Recurrent & Persistent Disease

Management Recommendations

Definitions

Persistent Disease: disease left following initial surgery due to less than an R0 resection of the primary and/or regional lymph node disease.

Recurrent Disease: a biochemical and/or identification of new structural disease in a patient believed to have been rendered disease free.

Local Recurrence: evidence of thyroid cancer in the thyroid bed.

Regional Recurrence: nodal disease in either the central, retropharyngeal or the lateral compartments or a combination of these nodal basins.

Distant Recurrence: disease recurrence beyond the regional nodal basins. 

1. Local Recurrence

Important to distinguish primary recurrence in the thyroid bed vs. residual thyroid tissue vs. nodal recurrence in the central neck. Primary thyroid recurrences are usually found at the insertion of the RLN and the cricothyroid muscle—as such it may result in the loss of the RLN function. This is in contrast to central lymph node recurrences that usually can be dissected free of the RLN. Residual thyroid may have been left to protect the RLN and parathyroid glands and it is important to read the operative note for clues that this is the case.

2. Regional Nodal Disease

ATA // NCCN

Small volume (< 1 cm) recurrent nodal disease can often be indolent and managed through active surveillance. However, bulky, progressive or invasive nodal disease is often best treated surgically.

The primary factors to consider prior to surgery for recurrent disease in the neck is the balance between:

1. Risks of revision surgery, which are often greater than primary surgery, and 
2. Surgical resection generally represents the optimal treatment of macroscopic nodal disease. 
3. The availability of surgical expertise in performance of revision thyroid cancer surgery must be considered.¹

Key considerations to choose when surgery is indicated for recurrent or persistent nodal disease.^​1–3​

1. Absolute size of the lymph nodes.
2. The location of the nodal disease—level VII may require sternotomy, level VI reoperation may place the parathyroid glands and RLN are at risk, retropharyngeal nodes may place cranial nerves as well as key vascular structures at risk.
3. Virgin versus re-operative territory. 
4. Rate of growth of structural disease or doubling time of thyroglobulin.
5. Vocal cord paralysis contralateral to the persistent central disease.
6. Known systemic metastases.
7. Significant comorbidities for surgery. 
8. The patient’s prognosis/life expectancy.
9. Invasion into visceral/critical anatomic structures.
10. Patient preferences.

Several biologic factors can also predict the risk of active surveillance versus the need for recurrent surgery and should factor into the decision-making process. Factors which support the need for surgery include:^​2,3​

1. Non-iodine avid disease/FDG-PET-avid disease
2. Aggressive histology
3. More advanced initial staging and extrathyroidal extension
4. Extranodal extension at primary surgery
5. Molecular factors that predict more aggressive biology

Workup for metastatic disease and impact of distant metastases on treatment of nodal and visceral recurrences 

All guidelines are silent on the work up needed for distant metastases when considering treatment of locoregional disease. Likewise, the impact of distant metastases on whether patients with locoregional disease should undergo treatment is not delineated. 

CT imaging of the chest, abdomen, and pelvis, brain MRI, or CT/PET imaging is warranted in patients who are clinically suspected of having extensive disease burden. Advanced metastatic disease involving visceral organs or bones may impact performance status and pose a significant threat to the patient’s life, thus compromising the potential success or wisdom of treatment of locoregional recurrent disease.

3. Distant Disease Recurrence

ESMO // JAES // NCCN

A. Workup & Decision-Making^​3–5​

Rising Tg in Absence of Demonstrable Structural Disease

Early detection of distant metastases does not likely improve survival, and distant metastases are primarily diagnosed by incidental findings from laboratory/imaging studies (or sometimes clinically).

Presently, there is no panel consensus regarding the work up of patients with rising Tg levels or persistently elevated Tg levels.

Routine imaging is not warranted. However, neck ultrasounds, CT or FDG-PET imaging should be considered to evaluate for distant disease in patients with elevated Tg levels whose post-iodine scans are negative.

B. Specific Site Management

Role of Directed Therapy in Addition to Local Therapy

Local therapies include surgery, thermal ablation (including radiofrequency ablation, laser ablation, cryotherapy) and/or external beam radiation therapy (EBRT) (including stereotactic radiotherapy and intensity-modulated radiotherapy).^{​1,3–5​}

Local therapy for distant metastases should be considered in isolated metastases or oligometastatic disease when metastases are progressive, symptomatic or at high risk of causing symptoms or complications.^​1,3,4​

Lung metastases: Local therapy should be considered for progressive or symptomatic, oligometastatic or oligoprogressive lesions. Thermal ablation or stereotactic radiotherapy are valid alternatives to surgery.^​1,3,4​

Bone metastases: Local therapy should be considered for symptomatic lesions or preventively for asymptomatic lesions in weight-bearing sites or at high risk of fracture.^​1,3,4​

Brain metastases: Radiation therapy (stereotactic or intensity-modulated) or neurosurgery should be considered for solitary brain metastases. EBRT (stereotactic or intensity-modulated radiation therapy) should be considered for multiple brain or central nervous system metastases.^​1,3,4​

4. Management of Recurrent/Persistent Thyroid Cancer

ATA // AAES // NCCN

Prior to embarking on surgical management or any of the alternative therapeutic maneuvers such as radiofrequency ablation or alcohol injection, the lymph node(s) should be biopsied in order to confirm recurrence, unless it is located in a precarious position (i.e. retrojugular, retrocarotid, mediastinal, or retropharyngeal).

A. How to Manage a Patient with Recurrent/Persistent Nodal Disease

i. Patient Specific Variables

Variables	Active Surveillance	Surgery
Absolute size of lymph nodes (any dimension)	≤ 0.8 cm (central compartment) < 1 cm (lateral compartment)	> 0.8 cm (central compartment) ≥ 1 cm (lateral compartment)
Rate of lymph node growth on serial imaging	Minimal/slow ( < 3–5 mm/year )	Progressive ( > 3–5 mm/year )
Vocal cord paralysis contralateral to the paratracheal nodal basin where the positive lymph node is located (next to only working RLN)	Strongly consider if node is stable	Consider surgery if node is increasing in size and expertise for preoperative surgery available
Known systemic metastases	Progressive distant disease outpacing nodal metastasis	Stable distant metastasis, but nodal disease threatens vital structures
Comorbidities for surgery	Yes	No
Invasion into/proximity to critical anatomic structures	No	Yes
Good long-term prognosis	No	Yes
Patient wishes to undergo surgery	No	Yes
Disease likely to be identified intraoperatively	No	Yes
Risk of postoperative functional deficit(s)	Yes	No

ii. Biological Considerations

Variables	Active Surveillance	Surgery
RAI-avid	Yes	No (unless other criteria for surgery met)
FDG-PET-avid	No	Yes
Aggressive histology	No	Yes
Extrathyroidal extension of primary tumor	No	Yes
More advanced initial T stage ( > 4 cm) and more advanced nodal disease	No	Yes
Extranodal extension (features of nodes at initial surgery)	No	Yes
Molecular prognosticator for aggressive biology	No	Yes
Thyroglobulin*	Thyroglobulin levels stable	Thyroglobulin levels increasing

iii. Surgical Technical Considerations

Variables	Active Surveillance	Surgery
First recurrence in that compartment?	No	Yes
Recurrent or persistent disease in previously formally dissected compartment or multiple dissections in same compartment	Stable disease	Limited/focused dissection if progressive disease and threatening important structures
Availability of surgical expertise to perform the surgery	No	Yes

B. Nodal Disease: Type of Intervention

• Active surveillance
• Surgery, extent
• Alcohol ablation
• Radiofrequency Ablation (RFA)

Surgery for patients with residual/recurrent neck disease in a previously unoperated compartment follows the general principles of complete compartmental resection (e.g. lateral neck dissection for a patient with residual/recurrent lateral neck disease after previous thyroid/central compartment surgery). Therapeutic revision central and/or lateral compartmental neck dissection in a previously operated compartment may be performed as a focal resection of specific regions and nodes rather than a comprehensive compartmental dissection, depending on the extent of previous surgery in that compartment. In either case, there are a number of variables which should be considered in the setting of a multidisciplinary discussion (See table). 

The decision to offer surgery for recurrent disease in the neck is made considering several opposing decision elements: 

1. risks of revision surgery; 
2. the understanding that surgical resection generally represents the optimal treatment of macroscopic gross disease; and 
3. the understanding that active surveillance is often a safe short-term strategy for all but the most aggressive differentiated thyroid cancers.^{​1–3,6​}

RAI: Empiric RAI therapy is generally not recommended in patients with structurally identifiable disease that is not RAI avid. Empiric RAI is unlikely to have a significant tumoricidal effect due to low iodine uptake.^​1,3​

EBRT: External beam radiation therapy can be used to treat isolated metastatic disease foci, but it has no role in most patients with resectable lymph node metastases. In patients with loco-regional recurrence that is not surgically resectable modern ERBT techniques (intensity modulated radiotherapy and stereotactic radiation) should be considered, particularly in patients with no evidence of distant disease. This treatment modality’s efficacy has been suggested only in retrospective studies on limited numbers of patients.^​1,3​

Systemic Therapy: Systemic therapies such as kinase inhibitors for recurrent loco-regional disease are considered only after surgical options have been exhausted.^​1,3​

Ethanol Ablation: Ethanol ablation may be considered in patients who are poor surgical candidates. Focal ethanol ablation treatment represents a nonsurgical form of berry picking, and formal neck compartmental dissection is still first-line therapy in DTC patients with residual/recurrent disease in the neck.^​1,3​

RFA: The use of radiofrequency ablation (RFA) in the treatment of recurrent thyroid cancer has been associated with a mean volume reduction in a majority of cases and complete disappearance of the metastatic foci in some cases. Multiple treatment sessions are often required. Complications include pain, skin burn, and voice changes. RFA represents a nonsurgical form of berry picking, and formal neck compartmental dissection is still first-line therapy in DTC patients with residual/recurrent disease in the neck. RFA may be most useful and preferred over surgical resection in high-risk surgical patients or in patients refusing additional surgery.^​1,3​

5. Management of Recurrent DTC Involving the Upper Aerodigestive Tract (UADT)

ATA // ESMO // JAES // NCCN

A. General Management Considerations

• Biopsy of persistent/recurrent disease should be performed to document presence of disease and determine histology (expert opinion)
• Consideration of grade progression should be determined by an experienced pathologist (expert opinion)
• For gross residual/recurrent PTC or FTC in the neck, cross-sectional imaging with either contrast enhanced CT or MRI should be performed.^​3​
• Potential delay of using RAI treatment is not deemed to be harmful.^​1,3​
• Consider iodine total body scan to assess RAI avidity of recurrent/persistent disease and the presence of regional and distant metastases.^​3​
• FDG PET CT should be considered in patients with recurrent DTC to determine the full extent of local disease and the presence of regional and distant disease.^​1,3​
• Endoscopy should be performed in cases of suspected aerodigestive tract invasion.^​3,4​
• Assessment of laryngeal function by fiberoptic laryngoscopy, indirect mirror laryngoscopy or ultrasound should be performed.^​3,4​
• Strong consideration should be given to referral to a high-volume institution with access to a multidisciplinary treatment team.^​3,7​
• The goals of therapy are either to treat for cure or to treat with palliative intent to prevent asphyxiation due to local tumor growth and invasion.^​1​

B. Observation of Patients With Recurrent/Persistent PTC or FTC

• In disease that is threatening visceral structures, monitoring is not usually considered.^​3​
• If unresectable disease has been radiated and is not RAI avid, then monitoring may be considered if patient is not a candidate for systemic therapy.^​3​

C. Patients With Residual/Recurrent PTC or FTC Disease Amenable to Surgical Resection

• If disease is deemed resectable then consideration of surgery should be given.^​1,3,7​
• Preoperative assessment of vocal cord mobility should be performed and documented.^​3​
• Surgical resection may be done in combination with RAI treatment if RAI imaging is positive.^​1,3,7​
• RAI therapy alone is not considered optimal treatment.^​7​
• Consideration should be given to measuring stimulated Tg and TgAB.^​3​
• A postoperative I¹²³ or I¹³¹ whole body scan should be performed with TSH stimulation. If adequate uptake is confirmed, then administer Radioiodine treatment and obtain post treatment whole body scan.^​3​

If no uptake on diagnostic scan then consider either external beam radiotherapy or monitoring of residual disease or systemic therapy.

D. Role of Adjuvant Therapy in Patients With Resectable Disease

• Consider pretreatment whole body imaging with TSH stimulation
• Administer RAI for remnant ablation or adjuvant therapy

EBRT

E. Management of Patients With Unresectable Recurrent Thyroid Cancer

• For patients with unresectable thyroid cancer invading visceral structures, measurement of stimulated Tg and Tg Antibodies should be done. An I¹²³ or an I¹³¹ whole body scan with TSH stimulation should be done.
  • If adequate RAI uptake, then treat with RAI. 
  • Continue TSH suppression
• For select patients with progressive local disease that is invading visceral structures that are deemed to be unresectable and non-RAI avid, then initial management with external beam radiotherapy should be considered.^​3​
• Systemic therapies may be considered.    
• Genomic testing should be considered and if actionable mutations are identified then consider systemic therapy.^​3​
• Lenvatinib or sorafenib should be considered.
• Vemurafenib and/or Dabrafenib should be considered for BRAF positive cancers.
• Larotrectinib or entrectinib should be considered for patients identified with NTRK gene fusion cancers.    
• Selpercatinib should be considered for patients with RET fusion positive cancers.
• Pembrolizumab should be considered for patients with tumor mutational burden high tumors (TMB-H, > 10 mut/Megabase).
• Consider referral to Clinical trial.
• In patients with symptomatic invasive tumors causing bleeding and/or obstruction, local treatment such as laser resection should be considered prior to the start of antiangiogenic multikinase inhibitors.^​4​

F. Recurrent Hurthle Cell Cancers

• For recurrent Hurthle Cell cancers involving visceral structures, surgery is preferred if deemed resectable.^​3​
• Consider RAI therapy either instead of surgery or postoperative, if RAI imaging positive (round table topic).
• For select patients with unresectable progressive disease that is not RAI avid then consider EBRT.^​3​
• For unresectable progressive disease consider genomic testing to identify mutations that can be targeted and tumor mutational burden (TMB).
• Consider Lenvatinib or Sorafenib.^​3​
• In patients with TMB-H (> 10 mut/Mb) tumors consider Pembrolizumab.^​3,7​

G. Decision to Intervene

Resection of disease involving the visceral structures and the decision to sacrifice the RLN if invaded by disease should be based on consideration of the following factors:

• Disease stage
• Location and extent of disease in the neck
• Risk of surgically related complications
• Comorbid conditions
• Overall prognosis related to the disease and other conditions
• Anticipated quality of life following surgery
• The available skills and experience of the treatment team
• Patient and caregiver preference
• The patient’s life expectancy^​7​

Surgical management of recurrent thyroid cancer involving visceral/neurologic/vascular structures.

6. Role of RAI in Recurrent/Persistent Thyroid Cancer

ATA // ESMO // JAES // NCCN

There are several roles for RAI in the management of recurrent/persistent thyroid cancer. Diagnostic whole body scanning may be a useful tool in the follow-up of patients with biochemical or structural evidence of persistent disease, or indeterminate structural findings.  

18F-FDG-PET scanning may also be appropriate to stage the extent of locoregional recurrent/persistent disease, particularly in the presence of poorly differentiated thyroid cancers, or widely invasive follicular carcinoma or invasive Hurthle cell cancer particularly if Tg elevated and/or high risk pathology.^​1,3,4​

If locoregional recurrent or persistent thyroid cancer is identified, surgery is the preferred treatment particularly in the presence of bulky or otherwise resectable disease. However, RAI therapy is recommended in several scenarios for recurrent / persistent thyroid cancer.

• Locoregional disease detected by RAI diagnostic scan (I¹²³ or low dose I¹³¹), particularly if small volume disease.
• Post-surgical adjunctive treatment, particularly if disease previously identified on RAI imaging (diagnostic I¹²³ / I¹³¹ or post-therapy scan) and residual disease is suspected.
• Empiric therapy if significantly elevated Tg level but negative RAI diagnostic scan.

Appropriate preparation for RAI treatment should be used, including low iodine diet, baseline testing and a preference for thyroid hormone withdrawal in high-risk patients. It is recognized that recombinant human TSH preparation is an alternative for patients with intermediate risk disease or significant comorbidity that may preclude thyroid hormone withdrawal.^{​1,3,4,7​}

It is important that a post therapy whole body scan (with or without SPECT/CT) is performed after RAI administration to assist in disease staging and document the RAI avidity of any structural lesion.^​1,3,7​ If there is a satisfactory response to RAI-avid disease, treatment may be repeated after 6–12 months. However, it is important that characteristics of RAI refractory disease are identified and if present, no further RAI therapy is administered.

References

1. 1.

   Haugen B, Alexander E, Bible K, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-133. doi:10.1089/thy.2015.0020
2. 2.

   Tufano R, Clayman G, Heller K, et al. Management of recurrent/persistent nodal disease in patients with differentiated thyroid cancer: a critical review of the risks and benefits of surgical intervention versus active surveillance. Thyroid. 2015;25(1):15-27. doi:10.1089/thy.2014.0098
3. 3.

   Haddad RI, Nasr C, Bischoff L, et al. NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2018. J Natl Compr Canc Netw. Published online December 2018:1429-1440. doi:10.6004/jnccn.2018.0089
4. 4.

   Filetti S, Durante C, Hartl D, et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019;30(12):1856-1883. doi:10.1093/annonc/mdz400
5. 5.

   Sugitani I, Ito Y, Takeuchi D, et al. Indications and Strategy for Active Surveillance of Adult Low-Risk Papillary Thyroid Microcarcinoma: Consensus Statements from the Japan Association of Endocrine Surgery Task Force on Management for Papillary Thyroid Microcarcinoma. Thyroid. 2021;31(2):183-192. doi:10.1089/thy.2020.0330
6. 6.

   Patel K, Yip L, Lubitz C, et al. Executive Summary of the American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults. Ann Surg. 2020;271(3):399-410. doi:10.1097/SLA.0000000000003735
7. 7.

   Ito Y, Onoda N, Okamoto T. The revised clinical practice guidelines on the management of thyroid tumors by the Japan Associations of Endocrine Surgeons: Core questions and recommendations for treatments of thyroid cancer. Endocr J. 2020;67(7):669-717. doi:10.1507/endocrj.EJ20-0025