Outcomes for Older MTC Patients are Poor, Limited Treatment Options Exist

In medullary thyroid cancer (MTC), older patients are more likely to have more aggressive disease and disease specific mortality, according to research published in the American Journal of Surgery.1

MTC accounts for approximately 5% of new thyroid cancer diagnoses, however, incidence rates are rising. Additionally, MTC accounts for approximately 13% of all thyroid cancer-related deaths. Currently, the standard minimum surgical management of MTC without evidence of nodal involvement is a total thyroidectomy with a bilateral prophylactic central neck dissection. As the population ages, it’s important to understand age as a risk factor for thyroidectomy complications. 

The analysis was conducted using data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. Cases were collected between 2004 to 2015. Ultimately, 1457 patients were included with the study. Over half, 59.8% were female and 85.2% were White and 7.7% were Black. The vast majority, 89.3%, had undergone total thyroidectomy and 6.2% had undergone a thyroid lobectomy. Less than 5 percent received non-operative management.

The majority of patients included, 69.2% were less than 65 years of age. Twenty-five percent were between 65-79 and 5.4% were 80 years or older. The disease specific mortality for all patients was 7.5%. For younger adults, it was 6%, for older adults it was 8.9%, and it was 20.5% among those 80 years of age and older.

The 5-year overall survival was 90.3% for younger adults. For older adults it was 76.8% and for the super-elderly it was 57.8%. The 10-year overall survival rate for younger adults was 89.9%, 74.7% for older adults, and 56.4% for the super elderly. 

“Despite these limitations, the results presented in this paper illustrate that regardless of disease stage or surgical management of MTC, DSM is increased among older patients. Due to MTC’s low incidence and lack of prospective studies, there is a paucity of convincing evidence to demonstrate a significant correlation be-tween prognostic indicators and DSM. Moreover, our results also show an increased DSM among African American patients,” study authors wrote.

For patients who are not able to be cured through surgery, new novel targeted therapies and immunotherapy are options.2 Options include multiple kinase inhibitors (MKI) and immunotherapy.

Currently, there are 4 FDA approved drugs that target the mitogen-activated protein kinase (MAPK) pathway. Of those 4, cabozantinib (Cometriq) and vandetanib (Caprelsa) are approved for MTC. According to research, blocking the MAPK pathway has been found to increase progression-free survival.

Preclinical studies have suggested that immunotherapy would be useful in MTC by leveraging the immune system’s natural response to thyroid cancer. Currently, a study (NCT01525602) is recruiting patients with advanced solid tumors to test the effects of PLX3397, a CSF-1R inhibitor plus paclitaxel. Another study (NCT01346358) is also recruiting patients with thyroid cancer to evaluate the efficacy of the CSF01R antibody LY3022855.

Efforts are also underway to develop a vaccine. For example, dendritic cell vaccines, which are common in MTC, have shown clinical promise. In a study of 7 patients who were injected with mature dendritic cells, 3 showed a complete regression of metastatic hepatic and pulmonary nodules.

Currently, 2 vaccines trials are underway. One study is testing GI-6207 (NCT01856920), a vaccine made from baker’s yeast targeting the CEA in patients with MTC. Another (NCT02239861) is testing specific adoptive cytotoxic T cells targeting NY-ESO-1, MAGEA4, PRAME, survivin, and SSX.

Some evidence suggests that the duel targeting of the immune system could provide clinical benefit. One study (NCT02452424) is testing PLX3397 plus the PD-1 inhibitor pembrolizumab (Keytruda) in solid tumors. Another study (NCT02718911) is testing LY3022855 plus tremelimumab or durvalumab (Imfinzi) in solid tumors.

“Recent data showing a role for kinase inhibitors in immune modulation brings the promise that perhaps both strategies can be utilized simultaneously to achieve better responses in advanced thyroid cancer. Regulatory T cells express VEGFR-2, and both VEGF-A and BRAF-V600E are associated with upregulation of PD-1 expression, leading to inhibition of cytotoxic T cells,” study authors write. “Therefore, currently available MKIs could potentially reverse the inhibitory effects of pathologic kinase activities on the immune system.”

_REFERENCES:

_{1.Sahli Z, Canner J, Zeiger M, et al. Association between age and disease specific mortality in medullary thyroid cancer. Am J Surg 2021;221(2):478-484. DOI:https://doi.org/10.1016/j.amjsurg.2020.09.025}

_{2.Naoum G, Morko M, KimB, et al. Novel targeted therapies and immunotherapy for advanced thyroid cancers. Mol Cancer 2018;17(15). https://doi.org/10.1186/s12943-018-0786-0}