Treatment of Anaplastic Thyroid Carcinoma with Paclitaxel: Phase 2 Trial Using Ninety-Six-hour Infusion

Abstract

Anaplastic thyroid carcinoma is a rare, lethal disease with no effective systemic therapies. Preclinical studies demonstrated antineoplastic activity of paclitaxel. This prompted a prospective phase 2 clinical trial to determine activity of paclitaxel against anaplastic thyroid carcinoma in patients with persistent or metastatic disease despite surgery or local radiation therapy. Twenty patients, entered through 6 of 12 study sites, were treated with 96-hour continuous infusion paclitaxel every 3 weeks for 1 to 6 cycles; the first 7 patients received 120 mg/m2 per 96 hours and the rest received 140 mg/m2 per 96 hours. Total responses to therapy were assessed using modified criteria with response durability acceptable at 2 or more weeks, due to the exceedingly rapid growth rate of this tumor. Plasma samples were obtained for pharmacokinetic analyses. Off-protocol, data showed that 9 patients were later treated with 225 mg/m2 paclitaxel as weekly 1-hour infusions. Nineteen evaluable patients demonstrated a 53% total response rate (95% confidence interval, 29%-76%) with one complete response and nine partial responses (including one off protocol). Results of historical review off-protocol showed 2 of 7 patients, with prior partial responses to the 96-hour infusion, had subsequent partial responses to weekly treatment and 1 of 2 prior nonresponders gained a partial response to weekly therapy. No toxicities greater than grade 2 were seen with 96-hour infusions, while peripheral neuropathy (up to grade 3) was most common with postprotocol weekly infusions. Paclitaxel appears to be the only agent with significant clinical systemic activity against anaplastic thyroid carcinoma; however, it is not capable of altering the lethality of this malignancy, suggesting the need for additional therapeutic innovations. Decreased time intervals between paclitaxel infusions may be more efficacious.

Novel high-affinity PPARγ agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1

“…Paclitaxel has demonstrated prolongation of life for ATC patients in a clinical trial and appears the standard of care with regards to chemotherapeutic intervention for patients diagnosed with ATC (Ain et al, 2000). Aldred et al (2003) described PPARg expression in thyroid cancer subtypes demonstrating that ATCs were positive by IHC in 9/14 cases and percentage-wise, PPARg expression was higher than any other thyroid cancer subtype.…”

“…The rationale for this is based upon a recent report demonstrating that p21 WAF1/CIP1 enhanced apoptosis induced by manumycin and paclitaxel in ATC cells (Yang et al, 2003) along with the efficacy demonstrated for paclitaxel in a clinical trial of ATC patients (Ain et al, 2000). We reasoned that RS5444 strongly upregulated p21 WAF1/CIP1 and that increased p21 WAF1/CIP1 may lead to enhanced antitumor activity in the presence of paclitaxel.…”

“…They present with widespread local invasion and often with metastases to lungs, pleura, bone, and/or brain. Paclitaxel has been found to be effective in preclinical models (Ain et al, 1996), and its efficacy in a clinical trial led to its use for ATC (Ain et al, 2000). Our work is focused upon identifying compounds with antitumor activity against ATC and then to identify which of these in combination are most effective as chemotherapeutic agents.…”

Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Taskforce

“…Most studies of combination chemotherapy show no increased response over single agent doxorubicin and increased toxicity (292). Some specialists recommend consideration of single agent doxorubicin or paclitaxel, or a combination of these agents based on limited data in anaplastic thyroid carcinoma (293). One recent study evaluated the effect of combination chemotherapy (carboplatinum and epirubicin) under TSH stimulation (endogenous or rhTSH) (294), demonstrating an overall rate of complete and partial response of 37%.…”

Anaplastic Thyroid Carcinoma with Humoral Hypercalcemia of Malignancy (HHM): An Autopsy Case Report

“…This carcinoma is highly malignant, nonencapsulated, extends widely, and has a poor prognosis [6][7][8][9][10][11]. In several anaplastic thyroid carcinoma cell lines, many cytokines such as granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), IL-1a, IL-6, and TGF-a are produced [12][13][14][15].…”