. 2020 Aug 3;44(3):403–419. doi: 10.1007/s40618-020-01374-7

Table 2.

Recommendations of the American Thyroid Association (ATA) guidelines (2015), Italian Consensus (2018), National Comprehensive Cancer Network (NCCN) (2019), and European Thyroid Association (ETA) Guidelines (2019) regarding the management of BM in DTC

Active surveillance^a	Local treatments	Systemic treatments
ATA guidelines (2015) [32]
Serial controls (3–12 months) In asymptomatic, stable or minimally progressive RAI-refractory disease, with low probability of complications	In case of single or few threatening and/or symptomatic BM. Before or during systemic therapy: • Surgery • RT Alone (for pain relief or palliation) or complementary to surgery (in case of incomplete resection). SBRT (different protocols, maximum 30 Gy) preferable for higher efficacy and limited radiation to the spinal cord • Percutaneous procedures RFA or cryoablation, for rapid and long-lasting pain control; cryoablation can treat larger BM than RFA; frequently associated with cementoplasty (promising in purely lytic BM)	• RAI therapy RAI activity: 100–200 mCi or determined by dosimetry. In case of iodine-avid BM • KIs Approved as first line: sorafenib or lenvatinib. Alone or in combination with local treatments. In rapidly progressive, symptomatic and/or threatening RAI-refractory disease, not otherwise amenable to local control • Bone-directed agents. Bisphosphonates, especially zoledronate, and denosumab. Alone or concomitantly with other systemic/local therapies. For delaying occurrence of SREs and improving symptoms, in case of diffuse and/or symptomatic BM
Italian Consensus (2018) [48]
Controls at regular intervals (3–12 months) In asymptomatic, stable or slowly progressive RAI-refractory metastatic disease, without life-threatening lesions	Strongly suggested whenever progression of the disease or its riskiness are related to a single lesion: • Surgery • RT • Percutaneous procedures	• RAI therapy RAI activity: 100–200 mCi or determined by dosimetry. In case of iodine-avid BM • KI In case of RAI-refractory disease, rapidly progressive, significantly symptomatic and/or with life-threatening lesions not suitable for local therapies • Bone-directed agents Not mentioned
NCCN guidelines (2019) [49]
Periodical controls In asymptomatic and indolent RAI-refractory disease	In case of symptomatic lesions or asymptomatic but in weight-bearing sites: • Surgery • RT • Percutaneous procedures Consider embolization prior to surgical resection to reduce the risk of hemorrhage	• RAI therapy RAI activity: 100–200 mCi or adjusted by dosimetry. In case of known/suspected distant iodine‐avid BM. Consider alternative therapies before RAI administration to prevent invasion/compression of vital structures or pathologic fracture (as a result of TSH stimulation) • KIs Approved as first line: sorafenib or lenvatinib (preferable). For progressive and/or symptomatic RAI-refractory disease • Bone directed agents Intravenous bisphosphonates (e.g. pamidronate or zoledronate) or denosumab in RAI-refractory BM to prevent SREs
ETA guidelines (2019) [50]
Serial controls (4–6 months) In case of slow growth (< 20% in 12–14 months)	In case of progression of a single lesion or more than one lesion within the same organ. Before or during systemic therapy • Surgery • RT For local disease control and pain relief • Percutaneous procedures RFA employed in case of no surgical indication or prior to surgery, to reduce the volume of a lesion. Cementoplasty (alone or in combination with RFA or RT) for lytic BM to prevent pathological fractures and to reduce pain	• RAI therapy Not mentioned^b • KIs Approved as first line: sorafenib or lenvatinib. Alone or in combination with local treatments. In progressive RAI-refractory disease with considerable tumour load and potential clinical complications without systemic treatment • Bone-directed agents Especially zoledronate and denosumab

Active surveillance^a

Local treatments

Systemic treatments

ATA guidelines (2015) [32]

Serial controls (3–12 months)

In asymptomatic, stable or minimally progressive RAI-refractory disease, with low probability of complications

In case of single or few threatening and/or symptomatic BM. Before or during systemic therapy:

• Surgery

• RT

Alone (for pain relief or palliation) or complementary to surgery (in case of incomplete resection). SBRT (different protocols, maximum 30 Gy) preferable for higher efficacy and limited radiation to the spinal cord

• Percutaneous procedures

RFA or cryoablation, for rapid and long-lasting pain control; cryoablation can treat larger BM than RFA; frequently associated with cementoplasty (promising in purely lytic BM)

• RAI therapy

RAI activity: 100–200 mCi or determined by dosimetry. In case of iodine-avid BM

• KIs

Approved as first line: sorafenib or lenvatinib. Alone or in combination with local treatments. In rapidly progressive, symptomatic and/or threatening RAI-refractory disease, not otherwise amenable to local control

• Bone-directed agents.

Bisphosphonates, especially zoledronate, and denosumab. Alone or concomitantly with other systemic/local therapies. For delaying occurrence of SREs and improving symptoms, in case of diffuse and/or symptomatic BM

Italian Consensus (2018) [48]

Controls at regular intervals (3–12 months)

In asymptomatic, stable or slowly progressive RAI-refractory metastatic disease, without life-threatening lesions

Strongly suggested whenever progression of the disease or its riskiness are related to a single lesion:

• Surgery

• RT

• Percutaneous procedures

• RAI therapy

RAI activity: 100–200 mCi or determined by dosimetry. In case of iodine-avid BM

• KI

In case of RAI-refractory disease, rapidly progressive, significantly symptomatic and/or with life-threatening lesions not suitable for local therapies

• Bone-directed agents

Not mentioned

NCCN guidelines (2019) [49]

Periodical controls

In asymptomatic and indolent RAI-refractory disease

In case of symptomatic lesions or asymptomatic but in weight-bearing sites:

• Surgery

• RT

• Percutaneous procedures

Consider embolization prior to surgical resection to reduce the risk of hemorrhage

• RAI therapy

RAI activity: 100–200 mCi or adjusted by dosimetry. In case of known/suspected distant iodine‐avid BM. Consider alternative therapies before RAI administration to prevent invasion/compression of vital structures or pathologic fracture (as a result of TSH stimulation)

• KIs

Approved as first line: sorafenib or lenvatinib (preferable). For progressive and/or symptomatic RAI-refractory disease

• Bone directed agents

Intravenous bisphosphonates (e.g. pamidronate or zoledronate) or denosumab in RAI-refractory BM to prevent SREs

ETA guidelines (2019) [50]

Serial controls (4–6 months)

In case of slow growth (< 20% in 12–14 months)

In case of progression of a single lesion or more than one lesion within the same organ. Before or during systemic therapy

• Surgery

• RT

For local disease control and pain relief

• Percutaneous procedures

RFA employed in case of no surgical indication or prior to surgery, to reduce the volume of a lesion. Cementoplasty (alone or in combination with RFA or RT) for lytic BM to prevent pathological fractures and to reduce pain

• RAI therapy

Not mentioned^b

• KIs

Approved as first line: sorafenib or lenvatinib. Alone or in combination with local treatments. In progressive RAI-refractory disease with considerable tumour load and potential clinical complications without systemic treatment

• Bone-directed agents

Especially zoledronate and denosumab

BM bone metastases, Gy gray, mCi milliCurie, RAI radioactive iodine, RT radiotherapy, SBRT stereotactic body radiotherapy; RFA radiofrequency, SREs skeletal-related events, KIs kinase inhibitors

^aUnder TSH suppressive thyroid hormone therapy

^bThese guidelines specifically regards RAI-refractory disease