Year : 2022 | Volume
: 10 | Issue : 1 | Page : 6--13
Utility of American Thyroid Association Guidelines 2021 for management of anaplastic thyroid carcinoma in Indian setting
Kaustubh D Patel1, Dushyant Mandlik1, Aditya Joshipura1, Karan Gupta2,
1 Department of Head and Neck Surgical Oncology, Aastha Oncology Associates, HCG Cancer Centre, Ahmedabad, Gujarat, India
2 Department of Head-Neck Surgery, Medanta-The Medicity, Gurugram, Haryana, India
Kaustubh D Patel
Department of Head and Neck Surgical Oncology, Aastha Oncology Associates, HCG Cancer Centre, Ahmedabad, Gujarat
Though the incidence of anaplastic thyroid cancer (ATC) is minimal amongst thyroid cancers, the outcomes have remained dismal. As significant advances have happened after the 2012 guidelines, American Thyroid Association (ATA)-is a leading body, has recently released updated evidence-based guidelines of ATC in 2021. A need to interpret this guideline in the Indian context was perceived. The 2021 ATC guidelines by ATA, with relevant literature, were reviewed. The recommendations for specific subcategories were compiled. Relevant information pertaining to the Indian scenario was discussed with specific subcategories with Indian evidence. Future direction observations were shared. ATA has provided practical and updated guidelines for ATC. There are some region-specific considerations in the implementation of recommendations. A well-organized research approach and resource allocation are required to optimize ATC management in India.
|How to cite this article:|
Patel KD, Mandlik D, Joshipura A, Gupta K. Utility of American Thyroid Association Guidelines 2021 for management of anaplastic thyroid carcinoma in Indian setting.J Head Neck Physicians Surg 2022;10:6-13
|How to cite this URL:|
Patel KD, Mandlik D, Joshipura A, Gupta K. Utility of American Thyroid Association Guidelines 2021 for management of anaplastic thyroid carcinoma in Indian setting. J Head Neck Physicians Surg [serial online] 2022 [cited 2022 Jul 4 ];10:6-13
Available from: https://www.jhnps.org/text.asp?2022/10/1/6/347996
The incidence of thyroid cancer has been on an increase around the world in the last three decades. The majority of the newly diagnosed cases are of differentiated thyroid cancers (DTC), with papillary thyroid cancer being the most common. Less than 1% of these newly diagnosed cancers are reported as anaplastic thyroid carcinomas.,
Globocan 2020 data suggested that an estimated 20,432 new cases of Thyroid cancer were diagnosed in India in 2020, with Crude rate of 1.5 per million population, and age-standardized rate for India of 1.4., The last population-based cancer registry from India projects that 38,574 new cases of thyroid cancer would be seen in India in 2025.
Anaplastic thyroid cancer (ATC) is the most aggressive form of cancer of the thyroid, with a dismal median survival of 5 months and 20% 1 year overall survival. Seshadri in his editorial has rightly named ATC as “the viper in the pit” because of its rapid progress and high mortality.
American Thyroid Association (ATA) first released a comprehensive guideline for ATC Management in 2012. Over the last few years, there has been a tremendous development in the management of this disease, resulting in the release of a new guideline in 2021. This guideline takes into account the current evidence, ongoing research, and best practice recommendations.
In this article, we have tried to evaluate the recommendations, understand the rationale behind them and assess their applicability in the Indian context.
Diagnosis of Anaplastic Thyroid Cancer: Cytology and Core Biopsy, Histopathology Cytology and Pathology Procedures
Fine-needle aspiration (FNA) cytology is the first investigation for any thyroid swelling to reach a diagnosis and in majority (>60%) of the cases diagnosis can be reached with certainty on fine-needle aspiration cytology (FNAC) only, At the same time, it also has inherent diagnostic challenges including inter-observer variability and low diagnostic yield which may need another modality, like core biopsy (preferably ultrasound guided) to reach a definitive diagnosis. In a series by Pradhan et al., 17% of the patients required diagnosis by core biopsy as FNA was not conclusive. In addition, ATC has many histopathological variants. For diagnosis of the same and to run immunohistochemistry (IHC), molecular analysis, or genomic study, sometimes the yield of FNAC and cell blocks is not adequate, requiring core biopsy. Open biopsy should be a rarity.
Although there is always a high index of suspicion of ATC for a rapidly growing thyroid tumor, there are many differential diagnoses for the same which can be confirmed on IHC. The following panel is recommended to help differentiate between differentiated thyroid cancer, poorly differentiated thyroid cancer, ATC, medullary thyroid cancer, Squamous cell carcinoma, and lymphoma of thyroid: pan-cytokeratins, Thyroglobulin, Thyroid-transcription factor 1, BRAFV600E, PAX8, Ki-67, Chromogranin, Calcitonin, Carcinoembryonic antigen, p53, CD45, other lymphoid markers. Other rare differentials can be sarcomas, spindle cell form of melanoma, metastasis from other solid tumors, and squamous metaplasia.,
ATA 2021 recommends: 
- FNA cytology can play an important diagnostic role in the initial evaluation of ATC, but parallel core biopsy may be necessary for definitive diagnosis and to obtain sufficient material for molecular interrogation
- Every effort should be made to establish a diagnosis via biopsy before proceeding with surgical resection, as surgical resection may be inappropriate.
Jambhekar et al. in their study have evaluated the role of IHC in the Indian scenario. They have stressed on the need for quality assurance, standardization, cost, need to develop standard algorithms, addressing issues of nonconcordance and long turnaround time, in the Indian scenario. All these factors need to be kept in mind while dealing with ATC, where the diagnosis can be challenging and timing of diagnosis and timely initiation of treatment is critical.
Intraoperative Frozen Section
Intraoperative frozen section should be used to guide assessment of margin and tumor extent and to get a representative tissue for final diagnosis in case of query when a high index of suspicion is found in an unequivocal DTC by the surgeon. Final diagnoses of ATC should not be made on the frozen section.
Most of the tertiary care cancer centers in India are well equipped with frozen section facilities and dedicated surgical pathologists.
Histopathological diagnosis still remains the gold standard of diagnosis. It also helps to establish if there is a component of coexistent differentiated thyroid carcinoma. This also rules out the possibility of metastatic tumor, thus confirming the primary diagnosis of ATC.
ATA 2021 recommends:
- Routine surgical pathology evaluation of resection specimens should focus on confirming a definitive diagnosis of ATC, documenting the extent of disease, and defining the presence of any coexisting DTC and/or other pathologies. The proportion of tumor that represents ATC should also be documented
- Once ATC diagnosis is considered, assessment of BRAFV600E mutation should be expeditiously performed by IHC and confirmed/expeditiously assessed by molecular testing
- Molecular profiling should be performed at the time of ATC diagnosis to inform decisions related to the use of targeted therapies, especially as there are now Food and Drug Administration approved mutation-specific therapies in this context.
Gene mutation studies may be helpful to obtain information on mutational profiles of ATCs in a primary diagnostic setting or as a tool to initiate or monitor response to targeted therapy.
Targeted next-generation sequencing panels, pan-cancer or thyroid specific, which offers results in 1–2 weeks, are all available in India and should be sent as early as possible in the diagnostic work-up of thyroid swelling suspected to be an ATC clinically to help in timely initiation of treatment.
Initial Evaluation: Laboratory, Biopsy and Imaging Procedures
Initial important staging investigations for a case of rapidly increasing thyroid swelling, suspected or diagnosed as ATC on pathology are laboratory test (complete blood count, blood chemistry panel, thyroid function test), cross-sectional imaging (fluorodeoxyglucose [FDG] positron emission tomography-computed tomography [PET CT], CT scan, magnetic resonance imaging [MRI]), office laryngoscopy, gene mutation assessment (e.g., BRAF), etc., These help to formulate an initial treatment strategy for the case.
ATA 2021 recommends:
- Initial radiological tumor staging should include cross-sectional imaging, in particular, CT neck, chest, abdomen, and pelvis with contrast (or MRI), and, if available, FDG PET/CT. Contrast-enhanced imaging of the brain (MRI preferred) should also be performed, if clinically indicated
- Every patient with ATC should undergo evaluation of the vocal cords at initial presentation, and thereafter based upon changing symptoms.
Shoukat Hussain Khan in his article has discussed the availability of PET imaging in India and its future. The approximate total installed PET-CT machines were 108 in the year 2015, with a significant number of CT and MRI machines across the Country. Practically every tertiary cancer care center in India now has a PET-CT installation and every major city in the Country has the facility of cross-sectional imaging available. Although India is far behind if we talk about PET units per million population compared to China, Japan, and Korea, the centers are rapidly coming up. This eases up the burden and challenge of the initial evaluation of ATC in India and thus any patient suspected to have ATC should undergo an upfront cross-sectional imaging and PET-CT if available as a part of the initial diagnostic work-up.
Establishing Goals of Care
A multidisciplinary team discussion with subspecialists who may be involved in the patient's care including palliative care experts should be convened in every case of ATC before starting treatment. The decision-making ability of the patient should be taken into consideration, and in case the patient is incapable, a surrogate decision-maker must be identified for future decisions.,
ATA 2021 recommends:
- Comprehensive disease-specific multidisciplinary input should be attained before defining “goals of care” or undertaking therapeutic discussions with patients. Those involved in management decisions should include specialists highly experienced in treating ATC
- The treatment team should include palliative care expertise at every stage of patient management to help with pain and symptom control, as well as addressing psychosocial and spiritual issues
- The treatment team should engage hospice care for ATC patients who decline therapies against their tumor intending to prolong life, yet who still require symptom and pain relief spanning the remainder of their illness
- At all stages of palliative care and hospice care in ATC patients, practitioners should be aware of family systems, and how they affect patient decision-making.
Goyal et al. reported that a patient of advance thyroid malignancy should receive palliative support in the form of disease management, symptom control, and psychosocial care. Palliative care should not only include physical symptoms management but also cover psychological, spiritual, and social aspects of care. Integrated care pathway should be opted, especially for the patients who are at the last stage. In India, except for high-end tertiary cancer centers, there is a lot of work that needs to be done to establish multidisciplinary tumor board management and palliative care departments. Furthermore, there are very few onco-psychology training centers to provide for the huge need across the country. Hence, a dedicated effort is needed to look after the psychological and emotional needs of the patient with a grave diagnosis.
Surgical Management of Anaplastic Thyroid Cancer
Evaluation of extent of disease for surgical intervention
Patients with ATC should have rapid and accurate staging, as this will determine whether the patient is a surgical candidate or not and what type of surgical intervention is needed or possible.
Office endoscopy is a standard examination practice to assess the mucosal surfaces adjacent to the thyroid gland. Inspection should extend from the pharynx, through the larynx and subglottis and into the trachea using topical anesthesia, which is followed by imaging as discussed in initial assessment.
Two important criteria are used to determine curative resectability:
- Distinguishing between locoregionally confined disease and those with distant metastatic disease
- Defining the extent of local invasion and the structures involved.
In patients with only locoregional disease (stage IVA/IVB), the determination of whether the tumor is resectable should be based on what structures are involved, whether a satisfactory resection could be achieved (R0/R1), and whether resection of the involved structure would result in significant morbidity or mortality in the context of the patient's goals of care.
ATA 2021 recommends:
- For patients with confined (stage IVA/IVB) ATC in whom R0/R1 resection is anticipated, ATA strongly recommends surgical resection
- Radical resection (including laryngectomy, tracheal resections, esophageal resections, and/or major vascular or mediastinal resections) is generally not recommended given the poor prognosis of ATC and should be considered only very selectively after thorough discussion by the multidisciplinary team, also considered in light of new information based upon mutations present and the availability of targeted therapies.
In summary, the resectability of ATC should be determined by routine preoperative imaging (ultrasound, CT, MRI, and/or PET scan) as well as laryngoscopy and often also esophagoscopy and bronchoscopy.
If locoregional disease is present and a negative margin (R0/R1 resection) can be achieved, surgical resection should be considered and is independently associated with longer overall survival.,
In patients with systemic disease, resection of the primary tumor for palliation or prevention of future complications can be considered to avoid current or eventual airway, esophageal obstruction, or major bleeding complications.
Optimal extent of surgery
At the time of initial presentation, only 10% of patients have the intra-thyroid disease, with 40% of patients having extra-thyroid extension of the tumor with or without cervical nodal metastasis and the majority present with widely metastatic disease., It has been seen that patients who had surgical intervention for ATC had a significantly longer median overall survival (8 months) compared with patients who did not have any surgical intervention (median overall survival of 3 months). This may be due to a bias in patient selection (patients with less advanced disease having surgical intervention) as the distribution of extent of disease in these patients was 48.1% stage IVA, 44.4% stage IVB, and 7.5% stage IVC.
Total or near-total thyroidectomy with therapeutic lymph node dissection of the central and lateral neck lymph node compartments is considered optimal surgical treatment in patients with resectable disease. Prophylactic central or lateral neck node dissection in patients with ATC is not indicated.
Given ATC's characteristic rapid progression, attempted surgery should be such that allows for the initiation of systemic therapy in 2–3 weeks. For a scenario requiring tracheal or esophageal resection and reconstruction, such cases would pose risks of significant surgical morbidity along with the prolonged time of healing and delaying the initiation of systemic therapy and thus should be avoided.
Debulking surgery is contraindicated for ATCs as most progress rapidly after surgery.
Gastrostomies and tracheostomies should be used judiciously in patients with ATC considering their extent of disease and metastases.
Considering the healthcare infrastructure in India and the potential morbidities associated with high-risk ATC surgeries, surgical management of ATCs should be attempted at high volume centers with facilities to deal with complications and unpredictable eventualities which might result from such surgeries, and where systemic therapies are readily available.
Radiotherapy and systemic chemotherapy in loco-regionally confined anaplastic thyroid cancer
The decision to give radiotherapy and/or systemic chemotherapy with or without specific targeted therapy and immunotherapy either in the adjuvant settings after surgery or in upfront setting for patients with loco-regionally confined (IV A/IV B) ATC needs to be tailored for an individual based on certain factors like the treatment goal defined for that patient; the performance status; the availability of various treatment modalities at a center; the cost of the treatment and the impact of the treatment on the quality of life of the patient.
The best oncological outcomes in terms of local control and overall survival for loco-regionally confined (IV A/IV B) ATC is classically attained with tri-modality treatment, i.e., Complete or near-complete (R0 or R1) resection of the primary whenever feasible, followed by adjuvant Chemo-radiotherapy. Various studies like the NCDB data analysis or the study by Prasongsook et al. showed survival benefit with tri-modality treatment.,
Furthermore when the various radiation techniques were compared, the survival outcome was found to be significantly better in patients treated with chemotherapy along with intensity-modulated radiotherapy (IMRT) as compared to older modalities of chemo-radiotherapy, with 1-year overall survival improving from 10% to 43%.
However in cases where upfront surgical resection in not feasible, or it is thought that there might be gross disease left behind after surgery (R2 resection), upfront chemo-radiotherapy can be considered both to local control of disease and delay or prevent complications of airway compromise, etc., and also rarely to shrink the primary tumor enough to make it resectable, especially in patients with good performance status and no distant metastasis, like neoadjuvant chemo-radiotherapy.
In the past for thyroid cancer, doxorubicin was given along with radiotherapy. But there is increasing evidence that taxanes (like docetaxel) are better radio sensitizing agents and give better results compared to doxorubicin in ATC. In various studies by Troch et al. and Foote et al. the overall survival improved in patients treated with IMRT along with docetaxel.,
Based on all this literature, ATA in March 2021 came out with the following recommendations for ATC.
- Following R0 or R1 resection, we recommend that good performance status patients with no evidence of metastatic disease who wish an aggressive approach should be offered standard fractionation IMRT with concurrent systemic therapy
- We recommend that patients who have undergone R2 resection or have unresectable but nonmetastatic disease with good performance status and who wish an aggressive approach be offered standard fractionation IMRT with systemic therapy. Alternatively, in BRAFV600E-mutated ATC, combined BRAF/MEK inhibitors can be considered in this context
- In patients with the unresectable disease during initial evaluation in whom radiotherapy and/or systemic (chemotherapy or combined BRAF/MEK inhibitors) therapy render the tumor potentially resectable, we recommend reconsideration of surgical resection
- Among patients who are to receive radiotherapy for unresectable thyroid cancer or in the postoperative setting, IMRT is recommended
- The use of cytotoxic chemotherapy involving a taxane (paclitaxel or docetaxel), administered with or without anthracyclines (doxorubicin) or platin (cisplatin or carboplatin), is recommended in patients treated with definitive-intention radiation
- Among ATC patients with unresectable or advanced disease wishing aggressive therapy, we suggest early initiation of cytotoxic chemotherapy as an initial and potentially bridging approach until mutational interrogation results and/or mutationally specified therapies might be available, and if appropriate.
In the context of India, it needs to be stressed that anaplastic carcinoma thyroid is a rare disease and management of these cases should be done only centers equipped with at least linear accelerator (LINAC) machine to deliver IMRT and medical oncology services. But the big concern in the Indian context is the sparse availability of LINACs throughout the country and a much skewed geographical distribution of LINACs across the country, with majority of the machines concentrated in the North, South, and West zones of the country. The World Health Organization recommends a minimum of 1 teletherapy machine per 1 million population. Even with this minimum criterion, India needs at least 1300 teletherapy machines against the present 545 units in the Country. The aim of treatment at centers which are equipped with both Radiation and Medical Oncology services is to treat the patients of ATC with the desired modalities without any delays, as timely treatment is of the essence when it comes to the management of ATC. Furthermore, the centers should be equipped to manage the toxicities and complications resulting from the treatment to minimize any treatment disruptions.
Systemic therapeutic approaches to locally advanced unresectable/metastatic anaplastic thyroid cancer
If the primary tumor is deemed unresectable or if the disease presents with distant metastasis (IV C) decision to give systemic therapy or just local palliative treatment to ameliorate local symptoms depend on the aim of treatment discussed with the patient; volume of distant metastasis; performance status of the patient; wishes of the patient and the family; financial constraints and availability of newer therapeutic options like targeted therapy, immunotherapy, etc.
As ATC is a very aggressive disease, stress should be placed on molecular testing for actionable targets as early in the diagnosis making as possible so that the targeted therapy if available can be initiated as soon as possible. However in case there is delay in molecular testing, systemic chemotherapy with or without local radiotherapy can be used as “bridging” treatment till the time-specific targeted therapy can be started.
At present, there are many actionable molecular targets identified in ATC with specific drugs available for the same. These targeted therapy and immunotherapy have shown really promising results in the management of ATC, with significantly improved survival. The most common actionable mutation found in ATC is BRAFV600E, which is seen in nearly 50-70% of ATC.,, BRAF-directed therapy with BRAF/MEK inhibitor combination like dabrafenib with trametinib can induce prompt and impressive tumor regression and improved survival.,, Similarly many other actionable mutations, immune markers, antiangiogenic drugs, and mTOR inhibitors have been studied which have shown improvement in survival of advanced ATC.,,,,,,,,,,,,,,,
Based on all this literature, ATA in March 2021 gave the following recommendations for advanced ATC,
- In BRAFV600E-mutated IVC and in unresectable IVB ATC patients who decline radiation therapy, initiation of BRAF/MEK inhibitors (dabrafenib plus trametinib) is recommended over other systemic therapies if available
- In BRAFV600E-mutated unresectable stage IVB ATC in which radiation therapy is feasible, chemoradiotherapy or neoadjuvant dabrafenib/trametinib represents alternatives to initial therapy
- In BRAF nonmutated patients, radiation therapy with concurrent chemotherapy should be considered in an effort to maintain the airway in patients with low burden of metastatic disease
- In NTRK or RET fusion ATC patients with stage IVC disease, we suggest initiation of a TRK inhibitor (either larotrectinib or entrectinib) or RET inhibitor (selpercatinib or pralsetinib), preferably in a clinical trial, if available
- In IVC ATC patients with high PD-L1 expression, checkpoint (PD-L1, PD1) inhibitors can be considered first-line therapy in the absence of other targetable alterations or as later line therapy, preferably in the context of a clinical trial
- In metastatic ATC patients lacking other therapeutic options including clinical trials, we suggest cytotoxic chemotherapy including a taxane and/or an anthracycline or taxane with or without cis-or carboplatin.
In the context of India, it needs to be taken into consideration that the cost of all these therapies is exceptionally high and also not all these targeted drugs and immunotherapy molecules are available in the country. Thus, before making any decision about the initiation of these drugs, the patient and the family should be explained in detail about the intended benefit, financial burden associated with the treatment and also the ease of availability of the drugs.
Future Directives for India
It is the need of the hour to have a multi-institutional database for ATC to compile all the cases from across the country together as the disease is very rare, with each center in the country only seeing few cases every year. With this collaboration and collation of data, it would be possible to devise standard treatment guidelines with the aim of improving the survival for a disease which has a dismal outcome at present. The aim should be to at least attain the survival results of the West. Furthermore, at the same time, there should be stress from the Government to develop more centers of excellence in the field of oncology to overcome the shortage of well-trained oncologists and medical equipment (like LINACs) and drugs and improve the infrastructure at centers already functional across the Country. According to the World Bank data, India spent only 3.54% of its Gross Domestic Product (GDP) on health in 2018. This was even less as compared to our neighbors like Nepal (5.84%) and Afghanistan (9.40%). Our annual % GDP contribution to health is way lower than the world average of 9.85% and way lower than the west like the USA which spends nearly 17% of its GDP on health. Hence, it is essential that the Country and the government realize the shortcomings of our health-care infrastructure and should work to strengthen the same.
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