**6. Staging**

The American Joint Committee on Cancer (AJCC) 8th edition considers all anaplastic cancers as Stage IV. The T category follows the same definitions as those for differentiated thyroid cancers. Intrathyroidal anaplastic cancers form Stage IVA, whereas gross extrathyroidal extension or nodal metastasis form Stage IVB and distant metastasis form Stage IVC.

#### **7. Treatment approach**

Initial therapy in these patients mainly depends on the stage of disease and mutation status. Based on this, various treatment options include surgery, radiation with or without chemotherapy, systemic therapy, and palliation.

Gross resection is the main goal in patients with ATC, but the extent of resection should always outweigh the potentially devastating complications and morbidity of the procedures. Airway assessment and prompt treatment without delay are most important. Securing and maintaining a patent airway is challenging in these patients, but, routine tracheostomy is not recommended as it has not shown any improved outcome in survival or quality of life.

Tracheostomy is recommended in impending airway compromise and in those tumors that will not benefit from debulking.

#### **7.1 Stage IVA**

Stage IVa includes disease confined within the thyroid capsule. Around 2–15% of patients present with Stage IVa disease, in which, total thyroidectomy with a therapeutic central and lateral neck node dissection is recommended [25, 26]. Attaining gross negative margins have shown a significantly better prognosis than those with tumor residue (p < 0.005) [26]. Sugitani et al. reported that, although the benefit from additional therapies for completely resected Stage IVa ATC was not significant, they tend to show better survival with adjuvant radiation compared to those who underwent radical surgery alone (HR: 0.37; 95% CI: 0.121.13; p = .081) [27]. However, for completely resected ATC (R0 resection), additional therapies are not routinely indicated.

#### **7.2 Stage IVB**

Around 35% of the patients present as Stage IVb with extrathyroidal extension or cervical nodal involvement. They benefit from a combined modality approach.

For resectable tumors, total thyroidectomy with central and lateral therapeutic neck dissection followed by adjuvant chemoradiation has shown significantly prolonged cancer-specific survival compared to those who underwent surgery alone or with adjuvant RT alone (HR: 0.45; 95% CI: 0.250.81; p = .0083) [27].

The intensity-modulated RT technique is recommended to get better dose distribution and reduced toxicities [28]. Several authors have reported a dose–response relationship and showed that a dose of more than 60 Gy has shown a good outcome [14, 29, 30]. Commonly delivered radiation dose includes 70 Gy to the gross tumor or 66–70 Gy to the postoperative bed and 54 Gy to the potential microscopic spread region using a standard fractionation schedule [31, 32].

Several chemotherapy agents are used as concurrent, but mostly Doxorubicin 20 mg/m<sup>2</sup> or Paclitaxel 50 mg/m<sup>2</sup> weekly is given [14, 33, 34].

The role of hyperfractionation is not known, as there is poor evidence to show that it is better than conventional fractionation. Also, hyperfractionation is associated with increased toxicity [31, 35, 36].

However, careful patient selection is required as the procedure has an impact on quality of life. Hence, those who get a meaningful clinical benefit should be offered combined modality treatment. The best outcome is seen when adjuvant radiation is started as early as possible, once the patient has recovered from surgery [37].

For unresectable tumors with BRAF mutation, neoadjuvant treatment with Dabrafenib (150 mg twice daily) and Trametinib (20 mg daily) is started to downsize the tumor to facilitate a complete surgical resection [38, 39]. For poor responders of mutation-directed therapies, palliative radiation is an option.

#### **7.3 Stage IVC**

Around 55% of ATC patients present with distant metastasis. Stage IVc has no curative treatment and is fatal. One case series has reported a median survival of 4.2 months in those with distant metastasis at presentation compared to 6 months in

nonmetastatic ATC [34]. Stage IVc is managed with palliative radiation or debulking with or without systemic therapies.

Palliative resection or debulking should be considered to avoid a future or to treat current airway compromise, which may prolong and improve quality of life. As discussed initially, most of the patients are in their 6th or 7th decade. Hence, airway preservation is enough for old age life preservation.

Palliative external beam radiotherapy (EBRT) has a definite role in symptom control for those who have unresectable/metastatic diseases. It helps in reducing the growth of neck mass and thereby alleviates the pressure symptoms. Various schedules are there, but commonly followed ones are 20 Gy in 5 fractions or 30 Gy in 10 fractions.

Systemic therapies include cytotoxic agents, targeted agents, and immunotherapies. If patients have another targetable mutation, such as NTRK, RET fusion, or ALK, they should be enrolled in clinical trials in mutation-directed systemic therapy.

#### **8. Role of cytotoxic therapy**

Chemotherapy is an important independent prognostic factor associated with improved survival [13, 40, 41]. However, data on comparing different chemotherapy regimens in these patients are very limited and underpowered due to the low incidence and aggressiveness of the tumor. In the absence of molecular abnormalities, most commonly given chemotherapy includes a combination of Paclitaxel and carboplatin, Cisplatin and Doxorubicin, Docetaxel and Doxorubicin, Paclitaxel alone or Doxorubicin alone [25]. The role of the combination of Cisplatin and Doxorubicin as well as Paclitaxel as a single agent is being studied in ATC and has shown moderate response [19]. However, all these are based on fairly small single studies that need further validation.

ATC has a very rapid doubling time of 3–12 days, hence, some authors recommend that the chemotherapy regimens should be administered in shorter intervals, on weekly basis rather giving every 3–4 weeks [3, 31]. Systemic therapy protocols are listed in **Table 3**.


**Table 3.** *Systemic therapy protocols.*
