Prognosis in Thyroid Cancer as Diverse as the Disease

Ezra E. W. Cohen, MD

Factors in Survival

With appropriate treatment, individuals with thyroid cancer have good odds for survival—the 5-year survival rate is 98%. Many factors influence the risk of survival after thyroid cancer is diagnosed.

“Histology is really critical,” said Ezra E. W. Cohen, MD, professor of medicine, University of California San Diego, and associate director for translational science, Moores Cancer Center, San Diego.

“We know that papillary thyroid cancer at diagnosis does the best, with a cure rate upwards of 90%, followed by follicular cancer and some rarer variants. At the bottom of the list is anaplastic thyroid carcinoma (ATC), which is almost universally fatal but is fortunately the rarest form of thyroid cancer we see,” Cohen said.

Papillary carcinoma is the most common type of thyroid cancer, accounting for 80% of cases, and can be relatively indolent. More than 95% of people with this histology survive at least 10 years.¹The proportion of thyroid cancers identified as ATC varies globally, ranging from 1.3% in the US to 8% in the Netherlands. Median survival for patients with ATC is 5 months, and only 20% survive a year after diagnosis.²

The American Joint Cancer Committee (AJCC) TNM classification at thyroid cancer diagnosis (eg, size, extent of infiltration, and lymph node involvement) is another important indicator of prognosis, according to Cohen. For patients with well-differentiated thyroid cancer, such as papillary, follicular, and Hürthle cell carcinoma, age is also highly relevant.

“We know that the older an individual is when diagnosed, the worse the outcome,” Cohen explained. The AJCC considers an age younger than 45 years an independent predictor of low-risk disease, but experts continue to debate the most accurate cut-off age between high-risk and low-risk disease.³A recent Canadian study of 2115 patients who received a thyroid cancer diagnosis between 1970 and 2010 proposed changing the age threshold for risk stratification to 55 years.³Between 20% and 30% of patients with differentiated thyroid cancer experience disease recurrence.⁵Different prognostic factors are applied to patients with recurrent thyroid cancer.⁵

Rate of 5-Year Survival⁴

“With recurrence, we look at the size of the tumor, fluorodeoxyglucose (FDG)-positron emission tomography (PET) avidity, and iodine I-131 avidity. Patients with FDG-PET avid tumors that do not take up radioactive iodine have the worst prognosis,” Cohen said.

Prognostic Factors and Treatment

Tumors with greater FDG-PET avidity or tumors refractory to iodine radiotherapy signify much poorer outcomes in the recurrent and metastatic settings of thyroid cancer.⁵Metastatic disease is rare among patients with differentiated thyroid cancer. In a study of 1810 patients seen at Memorial Sloan Kettering Cancer Center (MSKCC) over 20 years, less than 3% of patients (n = 52) had metastases—1.7% at diagnosis and 1.2% within 6 months of surgery.⁶Half the patients with metastases died within 5 years of initial diagnosis, for a 5-year overall survival rate of 65%. Significant predictors of poor outcomes included age older than 45 years, extrapulmonary metastases, and follicular pathology.Widely accepted prognostic factors are considered in treatment decisions from the outset, according to Cohen.

“For instance, a patient with very good prognostic features—young, small tumor, no lymph node involvement, and papillary histology—will get a partial thyroidectomy instead of a total thyroidectomy followed by observation. So, minimal treatment. Patients with larger tumors who are older would get a total thyroidectomy followed by radioactive iodine,” said Cohen.

Historically, patients with current or metastatic thyroid cancer that is nonresectable and refractory to radioactive iodine have had few options, but treatment options for this group are expanding. In 2013, the US Food and Drug Administration (FDA) approved sorafenib (Nexavar) for metastatic, differentiated thyroid cancer after the randomized, placebo-controlled, phase III DECISION trial showed sorafenib significantly improved progression-free survival.⁷Many head and neck cancer oncologists expect that lenvatinib, a multikinase inhibitor recently granted orphan drug status by the FDA, will also be approved soon, according to Cohen.

Biomarkers as Prognostic Indicators in Differentiated Thyroid Cancer

“Lenvatinib targets multiple kinases in vascular endothelial growth factor (VEGFR), especially VEGFR-2. It produced a 60% response rate in patients with recurrent or metastatic disease who could no longer be treated with radioactive iodine,” said Cohen.⁸He added that lenvatinib even proved effective in patients who had disease progression or who had not responded to sorafenib.Genetic or other molecular biomarkers are used to inform prognosis for many types of cancer, but Cohen said their use in thyroid cancer is controversial.

“About half of patients with papillary thyroid cancer have aBRAFmutation, and previously it was thought that aBRAFmutation was a prognostic factor. Findings from a large, well-conducted study suggested aBRAFmutation probably does have a little prognostic utility, but much less than we thought,” Cohen said.

He added thatRASmutations (KRAS,HRAS, orNRAS), which occur more often in follicular carcinoma, also appear to have some value in predicting patients at risk of worse outcomes, but confirmatory data are needed. In addition,RET/PTCrearrangements have been reported to occur in 40% of adults with papillary thyroid carcinoma, although the prognostic implications of this genetic aberration are undetermined.

Clinical Pearls

• With appropriate treatment, individuals with thyroid cancer have a 5-year survival rate of 98%.
• Histology is a critical factor in determining survival.
• The TNM classification is another important indicator of prognosis.
• The AJCC considers an age <45 years an independent predictor of low-risk disease.
• Patients with FDG-PET–avid tumors that do not take up radioactive iodine have the worst prognosis.
• Older patients with larger tumors would likely receive a total thyroidectomy followed by radioactive iodine.
• In 2013, the FDA approved sorafenib (Nexavar) for metastatic, differentiated thyroid cancer.
• Use of genetic or other molecular biomarkers to inform prognosis in thyroid cancer is controversial.
• Medullary thyroid cancer has a different cellular origin than differentiated thyroid cancer.
• Vandetanib (Caprelsa) was approved in 2011 by the FDA for the treatment of symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease.
• A new prognostic nomogram may help predict which patients with MTC are at highest risk of recurrence and death.

Because of the lack of conclusive data on the prognostic value of these molecular markers, they are not used to guide initial treatment decisions. However, Cohen said he routinely tests refractory patients for aBRAFmutation because severalBRAFinhibitors have been approved for melanoma, and programs or trials investigating these agents in relapsed or refractory thyroid cancer may be available.

“BRAF inhibitors are not approved for thyroid cancer, so their use is not part of any official recommendation,” said Cohen. Clinical trials are also looking at whetherMEKorBRAFinhibitors can be used to resensitize patients who are refractory to radioactive iodine.

Medullary Thyroid Cancer

“Pilot data suggest this may be effective,” Cohen said.Medullary thyroid cancer (MTC) has a different cellular origin than differentiated thyroid cancer and ATC, which have a follicular histology. In contrast, MTC arises from the parafollicular cells of the thyroid. It accounts for 3% to 10% of thyroid cancer cases.⁹Five-year overall survival in MTC is 86%, and 10-year overall survival is 65%. Vandetanib (Caprelsa) was approved in 2011 by the FDA for the treatment of symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease.¹⁰

A prognostic nomogram developed at MSKCC may help predict which patients with MTC are at highest risk of recurrence and death.

Ian Ganly, MD, head and neck surgeon at MSKCC, said, “This will allow these patients to be identified and treated with more aggressive therapies in the future.”

Ganly added that the benefit of using the nomogram over the AJCC TNM system for prognosis is that the nomogram predicts outcomes for an individual patient, while the AJCC TNM system gives a population-based estimation of mortality.

The nomogram tool, available at the MSKCC web site, is designed to be used by physicians.

“Variables needed are the TNM status, age, gender, presence of vascular invasion, and the postoperative calcitonin level,” said Ganly.

References

1. National Institutes of Health. MedlinePlus: thyroid cancer-papillary carcinoma. http://www.nlm.nih.gov/medlineplus/ency/article/000331.htm. Updated March 23, 2014. Accessed January 23, 2015.
2. Smallridge RC, Copland JA. Anaplastic thyroid carcinoma: pathogenesis and emerging therapies. Clin Oncol (R Coll Radiol). 2010;22:486-497.
3. Mazurat A, Torroni A, Hendrickson-Rebizant J, et al. The age factor in survival of a population cohort of well-differentiated thyroid cancer. Endocr Connect. 2013;2:154-160.
4. National Cancer Institute. SEER stat fact sheets: thyroid cancer. http://seer.cancer.gov/statfacts/html/thyro.html. Accessed January 23, 2015.
5. Schreinemakers JM, Vriens MR, Munoz-Perez N. Fluorodeoxyglucose-positron emission tomography scan-positive recurrent papillary thyroid cancer and the prognosis and implications for surgical management. World J Surg Oncol. 2012;10:192.
6. Nixon IJ, Whitcher MM, Palmer FL, et al. The impact of distant metastases at presentation on prognosis in patients with differentiated carcinoma of the thyroid gland. Thyroid. 2012;22:884-889.
7. Brose MS, Nutting CM, Jarzab B. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384:319-328.
8. Schlumberger M, Tahara M, Wirth LJ, et al. A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT). J Clin Oncol. 2014;23(suppl): Abstract LBA6008:5s.
9. University of Texas MD Anderson Center. Thyroid cancer. http://www.mdanderson.org/patient-and-cancer-information/cancer-information/cancer-types/thyroid-cancer/index.html. Accessed January 23, 2015.
10. Caprelsa (vandetanib) Prescribing Information. AstraZeneca 2013.

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