Successful Treatment of Anaplastic Thyroid Carcinoma with a Combination of Oral Valproic Acid, Chemotherapy, Radiation and Surgery

Abstract

Abstract. Anaplastic thyroid carcinoma (ATC) is the most aggressive of thyroid cancers whose treatment is not yet established and mortality is extremely high. Recent in vitro studies have shown that valproic acid (VA), a newly identified histone deacetilase (HDAC) inhibitor, induces apoptosis, modulates differentiation gene expression of thyroid tumors and enhances the sensitivity of anaplastic cancer cell lines to doxorubicin. We report a case of successful treatment of anaplastic thyroid carcinoma with a combination of oral valproic acid, chemotherapy consisting of cisplatin and doxorubicin, external and intra-operative radiation and surgery. Tumor volume decreased by 50.7% under CT measurement and 44.6% under sonogram measurement over the course of the treatment. No significant rebound of tumor size was observed between each cycle of chemotherapy. Serial cytology performed via fine needle aspiration (FNA) presented a rapidly changing profile of cell types, starting with anaplastic and proceeding through increasingly well differentiated presentations. Only microscopic remnants of ATC cells were found in the histological examination of the resected thyroid. Ga scintigraphy and whole body PET scan six months after surgery revealed no evidence of recurrence or metastasis. As of Nov. 22, 2008, the patient is alive and disease free two years after diagnosis. Case ReportCase A 51 year old male, in otherwise good health, presented with a rapidly growing nodule with mild tenderness on the right side of his throat. He noticed a vague discomfort in his throat on November, 15, 2006, but could not locate the tumor by palpation. By the time he visited his local ENT on Nov. 18, the tumor was not only palpable but also visible as a protruding mass of finger tip size. He was referred to Noguchi Thyroid Clinic on Nov. 22 by his ENT as a possible case of subacute thyroiditis. The thyroid mass was hard and immobile on palpation. Sonogram and rapid FNA revealed the tumor to be ATC. Computerized tomography on the same day showed a thyroid mass of 30 × 41 × 35 mm occupying most of the right lobe of the thyroid with involvement of the anterior neck muscle. The tumor presented with acute pain. There was no evidence of lymph node or pulmonary metastasis. White blood cell count was 8460/µl. The case gauged 1/4 in the Sugitani Prognostic Index. Tc-99m scintigraphy presented a defect in the right lobe of the thyroid compatible to sonogram and CT findings. The patient had no previous history of cancer or thyroid ailments. Clinical CourseThe patient was immediately admitted and started on 1200 mg of oral VA daily, the upper therapeutic dose for epilepsy, and pre-hydrated for chemotherapy

MiR-129-5p is required for histone deacetylase inhibitor-induced cell death in thyroid cancer cells

“…Over the last decade, the explosion of efforts into drug discovery has led to the development of a large group of HDACi, many of which have been shown preclinically to have potent antitumor activity. Moreover, HDACi have been shown to synergize with many anti-cancer agents, including cytotoxic agents such as paclitaxel (Dowdy et al 2006), cisplatin (Strait et al 2005), etoposide and doxorubicin (Marchion et al 2004), HAMLET (Brest et al 2007), or radiotherapy (Noguchi et al 2009). In this study, we showed that miR-129-5p enhanced the antitumor effects of staurosporine, etoposide, and HAMLET when used in combination (Fig.…”

“…In thyroid cancer, several studies have reported that HDACi induce cell death through caspase activation and B-cell CLL/lymphoma 2 (BCL2) downregulation (Greenberg et al 2001, Catalano et al 2005, Mitsiades et al 2005. Moreover, HDACi were shown to sensitize tumor cells to chemotherapy, radiation, and surgery (Catalano et al 2006, Noguchi et al 2009). However, the molecular mechanisms responsible for the antitumor activity of HDACi remain elusive.…”

Autophagy and thyroid carcinogenesis: genetic and epigenetic links

“…The HDAC inhibitor valproic acid (VPA) has been successfully employed in a combination therapy in ATC (Noguchi et al 2009). VPA sensitized ATC cells to paclitaxel (Catalano et al 2007) and to doxorubicin (Catalano et al 2006).…”

The Histone Deacetylase Inhibitor Valproic Acid Sensitizes Gemcitabine-Induced Cytotoxicity in Gemcitabine-Resistant Pancreatic Cancer Cells Possibly Through Inhibition of the DNA Repair Protein Gamma-H2AX

“…Moreover, irradiation-induced DNA repair responses were inhibited by VPA treatment through reduced protein expression of the heterodimers of the 70 and 80 kDa Ku auto-antigens (Ku70/80) and DNA-dependent protein kinase (DNA-PK) in colorectal cancer cell lines LS174T and HCT116 [13]. Clinical studies of VPA in combination with radiation have been reported in various malignant diseases, including anaplastic thyroid carcinoma, high-grade glioma in children, cervical cancer and glioblastoma [14][15][16][17]. Therefore, it is necessary to clarify whether VPA could also be used in combinatorial therapy for PC.…”