follicular, and Hürthle cell carcinomas.

Use of levothyroxine is considered optimal to maintain low TSH levels and minimize risk of stimulating the growth of cells derived from thyroid follicular epithelium, the guidelines say. The panel noted, however, that there are insufficient data to recommend appropriate serum TSH levels. Instead, “in general, patients with known residual carcinoma or at high risk for recurrence should have TSH levels maintained below 0.1 mU/L, whereas disease-free patients at low risk for recurrence should have TSH levels maintained either slightly below or slightly above the lower limit of the reference range.” Also, patients who remain disease free for several years can probably have TSH levels maintained within the reference range.

The TSH suppression guidelines come with a caveat to balance risks and benefits of levothyroxine therapy for each patient. There is potential for cardiac tachyarrhythmias, bone demineralization, and frank symptoms of thyrotoxicosis when prescribed at TSH-suppressive doses. In addition, the NCCN recommends counseling patients who are on long-term suppression about adequate daily intake of calcium (1,200 mg/day) and vitamin D (800 U/day).

The NCCN changed its recommendations for evaluation of patients with thyroid carcinoma post thyroidectomy, especially concerning use of radioiodine therapy.

Radioiodine (RAI) therapy is now an option for patients with no gross residual disease in the neck after surgery. “Postoperative RAI therapy is to destroy any remaining normal thyroid tissue as a source of thyroglobulin production, to improve accuracy of follow-up testing,” said Dr. Sherman.

The guidelines now list RAI as an alternative at 1-12 weeks post thyroidectomy to a total body radioiodine scan. Clinical indications for RAI are based on pathology, postoperative thyroglobulin, and intraoperative findings.

The recommendations are specific by cancer stage. For example, radioiodine therapy for stage II disease “for the first time is associated with a survival advantage ... with total or near-total thyroidectomy,” Dr. Sherman said. “Stage I is the problem. This is the largest group of patients, but overall survival is worse with radioactive iodine therapy.”

“Clearly there is no evidence of a benefit among stage I patients. This is a very important pullback in terms of the recommendations,” Dr. Sherman said.

“It is our particular opinion at M.D. Anderson that a total body radioiodine scan should be performed prior to treatment because of its diagnostic usefulness,” he added.

Dr. Sherman is a consultant for Bayer HealthCare, Celgene Corporation, Eisai Inc., Exelixis Inc., OXiGENE Inc., Plexxikon Inc., and Semafore Pharmaceuticals Inc. He receives grant and research support from Amgen, AstraZeneca, Eisai, Genzyme, and the U.S. National Cancer Institute, and is on the speakers bureau for Genzyme.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

佛罗里达州好莱坞（EGMN）——美国国家综合癌症网络（NCCN）更新了甲状腺癌指南，增加了考虑使用小分子激酶抑制剂治疗转移病灶的内容，改进了基于细针穿刺进行诊断和治疗的策略，并增加了关于抑制促甲状腺激素（TSH）新的内容。

由26名医生组成的该专家小组回顾了会议资料和已公布的试验结果，并指出超适应证使用小分子激酶抑制剂治疗甲状腺癌的情况在增加。他们认为如果临床试验不适合或不能够进行，可考虑将此类制剂用于乳头状、滤泡型、嗜酸细胞型或髓样甲状腺癌治疗。

尽管这是一个药品类建议，“我们特别提到了索拉非尼(sorafenib)和舒尼替尼(sunitinib)可作为备选，”Steven I. Sherman博士在NCCN的年度会议上说道。对于有临床进展或症状性疾病患者，最佳支持疗法仍可考虑。

甲状腺癌不是激酶抑制剂的适应证。美国FDA已经批准索拉非尼用于治疗晚期肾细胞癌和肝细胞癌，舒尼替尼用于治疗胃肠道间质瘤（GIST）和转移性肾细胞癌。两者在其他肿瘤的应用正在研究中。

NCCN修订了甲状腺结节评估方法，尤其是细针穿刺活检（FNA）不能确诊的滤泡型或嗜酸细胞型甲状腺癌和性质未能明确的滤泡型病灶。例如，对未能明确病灶的处置取决于促甲状腺激素（TSH）的水平是过高、正常或偏低。如果TSH过高或正常，则再次活检，并在临床发现结节生长或超声发现可疑迹象的基础上，考虑外科手术。如果激素偏低，则行甲状腺核素扫描。如果是冷结节，则基于上述同样因素重复活检；如果是热结节，则考虑是甲状腺毒症并进行治疗。

性质未定的滤泡型病灶仍然具有5%～10%的癌变风险，Sherman博士说。

根据细针穿刺活检结果诊断的疾病类别在新的指南中也有所改变。例如，其中一类是已经或怀疑罹患乳头状、髓样或甲状腺未分化癌患者。这些患者罹患癌症的风险高达99%，并应直接进行首次治疗，休斯敦市得克萨斯大学安德森癌症中心(Anderson Cancer Center)内科系内分泌肿瘤和内分泌疾病科主任Sherman博士说。

如果活检提示甲状腺淋巴瘤，请参阅NCCN非霍奇金淋巴瘤指南。如果细针穿刺组织不足以或不可进行活检者，治疗则取决于是囊性包块还是实体包块。“组织不足以活检者仍然具有1%~7%罹患癌症的风险。”Sherman博士说。

他说，对于良性结节，癌变风险最多为1%，建议观察。但是当结节增大，则应考虑再次活检或考虑手术治疗。

新的指南指出，若患者年龄超过45岁，孤立甲状腺结节直径大于1cm、TSH水平未知已不再是提高甲状腺癌临床疑似诊断的因素。

此外，该专家小组建议对细针穿刺阳性患者不必立即进行胸部X光检查——“考虑胸部X光检查”而不是“如果近期没有做过，则立即进行胸部X光检查”。现在对于此类患者，除了指南建议外，行侧颈部超声检查已取得更多的共识。

此外，NCCN指南中还加入了抑制促甲状腺激素的规范，对使用左旋甲状腺素抑制促甲状腺激素治疗乳头状、滤泡型和嗜酸细胞型甲状腺癌提出了具体建议。

目前认为，左旋甲状腺素是维持低水平TSH、减少刺激甲状腺滤泡上皮细胞增殖风险的最佳选择，指南中写道。该专家小组指出，但根据现有数据，仍不足以推荐合适的血清TSH水平。“一般来说，对于已知有残余癌灶或复发高危患者，TSH水平应保持在0.1 mU/L以下；而对于无病灶低复发风险患者，TSH水平应保持略低于或略高于参考范围的下限。”此外，维持数年无病状态的患者TSH水平可保持在参考范围之内。

指南关于抑制促甲状腺激素的规范中告诫说，应权衡单个患者左旋甲状腺素治疗的风险和收益。患者有可能出现心脏心律失常、骨脱矿质化及TSH抑制剂量下的甲状腺毒症状。NCCN还建议向TSH长期抑制患者提供咨询，建议患者每天应摄入充足的钙剂（每天1,200 mg）和维生素D （每天800 U）。

NCCN修订了甲状腺癌术后患者评估的建议，尤其是关于使用放射性碘治疗方面。

目前，对于甲状腺癌切除术后患者，如颈部残余病灶较小，可选择采用放射性碘（RAI）治疗。“术后放射性碘治疗可摧毁所有分泌甲状腺激素的残余正常甲状腺组织，以提高后续检查的准确性。” Sherman博士说。

现在，新的指南将放射性碘治疗作为甲状腺癌切除术后1～12周放射性碘核素全身扫描的替代方案列入清单。该放射性碘治疗临床适应证是基于病理学类型、术后甲状腺球蛋白水平和术中冰冻切片的检查结果。

这些建议是肿瘤分期特异性的。例如，“对于II期甲状腺癌甲状腺全切或次全切患者，首次提出术后放射性碘治疗与存活时间增加相关。”Sherman博士说。“I期甲状腺癌是个问题。该期的患者群最大，但术后放射性碘治疗患者的总存活时间减少。”

 “显然，没有证据证明I期甲状腺癌患者可从术后放射性碘治疗中受益。这是关于该建议一个非常关键的障碍。”Sherman博士说。

 “但在安德森肿瘤中心，我们还是认为应在治疗前进行放射性碘核素全身扫描，这样可以帮助诊断。”他补充说。

Sherman博士在拜尔医药保健公司、Celgene公司、Eisai公司、Exelixis公司， OXiGENE公司、Plexxikon公司和Semafore制药公司担任顾问，接受来自安进、阿斯利康、卫材、健赞及美国国立癌症研究所（NCI）的基金资助和研究支持，是健赞公司讲师团成员之一。 

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