The role of chemotherapy and latest emerging target therapies in anaplastic thyroid cancer

Figures & data

Figure 1 The main route of tumor progression and dedifferentiation.

Abbreviations: FA, follicular adenoma; FTC, follicular tumor cell; PTC, papillar thyroid carcinoma; FVPTC, follicular variant of papillary thyroid carcinoma; PDTC/ATC, poorly differentiated anaplastic tumor cancer; PPFP, paired box gene 8-peroxisome proliferator activated receptor; PI3K, phosphoinositide 3 kinase; RAS, rat sarcoma; RAF, rapidly accelerated fibrosarcoma; MEK, mitogen activated kinases; RET, rearranged during transfection; AKT, alpha serine/threonine-protein kinase.

Table 1 Treatment of anaplastic thyroid cancer

Series	Year	No	Therapies	Outcomes	Notes
Voutilainen et al^Citation23	1999	33	S → CRT	1-y DSS = 9.7% (CI: 2.0–25.9)	Resectability (P = 0.0002), metastases (P = 0.0014), RT (P = 0.014), and radioiodine ablation (P = 0.039) = PrF
Tan et al^Citation24	1995	21	S → RT ± CT	mOS = 4.5 m After radical S, mOS = 131 m	T > 6.0 cm (P = 0.004) and female (P = 0.02) = PrF
Pierie et al^Citation84	2002	67	S → RT ± CT	1-y OS = 92%a 3-y OS = 83%a After debulking: 1-y OS = 35% 3-y OS = 0% After no resection: 1-y OS = 4% 3-y OS = 0% (P < 0.0001)	Better OS for RT > 45 Gy than <45 Gy (P = 0.02) – Age ≤70 y – Absence of dyspnea or dysphagia at presentation, T ≤ 5 cm, and surgery (P < 0.05)
Schlumberger et al^Citation26	1991	20	<65 y → doxorubicin (60 mg/m^2) + cisplatin (90 mg/m^2) + RT >65 y → mitoxantrone (14 mg/m^2) + RT	OS > 20 m in 3/20 patients	Multimodal treatment improves OS and LRC. Gross tumor resection should be performed whenever possible
Mitchell et al^Citation27	1999	17	RT twice daily, DT 60.8 Gy	5/17 CR, 7/17 PR, 5/17 SD	High toxicity from esophagitis and dysphagia RR to RT but toxicity was unacceptable
Besic et al^Citation28	2005	188	S → CT ± RT	mOS = 3 m 1-y OS = 13% 2-y OS = 6%	Age, PS, tumor growth, tumor extension, and distant metastases = independent PrF
De Crevoisier et al^Citation29	2004	30	S→2 × CT → RT → 4 × CT CT = doxorubicin (60 mg/m^2) and cisplatin (120 mg/m^2)	3-y OS = 7% (95% Cl: 10%–44%) mOS = 10 m Death due to local PD in 5% and distant PD in 68%, and to both in 27%	Main toxicity was hematologic. High long-term OS with postop CRT
Brignardello et al^Citation22	2007	47	CRT → S → CT or S → CRT or CT		Maximal debulking followed by adjuvant CRT was the only treatment that modified OS (hazard ratio = 0.23, 95% CI: 0.07–0.79)
Haigh et al^Citation21	2000	33	CRT*/CRT* → S	OS = 3.8 m	Surgery improved outcome
Kobayashi et al^Citation30	1996	37	CRT* exclusively	NR	Main toxicity was hematologic. Some long-term OS with postop CRT
Swaak-Kragten et al^Citation31	2009	75	CRT*	1-y OS = 9%	LRC higher in R0/R1 resection or CRT, with best results with S + CRT (CR in 89%)
Vrbic et al^Citation32	2009	16	CRT**	ORR = 25% (95% CI: 7–55) OS = 11.0 m (95% CI: 8.56–13.44)	Long OS with Doxo + cisplatin
Yau et al^Citation33	2008	50	S S + T S + CRT	OS = 97 d	Age ≤65 (P ≤ 0.01), no metastatic disease at presentation (P < 0.01), surgery (P < 0.01), and postop RT = prF CT was not associated with longer OS
Lim et al^Citation34	2007	37	aRT	2-y LRC = 25% PFS = 8% OS = 18%	Better RR and LRC
Yau et al^Citation33	2006	15	S → RT	OS = 237 d	6, 12, 18, and 24-m OS = 33%, 26%, 13%, and 0%, respectively
Wang et al^Citation20	2006	47	SRT vs HRT	OS = 11 m	6-m LRC = 95% (P = 0.0001) with RT at 40 Gy vs 64% RT at <40 Gy. mOS with HRT: 13 m vs 10 m SRT (P = 0.3)
Veness et al^Citation25	2004	18	S + RT	OS = 6.2 m	Single modality correlates with worst prognosis
Haigh et al^Citation21	2001	33	S + RT	OS = 43 m (R0)	mOS = 3.3 m with only CT and RT and palliative resection (P = 0.63)
McIver et al^Citation36	2001	134	S → RT vs S	mOS = 3–5 m	Extent of resection did not affect survival (P > 0.4)
Besic et al^Citation28	2001	162	S → CRT CRT → S		1-y OS preop versus postop CRT (P = 0.17)
Heron et al^Citation38	2002	32	SRT aRT + CT***	2-y OS = 44% PFS = 53% 2-y OS = 52% PFS = 38%	HRT + CT is associated with better OS but not PFS
Nilsson et al^Citation39	1998	81	CRT*/CRT* → S	2-y OS = 90% OS = 4.3 m	OS > 2 y in 10% pts treated with CT + RT + S
Tennvall et al^Citation40	1994	33	aRT + doxorubicin + S	LF = 24%	Preop RT 30 Gy and postop RT 46 Gy + 20 mg doxo-weekly aRT > LRC
Junor et al^Citation41	1992	91	S + RT		Postop RT improve outcomes
Levendag et al^Citation42	1993	51	S + RT	OS = 7.5 m	Achievement of CR is an important goal of therapy
Derbel et al^Citation43	2011	44	S S + RT S + CRT RT	mOS of responders = 28.4 m; mOS of progressive = 5.1 m	mOS significantly lower in pts undergoing palliative surgery
Kim and Leeper^Citation10	1987	41	aRT + CT	CR = 84% LRC = 68% OS = 1 y	aRT + CT is feasible and achieves good response

Notes:

a After complete resection;

* doxorubicin;

** doxorubicin 60 mg/m² and cisplatin 40 mg/m² every 3 weeks;

*** doxorubicin, paclitaxel, vincristine, or cisplatin.

Abbreviations: T, tumor; PrF, prognostic factors (for OS); y, years; m, months; D, days; OS, overall survival; ORR, overall response rate; CI, confidence interval; LRC, loco-regional control; CRT, chemoradiation; CR, complete remission; aRT, altered fractionated RT; SRT, standard RT; HRT, hyperfractionated RT; R0, radically resected; Doxo, doxorubicin; DSS, disease specific survival; RR, response rate; CR, complete response; PR, partial response; SD, standard response; PS, performance status; PD, progressive disease; Preop, preoperative; Postop, postoperative; mOS, median overall survival; S, surgery; CT, chemotherapy; pts, patients; RT, radiotherapy; vs, versus; R1, resection indicated that the margins of the resected parts show tumor cells when viewed microscopically; CDDP, cisplatin.

Table 2 Most significant trials on molecular target therapies used in anaplastic thyroid cancer treatment

Study	Drug	Target	Phase	Outcome
Kim et al^Citation44	Aee788	EGFR VEGFR	P**	Increase apoptosis, inhibit cell proliferation
Fury et al^Citation51	Gefitinib	Multikinase	Phase I	Growth inhibition
Gupta-Ambramson et al^Citation53	Sorafenib	Multikinase	Phase II–III	Growth inhibition
Jin et al^Citation77	AZD6244 + everolimus	MEK inhibitors + mTOR inhibitor	P**	60% growth inhibition with combined MEK and mTOR inhibition
Rosove et al^Citation59	PLX4720	BRAF inhibitors	Case report	^18F-FDG–PET and computed tomography of the chest on day 38 showed nearly complete clearing of metastatic disease
Catalano et al^Citation16	VPA	Deacetylase inhibitors	Phase II	Enhance chemo-sensitivity and radio-sensitivity
Gule et al^Citation56	Vandetanib	Cellular matrix	P**	66%–69% growth inhibition
Cohen et al^Citation52	Axitinib	Multikinase	Phase II	Median PFS = 18.1 m. Decreased sVEGFR-2 and sVEGFR-3 plasma concentrations versus sKIT
Liu and Xing^Citation8	MK2206	PI3K inhibitors	P**	Growth inhibition
Catalano et al^Citation78	Panobinostat	Deacetylase inhibitor	P* and P**	Significant reduction of Ki67 reduce tumor volume and growth
Papewalis et al^Citation79	Everolimus	mTOR inhibitor	P**	Growth inhibition
Nehs et al^Citation70	PLX4720	BRAF inhibitors	P*	Neoadjuvant PLX4720 could be an effective therapeutic strategy for early anaplastic thyroid cancers that harbor the BRAF(V600E)
Savvides et al^Citation71	Sorafenib	Multikinase	Phase II	10% PR 25% stable disease: PFS = 1.9 m, mOS = 3.9 m, 1-y survival OS = 20%
Cooney et al^Citation75	Combretastatin	Tubulin binding vascular disrupting agent	Phase II	33% DCR 1 patient had 30 m PFS
Ha et al^Citation76	Imatinib	Multikinase	Phase II	DCR 75%
Sosa et al^Citation83	Combretastatin	Multikinase	Phase III	mOS = 5 m

Notes:

* Orthotopic mouse model;

** ATC cell lines.

Abbreviations: P, preclinical; mTOR, mammalian target of rapamycin; PR, partial response; SD, stable disease; m, months; OS, overall survival; DCR, disease control rate; PFS, progression free survival; EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor; MEK, mitogen activated kinases; PI3K, phosphoinositide 3 kinases; mOS, median overall survival; ¹⁸F-FDG–PET; ¹⁸F-fluorodeoxyglucose positron emission tomography; VPA, valproic acid; s, serum.

Figure 2 Anaplastic thyroid cancer growth pathways.

Note: The MAPK/ERK/PTEN pathway is a chain of proteins that communicates a proliferation signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
Abbreviations: MAP, Mitogen-activated protein; ZO, zonula occludens; MAPK, MAP kinase; mTOR, mammalian target of rapamycin; ERK, extracellular signal-regulated kinase; PI3K, phosphoinositide 3 kinase; RET, rearranged during transfection; EGFR, epidermal growth factor receptor; RAS, rat sarcoma; RAF, rapidly accelerated fibrosarcoma; PIP, phosphatidylinositol phosphate; PTC, papillary thyroid cancer; AKT, alpha serine/threonine-protein kinase; PTEN, phosphatase and tensin homolog; P, phosphate; PCL, phospholipase C.

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