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A Phase II Trial of Imatinib Therapy for Metastatic Medullary Thyroid Carcinoma

Department of Endocrinology (J.W.B.d.G., M.M.d.V., T.P.L.), University Medical Center Groningen, University of Groningen, 9700 AB Groningen, The Netherlands; Departments of Medical Oncology (B.A.Z., E.E.V.) and Endocrinology (C.J.M.L.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Medical Oncology (P.Q.v.U.-M.), Gosford Hospital, Gosford, New South Wales 2250, Australia

Address all correspondence and requests for reprints to: B. A. Zonnenberg, M.D., Ph.D., Department of Medical Oncology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. E-mail: b.zonnenberg{at}umcutrecht.nl.

	Abstract

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Context: Medullary thyroid carcinoma (MTC) metastasizes early in its clinical course. No effective systemic therapy is available. Generally (somatic or germline), mutations in the rearranged during transfection gene are considered essential in the pathogenesis of MTC.

Objective: We investigated imatinib, a tyrosine kinase inhibitor, as a potential treatment in patients with disseminated MTC.

Design: A phase II study was initiated using 600 mg imatinib daily with a possible dose increase to 800 mg in case of progression. Standard Response Evaluation Criteria in Solid Tumors were used using computed tomography or magnetic resonance imaging every 2 months.

Results: There were 15 patients with disseminated MTC treated for up to 12 months. No objective responses were observed. Four patients had stable disease over 24 months. Three patients stopped treatment due to toxic effects [fatigue (n = 2) and nausea (n = 1)]. In four cases the dose of imatinib was decreased because of toxicity [rash and malaise (n = 2) and laryngeal swelling (n = 2)]. Emergency tracheotomy was performed in two cases due to mucosal swelling of the larynx in patients with recurrent nerve palsy and a narrow vocal cleft. In nine patients with a history of a thyroidectomy, the dose of supplemental thyroid hormone was increased because of serious hypothyroidism.

Conclusions: Imatinib therapy yielded no objective responses and induced considerable toxicity in patients with MTC. A minority of patients had stable disease. Patients with supplemented hypothyroidism or with recurrent nerve palsy are specifically at risk for serious adverse events and need special attention when treated with imatinib.

	Introduction

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MEDULLARY THYROID carcinoma (MTC) is a rare tumor originating from the calcitonin-secreting C cells. It may be sporadic or hereditary, including multiple endocrine neoplasia (MEN) type 2A, MEN 2B, and familial MTC. Hereditary MTC (occurring in about 25% of cases) is caused by a germline mutation in the rearranged during transfection (RET) gene. Around 40% of sporadic MTCs harbor a somatic RET mutation (1, 2). Mutations in RET lead to a constitutive active RET tyrosine kinase, causing the malignant behavior of the C cells (3). Besides calcitonin, MTC also secretes carcinoembryonic antigen (CEA), making calcitonin and CEA excellent tumor markers (1).

MTC metastasizes early in its clinical course, often even before the primary tumor is diagnosed. At present, only surgery can cure patients with MTC as long as the disease is treated at an early stage (4, 5). Around 20% of patients have distant metastases at diagnosis, and only in 34–44% of patients do serum calcitonin levels become undetectable (2). No effective treatment options are available for patients with advanced MTC (1). The lack of successful systemic therapy and the early metastatic nature of MTC underline the importance of developing new approaches to treatment. Clinical studies with agents that inhibit RET seem feasible because all MTCs express RET (6, 7), mutated RET plays a key role in at least 50% of all MTCs, and in vitro studies demonstrated that RET inhibition led to decreased proliferation of MTC cell lines (8, 9).

Imatinib (Glivec, Gleevec; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a 2-phenylaminopyrimidine tyrosine kinase inhibitor that affects several protein-tyrosine kinases, including Bcr-Abl, platelet-derived growth factor receptor (PDGFR) , PDGFRß, c-Fms, c-Kit, and RET (8, 9, 10). Currently, imatinib is used in the treatment of chronic myeloid leukemia, gastrointestinal stromal tumors, and dermatofibrosarcoma protuberans (11, 12, 13). In this study the clinical activity of imatinib was evaluated in patients with advanced MTC.

	Patients and Methods

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Eligibility

Eligibility requirements included: histologically confirmed MTC that was not amenable to curative resection; age older than 18 yr; measurable tumor; Eastern Cooperative Oncology Group performance status score of 0–2; absolute neutrophil count more than 1.5 x 10⁹/liter; platelet count more than 100 x 10⁹/liter; serum bilirubin less than 1.5x the upper reference limit; transaminases less than 2.5x the upper reference limit; serum creatinine less than 1.5x the upper reference limit; no previous radiotherapy or chemotherapy within 4 wk of starting of imatinib; and no history of prior malignancy within 5 yr, except nonmelanoma skin cancer or cervical carcinoma in situ. Women of childbearing potential had to have a negative pregnancy test before enrollment. Patients did not need to exhibit progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) (14) or biochemical tumor markers before enrollment. Exclusion criteria included patients with brain metastases, a history of a class 3–4 cardiovascular disability status according to the New York Heart Association Functional Classification, or other life-threatening diseases. Patients using warfarin or with a history of noncompliance to medical regimens were not eligible. All patients gave written informed consent before study entry. The study and consent forms were approved by both institutional review boards.

Study design and treatment schedule

The starting dosage of imatinib for all patients in this phase II trial was 600 mg/d administered orally. In case of objective progression, the dosage could be increased to 800 mg/d. Disease status was assessed after 2 months or less at the physician’s discretion. Patients were treated for up to 12 months. Thereafter, patients were followed for duration of response, safety, and survival for 2 yr.

Guidelines for dose reduction or interruption in the event of either hematological and/or nonhematological toxicities were instituted. All patients received standard supportive care when appropriate, including blood and platelet transfusions, antiemetics, and antibiotics.

Study parameters

Pretreatment evaluation included a complete history and physical examination, complete blood count with differential, liver function tests, renal function, serum chemistries, serum calcitonin and CEA, and urinalysis. Baseline electrocardiogram, chest x-ray, computed tomography scans or magnetic resonance imaging of the chest, abdomen, and pelvis with quantification of measurable disease, and bone scan (if relevant) were also performed. In four patients, ¹⁸F-fluoro-2-deoxy-D-glucose (¹⁸FDG) positron emission tomography (PET) and ¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-DOPA) PET scans were also performed as part of clinical routine. Whenever possible, we screened for germline RET mutations in patients with MEN 2A and for somatic RET mutations in tumor tissue from patients with sporadic MTC, as described previously (15). During treatment, patients were clinically evaluated and assessed for toxicity at wk 1, 2, 4, 8, 12, 16, 24, 38, and 52. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (CTC) version 2.0 (http://ctep.cancer.gov/forms/CTCv20_4–30-992.pdf). Disease response was evaluated every 2 months with tumor imaging via computed tomography or magnetic resonance imaging. Response to therapy was evaluated according to RECIST (14).

Statistical considerations

The primary objective was to determine the objective response rate. Secondary objectives were to determine the time to tumor progression, evaluate survival, and evaluate the safety profile of imatinib. Descriptive statistics were used to characterize patients at baseline and laboratory correlates.

	Results

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Patient characteristics

We enrolled 15 patients from January 2003 to January 2005. Table 1 shows the patient characteristics. Median age was 50 yr (range 32–69). All patients were rated as Eastern Cooperative Oncology Group performance status 1. Most patients (67%) had undergone a total thyroidectomy, and all had extensive locoregional and distant metastases. Median calcitonin level was 31,050 ng/liter (range 1430–183,000, mean 48,068 ± 49,250), and median CEA level was 78 µg/liter (range 4–2108, mean 504 ± 760).

Treatment and toxicity

Median duration of treatment was 4 months. All patients were evaluable for toxicity (Table 1). We observed two grade 4 toxicities: laryngeal mucosal swelling in patients with recurrent nerve palsy for which emergency tracheotomy was necessary within 1 wk after starting imatinib. The most frequently observed toxicity was hypothyroidism, which occurred in nine patients and was grade 3 in three cases (33%). All patients who developed hypothyroidism had undergone a total thyroidectomy and were on thyroid hormone substitution therapy. The patients who did not develop hypothyroidism had functioning thyroid remnants in situ and were not on thyroid hormone substitution. In patient 4 (Table 1), who had undergone a total thyroidectomy, thyroid function was not measured. Hypothyroidism could be reverted by increasing the substitution doses of thyroid hormone in all cases by on average 210% (range 150–350%). We observed one serious hematological toxicity (grade 3 thrombocytopenia). Dose reduction was necessary in four patients (27%) because of grade 3 rash, malaise, and laryngeal mucosal swelling (n = 2). Three patients discontinued treatment because of toxicity [fatigue (n = 2), and nausea and vomiting (n = 1)]. One patient developed a chylothorax, and one developed a desmoid cyst while on imatinib.

Efficacy and outcomes

Of 15 patients, five completed treatment. We observed no responses in these patients: one patient had progressive disease, and four had stable disease, which they also had before enrollment. After 24-month follow-up, these patients still had stable disease. Seven patients discontinued treatment for disease progression a median of 3 months (range 2–8) after starting imatinib. Of the three patients who discontinued treatment due to toxicity, two had no clinical evidence of progression. Median follow-up for all patients after stopping imatinib was 12 months. Eight patients died of MTC, on average 9 months (range 3–20) after discontinuing imatinib. One patient died of unrelated causes 12 months after stopping imatinib.

¹⁸FDG and ¹⁸F-DOPA-PET scans were performed in patients 2, 3, 8, and 9 as part of clinical routine (Table 1). In two patients assessed at baseline and 6 and 8 months after initiating treatment, we observed an increase in tumor ¹⁸FDG and ¹⁸F-DOPA uptake. In the others we observed no change in tracer uptake.

We also compared the rate of increase from serum calcitonin and CEA levels measured during treatment with imatinib. Figure 1 depicts the serum levels of calcitonin before and during treatment. No significant decreases in serum calcitonin or CEA levels were observed. In three patients serum calcitonin levels stabilized under imatinib treatment. However, all these patients (Table 1, patients 4, 12, and 15) clinically had progressive disease.

View larger version (11K): [in this window] [in a new window]   FIG. 1. Serum calcitonin (A) and CEA (B) levels during imatinib treatment. For clarity, the serum calcitonin levels are presented on a linear scale, whereas the serum CEA levels are presented on a logarithmic scale. Only seven patients had sufficient CEA levels measured for follow-up. The arrows depict patients in whom serum calcitonin levels stabilized after imatinib; however, clinically, they had progressive disease.

	Discussion

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The lack of tumor response is in line with our recent in vitro observations that imatinib effectively inhibits RET but only at concentrations that cannot be reached in human beings (9). Others have had similar experiences with imatinib in patients with metastasized MTC (16, 17). Nevertheless, targeting RET with more potent inhibitors seems an attractive treatment option for patients with disseminated MTC, and preliminary data are promising (3, 18).

An ongoing discussion in the field of oncology concerns RECIST criteria. Are these criteria applicable in trials of noncytotoxic drugs such as imatinib? It has been argued that newer noncytotoxic agents will perhaps control tumor growth rather than cause objective response (19). Moreover, in a generally slow-growing tumor such as MTC we do not know whether stable disease represents drug effect or that it is just the natural course of the disease. Furthermore, the presence of amyloid in MTC, which can calcify, may lead to a target lesion that does not regress by radiological studies. Therefore, we incorporated the effect of imatinib on the dynamics of calcitonin and CEA, but we could not demonstrate any decrease in tumor markers.

It is likely that RET is not the only contributor to MTC development and tumor growth. Imatinib is a potent inhibitor of Bcr-Abl, PDGFR, PDGFRß, c-Fms, and c-Kit tyrosine kinases, and exerts its effects in concentrations that actually can be reached in humans. The lack of antitumor effects of imatinib in patients with MTC demonstrates that these tyrosine kinases likely do not play a major role in MTC.

One could argue that because not all patients had a proven germline or somatic RET mutation, the results of this study would have been better if only patients with known RET mutations had been included. However, because all MTCs express RET (6, 7), such a strict selection may not be necessary. Furthermore, although the role of germline RET mutations is well established in the development of hereditary MTC (3), it is not yet known whether RET needs to be mutated to play a major role in sporadic MTC or that mere RET expression is sufficient. In addition, response rates in the seven patients with known RET mutations were not very different from response rates in the remaining eight without known RET mutation status.

In general, imatinib seems to be well tolerated. Nevertheless, dose reduction because of toxicity is needed in 10%–50% of patients treated with imatinib, regardless of the underlying malignancy (20). In the present study, 20% of patients stopped imatinib due to toxicity. However, as we have previously reported, imatinib has specific adverse effects in patients on thyroid hormone supplementation (21). This study revealed a novel and clinically very important side effect of imatinib in patients who have a narrow vocal cleft due to palsy of the recurrent nerve. Two of these patients needed emergency tracheotomy within 1 wk after starting imatinib because of laryngeal edema. Physicians who treat cancer patients with imatinib need to be aware of these potentially life-threatening effects in a subset of patients.

In conclusion, treatment with imatinib yields no objective responses and considerable toxicity in patients with metastasized MTC. Hypothyroid patients on thyroid hormone supplementation therapy or patients with recurrent nerve palsy are specifically at risk for serious adverse events and need special attention when treated with imatinib.

	Footnotes

 
Clinical trial registration: http://www.controlled-trials.com/ISRCTN13256080/.

This work was supported by Novartis Pharma B.V., Arnhem, The Netherlands.

Disclosure Statement: The authors have nothing to declare.

First Published Online June 19, 2007

¹ J.W.B.d.G. and B.A.Z. contributed equally to this work.

Abbreviations: CEA, Carcinoembryonic antigen; CTC, Cancer Institute Common Toxicity Criteria; ¹⁸FDG, ¹⁸F-fluoro-2-deoxy-D-glucose; ¹⁸F-DOPA, ¹⁸F-fluorodihydroxyphenylalanine; MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; PDGFR, platelet-derived growth factor receptor; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors; RET, rearranged during transfection.

Received March 27, 2007.

Accepted June 11, 2007.

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