Completely resected anaplastic thyroid carcinoma combined with ...

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Completely Resected Anaplastic Thyroid Carcinoma Combined with Adjuvant Chemotherapy and Irradiation Is Associated with Prolonged Survival Philip I. Haigh, M.D.1 Philip H. G. Ituarte, Ph.D., M.P.H.2 Hurng Sheng Wu, M.D.3 Patrick A. Treseler, M.D.4 Marc D. Posner, M.D.5 Jeanne M. Quivey, M.D.5 Quan Yang Duh, M.D.6 Orlo H. Clark, M.D.2 1

Department of Surgical Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.

2

The Department of Surgery, University of California at San Francisco Mount Zion Medical Center, San Francisco, California.

3

Division of General Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.

4

Department of Pathology, University of California at San Francisco, San Francisco, California.

5

Department of Radiation Oncology, University of California at San Francisco, San Francisco, California.

6

The Department of Surgery, University of California at San Francisco, San Francisco Veterans Affairs Medical Center, San Francisco, California. Presented at the American College of Surgeons Clinical Congress 2000, Chicago, IL, October 22– 27, 2000. Supported in part by the Friends of Endocrine Surgery and also in part by a visiting fellowship for Dr. Philip I. Haigh funded by the John Wayne Cancer Institute, Santa Monica, CA. The authors thank Nancy Drungilas from the UCSF Cancer Registry for her technical assistance. Address for reprints: Philip I. Haigh, M.D., Department of Surgical Oncology, Princess Margaret Hospital, University of Toronto, 610 University Avenue, Suite 3-130, Toronto, ON, Canada, M5G 2M9; Fax: (416) 946-6590; E-mail: philip.haigh@ uhn.on.ca Received March 2, 2001; accepted March 12, 2001.

© 2001 American Cancer Society

BACKGROUND. The prognosis of anaplastic thyroid carcinoma (ATC) has been dismal. The objective of this study was to identify prognostic factors in patients who had prolonged survival. METHODS. Patients with ATC were identified from a computer database at a tertiary referral center. Univariate and multivariate analyses for survival differences were performed using the Kaplan–Meier log-rank statistic and the Cox proportional hazards model, respectively. RESULTS. Of the 33 evaluable patients, median survival was 3.8 months. Median age was 69 years. Prior goiter was present in 6 patients (18%), and 6 (18%) had prior thyroid carcinoma. Median tumor size was 6 cm, and 12 (36%) had adjacent well-differentiated carcinoma. Of the 26 patients who underwent neck exploration, 8 patients were potentially cured and received postoperative chemotherapy and irradiation; 4 (50%) were surgically macroscopically free of disease, and 4 (50%) patients had minimal residual disease after total thyroidectomy and resection of tumor adherent to adjacent structures. Four of these 8 patients survived longer than 2 years; their 5-year survival estimate was 50%. Eighteen patients underwent palliative resection of neck disease, leaving macroscopic residual disease or distant metastases; postoperative adjuvant chemotherapy and irradiation were administered in 16 of these 18 patients. Seven patients were treated with only chemotherapy and irradiation. In patients treated with potentially curative resection, median survival was 43 months compared with 3 months with palliative resection (P ⫽0.002); the median survival of 3.3 months with only chemotherapy and irradiation was no different than palliative resection (P ⫽0.63). No association was found between survival and age, prior goiter, prior thyroid carcinoma, adjacent differentiated carcinoma, or tumor size. CONCLUSIONS. Although the prognosis of most patients with ATC continues to be poor, complete resection of ATC combined with postoperative adjuvant chemotherapy and irradiation resulted in long-term survival, even with persistent minimal disease that remained on vital structures. An aggressive attempt at maximal tumor debulking followed by adjuvant therapy was found to be warranted in patients with localized ATC. Cancer 2001;91:2335– 42. © 2001 American Cancer Society. KEYWORDS: anaplastic thyroid carcinoma, surgery, adjuvant chemotherapy and irradiation.

A

naplastic thyroid carcinoma (ATC) is an extremely aggressive neoplasm, and patient death usually occurs a few months after diagnosis.1– 8 Management is particularly difficult for this cancer because patients usually present with both extensive local disease and distant metastases.9 –13 The aggressive behavior of ATC, even if ATC is

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CANCER June 15, 2001 / Volume 91 / Number 12

discovered when it is still localized to the thyroid gland, usually portends such a poor outcome that it is classified by the American Joint Committee on Cancer (AJCC) as Stage IV regardless of its tumor, node, or metastasis (TNM) status.14 The rarity of ATC also contributes to the difficulty that physicians have in determining the optimal modality of treatment. It is difficult to estimate true disease incidence, but in North America, the incidence is declining, so that the proportion of ATC out of all thyroid cancers is approximately 2%.15 For this reason, a low number of patients is usually reported in individual research series of ATC patients. Treatment of ATC has ranged from surgery, radiotherapy, chemotherapy, or a combination of these regimens. Any modality used alone usually fails to control local disease, which is often the cause of death. Complete resection of ATC in the neck usually is not possible, but surgery can be an effective palliative modality. Extensive radical neck operations with en bloc adjacent organ resection are associated with high morbidity and are probably not warranted for this disease.16 –18 Radiotherapy alone cannot control bulky ATC in the neck;19 however, evidence suggests that surgery in combination with irradiation and chemotherapy may provide optimal disease control.11,20 –24 This study was initiated to assess the outcome of patients with ATC treated at an institution that has extensive experience in the management of all types of thyroid diseases, with a particular objective to identify host, tumor, and treatment factors present in patients who had prolonged survival during the studied period.

MATERIALS AND METHODS All patients who were treated by consultant surgeons at the University of California at San Francisco (UCSF) from 3 participating hospitals from 1973 to 1998 and who had a diagnosis of ATC were identified from the endocrine surgery database. All patients were AJCC Stage IV by default of histologic type.25 Records were reviewed to extract demographic, clinical, and pathologic data, treatment received, and follow-up information. All pathology slides were diagnosed as ATC by staff pathologists at UCSF, and all available slides were again reviewed by a single pathologist to confirm the diagnosis of ATC. If the data were not present in the endocrine surgery database, then the UCSF Cancer Registry was used to access follow-up survival information, as approved by the UCSF Committee on Human Research. Overall survival was determined from the date of diagnosis to death or date of last follow-up. Factors examined for survival differences were age at diagnosis (analyzed as a continuous variable and as a cate-

TABLE 1 Characteristics of Anaplastic Thyroid Carcinoma Study Group Characteristic

No. (%)

Median age, yrs (range) Gender Female Male Prior Goiter Prior WDTC Synchronous distant metastases CNS Bone Lung Treatment Surgical Total thyroidectomy Near-total thyroidectomy Total thyroid lobectomy Minor excision/isthmusectomy Node dissection alone Concomitant neck dissection Concomitant tracheostomy Adjuvant Therapy Preoperative Postoperative Both Chemotherapy and/or radiation alone

69 (47–80) 20 (61) 13 (39) 6 (18) 6 (18) 21 (64) 1 (5) 3 (14) 20 (95) 26 (79) 14 (54) 5 (19) 3 (12) 2 (8) 2 (8) 8 of 26 (31) 3 of 26 (12) 24 (92) 4 (17) 19 (79) 1 (4) 7 (21)

gorical variable with median age as the cutoff point), gender, presence of distant metastases at diagnosis, size of primary tumor (analyzed only in the surgical patients both as a continuous variable and as a categorical variable with 5 cm as the cutoff point), presence of adjacent, contiguous, well-differentiated thyroid carcinoma (WDTC) in the pathology specimen, prior well-differentiated thyroid carcinoma, and treatment received, either potentially curative resection, palliative resection, or no surgery. Univariate analysis was performed using the Kaplan–Meier method with the log-rank statistic to test for group differences in survival. Multivariate analysis was performed using Cox proportional hazards modeling on the significant variables that had been identified by univariate analysis. Statistical significance was determined using an ␣-level of 0.05 and Student (two-sided) t tests.

RESULTS Patient Demographics There were 37 patients identified from the database query. Upon review of the charts and pathology review of slides, we found that three patients had poorly differentiated thyroid carcinoma, and one patient had no accessible information. Of the remaining 33 evaluable patients, their median age was 69 (range, 47– 80 yrs) years (Table 1). There were 20 (61%) females and

Anaplastic Thyroid Carcinoma and Survival/Haigh et al.

13 (39%) males. Six (18%) patients had a prior history of goiter for at least 5 years, and 3 (9%) patients had a history of radiation exposure. Six (18%) patients had a prior well-differentiated thyroid carcinoma; 4 of these were treated in the past with thyroid lobectomy or subtotal thyroidectomy, and ATC had arisen in the residual thyroid gland. Two patients who were treated in the past with total thyroidectomy recurred with metastatic well-differentiated thyroid carcinoma and concurrent microscopic foci of ATC in the regional nodes 2 and 6 years after initial operation. Synchronous distant metastases were found in 21 (64%) patients (Table 1).

Surgical Treatment and Pathology In the 26 patients treated with neck exploration, total thyroidectomy was performed in 14 patients, neartotal thyroidectomy in 5 patients, thyroid lobectomy in 3 patients, isthmusectomy or minor excision in 2 patients, and neck dissection alone in 2 patients (Table 1). Concomitant functional neck dissection was performed in 6 of the 24 patients who had thyroid surgery. Potentially curative surgery entailed resection of all visible disease, which included leaving minimal residual disease adherent to important neck structures such as the recurrent laryngeal nerve, carotid artery, trachea, or esophagus. Of the 26 operative patients, 8 (31%) underwent potentially curative surgery with results as follows: 4 (15%) had no macroscopic disease remaining in the neck, and 4 (15%) had minimal residual disease adhering to important structures after resection. Palliative neck surgery, in which macroscopic extrathyroidal disease or persistent distant disease remained, was performed in 18 patients for control of local symptoms of neck mass or impending tracheal obstruction. Only one of these palliative surgery patients was rendered free of disease in the neck. Tracheostomy was performed in three patients. No patients were treated with en-bloc resections of the esophagus, trachea, or larynx. Complications occurred in two patients. One patient who presented with a huge exophytic mass and brachial plexus palsy had wound dehiscence and infection after resection. One patient required intensive care unit admission for respiratory compromise. Two patients died of respiratory arrest within 3 days after tracheostomy, 1 from tracheal compression in the mediastinum and the other from a combination of diffuse lung metastases and tracheal compression. In the 24 patients who underwent exploration and thyroid surgery, median tumor size was 6 cm (Table 2). Extrathyroidal extension was present with invasion into muscle, trachea, nerves, or arteries in 20 patients. Pathology in the resected specimen was isolated giant-

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TABLE 2 Pathology of 24 Patients with Thyroid Resections for Anaplastic Thyroid Carcinoma Pathologic feature Size (cm) ⬍ 1.0 1–2 2.1–3.0 3.1–4.0 4.1–5.0 ⬎ 5.0 Unknown Local invasion Microscopic margin positive Adjacent contiguous WDTC Residual disease None Minimal Gross

No. (%)

1 (4) 2 (8) 1 (4) 3 (13) 2 (8) 10 (42) 5 (21) 20 (83) 20 (83) 8 (33) 5 (21) 10 (42) 9 (38)

WDTC: well-differentiated thyroid carcinoma.

or spindle-cell ATC in 13 patients. ATC was associated with adjacent contiguous WDTC in eight patients who had had no prior WDTC. Three patients who had a history of WDTC and recurred also had foci of ATC in a background of WDTC.

Chemotherapy and Radiotherapy There was no standardized protocol in selecting patients for chemotherapy or radiotherapy. Agents used for chemotherapy usually were based on doxorubicin, but paclitaxel, cisplatin, carboplatinum, VP-16, cyclophosphamide, melphalan, and bleomycin were also used. External beam radiation to the neck or mediastinum was administered to total doses ranging from 45–75 Gy. In the surgical patients, 24 (92%) received some form of adjunctive therapy, and 2 (8%) received no further treatment. Adjuvant therapy was used in 19 patients; 13 received combination chemotherapy with external beam radiation, and 6 patients were treated with either postoperative chemotherapy or radiation alone. Neoadjuvant therapy consisting of a combination of chemotherapy and irradiation was used in four patients, and sandwich preoperative plus postoperative chemotherapy and irradiation was used in one patient. Therefore, of the patients treated with adjunctive therapy, 18 of 24 (75%) received combination chemotherapy and irradiation. Postoperative radioactive iodine-131 (131I) was used to treat three surgical patients in addition to chemotherapy and irradiation, because all had elevated thyroglobulin and adjacent contiguous papillary or follicular WDTC within the

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FIGURE 1. Kaplan–Meier survival curve of 33 patients with anaplastic thyroid carcinoma. Overall median survival was 3.8 months.

surgical specimen and lung metastases that could not be differentiated between ATC and WDTC. Seven patients received nonoperative treatment after biopsy. In three of these patients, both chemotherapy and radiation therapy were used concurrently. In one patient, chemotherapy alone was used as the primary treatment modality. External beam radiation was the sole treatment given palliatively to the neck and/or mediastinum in two of the patients. The remaining patient received external beam radiation and 131 I.

Survival Median follow up was four months. Median overall survival was 3.8 months (range, 0 – 67 mos) for the 33 patients. Overall 2- and 5-year survival was 20% and 14%, respectively (Figure 1). Five patients (15%) lived more than 2 years; 4 of these had had potentially curative surgery. The median survival was 43 months for the 8 patients resected for potential cure who had no residual or minimal residual disease compared with 3 months in the 18 patients who had undergone palliative surgery (P ⫽.001). Estimated 2- and 5-year survival for the surgically cured patients was 75% and 50%, respectively (Figure 2). The estimated 2-year survival for patients treated with palliative resection was 6%, with only one patient alive after 2 years (Figure 2). The median survival for the 7 nonoperative patients was 3.3 months, and all patients in this group died within 10 months. There was no difference in survival between the patients treated with palliative resection and those treated with only chemotherapy and irradiation (P ⫽0.63). As of last follow-up, of the eight patients who had had potentially curative surgery, four patients were alive with no evidence of disease; two of these four

FIGURE 2. Survival curves of patients with anaplastic thyroid carcinoma who were treated with potentially curative resection, palliative resection, or nonoperatively with only chemotherapy and irradiation. Patients whose tumors were resected for curative intent with minimal or no remaining macroscopic residual disease enjoyed a median survival of 43 months, compared with 3 months in patients treated with palliative resection and 3.3 months in patients treated with only chemotherapy and irradiation. The survival of the patients treated with a palliative resection was similar to that of the patients treated with only chemotherapy and irradiation. were alive after complete resection, and two were alive after resection which had left minimal residual disease. Of the 2 patients whose thyroids were resected completely, 1 was alive and free of disease at 20 months after resection of a 3.5 cm ATC and treatment with postoperative doxorubicin and external beam radiation; 1 patient with a 1.7 cm ATC resected and treated with postoperative adjuvant carboplatin and paclitaxel plus external beam radiation recurred with metastases in the brain and lung, which were treated with gamma-knife radiation and lung lobectomy, respectively, to render this patient free of disease at 15 months follow-up. Both of these patients, whose thyroids were resected with minimal residual disease remaining on adjacent structures, were alive with no evidence of disease at 32 and 62 months. One had a 7.4 cm ATC treated with surgery and postoperative doxorubicin combined with external beam radiation, and the other had a 1.5 cm ATC treated with surgery and postoperative external beam radiation. Of the 4 patients who died from recurrent ATC, 1 patient recurred distantly after complete resection and died at 43 months. Two patients recurred locally, 1 after complete resection who died at 67 months and the other at 4 months after a resection that had left minimal residual disease. One patient with WDTC had a regional recurrence and was found to have nodal ATC metastases after neck dissection; this patient died from repeated recurrences of regional and distant disease at 7 months.

Anaplastic Thyroid Carcinoma and Survival/Haigh et al. TABLE 3 Univariate Survival Analysis of Anaplastic Thyroid Carcinoma Study Population

TABLE 4 Multivariate Analysis of Anaplastic Thyroid Carcinoma Study Population

Factor

Factor

Surgical treatment Potentially curative vs. palliative surgery Potentially curative vs. chemoradiation alone Palliative vs. chemoradiation alone Synchronous distant metastases Age Gender Coexistent WDTCa Prior treated WDTC Prior goiter Sizeb

P value

0.001 0.002 0.630 0.004 0.150 0.410 0.250 0.080 0.100 0.250

WDTC: well-differentiated thyroid carcinoma. a Analyzed only in the surgical patients with no prior diagnosis of WDTC. b Analyzed only in 19 surgical patients with known tumor size.

Univariate analysis, performed to determine the influence of various factors on survival, revealed that the absence of distant metastases, and curative resection compared with palliative surgery, and curative resection compared with chemotherapy and irradiation without surgerywere associated with prolonged survival. Age, gender, prior WDTC, prior goiter, concurrent contiguous WDTC, and tumor size were not associated with survival differences (Table 3). Multivariate analysis of the factors associated with significant survival differences revealed potentially curative surgery was the only discriminating variable that retained a significant association with prolonged survival (Table 4).

DISCUSSION At initial diagnosis of this type of thyroid carcinoma, distant metastases from ATC usually are already present, and patient death occurs within months of diagnosis. Similarly, local disease at presentation is often extensive and unresectable. Occasionally, however, there are patients with tumors that are either completely resectable or mostly resectable, leaving minimal residual disease, who may survive for an appreciable period after receiving chemotherapy and irradiation as adjuvant therapy. In our study series, 8 such patients were identified who were deemed candidates for an aggressive multimodal approach, and their median survival was 43 months compared with 3 months in patients with advanced disease whose tumors were incompletely resected. Selection bias inherent in this retropective study can easily explain this

Treatment Potentially curative surgery Palliative surgery Chemotherapy and irradiation (without surgery) Synchronous distant metastases

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Risk ratioa

95% CI

P value

0.10 0.81

0.02–0.63 0.29–2.22

0.01 NS

1.00 0.97

— 0.25–3.85

NS NS

CI: confidence interval; NS: not significant. a Values ⬍ 1 represent a reduction in risk of death compared with the reference group. For the three treatment factors, chemotherapy and irradiation without surgery is the reference group. Synchronous distant metastases are compared with the reference group of no distant metastases.

survival difference, but remaining is the fact that prolonged survival and local control were achieved in this small group of patients without excess morbidity. In the curative surgical group, four patients had resection that left minimal residual disease adhered to important structures. Chemotherapy and irradiation were used in these patients, and survival time was prolonged in some patients. Sacrifice of structures with radical en-bloc resections of the larynx or esophagus was not performed, nor were recurrent laryngeal nerves resected unless vocal cord paresis was documented preoperatively and unless tumor invasion of the nerve was assessed intraoperatively. This strategy of aggressive surgical management with organ preservation was used throughout the study period and may be the preferred approach to spare patients the morbidity of radical resections.4,18 Adjuvant chemotherapy and irradiation was used for most of our patients. Many reports have advocated adjuvant therapy to enhance local control, which has developed over the last 25 years to predominantly combination chemotherapy and irradiation (Table 5). Simpson20 first used hyperfractionated radiotherapy consisting of 100 cGy administered 4 times a day up to a total dose of 3600 cGy in 14 of 91 patients with ATC. Complete responses occurred in 6 (43%) patients, but radiation toxicity was severe in 6 patients, and 4 patients died from treatment. In 12 of the 91 patients who received concurrent chemotherapy with doxorubicin and irradiation, but not necessarily hyperfractionation, complete regression occurred in 4 (33%) patients.20 Kim and Leeper21 next reported the outcome of nine patients who received doxorubicin and irradiation; eight responded with complete regression, the majority after partial tumor resection. Most died within 12 months after treatment from distant disease, except the single patient who had a primary tumor resected completely. Local recurrence occurred in two

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TABLE 5 Published Series of Anaplastic Thyroid Carcinoma Studies That Have Categorized Treatment Modalities Treatment modalities

Series

Year

No.

None

S only

Jereb et al.1 Aldinger et al.9 Simpson20 Kim and Leeper21 Spires et al.2 Demeter et al.10 Schlumberger et al.11 Junor et al.3 Tan et al.4 Kobayashi et al.12 Nilsson et al.6 Lo et al.5 Haigh et al. (current)

1975 1978 1980 1983 1988 1991 1991 1992 1995 1996 1998 1999 2000

79 84 94 9 14 17 20 91 21 37 81 28 33

5 17 7 0 2 0 0 0 2 1 0 0 0

7 16 1 0 0 3 0 5 1 0 0 18 2

C/R only

C/R 3S

S3 C/R

Overall survival (mos)

No. of survivors > 2 yrs (%)

No. of survivors > 2 yrs with curative resection (%)

38 19 40 3 3 0 8 58 9 12 32 0 7

0 0 0 6 0 0 1 0 0 0 48b 1 5c

27 28 46 0 9 14 11 28 9 24 1 9 19

2.5a (mean) 6.2 (mean) NR 10a (mean) 4 (median) 12 (median) NR 5 (median) 4.5 (median) NR 4.3a (mean) 2.3a (median) 3.8 (median)

1 (1) 8 (10) 0 0 0 5 (29) 2 (10) 10 (11) 3 (14) 3 (8) 8 (10) 1 (4) 5 (15)

1 (100) 6 (75) — — — 4 (80) 2 (100) NR 3 (100) 3 (100) NR NR 4 (80)

S: surgery; C/R: chemotherapy or radiation or both; 3: followed by; NR: not reported. a Converted to months using 30 days equal to one month. b 29 patients also had postoperative C/R. c One patient also had postoperative C/R.

patients. In a later study reported by Schlumberger et al.,11 local control was achieved in 5 of 20 patients treated with either doxorubicin, cisplatin and concurrent radiotherapy or with mitoxantrone and concurrent radiotherapy. The largest experience in using a multimodality approach consisting of hyperfractionated radiotherapy combined with doxorubicin-based chemotherapy originates from the Karolinska Hospital in Stockholm, Sweden. A recent report by Nilsson et al.6 is an aggregate of prospective chemotherapy and irradiation protocols that took place over a 25-year period from 1971 to 1997; they treated 81 patients who had ATC, and demonstrated that only 8 (10%) patients overall survived more than 2 years (Table 5). Of 26 patients treated in the last 8 years, only 1 patient had a recurrence in the neck. Many of these patients received doxorubicin concurrent with the most recent modification of hyperfractionated radiotherapy, which consisted of a preoperative 4600 cGy total dose given in 160 cGy doses twice a day. These attempts at improving palliation for local control are certainly important in a disease that often causes death by suffocation.6 Even with a combined treatment approach to ATC, however, very few patients survive more than 2 years, and most die from the disease (Table 5). Combined chemotherapy and irradiation plus surgery can be effective in ATC, but clearly newer regimens need to be studied. More recently, taxol and angiogenesis inhibitors have shown some effect against human ATC xenografts in nude mice.26,27

These results provided the impetus for the National Cancer Institute (NCI) to sponsor a Phase II trial of single-agent intravenous paclitaxel for ATC in chemotherapy-naive patients, which is now closed, and results are pending. Further, a search using the NCI CancerTrials online service revealed a multicenter NCI-sponsored trial that is actively accruing patients in a trial of intensified concurrent chemotherapy and irradiation consisting of hydroxyurea, 5-fluorouracil, paclitaxel, filgrastim, and hyperfractionated radiation followed by surgery. The influences of pathologic and treatment factors in patients with ATC have been analyzed in other studies to determine their prognostic value, and the results have varied. Although we found no effect, tumor size has correlated with survival in some study series. Tumors ⬍ 6 cm in size have been documented to have a better prognosis than larger tumors,4,5,18 especially those that are only microscopic foci.9,10 In our series, only one patient had a focus of ATC, which was found in a recurrence of follicular carcinoma, but extensive carcinoma remained in the neck after subtotal lobectomy, and the patient died 5 months after diagnosis. The presence of synchronous distant metastases correlated adversely with survival by univariate analysis, and this expected result has been shown in prior studies.5,16,18,23 We found no effects from age or gender on survival, but other series have reported effects from these variables.4,5 In our study, the prognosis of patients with ATC

Anaplastic Thyroid Carcinoma and Survival/Haigh et al.

that had arisen from a contiguous area of WDTC was as poor as that for patients with ATC that had arisen de novo. Concurrent or previous WDTC in patients with ATC is well known;2,16 however, the prevalence of anaplastic transformation of microscopic papillary thyroid carcinoma is ⬍ 1%.28 An experiment in a murine model supported the hypothesis that ATC arises from dedifferentiation of thyroid epithelial tumor cells.29 Our results mirror those reported by others that with equivalent size and extent of ATC in patients with or without associated WDTC, the prognosis is similar.2,8,16,18 It is noteworthy that patients with multiple metachronous regional recurrences of WDTC who have been treated with multiple surgeries develop increasing anaplasia with each recurrence.30 Once these tumors become anaplastic, the prognosis in these patients is grave. Our study identified two patients who had recurrent regional WDTC accompanied by nodal ATC that had been treated with prior total thyroidectomy, and they survived for 2 and 7 months, respectively, after their diagnosis of ATC. The presence of a long-standing goiter is a putative risk factor and also a prognostic factor of ATC.10,18,31 It is difficult to determine the true incidence of anaplastic thyroid carcinoma arising in patients with goiter, but it is probably extremely low. Although we did not find any population study in the literature that had determined ATC incidence from multinodular goiter, a study from Italy in patients with multinodular goiter who had undergone total thyroidectomy did identify malignancy in 41 (7.6%) patients, but none of these cases were ATC.32 As a prognostic factor, the presence of a prior goiter was found not to influence survival statistically in our study group. The median survival was 3 months in 6 patients who had a long-standing history of goiter and 4.5 months in 27 patients who had no history of goiter. Nel et al.18 also found that a prior goiter diminished survival by a few months, but this finding did not reach statistical significance. With the decreasing incidence of ATC,33 coupled with the fact that most goiters will not develop into ATC, total thyroidectomy for all patients with multinodular goiter in an attempt to prevent ATC is unwarranted. Our study identified complete resection of tumor as the primary factor responsible for prolonged survival. Complete resection has been identified as a prognostic factor in other study series.3,4,12,18,23 Usually only those patients with completely resected ATC will enjoy prolonged survival (Table 4). This subgroup will be a small minority, however, because of their advanced disease at diagnosis. Although it is difficult to separate treatment effect from tumor behavior as the reason for prolonged survival, in a disease that

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usually has such rapid growth, resection plus combined chemotherapy and irradiation seems warranted, if at all possible. In summary, ATC is extremely aggressive, and, at the time of diagnosis, resection of all macroscopic disease in the neck usually is not feasible. Survival is dismal for all but a few patients. Those patients with resectable disease whose tumors are managed by aggressive surgery with preservation of organ function have the best opportunity for prolonged survival. Resection also should be accompanied by adjuvant chemotherapy and irradiation. Realizing that only a highly selected group of patients can undergo surgery for potential cure, novel regimens are urgently needed to improve the outcome in patients who have ATC.

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