There is no role for cytotoxic chemotherapy in metastatic disease, but depending upon resectability and risk related to radiation, you could consider a clinical trial protocol or a tyrosine kinase inhibitor.
— Manisha H. Shah, MD
Differentiated thyroid cancer—papillary, follicular, and Hürthle cell carcinomas—has historically been managed by endocrinologists, surgeons, and radiation oncologists, but recent progress in the field has led to greater involvement by medical oncologists, especially in the care of patients with advanced disease. While differentiated thyroid cancer is typically indolent and highly curable, when it recurs, the therapeutic plan is not always straightforward. The ASCO Post asked thyroid cancer specialist Manisha H. Shah, MD, Associate Professor of Internal Medicine at The Ohio State University Comprehensive Cancer Center, Columbus, for guidance.
Primary Concerns and Standard Treatment
Since the vast majority of patients with differentiated thyroid cancer can be cured, what are the concerns for oncologists treating these patients?
For patients who develop distant metastasis, differentiated thyroid cancer is potentially fatal, with a 5-year disease-specific survival rate of less than 50%. You first establish whether the goal of treatment is curative or palliative. Even lung metastases are potentially curable. The management of these patients can be complex, and should be multidisciplinary. Medical oncologists should be familiar with all forms of treatment.
What is standard treatment for newly diagnosed patients?
Upon initial diagnosis, treatment for the majority of patients includes total thyroidectomy, thyroid-stimulating hormone (TSH) suppression, and radioactive iodine. For high-risk patients, you can consider external-beam radiation therapy to the neck. In the adjuvant setting, there is no role for cytotoxic chemotherapy or tyrosine kinase inhibitors.
Recurrence and Metastases
When patients develop recurrence, what is your first consideration?
Not all patients with differentiated thyroid cancer need treatment upon the diagnosis of metastatic disease. The oncologist should determine the need to initiate treatment based on an assessment of clinical symptoms, tumor histology, radioiodine avidity status, and disease staging with serum thyroglobulin and thyroglobulin antibody, TSH, CT of the neck and chest (with or without CT of the abdomen/pelvis and head), or PET scans. Treatment may be warranted at diagnosis in the presence of symptoms or aggressive histology, such as tall-cell, insular variant, or poorly differentiated papillary carcinoma.
We offer treatment (surgery or radioactive iodine but never a tyrosine kinase inhibitor) for patients with metastatic differentiated thyroid cancer who are radioiodine-avid and asymptomatic but have rising serum thyroglobulin or a positive whole-body iodine scan. In other cases, we watch and wait, with staging studies done every 3 to 6 months, for patients who are radioiodine-refractory and asymptomatic with a stable or slowly progressing tumor or minor tumor burden, or who have favorable histology or genotype.
We offer a tyrosine kinase inhibitor or clinical trial protocol to radioiodine-refractory patients who are symptomatic or have any of the following indications: bulky tumor burden, moderate-to-rapid progression of disease, disease in an unsafe location, or unfavorable histology or genotype. We do not base treatment with a tyrosine kinase inhibitor simply on a rising thyroglobulin, even in the setting of established measurable disease.
Once you decide to treat metastatic disease, how do you proceed?
Patients can receive the same treatment as for initial disease (surgery, levothyroxine, radioiodine). If the patient has radioiodine-refractory disease, you can consider palliative surgery and/or local radiotherapy. Again, there is no role for cytotoxic chemotherapy, but depending upon resectability and risk related to radiation, you could consider a clinical trial protocol or a tyrosine kinase inhibitor.
What is the optimal approach to TSH suppression?
TSH suppression with levothyroxine is critical, and oncologists may need help from an expert endocrinologist in terms of maintaining the optimal dose and achieving efficacy. Proper dosing is critical, as is periodic long-term monitoring. For patients with known recurrent differentiated thyroid cancer (vs those treated in the adjuvant setting), the target TSH level is < 0.1 mU/L. The typical levothyroxine dose necessary to achieve suppression is > 1.6 µg/kg/d. When patients request a higher dose, this should prompt discussion about the potential for side effects, including atrial fibrillation and osteoporosis. Lifetime replacement therapy is necessary, not only because we have removed the thyroid gland but also because levothyroxine suppresses the growth of cancer.
Radioiodine Treatment Considerations
What is the optimal use of radioiodine therapy?
Radioactive iodine can be used in the adjuvant or metastatic setting, but the majority of patients receive it as adjuvant treatment after thyroidectomy. In the metastatic setting, radioiodine is often given to patients with rising serum thyroglobulin levels (velocity, or absolute increase > 10 ng/mL) or evidence of iodine-avid evaluable metastases, but the selection of patients for radioiodine is not always clear. Some clinicians advocate treating most patients with thyroglobulin levels > 10 ng/mL, whereas others support using radioiodine primarily for patients believed to be at high risk for clinically relevant sequellae due to progressive disease.
How do you determine whether the patient is refractory to radioactive iodine treatment?
The oncologist should confirm that the patient is radioiodine-refractory. It is generally agreed that disease is radioiodine-refractory if there is a negative whole-body iodine scan following radioiodine administration, lack of thyroglobulin response or objective response to radioiodine treatment, and receipt of a cumulative radioiodine dose > 600 mCi. Because of the inverse relationship between FDG-PET avidity and radioiodine uptake, some clinicians consider a positive FDG-PET scan itself as a definition of radioiodine-refractory disease.
Roles of Surgery and Radiation
Is there a role for surgery in metastatic disease?
In the setting of metastatic disease, we can treat the primary and metastatic tumors with surgery, external-beam radiation therapy, or ethanol ablation. Metastatic differentiated thyroid cancer is one of the few solid tumors where resection of the primary tumor is done even in stage IV disease. The goals of total thyroidectomy are to prevent local complications, facilitate monitoring (allow interpretation of thyroglobulin and whole-body iodine scan), and increase the effectiveness of radioiodine. Resection of metastases can be considered for lymph nodes in the neck or mediastinum or for isolated lung or bony lesions. With resection, some of these patients can be cured.
Can you elaborate on the role of radiation?
Since these are radiosensitive tumors, we can offer external-beam radiotherapy to the thyroid bed and bilateral neck nodes in an adjuvant setting for high-risk patients or for patients with locoregionally recurrent disease following thyroidectomy and radioiodine. External-beam or stereotactic radiation can also be delivered for spinal cord compression or symptomatic bony lesions, impending fractures, or lytic lesions in the long bones.
When treating the high-risk patient with curative intent, the radiation dose is 6,000 to 7,000 cGy over 6 to 7 weeks. This is a toxic regimen, and patients need preparation and counseling, and possibly percutaneous endoscopic gastrostomy (PEG) tubes. In the palliative setting, lower doses—2,000 to 3,000 cGy over 2 to 3 weeks—are well tolerated. If the patient has had prior radiation to the neck, subsequent surgery will be difficult, and this should be kept in mind when considering the use of adjuvant external-beam radiation.
Role of Chemotherapy
Is there ever a role for cytotoxic chemotherapy, and where do tyrosine kinase inhibitors fit in?
There is no role for cytotoxic chemotherapy in the treatment of radioiodine-refractory thyroid cancer. There are hints, however, that the combination of gemcitabine plus oxaliplatin might be active, based on a 57% response rate shown in a small study.1 Tyrosine kinase inhibitors, on the other hand—especially antiangiogenic agents—have an emerging role [see sidebar, “Molecularly Targeted Treatment of Thyroid Cancer Rapidly Evolving”], but they should be used in selected cases by experienced physicians. ■
Disclosure: Dr. Shah has served as a consultant or in an advisory role for Bayer and has received research funding from Daiichi Sankyo, Eisai, and Exelixis.
1. Spano JP, Vano Y, Vignot S, et al: GEMOX regimen in the treatment of metastatic differentiated refractory thyroid carcinoma. Medical Oncology. September 25, 2011 (early release online).
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