Neoadjuvant Chemotherapy in 29 Patients with Locally Advanced Follicular or Hürthle Cell Thyroid Carcinoma: A Phase 2 Study

Abstract

Background:

It is believed that chemotherapy (ChT) is ineffective in follicular thyroid carcinoma (FTC) and Hürthle cell thyroid carcinoma (HCTC). The aim of our retrospective study was to find out whether neodjuvant ChT before thyroid surgery had any effect on the size of primary tumor in patients with FTC or HCTC.

Methods:

The study included 29 patients (20 women, 9 men; mean age: 60.8 years) with FTC or HCTC who had T3 or T4 tumor and were treated with neoadjuvant ChT from 1979 to 2004. A mean tumor diameter was 9.3 cm. Extrathyroid growth of tumor was present in 15 patients. Regional and distant metastases were detected in 6 and 12 patients, respectively. With respect to the site of metastatic spread, the lung was involved in eight patients and the skeleton in five. ChT consisted of vinblastine in 19 cases, vinblastine with adriamycin in 5 cases, or other ChT regimens in 5 cases.

Results:

Altogether, 67 cycles of ChT were given and tumor size decreased by >50% in 13 patients (=45%). ChT was effective in patients with FTC and HCTC in 47% and 43%, respectively. In the patients with and without distant metastases, the primary tumor size decreased by >50% in 17% and 65% (p=0.02), respectively. R0, R1, and R2 resection was performed in 15, 10, and 4 cases, respectively. Histopathology revealed that ChT (i.e., wide areas of tumor necrosis) was effective in seven patients (24%). The 5- and 10-year cause-specific survivals of the patients were 77% and 47%, while the 5- and 10-year disease-free intervals were 57% and 46%, respectively. Six patients are alive (median survival: 162 months), four of them have no evidence of disease, six patients died of other causes (median survival: 101 months), while 17 patients died of FTC or HCTC (median survival: 72 months). Among them, 16 died of distant metastases, while only one succumbed to locoregional recurrence and distant metastases.

Conclusions:

ChT before surgical procedure may be effective in order to decrease the tumor size in FTC or HCTC in 45% of patients.

Introduction

I t is generally believed that chemotherapy (ChT) is ineffective in follicular thyroid carcinoma (FTC) or Hürthle cell thyroid carcinoma (HCTC) (1,2). According to the literature, there are no data to support the use of adjunctive ChT in the management of differentiated thyroid carcinoma (1,2). American Thyroid Association guidelines permit the management with ChT only in the patients with thyroglobulin (Tg)-positive tumor without radioiodine (RAI) uptake that is incurable with surgery and evident on 18FDG-positron emission-computed tomography (PET-CT) scan (1). According to the European consensus for the management of patients with differentiated thyroid carcinoma, ChT has no role in routine management of papillary or follicular carcinoma (2). Its use is restricted to the patients with progressive disease uncontrolled by surgery, RAI, or other treatment modalities (2).

A neoadjuvant setting is really a logical choice to prove that ChT has an effect on primary tumor, which has many advantages in comparison to metastatic setting. However, the vast majority of studies about the effectiveness of ChT in differentiated thyroid carcinoma were performed in metastatic setting, many times in the patients pretreated with RAI and/or radiotherapy. Another advantage of neoadjuvant setting is that bioptic material of primary tumor is easily available, which is not the case in metastatic setting, when bioptic material for histopathology is usually not available.

Slovenia is a region of endemic goiter and adequate iodination of salt to prevent goiter is in use only for the last 13 years (3). Before adequate iodination of salt we were faced with high goiter prevalence in our population (3). It is well known that, in the regions with dietary iodine deficiency, the proportion of papillary thyroid carcinoma among thyroid cancers is relatively low, whereas that of FTC and anaplastic thyroid carcinoma is high (4). Searching for thyroid carcinoma among goiter population could be compared with searching for a needle in a haystack (3). Therefore, it is not surprising that, in Slovenia, the majority of patients with FTC or HCTC used to have locally advanced disease (5). In some of them, tumor invaded the surrounding organs; therefore, only mutilating surgery would be possible. Based on our good experience with preoperative ChT in patients with inoperable head and neck carcinoma and anaplastic thyroid carcinoma, we used nontoxic neoadjuvant ChT in our 29 patients with locally advanced FTC or HCTC. The aim of our retrospective study was to find out whether neodajuvant ChT before thyroid surgery had any effect on the size of primary tumor in patients with FTC or HTC.

Patients and Methods

Patients

Data were collected on the patients with FTC or HCTC treated at the Institute of Oncology in Ljubljana, Slovenia, in the years 1972–2010. During this period, 312 patients (207 females, 105 males; age: 10–89 years; mean age: 56 years) with FTC or HCTC were seen and T3 or T4 tumor stage was present in 215 patients (144 females, 71 males; age: 16–89 years; mean age: 60.1 years). The present study included 29 (20 women, 9 men; age: 37–77 years, mean age: 60.8 years) patients with T3 or T4 tumor stage who were initially treated with preoperative ChT in the years 1979–2004. In all the patients in the primary ChT group, the tumor was considered inoperable because of infiltrations into the surrounding tissues. Surgery was performed whenever the tumor was reduced after ChT and/or radiotherapy and the surgeon judged it resectable. The interval between the beginning of ChT and surgical procedure was 36 days (range: 4–173 days).

The data of the patients' gender, age, history, extent of disease, morphologic characteristics, therapy, locoregional control, and survival were collected. The tumor size, presence of regional or distant metastases, and residual tumor after surgery were assessed by TNM clinical classification according to the UICC criteria from 2009 (6). The patients' characteristics and therapy of patients in the ChT group are presented in Table 1.

Table 1.

Patients and Tumor Characteristics

Factor	Patients with T3 or T4 tumor with preoperative ChT (n=29)
Mean age (years)	60.83
Mean tumor size (cm)	9.3
Gender
Female	20
Male	9
Age (years)
44 or less	2
45 or more	27
Tumor diameter (cm)
0–5.99	4
6–9.99	15
10 and more	10
pT tumor stage
pT3	12
pT4	17
N stage
N0	23
N1 or N2	6
M stage
M0	17
M1	12
Tumor type
Follicular	16
Hürthle cell	13
Tumor differentiation
Well/moderate/unknown	8
Poor	21
Thyroid surgical procedure
Total or near-total thyroidectomy	24
Lobectomy	5
Subtotal thyroidectomy	0
Biopsy or no surgery	0
Residual tumor after surgery
R0	15
R1	10
R2+no surgery	4
Neck dissection
No	21
Yes	8
Radioiodine ablation after surgery
No	3
Yes	26
Therapy with radioiodine
No	15
Yes	14
Radiotherapy (any site)
No	9
Yes	20
Chemotherapy
No	0
Yes	29
Recurrence
No	9
Yes—distant	5
Yes—locoregional	3
Yes—distant+locoregional	0
Disease present permanently	12
Outcome
Alive without disease	4
Alive with disease	2
Dead because of disease	17
Dead because of other causes	6
Mean disease-free interval (months)	110
Mean cause-specific survival (months)	131

ChT, chemotherapy.

The study was reviewed by the appropriate ethics committee and performed in accordance with the ethical standards laid down in an appropriate version of the 1964 Declaration of Helsinki. The institutional review board has approved the study. Our study was conducted with the understanding and consent of the involved human subjects.

Tumor morphology

Histological specimens were retrieved by surgical removal of the thyroid tumor, while cytological samples were obtained by fine-needle aspiration biopsy of the primary or of its metastases. To determine the diagnosis by cytology from the primary tumor alone, the tumor had to be poorly differentiated. The aspirates of poorly differentiated follicular carcinoma present no problem for differential diagnosis between adenoma and nodular goiter, because the signs of malignancy are evident (7,8). Histology revealed the diagnosis of FTC or HCTC in 28 patients. In one patient, the diagnosis of poorly differentiated FTC was confirmed by cytology only; the pathologist, after neoadjuvant ChT, could not find transcapsular or vascular invasion and the diagnosis of thyroid neoplasm with unknown biological potential was established.

All histological slides for this study were reviewed by one pathologist (B.G.). The tumors were considered to be of the Hürthle cell type if all or at least 75% of their cells had eosinophilic, granular cytoplasm. Obvious transcapsular and/or vascular invasion was the essential criteria for histopathological diagnosis of malignancy. None of the patients with papillary carcinoma was included in this study. Also, the neoplasms associated with clear cell change involving 50% or more of the tumor mass were excluded from the study.

Tumor differentiation was determined by the grading system of Akslen (9), originally designed for the papillary thyroid carcinoma. The assessment of tumor differentiation was based on the presence or absence of three key features: vascular invasion, nuclear atypia, and tumor necrosis. The tumor was classified as poorly differentiated tumor if extensive vascular invasion, nuclear atypia, and/or tumor necrosis was evident. Conversely, well-differentiated tumor had no extensive vascular invasion, nuclear atypia, or tumor necrosis.

Therapy

It is well known that a natural course of FTC or HCTC is not uniform. Surgery has been considered as the most effective treatment for FTC or HCTC and has therefore remained its mainstay. During the 25 years, our patients were treated by different surgeons, and the extent of surgical treatment of primary tumor, distant metastases, and/or locoregional recurrences was not uniform. Nevertheless, we observed that RAI therapy, ChT, and external radiotherapy may also be effective in the patients with inoperable recurrent or metastatic FTC or HCTC.

In most cases, we presented each such patient to a team of physicians at our institution who take part in treating thyroid carcinoma patients (the core of the team are surgical oncologist, specialist of nuclear medicine, and radiotherapist, while other members of our team are cytopathologist, pathologist, radiologist, medical oncologist, and, whenever also needed, a neurosurgeon, orthopedic surgeon, and thoracic surgeon) and the treatment depended on the decision of the team mentioned. Of course, over the period of 25 years, various physicians with various preferences of treatment were the part of our thyroid team. Therefore, it is understandable that various proportions of patients were treated with RAI ablation of thyroid remnant, external radiotherapy, ChT, and RAI therapy after l-thyroxine withdrawal or using recombinant human TSH. So, our patients were treated with repeat surgery, RAI, external radiotherapy, ChT, or a combination of these modalities as circumstances dictated.

Chemotherapy

Various chemotherapeutic schedules were used for FTC or HCTC in preoperative and metastatic setting over the period of 25 years as a part of research protocol sponsored by the Slovenian Ministry of Science and Technology (principal investigator: M.A.). The treatment was started with the least aggressive schedule (i.e., vinblastine), and if necessary, more aggressive schedules were used. Vinblastine was used in the majority of cases in the present study, because it is a potent modulator of cellular kinetics in poorly differentiated carcinoma as already reported by Auersperg et al. (10). In 19 cases, ChT with low doses of vinblastine (2 mg over 12- or 24-hour infusion) was used. During the period 1972–1982, courses of vinblastine, methotrexate, 5-fluorouracil, and bleomycin alternated with courses of vinblastine, doxorubicin, and bleomycin at 7–14-day intervals were used (10). This regimen was abandoned because of toxicity. After 1982, we tried the combination of doxorubicin and vinblastine, alone or with concurrent radiotherapy. Whenever the tumor became operable after ChT, it was removed surgically.

At the time of our study, the use of ultrasound or other diagnostic investigations were not widely accessible and were used only when necessary. Therefore, the local effect of ChT was assessed by clinical findings only. Clinical measurement of locally advanced thyroid tumor with a meter is fast, is reliable, and does not depend on any diagnostic investigations with high-technology equipment. Our patients were hospitalized also after ChT because of the system of financing of the hospitals during the period when the majority of patients were treated. The size of primary tumor was measured clinically each day during the first week after ChT and a week later during the visit to the outpatients' clinic and before the next cycle of ChT. The extent of disease and possible effectiveness of ChT were evaluated before the first ChT and before surgical procedure by clinical examination, X-ray, CT scan, ultrasonography, and/or serum Tg concentration measurements. The overall effect of ChT on primary tumor size (=product of the longest perpendicular diameters of primary tumor) was defined as (1) progression if the tumor enlarged, (2) stagnation if the tumor size remained the same or decreased by <50%, (3) regression if the tumor size decreased by 50%–99%, and (4) complete response if the tumor disappeared.

Four patients had preoperative radiotherapy using a ⁶⁰Co unit and two opposed fields. The radiation field included the entire neck up to the level of the mastoid process, bilateral supraclavicular and infraclavicular regions, and the superior mediastinum. The patients received a daily dose of 2 Gy in one fraction. Preoperative radiotherapy was delivered in a median dose of 35 Gy (range: 30–44 Gy) in 4 weeks. All four patients preoperatively treated with radiotherapy and ChT received additional postoperative radiotherapy at a total dose of 45–64 Gy in combination with ChT. Another nine patients had postoperative external irradiation of the neck and superior mediastinum with a tumor dose of 45–57 Gy (median: 50.4 Gy).

Follow-up and survival

For all patients, follow-up check-ups were performed at our institute at least once a year. They consisted of obtaining a thorough medical history, physical exam, and determination of serum Tg concentrations. Whenever serum Tg concentrations were elevated, imaging (X-ray, ultrasound, CT, magnetic resonance, bone scintigraphy, methoxyisobutylisonitrile (MIBI) scintigraphy, PET-CT scan, and/or RAI scintigraphy) was performed to determinate the location and extent of residual disease or suspected recurrence.

Survival was defined as the period from the first day of treatment (i.e., preoperative ChT) to the death or the last follow-up. The disease-free interval was defined as the period from the beginning of ChT to the recurrence or last follow-up.

Statistical analysis

Characteristics of patients and treatment were compared by contingence tables. Because of the small number of patients in the ChT group, age of patients and size of tumor were compared by Mann–Whitney rank-sum test. Survival and disease-free interval were compared by log-rank test. Survival curves were calculated according to the Kaplan–Meier method (11). For statistical analysis, SPSS 16.0 for Windows was used.

Results

In the patients with neoadjuvant ChT, the mean tumor diameter was 9.3 cm (median: 9 cm). Regional metastases were detected in six patients. Extrathyroid growth of tumor was present in 15 patients. Distant metastases were detected on admission in 12 patients; of them, 11 patients had single-organ metastases, while 1 had multi-organ metastases. With respect to the site of metastatic spread, the lung was involved in eight patients and the skeleton in five. There were no differences of clinicopathological features or prognosis between the group of patients with FTC and HCTC.

ChT consisted of vinblastine only in 19 cases, vinblastine with adriamycin in 5 cases, or other ChT regimens in 5 cases. Altogether, 67 cycles of ChT were given and tumor size decreased by >50% in 13 patients (=45%). None of the patients had a complete clinical response. In the patients with FTC and HCTC, ChT was effective in 47% and 43%, respectively. In the patients with and without distant metastases, a primary tumor size decreased by >50% in 17% and 65% (p=0.02), respectively. Histopathology revealed that ChT (i.e., wide areas of tumor necrosis) was effective in seven patients (24%).

Resection of the tumor after primary ChT and/or radiotherapy could be performed in all patients. No residual tumor (R0), microscopic residual tumor (R1), and macroscopic residual tumor (R2) resection was performed in 15, 10, and 4 cases, respectively. Total thyroidectomy and lobectomy were performed in 24 and 5 patients, respectively. Modified radical neck dissection was performed in eight patients. Transient and permanent hypoparathyroidism occurred in seven (24%) and two (6.9%) patients, respectively. Transient vocal cord palsy occurred in one patient and permanent vocal cord palsy in another one (3.4%). In the latter one, a temporary tracheostomy was performed because of respiratory distress after surgery. In one patient, another surgical procedure was performed because of postoperative bleeding.

Table 2 presents data about clinicopathological features and prognosis of responders and nonresponders after neoadjuvant ChT. Figures 1 and 2 present disease-free interval and cause-specific survival of responders and nonresponders.

FIG. 1.

Disease-free interval and effect of chemotherapy (ChT). Bold line=effect 50%–99%; dashed line=effect<50%.

FIG. 2.

Cause-specific survival and effect of ChT. Bold line=effect 50%–99%; dashed line=effect<50%.

Table 2.

Effect of Neoadjuvant Chemotherapy in Patients with Follicular Thyroid Carcinoma or Hürthle Cell Thyroid Carcinoma

Factor	Subgroup	Effect of ChT 50%–99% (n=13)	Effect of ChT<50% (n=16)	p-value
Mean age (years)		63	59	0.46
Mean tumor size (cm)		10.3	8.5	0.055
Gender	Female	8	12	0.68
	Male	5	4
Age (years)	44 or less	0	2	0.49
	45 or more	13	14
Tumor diameter (cm)	0–5.99	0	4	0.051
	6–9.99	6	9
	10 and more	7	3
pT tumor stage	pT3	5	7	0.77
	pT4	8	9
N stage	N0	10	13	1.00
	N1 or N2	3	3
M stage	M0	11	6	0.02
	M1	2	10
Tumor differentiation	Well/moderate/unknown	3	5	0.70
	Poor	10	11
Tumor type	Follicular	7	9	1.00
	Hürthle cell	6	7
Thyroid surgical procedure	Total or near-total thyroidectomy	11	13	1.00
	Lobectomy	2	3
Residual tumor after surgery	R0	9	6	0.14
	R1	2	8
	R2	2	2
Neck dissection	No	10	11	0.695
	Yes	3	5
Radioiodine ablation after surgery	No	2	1	0.57
	Yes	11	15
Therapy with radioiodine	No	2	1	0.57
	Yes	11	15
Radiotherapy (any site)	No	6	3	0.23
	Yes	7	13
Vinblastine only	No	5	5	0.71
	Yes	8	11
Recurrence	No	6	3	0.085
	Yes—distant	3	2
	Yes—locoregional	2	1
	Disease present permanently	2	10
Outcome	Alive without disease	3	1	0.50
	Alive with disease	0	2
	Dead of disease	6	11
	Dead of other causes	4	2
Mean disease-free interval (months)		116	98	0.68 (log-rank)
Mean cause-specific survival (months)		125	120	0.70 (log-rank)

By the end of the study, 6 patients were alive, 4 of them have no evidence of disease (survival: 115–189 months; median: 162 months), 6 patients (5 of them without evidence of disease) died of other causes (survival: 36–126 months; median: 101 months), while 17 patients died of FTC or HCTC (survival: 7–201 months; median: 72 months). Among the latter patients, 16 died of distant metastases, while only 1 succumbed to locoregional recurrence and distant metastases at 65 months after neoadjuvant ChT.

Median survival of patients with T3 and T4 tumors was 111 months (range: 36–189) and 100 months (range: 7–201 months), respectively. Among 12 patients with T3 tumor, 4 are alive and 2 died of other causes, while among 17 patients with T4 tumor, only 2 are alive and 2 died of other causes.

Median survival of patients without and with distant metastases (Fig. 3) was 102 (range: 7–189) and 98 (range: 13–201) months, respectively. Among the patients with metastases, all but one died of thyroid carcinoma.

FIG. 3.

Presence of distant metastases and survival. Bold line=without metastases; dashed line=with metastases.

Among 17 patients who were without distant metastases, locoregional recurrence, distant metastases, and concomitant locoregional recurrence and distant spread occurred in two, three, and three cases, respectively. The disease-free interval was from 7 to 189 months (median: 101 months).

The 5- and 10-year cause-specific survivals of the patients treated with neoadjuvant ChT were 77% and 47%, while the 5- and 10-year disease-free intervals were 57% and 46%, respectively.

Discussion

We report on 29 patients with FTC or HCTC who were treated with neoadjuvant ChT. To our knowledge, this is the largest published series of patients with ChT in these two entities. Typically, the numbers of patients in studies about ChT in differentiated thyroid carcinoma are very small (22 patients or less) (12 –19) and a vast majority of included patients had papillary carcinoma, while only a minority had FTC or HCTC.

Of course, there are several limitations in our study. It is retrospective and nonrandomized; the local effect of ChT was assessed by clinical findings only and different ChT schedules have been used. But, for slowly progressing tumors with periods of stagnation for which various treatment modalities are used during the course of disease, it is very difficult to distinguish the impact of a single treatment modality from the impact of another one on disease course, outcome, or duration of survival. This is especially true for the entities that are very rare and have a wide variety of clinical course. Both advanced FTC and HCTC can be listed among such entities. Therefore, in these two entities, a randomized, prospective study of treatment results is very unlikely to be carried out in the future.

There is an important difference in ChT schedules (i.e., cytostatic drugs and its dosage) between those that were used for differentiated thyroid carcinoma in reports from the literature and those used in our patients. Namely, based on our good experience in treatment of anaplastic thyroid carcinoma (10) and head and neck carcinoma (20), vinblastine in low dose and long infusion (2 mg over 12- or 24-hour infusion) was used in the majority of our patients from the present study. This schedule was selected to cause as little side effects as possible. None of our patients treated with vinblastine reported any side effects (nausea, vomiting, or loss of hair) or had hematologic side effects. On the contrary, a majority of patients observed a rapid relief of symptoms related to local tumor or relief of pain caused by bone disease. We can state that low dose of vinblastine in long infusion is a safe treatment that can be effective in FTC or HCTC. Our data support the observation of O'Bryan et al. (15) that also low doses of ChT may be effective in differentiated thyroid carcinoma.

In our study altogether, 67 cycles of neoadjuvant ChT were given and tumor size decreased by >50% in 13 patients (=45%). ChT was equally effective in patients with FTC and HCTC. Interestingly, the response rate in our patients without distant metastases was high (i.e., 64%), but the response rate in our patients with metastases was lower (i.e., 17%), and the difference was significant (p=0.02). Our patients with metastases had a comparable response rate to the patients from a series in metastatic setting, which was about 30% (18).

Our study is comparable to the study published by Kim and Leeper, who treated their patients with inoperable primary thyroid carcinoma. They used low dose of adriamycin 10 mg/m² once weekly and external irradiation of the neck region and superior mediastinum in the patients with papillary carcinoma or FTC. They achieved response in 20 of 22 patients and local effect lasted for 7 years in 77% (12). Our multimodal approach in 29 patients with initially inoperable FTC or HCTC was even more effective. Only 1 of 29 patients (3%) succumbed to locoregional recurrence and distant metastases, while in all others, locoregional control of disease was achieved.

Neoadjuvant ChT followed by multimodal treatment resulted in a long median survival (i.e., 98 months) of patients with locally advanced primary tumor and distant metastases. One can assume that there was a selection bias that influenced long disease-free interval and cause-specific survival of patients treated with neoadjuvant ChT. But, among the patients with metastatic FCT, those who were treated with neoadjuvant ChT had a shorter 10-year survival (i.e., 20%) in comparison to those who were not initially treated with ChT. The 10-year survival of all patients with initially metastatic FCT treated at our institution was 26%. This is comparable to the studies of Segal et al. (21), Shoup et al. (22), Sugino et al. (23), Bottger et al. (24), and Shaha et al. (25), who reported 10-year cause-specific survivals of 24%, 26%, 31%, 34%, and 39% in patients with metastatic FTC, respectively.

We believe that ChT should be a part of the treatment of patients with advanced thyroid carcinoma. Namely, many times, a primary tumor or metastases consist also of poorly differentiated cells. As RAI therapy is effective in well-differentiated thyroid tumor (26), ChT may be effective in the poorly differentiated component of tumor (10). Different possibly effective systemic treatments should be used in advanced FCT or HCTC, which have a potential influence on various types of tumor cells. A long-lasting locoregional control rate of 97% in our patients with very advanced FTC or HCTC confirms that our multimodal treatment approach is effective.

Conclusion

Neoadjuvant ChT may be effective to decrease tumor size in FTC or HCTC before surgical procedure. ChT was effective in the patients with FTC and HCTC in 47% and 43%, respectively.

Footnotes

Acknowledgment

This study was supported by a research program P3-0289 by the Ministry of Education, Science, and Sport of Slovenia.

Disclosure Statement

The authors declare that no competing financial interests exist.

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