Systemic Therapy

Systemic Therapy

Clinical Outline

Educational Clips from TIROxMDS

1. RAI Refractory Metastatic Disease

A. Role of Resensitization for RAIR Disease

B. Multikinase Inhibitors

2. Consideration for Patients Who Fail Therapy

3. Neoadjuvant Therapy & Decision-making About Surgery with Systemic Therapy

4. The Role of External Beam Radiotherapy (EBRT)

5. Cytotoxic Chemotherapy

6. Bisphosphonate/Rank Ligand Inhibitor

7. Targeted Therapies Against Specific Tumor Alterations

8. Indications for Somatic Tumor Genetic Testing (DNA/RNA)

= Primers in Thyroidology

= Journal Club Presentation

= Case-based Discussion (inc. roundtables)

= Grand Rounds Lectureship

• Care Recommendations
  • Differentiated Thyroid Cancer
    • Initial Evaluation of Thyroid Nodules
    • Initial Management
    • Initial Staging & Response to Therapy
    • Systemic Therapy
    • Use of Radioactive Iodine
    • Recurrent & Persistent Disease
  • Medullary Thyroid Cancer
    • Initial Evaluation of Thyroid Nodules Suspicious of MTC
    • Surgical Management
    • Evaluation of Advanced Disease
    • Management of Specific Clinical Scenarios
  • Anaplastic Thyroid Cancer
    • Diagnostic Procedures
    • Initial Staging & Treatment Planning
    • Surgical Management
    • Systemic Therapy
    • End of Life Care
  • Analysis Tools
  • Clinical Trial Options
  • Tables & Figures
• Events
  • Upcoming Webinars
  • Past Webinars
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• About TIRO
  • What is TIRO?
  • How to Use TIRO
  • Contact
  • THANC Guide
  • THANC Foundation

Management Recommendations

1. RAI Refractory Metastatic Disease

ATA // ESMO // JAES // NCCN

A. Role of Resensitization for RAIR Disease

• In radioiodine refractory thyroid cancer several small studies have demonstrated the proof of principle that inhibitors of the MAPK pathway, such as selumetinib, dabrafenib and vemurafenib, can restore RAI avidity in some cases. Patients with RAI refractory DTC that is indolent should be considered for clinical trials investigating RAI resensitization.^​1–3​

Expert Commentary

There exists a major unmet need for optimal treatment options for patients with low-volume, slow-growing RAI refractory DTC. There is significant interest in the potential role for resensitization in this setting, pointing to a major imperative for definitive clinical trials to be conducted.

B. Multikinase Inhibitors

i. When to Start/Stop Therapy

Regulatory Approvals

Sorafenib and lenvatinib are both approved for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory (RAI-refractory) differentiated thyroid cancer (DTC).

C. Managing Toxicities of Therapy

• Because potential toxicities can negatively impact quality of life or even be fatal, patients must be appropriately selected for therapy and closely monitored after starting therapy.^​1,2,4​
• Adverse events caught early can be effectively managed, but prevention, when feasible, is always advisable. The ultimate goal is to manage side-effects without having detrimental effects on treatment efficacy.^​2,4​
• Due to the risk of fetal harm and the potential for infertility, fertility preservation approaches and pregnancy testing should be discussed before starting treatment.^​4​
• Informed patient consent should be done prior to initiating therapy.^​2​

2. Consideration for Patients Who Fail Therapy

ATA // ESMO // NCCN

• Clinical trials should be considered for second-line therapy.^​1,3​
• Patients who progress through first-line kinase inhibitor therapy should be considered candidates for second-line kinase inhibitor therapy, and therapy should be continued until any of the following occurs:
  • Disease progression,
  • Unacceptable toxicities, or
  • Patient desires to stop treatment.^​1,3,4​
• If there are no clinical trials to enroll patients, commercially available small-molecule inhibitors, such as axitinib, everolimus, pazopanib, suntinib, vandetinib, vemurafenib (BRAF positive), dabrafenib (BRAF positive, or cabozantinib can be considered as subsequent therapy.^​3​

3. Neoadjuvant Therapy & Decision-making About Surgery with Systemic Therapy

Expert Commentary

• Decisions regarding the use of systemic therapy in combination with other locoregional therapies such as surgery and external beam radiation therapy for patients with locoregionally advanced and/or recurrent differentiated thyroid cancer are complex and require multidisciplinary input, with consideration of the following factors (among others):
  • Biology of the disease, including extent and rate of progression of locoregional and distant disease.
  • Available targeted therapies, including efficacy and side effect profiles.
  • Patient-specific factors, including comorbidities, perceived ability to tolerate systemic therapy and local therapies, and patient preference. 
• Most patients with differentiated thyroid cancer do not have rapid disease progression, and therefore neoadjuvant systemic therapy approaches are rarely considered.  However, for rare DTC patients with fast-growing tumors and high disease burden, this approach may be considered to reduce the morbidity of surgery or to improve the opportunity for complete surgical resection, particularly for the following:
  • Patients with targetable mutations or with RET or NTRK fusion. 
  • Patients who have residual/recurrent disease following previous surgery, as neoadjuvant systemic therapy strategies can potentially prolong the time interval to the next surgery.  
  • Patients with locoregionally advanced disease and/or residual/recurrent disease who would require morbid surgery (e.g. sacrifice of recurrent laryngeal nerve or laryngectomy) for complete extirpation of disease, as neoadjuvant strategies can potentially prolong the time to the morbidity associated with this surgery.

Clinical trials are needed to further study the potential benefits and risks of therapeutic approaches combining targeted systemic therapy and surgery. 

4. The Role of External Beam Radiotherapy (EBRT)

ATA // AHNS // JAES // NCCN

A. Locally Advanced DTC

EBRT may be considered where there is residual gross unresectable macroscopic disease that is unlikely to be controlled by radioiodine or where it threatens critical structures or organs.^{​1,3–5​}

B. Locally Recurrent DTC

EBRT may be considered where there is gross unresectable macroscopic disease that is unlikely to be controlled by radioiodine or where it threatens critical structures or organs.^​1,3,4​

5. Cytotoxic Chemotherapy

ATA // ESMO // NCCN

Regulatory Approvals

Doxorubicin is FDA approved for thyroid cancer.

• In radioiodine refractory thyroid cancer, there is no strong evidence indicating clinical benefit for cytotoxic chemotherapy. However, cytotoxic chemotherapy may be considered in select cases.^​1,3,4​

6. Bisphosphonate/Rank Ligand Inhibitor

ATA // ESMO // NCCN

• Bone directed treatment; bisphosphonates or denosumab should be considered in patients with diffuse thyroid cancer bone metastases.

• Baseline dental review is advised due to risk of osteonecrosis of the mandible. Serum calcium and vitamin D levels should be checked before administration of bisphosphonates or denosumab and levels maintained with supplements if necessary.
• Frequency of administration may be every 4 weeks (bisphosphonate and denosumab) or every 12 weeks for bisphosphonate.

• Once initiated, the minimum duration of treatment should be 2 years.

7. Targeted Therapies Against Specific Tumor Alterations

ATA // ESMO // NCCN

Regulatory Approvals

Larotrectinib and entrectinib are FDA approved for NTRK fusion-positive advanced cancers. selpercatinib and pralsetinib are FDA approved for advanced RET fusion-positive thyroid cancers. Larotrectinib is European Medicines Agency approved. 

• In advanced unresectable and/or metastatic radioiodine refractory thyroid cancer, data support gene-specific therapy.  
• A TRK-specific drug may be considered in patients with NTRK fusion-positive advanced unresectable and/or metastatic radioiodine refractory thyroid cancer who are deemed to be in need of systemic therapy.  
• Patients with RET fusion-positive advanced unresectable and/or metastatic radioiodine refractory thyroid cancer in need of systemic therapy may be treated with a RET-specific drug, where available.  
• BRAF-specific inhibitors have demonstrated potential benefits for treating patients with BRAF V600E mutation-positive advanced unresectable and/or metastatic radioiodine refractory thyroid cancer who are deemed to be in need of systemic therapy 
• ALK fusions drive a small percentage of DTCs. Several case reports are available detailing activity of ALK-specific inhibitors.  
• There are no targeted therapies that have emerged that offer clear benefit to RAS mutation-positive advanced unresectable and/or metastatic radioiodine refractory thyroid cancer. Participation in gene-specific clinical trials is strongly encouraged.^​1,3,4​

8. Indications for Somatic Tumor Genetic Testing (DNA/RNA)

ESMO // NCCN

A. Aggressive Tumor Types, Progressive Metastases, RAI Refractory Disease

Regulatory Approvals

• In advanced, progressing radioiodine refractory thyroid cancer, patients should be considered for clinical trials. In the absence of an appropriate clinical trial, somatic tumor genetic testing should be considered to identify actionable targets such as:
  • BRAF mutations (US FDA approval for anaplastic thyroid cancer).
  • RET mutations (US FDA approval for medullary thyroid cancer).
  • NTRK fusions (US FDA agnostic indication).
  • RET fusions (US FDA approval for RET-mutated thyroid cancer including medullary, differentiated and anaplastic thyroid cancer.
• In addition, assessment of tumor mutational burden should be considered for progressive radioactive iodine refractory thyroid cancer, with consideration for immunotherapy in patients with high mutational burden.

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