Abstract
Background:
Although thyroid carcinoma is more indolent than other solid tumors, distant metastatic disease due to differentiated thyroid carcinoma (DTC) and medullary thyroid carcinoma (MTC) is often refractory to treatment and thus a challenge for clinicians. New agents such as tyrosine kinases inhibitors have been introduced recently for therapy of metastatic thyroid cancer but they have toxic side effects as well as therapeutic benefits. The objective of this study was to determine the hematologic toxicities of sunitinib, a multiple receptor tyrosine kinases inhibitor, when used to treat progressive, advanced DTC and MTC.
Methods:
Six patients with DTC and four with MTC who were treated with sunitinib were retrospectively studied for short-term hematological toxicities related to red cell and platelet mass and the major leukocyte series.
Results:
Before the start of sunitinib treatment, 5 of 10 patients (50%) received external beam radiation therapy and 6 of 10 (60%) had hematologic abnormalities. During sunitinib treatment, some grade of neutropenia was noted in 6 of 10 patients (60%), anemia in 1 of 10 (10%), thrombocytopenia in 7 of 10 (70%), and lymphocytopenia in 4 of 10 (40%). Monocytopenia was present in all 10 patients. Considering grades 3 and 4 hematologic toxicities, neutropenia was noted in 2 of 10 (20%), anemia in 1 of 10 (10%), and thrombocytopenia in 1 of 10 (10%). There was no grade 3 or 4 lymphocytopenia, but we noted a 52.4% (±17.47% standard deviation) decrease in monocyte counts. All patients had macrocytosis, despite normal circulating folate and cobalamin levels. In one patient with DTC, sunitinib had to be permanently discontinued because of hematological toxicity.
Conclusions:
Despite the fact that most patients with DTC had received large doses of radioiodine and some had received external beam radiation therapy, both of which have myelosuppressive potential, treatment with sunitinib was well tolerated in most patients with DTC as well as in the patients with MTC. These results are encouraging, but, as our series was small and did not evaluate efficacy, more extensive studies in DTC and MTC are needed to determine the possible roles of sunitinib in these very different tumors.
Introduction
The objective of this study was to determine the hematologic toxicities that occur in patients with progressive, advanced DTC and MTC who are treated with sunitinib, a multiple receptor tyrosine kinases inhibitor. We considered myelotoxicity of particular importance, as it is potentially one of the most life-threatening toxicities of agents used for treatment of malignant tumors.
Materials and Methods
The medical records of 10 patients with advanced progressive thyroid carcinoma, refractory to all conventional therapeutic modalities, which could not be enrolled in clinical trials, who were treated with sunitinib, were retrospectively studied. Their median age at treatment initiation was 57.7 years (range, 43–73). Six of the patients had metastatic DTC and four had metastatic MTC. One patient with DTC had tall-cell variant of papillary thyroid carcinoma with local recurrence and cervical lymph node and lung metastases, two had multifocal papillary thyroid carcinoma with cervical lymph node and lung metastases, one had follicular variant of papillary carcinoma with pelvic soft tissue metastasis and bone metastases, one had Hürthle cell carcinoma with lung metastases, and one had Hürthle cell carcinoma with local recurrence and lung metastases. All these patients with DTC received therapeutic doses of radioiodine in a median amount of 653 mCi (range, 450–900) (Table 1). Within the group of patients with MTC, one had cervical lymph node, bone, and leptomeningeal metastases, one had local recurrence and lung and liver metastases, one had local recurrence and intraabdominal and bone metastases, and one had local recurrence and liver, lung, and bone metastases.
Age (in years) at treatment initiation.
PTC, papillary thyroid carcinoma; FV, follicular variant; MTC, medullary thyroid carcinoma; LN, lymph node; EBRT, external beam radiation therapy; M, male; F, female.
Before sunitinib treatment, three patients with DTC and two patients with MTC had received external beam radiation therapy (EBRT). Patients 1, 3, and 8 (Table 1) had received EBRT to the neck and upper mediastinum, patient 4 had received EBRT to the neck, upper mediastinum, thoracic spine, and left femur, and patient 7 received pelvic EBRT.
Our institution's scientific board approved the therapeutic approach and all patients gave informed, written consent for treatment with sunitinib. Sunitinib 50 mg was administered, orally once daily for 4 consecutive weeks, followed by a 2-week rest period (schedule 4/2) to comprise a complete cycle of 6 weeks.
The complete blood cell count was monitored before initiation of treatment and at days +28 and +42 of every cycle for, at least, three cycles in every patient. The normal values for neutrophils were 2.5–7.5 × 109/L, for lymphocytes 1.5–3.5 × 109/L, for monocytes 0.2–0.8 × 109/L, for hemoglobin 13.5–17.5 g/dL (for male patients) and 11.5–15.5 g/dL (for female patients), and for platelets 150–400 × 109/L (5). The National Institutes of Health (NIH) grading of hematologic toxicity (6) was used in the present study. Patients needed to have a neutrophil count of 1.5 × 109/L or more, hemoglobin of 10 g/dL or more, and platelets of 100 × 109/L or more to be eligible for sunitinib treatment. If patients developed a grade 3 or greater hematological toxicity, treatment with sunitinib was discontinued and reinitiated at a lower dose after 4–6 weeks if their toxicity resolved. If the toxicity reappeared at the lower dose, sunitinib was permanently discontinued. Patients who developed grade 3 or 4 hematologic toxicity were adequately supported with red blood cells, platelets, or granulocyte colony-stimulating factor.
Results
The neutrophil count was reduced during sunitinib treatment in 6 of 10 patients, 4 patients developed grade 2 toxicity, and 2 patients developed grade 3 toxicity. The latter 2 patients (patients no. 4 and 9, Tables 1 –3) already had an affected neutrophil count before the initiation of the medication.
NE, neutrophil count (×109/L); LY, lymphocyte count (×109/L); Hgb, hemoglobin (g/dL); PLT, platelets (×109/L); MO, monocyte count (×109/L); BL, baseline values before treatment with sunitinib; ND, nadir values during treatment with sunitinib.
N, not affected.
The lymphocyte counts were reduced during sunitinib treatment in four patients. Grade 2 toxicity developed in two and grade 1 toxicity developed in the other two.
A decreased hemoglobin was noted in only one patient during sunitinib treatment. This patient, however, developed grade 3 toxicity.
A decrease in the platelet count occurred in seven patients during sunitinib treatment. Four developed grade 2 toxicity, two developed grade 1 toxicity, and one patient, who had a platelet count of 200 × 109/L before sunitinib treatment, developed grade 4 toxicity. There was a median decrease of 52.4% ± 17.47% standard deviation (range, 21–76) in the monocyte count in patients during sunitinib treatment.
Only one of our patients had grade 3 toxicity of more than one cell type. In this patient (patient no. 9, Tables 1 –3) we were obliged to permanently discontinue sunitinib as relapsing severe toxicity was observed after the dose was lowered. This patient was the only one in whom sunitinib treatment was permanently discontinued, but she did not have febrile neutropenia or infection. Her blood counts before the beginning of sunitinib treatment are illustrated in Table 2. All 10 patients had macrocytosis during sunitinib treatment, despite their folate and cobalamin levels being normal. None of our patients had macrocytosis before sunitinib treatment.
Discussion
Conventional treatment strategies for DTC include thyroidectomy, thyrotropin suppression therapy with levothyroxine, and in some patients, therapeutic doses of radioiodine and EBRT. Distant metastases are often challenging and refractory to conventional treatments (2,7) and they are associated with decreased survival (1,2). As far as MTC is concerned, the treatments available are not ideal (1,8). Thyroidectomy, EBRT, chemoembolization for liver metastases, and metastasectomy are only partially effective (8,9).
Humans have about 90 tyrosine kinases and 43 tyrosine kinase-like genes that regulate cellular proliferation and survival (10). Approximately 10 years ago an effort was begun to target these genes as a means of treating cancer (10). Sunitinib inhibits multiple receptor tyrosine kinases that are implicated in tumor growth, neoangiogenesis, and metastatic progression of cancer. The drug is indicated for unresectable and/or metastatic malignant gastrointestinal stromal tumors after failure of imatinib mesilate treatment due to resistance or intolerance, and the treatment of advanced or metastatic renal cell carcinoma (11 –13).
Sunitinib, in common with other antiangiogenic agents, has toxic side effects (4). Common side effects that were observed in large series of patients with renal cell carcinoma include fatigue, hypothyroidism, cardiovascular toxicity (including hypertension), gastrointestinal toxicity, dermatologic changes, hematologic toxicity, and tumor lysis syndrome (14,15). In different series of patients suffering from renal cell carcinoma treated with sunitinib, hematologic toxicities were not uncommon (14,15). All grades of neutropenia, anemia, and thrombocytopenia occurred in 60%–70% of all patients treated with this agent, but grade 3 or 4 toxicity was observed in <4% of patients (15).
In the present study, all grades of hematological toxicity were noted during sunitinib treatment. Neutropenia was seen in 60%, anemia in 10%, thrombocytopenia in 70%, and lymphocytopenia in 40%. Monocytopenia occurred in all patients. Some patients had grade 3 or 4 hematologic toxicity during sunitinib treatment. Grade 3 or 4 level toxicity was 20% for neutropenia, 10% for anemia, and 10% for thrombocytopenia. We did not observe grade 3 or 4 lymphocytopenia, but we noted a mean decrease of 52% in the monocyte counts for all patients. Rini et al. reported that among patients with renal cell carcinoma treated with sunitinib, the mean corpuscular volume (MCV) increased significantly and 67% of them had an MCV >100 fL at some point after the initiation of treatment, which was not associated with decreased levels of folate or cobalamin (16). In our series, all patients treated with sunitinib had macrocytosis, despite normal folate and cobalamin levels. None of them had macrocytosis before sunitinib treatment.
Data regarding the hematological toxicity of sunitinib when used to treat thyroid cancers are limited and have been generally presented in an abstract form. Side effects of sunitinib seem to be similar in three series of patients with DTC and MTC (17 –19). In thyroid cancer patients treated with sunitinib, Goulart et al. reported neutropenia in 28% of patients, anemia in 6%, and thrombocytopenia in 6%, but the number of patients enrolled in the trial was small (18 patients) (18). Ravaud et al. did not report hematologic toxicity in a clinical trial that included only a small number of patients (17 patients) (19). In a larger group of patients (43 patients), Cohen et al. observed neutropenia in 49% of patients; they reported grade 3–4 neutropenia in 26% of patients and thrombocytopenia in 16% (17).
It is important to determine the effects of sunitinib on the hematopoietic system in advanced thyroid cancer because most of these patients, or at least those with DTC, have been treated with radiation, a well-established myelosuppressive perturbation (20). Therefore, they would likely be at increased risk when receiving an agent with mylosuppressive properties. It is notable that our patients had a similar response to sunitinib in terms of hematological toxicity as patients who received sunitinib for other solid malignancies. Hematologic toxicities were common, but in most lowering the dose of sunitinib seemed to be sufficient for ameliorating its toxicities. Nevertheless, the number of patients in our study was small, we studied two groups of patients (DTC and MTC) with very different types of thyroid cancers, and we did not evaluate therapeutic efficacy. Therefore, more extensive studies to evaluate therapeutic efficacy as well as toxicity are needed to establish if there is a satisfactory role for sunitinib in the treatment of advanced thyroid cancers.
Footnotes
Disclosure Statement
The authors declare that no competing financial interests exist.