New Recommendations Streamline Guidelines in Thyroid Cancer

With 31 recommendations and 16 good practice statements, the 2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer (ATC) expand on discussions about treatment goals and palliative care. The guidelines were last updated in 2012, and the new recommendations cover approaches to locoregional disease (surgery, radiotherapy, targeted/systemic therapy, supportive care during active therapy), approaches to advanced/ metastatic disease, surveillance and long-term monitoring, and ethical issues such as end of life. Whereas there were 64 recommendations in the 2012 guidelines, the 31 recommendations in the 2021 version cleared out redundancies in the old guidelines (FIGURE).¹

“This provides clear and consistent recommendations regarding early discussions of palliative care and strongly encourages setting realistic expectations for patients with ATC, which remains a very aggressive disease,” Randall Kimple, MD, PhD, said during an interview with Targeted Therapies in Oncology. Kimple is an associate professor in the Department of Human Oncology at the University of Wisconsin School of Medicine and Public Health in Madison.

Diagnosis

Making the correct diagnosis can be challenging because results from biopsies can either indicate ATC or other cancers/diseases such as lymphoma, sarcoma, and other squamous cell carcinomas of the head and neck or lungs.¹ While waiting for results from biopsies, physicians can consider therapy that could incorporate targeted therapies such as dabrafenib (Tafinlar) and trametinib (Mekinist).¹

Advances in testing methods such as molecular profiling and digital radiology technology have made diagnosing easier. “The advancement in testing methods such as molecular profiling has improved our ability to match a given patient with a drug that may work for their cancer, but more research is needed to understand how best to use this information,” Kimple said.

“Ongoing research efforts have provided significant advances in our understanding of the molecular alterations seen in ATC—several of these advances have identified potential new treatment options to allow us to personalize treatment for patients with ATC,” Kimple said.

Therapy and Care Options

Although previously recommended in the 2012 guidelines, radioactive iodine (RAI) is no longer recommended for ATC treatment because it is ineffective. Rarely, however, in patients with differentiated thyroid cancer (DTC) and ATC, in which the ATC component is in complete remission, yet the DTC component is progressing and threatening, RAI may have a role—but only in treating the DTC component.¹ Many other treatment options have been implemented since 2012.

In May 2018, the FDA approved dabrafenib and trametinib in combination for the treatment of patients with locally advanced or metastatic ATC with BRAF V600E mutation and with no satisfactory locoregional treatment options. Approval was based on a 9-cohort, nonrandomized trial, NCT02034110. The overall response rate was 61% (95% CI; 39%-80%) in 23 patients with ATC who were evaluable for response. The complete and partial response rates (CR, PR) were 4% and 57%, respectively. Response duration was at least 6 months in 64% of responding patients.²

Neoadjuvant use of dabrafenib plus trametinib is also being explored to convert an unresectable primary tumor to resectable. There are now emerging data to suggest that surgical resection following favorable response to neoadjuvant BRAF inhibitory therapy can lead to prolonged survival (94% 1-year overall survival [OS], n = 20).¹

Dabrafenib (150 mg twice daily) combined with trametinib (2 mg daily) was studied in a prospective, nonrandomized clinical trial of patients with BRAF V600E-mutated ATC. CR was reported in 4% of patients and PRs in 57%. Response duration was 6 months or greater in 64% of patients, and OS was 80% at 1 year.¹

In a trial conducted by ECOG from 1976 to 1982, 84 patients with advanced progressive thyroid cancer of all histotypes (not specifically ATC) were randomized to receive doxorubicin (60 mg/m² intravenously [IV] every 3 weeks) or doxorubicin plus cisplatin (60 mg/m² IV doxorubicin, 40 mg/m2 cisplatin IV every 3 weeks). In 37 patients with ATC on this study, doxorubicin alone produced no CR and 1 PR in 21 treated patients with ATC, whereas doxorubicin plus cisplatin yielded 3 CRs and 3 PRs in 18 treated patients with ATC (PR + CR: 5% vs 33%; P < .03). Median survival in ATC was only 2.7 months, but 2 responses to doxorubicin plus cisplatin were durable at 41.3 and 34.7 months, suggesting a possible impact on survival in select patients with ATC. Doxorubicin, 20 mg/m² IV weekly or 60 to 75 mg/m² IV every 3 weeks, is the only cytotoxic chemotherapy specifically approved by the FDA for use in ATC.¹

Alternatively, vemurafenib (Zelboraf)/cobimetinib (Cotellic) in combination with immunotherapy is also undergoing evaluation in a prospective clinical trial (NCT03181100). Estimated enrollment was 50 patients. Depending on the outcome, it could be another treatment option for patients who do not respond well to other MEK inhibitors.¹

In a study conducted by Foote et al, it was reported that 5 patients were followed for more than 32 months with a median OS of 60 months. OS at 1 and 2 years was 70% and 60%, respectively, in response to intensity-modulated radiation therapy (IMRT) combined with adjuvant and radio-sensitizing chemotherapy, including docetaxel plus doxorubicin.³

In an updated report examining 30 patients receiving multimodal therapy and 18 treated with palliative intention, median OS was 21 months compared with 3.9 months in the pooled multimodal therapy versus palliative intention groups (HR, 0.32; P = .0006). Among patients with stage IVB disease, median OS was 22.4 months among patients on multimodal therapy, versus 4 months among patients with palliative intention (OR 0.12; [CI 0.03-0.44]; P = .0001), with 68% of patients on multimodal therapy versus 0% of patients with palliative intention alive at 1 year. However, the cohort size was small, all patients on multimodal therapy received both chemotherapy and IMRT, and the study was historical and not randomized. Hence, although this study suggests improved outcomes in response to multimodal therapy in IVA/IVB ATC, it does not specifically clarify the incremental value of the addition of chemo-therapy to IMRT.⁴

In patients whose tumors do not harbor a BRAF V600E mutation, application of systemic therapy should be considered. In cases where patients have stage IVB or stage IVC disease with a low risk of distant metastatic disease and/or symptomatic or imminently threatening locoregional disease that can be treated with radiation therapy to the neck, external beam radiation therapy with or without concomitant chemotherapy should be a priority to reduce risk of asphyxiation. If radiation is intended, a more definitive IMRT course is preferable, best with coadministration of cytotoxic chemotherapy such as a taxane with or without cisplatin or carboplatin or with doxorubicin, with restaging scans performed midway through any longer IMRT course to assess for early distant disease progression. If there is rapid progression of distant metastatic disease, the approach should be immediately reassessed and the patient should be offered a different treatment. If the patient is healthy enough, a clinical trial should be offered early in the diagnosis.¹

NTRK and RET fusions are rare events found in solid tumors—including in papillary thyroid cancer (PTC), poorly differentiated thyroid cancer, and ATC—and are almost always mutually exclusive of other oncogenic driver mutations. Thus, in a patient without another candidate oncogenic driver, fusion testing should be performed.¹

TRK inhibitors larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) are FDA approved for pediatric and adult patients with NTRK fusion but not NTRK-mutated, solid tumors. Although trials did enroll patients with thyroid cancer, specific histologies were not specified in initial reports. Thus, the guidelines recommend that patients who can participate in clinical trials with these drugs continue to do so until more data specifically relevant to response and progression-free survival are available. If a trial is not available, consideration of commercial use of TRK inhibitors is recommended if available, with parallel close monitoring for progressive disease. Currently, clinical trials with selective NTRK inhibitors are ongoing (NCT02576431, NCT02122913, NCT02568267, NCT02650401).¹

Larotrectinib is an inhibitor of TRK 1, 2, and 3 and was studied in 55 patients with NTRK fusion solid tumors, of whom 5 had thyroid cancer (histologies not specified).5 All patients with thyroid cancer achieved a response (4 PR and 1 CR), but it is unclear whether any of these were ATCs. Entrectinib also inhibits TRK 1, 2, and 3, but it also inhibits the ALK and ROS1 tyrosine kinases and is approved for NTRK fusion solid tumors. Five patients with thyroid cancer were included in the clinical trial that led to the FDA approval, however, histologies were not specified.6 One of 5 patients with thyroid cancer achieved a PR to therapy. ROS1 fusions, which are exceedingly rare in PTC, may be seen in ATC in very rare instances. A case of a patient with PTC successfully treated with entrectinib has been reported.⁷ Clinical trials for ROS1 fusion thyroid cancers should be sought, if available.

As of May 2020, the selective RET inhibitor selpercatinib (Retevmo) is also now FDA approved for patients with RET fusion thyroid and lung cancer, as well as for patients with RET-mutated medullary thyroid cancer.

This approval was based on the results of a phase 1/2 trial that enrolled 170 patients with thyroid cancer, of whom 19 had RET fusion thyroid cancer.⁸ Only 2 patients with ATC were enrolled in the trial, and 1 of these patients responded for 18 months to selpercatinib.

Given the sparse data in ATC with respect to selective RET inhibitors, the guidelines recommend their use in ATC in the clinical trial setting.

Palliative Care

Palliative care should be assessed at every stage of treatment to control pain as well as manage symptoms. This includes assessing the vocal cords during any changes in treatment or hoarseness in the voice to ensure there is no nerve damage or unexpected tumor growth. This is where patient goals come into play to assess their need for autonomy and comfort over aggressive therapy options.¹ Balancing toxicity levels while still maintaining optimal treatment in an aggressive therapy approach is the key to an optimal approach.

“Finding the appropriate balance of toxicity and effectiveness of therapy is a challenge in a disease [such as] ATC,” Kimple said. “It requires honest and open discussions with patients and their families to understand what is important to them. Shared decision-making [between the patient and provider] is a key component to management of ATC.”

Trials Underway

“Ongoing research efforts have provided significant advances in our understanding of the molecular alterations seen in ATC. Several of these advances have identified potential new treatment options to allow us to personalize treatment for patients with ATC,” Kimple said. “I certainly hope that some of these will be safe and effective and that in 5 years we will be able to offer better treatments to patients than we can today. There are multiple clinical trials underway hoping to identify improvements in the care of these patients.”

Future studies should take a personalized approach by matching patients to the treatment most likely to benefit them. “This could include molecular targeted drugs, shorter courses of radiation therapy, and using the patient’s immune system to fight their cancer through immunotherapy,” Kimple said.

_References:

_{1. Bible KC, Kebebew E, Brierley J, et al. 2021 American Thyroid Associa-tion guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2021;31(3):337-386. doi:10.1089/thy.2020.0944}

_{2. FDA approves dabrafenib plus trametinib for anaplastic thyroid cancer with BRAF V600E mutation. News release. FDA. May 4, 2018. Accessed May 17, 2021. https://bit.ly/2QrJtJy}

_{3. Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in locoregionally confined anaplastic thyroid carcinoma: a single-institution experience using aggressive multimodal therapy. Thyroid. 2011;21(1):25-30. doi:10.1089/thy.2010.0220}

_{4. Prasongsook N, Kumar A, Chintakuntlawar AV, et al. Survival in re-sponse to multimodal therapy in anaplastic thyroid cancer. J Clin Endocrinol Metab. 2017;102(12):4506-4514. doi:10.1210/jc.2017-01180}

_{5. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448}

_{6. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282. doi:10.1016/S1470-2045(19)30691-6}

_{7. Liu SV, Macke LA, Colton BS, et al. Response to entrectinib in differentiated thyroid cancer with a ROS1 fusion. JCO Precis Oncol. Published online December 8, 2017. doi:10.1200/PO.17.00105}

_{8. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. doi:10.1056/NEJMoa2005651}