Management of Severe Fatigue Induced by Tyrosine Kinase Inhibitor in Radioiodine Refractory Thyroid Cancer

Abstract Context: Medullary thyroid cancer (MTC) is a cancer of the parafollicular C cells that commonly presents with an inherited or acquired RET gene mutation. There is currently no effective systemic treatment for MTC. Objective: The objective of this study was to investigate a systemic therapeutic approach to treat MTC. We studied the sensitivity of an MTC cell line and xenograft to irinotecan, alone and in combination with the tyrosine kinase inhibitor, CEP-751. Results: In TT cell culture and xenografts, irinotecan treatment was highly effective. This effect was augmented by treatment with CEP-751. Treatment of TT cell xenografts resulted in durable complete remission in 100% of the mice, with median time to recurrence of 70 d for irinotecan alone and more than 130 d for irinotecan plus CEP-751. Although irinotecan induced an S phase checkpoint arrest in TT cells, CEP-751 in combination with irinotecan resulted in a loss of this arrest. CEP-751 induced a loss in the induction of the DNA repair program marked by phospho-H2AX and the checkpoint pathway marked by the activated Chk1 pathway. Conclusions: Irinotecan treatment was highly effective in a preclinical model of human MTC, resulting in complete remission in 100% of the xenografts treated. The duration of remission was further enhanced by combination with the kinase inhibitor, CEP-751. These results suggest that irinotecan, alone or in combination, may be useful for the treatment of MTC.

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Dabrafenib Induced Pancreatitis: A Rare Event During RAI- Refractory Treatment of Metastatic Papillary Thyroid Cancer

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1814 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A888-A889

Author(s):

Khary Edwards ◽

David McFadden ◽

Sarimar N Agosto Salgado

Keyword(s):

Acute Pancreatitis ◽

Thyroid Cancer ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Metastatic Melanoma ◽

Cancer Patients ◽

Papillary Thyroid Cancer ◽

Kinase Inhibitor ◽

Papillary Thyroid ◽

Thyroid Cancers

Abstract Dabrafenib, a BRAF selective tyrosine kinase inhibitor (TKI) has been associated with pancreatitis alone, and in combination with trametinib (a MEK pathway inhibitor). We report a case of dabrafenib induced acute pancreatitis in a patient undergoing treatment for metastatic papillary thyroid cancer (PTC). This adverse event has not been previously reported in thyroid cancer patients using dabrafenib. Case: A 61-year-old female with papillary thyroid cancer status post total thyroidectomy with pathology revealing right 7.6cm PTC with extrathyroidal extension and 13/72 metastatic lymph nodes. She received 100mCi of radioactive iodine (RAI). Ten months post-surgery, she underwent revision neck dissection with 3/36 nodes positive for metastatic disease and neck muscle invasion by PTC. Molecular testing demonstrated AKT1 and BRAFV600E mutations. Due to progressive neck and mediastinal tumors, recommendation was to proceed with systemic therapy. Initially started dabrafenib monotherapy; after 3 doses patient developed burning epigastric pain and fever. Examination revealed abdominal tenderness, elevated lipase at 2266 U/L (8-76U/L), mild hyperbilirubinemia and leukocytosis. CT abdomen/pelvis revealed peripancreatic fat stranding consistent with focal acute pancreatitis. No history of alcohol use. Dabrafenib was assessed to be culprit of pancreatitis; with immediate discontinuation of TKI and supportive management patient improved. At present patient is tolerating Lenvatinib therapy. BRAFV600E mutation occurs in 29-83% of thyroid cancers affecting growth, proliferation, survival, migration, and loss of tissue-specific differentiation via the intracellular MEK/ERK pathway1. RAI offers an important treatment modality for thyroid cancer patients, however patients with BRAFV600E are often poor responders or refractory to RAI1. Dabrafenib, a specific BRAFV600E tyrosine kinase inhibitor in combination with trametinib (a MEK inhibitor) is FDA approved for treatment BRAFV600E mutated anaplastic thyroid cancer; furthermore there is evidence on PTC responses including redifferentiation 2. Pancreatitis has been reported in <1% of dabrafenib treated patients as monotherapy and in combination with trametinib in unresectable or metastatic melanoma clinical trials. It was reported in 4% of patients in a NSCLC when used in combination with trametinib. Recurrent pancreatitis when dabrafenib was re-introduced at a lower dose has also been reported3. Furthermore, it was the cause of pancreatitis in a patient with metastatic melanoma 4 months into the treatment in combination with trametinib4. As this treatment option becomes increasingly utilized for metastatic or locally advanced anaplastic/papillary thyroid cancers, endocrinologists should be aware of the potential for dabrafenib induced pancreatitis during monotherapy use or in combination with trametinib.

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Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer

Oncotarget ◽

10.18632/oncotarget.26480 ◽

2018 ◽

Vol 9 (102) ◽

pp. 37662-37675 ◽

Cited By ~ 1

Author(s):

Karine Pozo ◽

Stefan Zahler ◽

Keisuke Ishimatsu ◽

Angela M. Carter ◽

Rahul Telange ◽

...

Keyword(s):

Thyroid Cancer ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Targeted Therapies ◽

Kinase Inhibitor

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Multimodal Treatments and Outcomes for Anaplastic Thyroid Cancer Before and After Tyrosine Kinase Inhibitor Therapy: A Real-World Experience

Acta Endocrinologica ◽

10.1530/eje-20-1482 ◽

2021 ◽

Author(s):

Jun Park ◽

Hyun Ae Jung ◽

Joon Ho Shim ◽

Woong-Yang Park ◽

Tae Hyuk Kim ◽

...

Keyword(s):

Thyroid Cancer ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Effective Treatment ◽

Cause Of Death ◽

Real World ◽

Distant Metastasis ◽

Kinase Inhibitor ◽

Therapy Group ◽

Anaplastic Thyroid Cancer

Background: Anaplastic thyroid cancer (ATC) has dismal prognosis, and there is no effective treatment. We aimed to evaluate the efficacy of tyrosine kinase inhibitor (TKI) therapy in real world clinic, and to suggest the most effective treatment modality according to the combination of treatments. Methods: This retrospective study evaluated clinical outcomes and cause of death with multimodal treatments in patients with ATC at Samsung Medical Center. Results: A total of 120 patients received anti-cancer treatment for ATC. Seventy-seven (64.2%) patients underwent surgery, 64 (53.3%) received radiotherapy, 29 (24.2%) received cytotoxic chemotherapy, and 19 (15.8%) received TKI therapy. In the TKI therapy group, 8 achieved partial response (3 with lenvatinib and 5 with dabrafenib plus trametinib), and 2 patients with lenvatinib showed stable disease. Median progression-free survival (PFS) of the TKI therapy group was 2.7 months (range: 0.1-12.7) and their median overall survival (OS) was 12.4 months (range: 1.7-47.7). Patients who received surgery or radiotherapy for local control showed superior OS than those who did not. In a multivariate analysis, surgery, TKI therapy, younger age, and no distant metastasis were associated with favorable OS. The combination of surgery, radiotherapy, and TKI therapy (median OS: 34.3 months, 6-month survival rates: 77.8%) was the most effective. Compared to the era without TKI therapy, distant metastasis has recently become the major cause of death in ATC over airway problems. Conclusions: Multimodality treatment including TKI therapy demonstrated prolonged survival with dabrafenib plus trametinib as the most effective therapeutic option demonstrated for BRAF mutant ATC patients.

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