What is the management plan for a patient with advanced Medullary Thyroid Cancer (MTC) characterized by multiple lung metastases, a large tumor invading the recurrent laryngeal nerve, and multiple nodal spreads?

Management of Advanced Medullary Thyroid Cancer with Lung Metastases and Locoregional Invasion

For this patient with progressive, metastatic MTC involving multiple lung metastases, large tumor with recurrent laryngeal nerve invasion, and extensive nodal disease, initiate first-line systemic therapy with cabozantinib or vandetanib immediately, combined with surgical debulking of the primary tumor (avoiding laryngectomy) and consideration of IMRT to the neck within 3 weeks postoperatively. 1

Immediate Surgical Management

• Perform total thyroidectomy with bilateral central neck dissection (level VI) and compartmental-oriented lymph node dissection of involved nodal basins 2
• Preserve the recurrent laryngeal nerve if technically feasible, even if tumor is adherent; laryngectomy is explicitly not appropriate 1
• Avoid elective tracheostomy unless absolutely necessary for airway protection 1
• Ensure preoperative screening for pheochromocytoma and hyperparathyroidism (MEN 2 syndrome) with appropriate α-blockade if positive 1
• Obtain germline RET mutation testing preoperatively or immediately postoperatively, as up to 25% of apparently sporadic cases are hereditary 2, 3

Molecular Testing Priority

• Obtain NGS analysis targeting cancer-associated genes, specifically RET mutations, as the preferred diagnostic approach 1
• RET mutation status directly determines systemic therapy selection and predicts prognosis 1, 4
• RETM918T mutations (present in ~50% of sporadic MTC) predict more aggressive disease and superior response to cabozantinib 1

Postoperative Radiation Therapy

• Administer IMRT to the neck within 3 weeks of surgery, particularly given the extensive nodal disease and recurrent laryngeal nerve invasion 1
• EBRT is indicated for locoregional disease control when there is extensive nodal involvement or invasion of critical structures 1

Systemic Therapy Selection

First-Line Options for Progressive Metastatic Disease:

Cabozantinib and vandetanib are both FDA-approved first-line systemic therapies for progressive, metastatic MTC 1:

• Cabozantinib offers significant PFS and OS advantages in patients with RETM918T or RAS mutations compared to wild-type MTC 1
• Vandetanib is FDA-approved for symptomatic or progressive MTC with unresectable locally advanced or metastatic disease 5
• Both agents have ESMO-MCBS scores of 2, indicating modest clinical benefit 1

Selective RET Inhibitors (Newer Agents):

• Selpercatinib is FDA-approved for RET-mutant MTC in treatment-naïve patients aged ≥12 years 1
• Pralsetinib is FDA-approved for RET-mutant MTC in patients aged ≥12 years 1
• In Europe, selpercatinib is approved only after prior treatment with cabozantinib or vandetanib 1
• These selective RET inhibitors demonstrate clinically important objective response rates in RET-mutant MTC 1

Treatment Algorithm:

Given this patient's presentation with multiple lung metastases, large tumor burden, and extensive nodal disease, systemic therapy should be initiated immediately rather than observed 1:

1. If RET mutation positive: Consider selpercatinib or pralsetinib as first-line (FDA approval) or cabozantinib/vandetanib 1
2. If RETM918T or RAS mutation: Cabozantinib is preferred due to demonstrated OS benefit in this subgroup 1
3. If RET wild-type or mutation unknown: Either cabozantinib or vandetanib are appropriate first-line choices 1

Postoperative Monitoring and Prognostication

• Obtain serum calcitonin and CEA levels at 2-3 months postoperatively 2, 6
• Calculate calcitonin and CEA doubling times from sequential measurements every 6-12 months; doubling times <24 months predict progressive disease and worse prognosis 1
• Postoperative calcitonin >150 pg/mL indicates high likelihood of distant metastases 1, 6
• Maintain TSH in the normal range (0.5-2.0 mIU/L) with levothyroxine replacement only; TSH suppression provides no benefit as C cells lack TSH receptors 1, 2, 6

Imaging Surveillance

• Multimodality imaging including contrast-enhanced CT of neck/chest/abdomen, three-phase liver CT or MRI, and bone scintigraphy 1, 2, 6
• Consider FDG-PET/CT if calcitonin >1,000 pg/mL or doubling time <12 months 2
• Neck ultrasound every 6-12 months for locoregional surveillance 2

Management of Lung Metastases

• Metastasectomy is not the standard approach for multiple lung metastases 1
• Systemic therapy with MKIs is the primary treatment for multiple lung metastases 1
• RFA may be considered only for solitary symptomatic lesions causing specific symptoms 1

Critical Pitfalls to Avoid

• Do not delay systemic therapy initiation in patients with progressive disease, high tumor burden, or symptoms, as these factors predict rapid progression 1, 7
• Do not use radioiodine therapy; MTC cells do not concentrate iodine 1, 2, 6
• Do not suppress TSH below normal range; this provides no benefit and increases cardiac risks 1, 2
• Do not perform "berry-picking" of individual lymph nodes; compartmental dissection improves biochemical cure rates to >80% 2
• Do not use conventional cytotoxic chemotherapy as first-line therapy; MTC responds poorly to these agents 1, 6

Multidisciplinary Care Requirements

This patient requires coordinated care involving surgical oncology, medical oncology, endocrinology, radiation oncology, and palliative care specialists 1:

• Decisions regarding systemic therapy timing must balance tumor aggressiveness against treatment-related toxicity 1, 7, 4
• Patient preference after careful discussion of expected benefits and risks is essential 1
• Management of hormonal symptoms (diarrhea, flushing) from peptide secretion should be addressed as first goal of treatment 1