Outcome after Treatment of High-Risk Papillary and Non-Hurthle-Cell Follicular Thyroid Carcinoma

  1. Terry Taylor, MD;
  2. Bonny Specker, PhD;
  3. Jacob Robbins, MD;
  4. Matthew Sperling;
  5. Mona Ho, MS;
  6. Kenneth Ain, MD;
  7. S. Thomas Bigos, MD;
  8. Jim Brierley, MB;
  9. David Cooper, MD;
  10. Bryan Haugen, MD;
  11. Ian Hay, MD;
  12. Vicki Hertzberg, PhD;
  13. Irwin Klein, MD;
  14. Herbert Klein, MD, PhD;
  15. Paul Ladenson, MD;
  16. Ronald Nishiyama, MD;
  17. Douglas Ross, MD;
  18. Steven Sherman, MD; and
  19. Harry R. Maxon, MD
     
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    Abstract

    Background: Treatment of differentiated thyroid cancer has been studied for many years, but the benefits of extensive initial thyroid surgery and the addition of radioiodine therapy or external radiation therapy remain controversial.

    Objective: To determine the relations among extent of surgery, radioiodine therapy, and external radiation therapy in the treatment of high-risk papillary and non-Hurthle-cell follicular thyroid carcinoma.

    Design: Analysis of data from a multicenter study.

    Setting: 14 institutions in the United States and Canada participating in the National Thyroid Cancer Treatment Cooperative Study Registry.

    Patients: 385 patients with high-risk thyroid cancer (303 with papillary carcinoma and 82 with follicular carcinoma).

    Measurements: Death, disease progression, and disease-free survival.

    Results: Total or near-total thyroidectomy was done in 85.3% of patients with papillary carcinoma and 71.3% of patients with follicular cancer. Overall surgical complication rate was 14.3%. Total or near-total thyroidectomy improved overall survival (risk ratio [RR], 0.37 [95% CI, 0.18 to 0.75]) but not cancer-specific mortality, progression, or disease-free survival in patients with papillary cancer. No effect of extent of surgery was seen in patients with follicular thyroid cancer. Postoperative iodine-131 was given to 85.4% of patients with papillary cancer and 79.3% of patients with follicular cancer. In patients with papillary cancer, radioiodine therapy was associated with improvement in cancer-specific mortality (RR, 0.30 [CI, 0.09 to 0.93 by multivariate analysis only]) and progression (RR, 0.30 [CI, 0.13 to 0.72]). When tall-cell variants were excluded, the effect on outcome was not significant. After radioiodine therapy, patients with follicular thyroid cancer had improvement in overall mortality (RR, 0.17 [CI, 0.06 to 0.47]), cancer-specific mortality (RR, 0.12 [CI, 0.04 to 0.42]), progression (RR, 0.21 [CI, 0.08 to 0.56]), and disease-free survival (RR, 0.29 [CI, 0.08 to 1.01]). External radiation therapy to the neck was given to 18.5% of patients and was not associated with improved survival, lack of progression, or disease-free survival.

    Conclusions: This study supports improvement in overall and cancer-specific mortality among patients with papillary and follicular thyroid cancer after postoperative iodine-131 therapy. Radioiodine therapy was also associated with improvement in progression in patients with papillary cancer and improvement in progression and disease-free survival in patients with follicular carcinoma.

    The treatment of thyroid cancer has been investigated extensively, but disagreement remains about the degree of aggressiveness needed in its management. Despite the general perception that the prognosis is excellent, 9% of patients with thyroid cancer die of the disease [1]. Patients with the less differentiated types of thyroid cancer or those presenting at a more advanced stage face higher mortality rates [2, 3]. In addition, the recurrence rate after surgery is more than 20% in persons with differentiated thyroid cancer [2]. Therefore, the ability to define the most effective therapeutic interventions on the basis of patient stratification by histologic type and stage of cancer at initial presentation should improve survival and decrease recurrence rates.

    The initial treatment for thyroid cancer is surgery, but the extent of surgery needed to improve outcome remains controversial [4-6]. Some studies have shown that more extensive thyroid resection reduces the recurrence rate but has a less definite effect on survival [2, 7]. More extensive surgery may be associated with a higher prevalence of complications, usually hypoparathyroidism or recurrent laryngeal nerve damage (or both), in 3% to 15% of patients [8-10].

    The indications for postoperative ablative radioiodine therapy and the required administered activity are also under debate. Multifocality and lymph node involvement at presentation in 46% of persons with papillary thyroid cancer (of whom 25% face persistent or recurrent disease) argue in favor of this therapy [2, 11, 12], despite the risk for sialoadenitis, gastrointestinal symptoms, occasional bone marrow suppression, and possible second cancers [13]. The role of external radiation in the treatment of differentiated thyroid cancer is also highly controversial. Increased recurrence [14], no therapeutic benefit [15-17], and improved local control [18, 19] have all been reported.

    The National Thyroid Cancer Treatment Cooperative Study Registry was established in 1986 to define clinical practice and to address the effectiveness of therapies on morbidity and mortality by prospectively enrolling a large population of patients from multiple institutions. Patients have been stratified by uniform criteria and followed prospectively from the time of initial diagnosis and treatment. This 9-year report from the registry describes outcomes in patients with high-risk, differentiated thyroid cancer, a group of patients expected to have substantial morbidity and mortality in this time period.

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    Methods

    A total of 1607 patients in whom thyroid cancer was diagnosed on or after 1 January 1987 were prospectively enrolled in the registry by the 14 participating institutions. No more than 20% of cases came from any single institution or city. Data forwarded to the registry were coded, and individual identifiers, such as name and Social Security number, were kept confidentially by the principal investigator at each institution. Because the patient's therapy was not altered by participation in the registry, requirements for informed consent were determined by the institutional review boards at each participating institution, and their mandates were followed.

    Age, sex, ethnic background, histologic diagnosis, size of primary tumor, multifocality, local invasiveness, and regional or distant metastases were documented. The histologic diagnosis was established at each institution. All variants of papillary cancer, including so-called mixed papillary and follicular carcinomas, were included in the papillary group. Analyses for papillary carcinomas that included and excluded the more aggressive tall-cell variant were performed. The Hurthle cell (oxyphilic) variant of follicular carcinoma was excluded from the follicular group.

    Patients were stratified on the basis of pathologic diagnosis, age, tumor size, local invasiveness, and extent of metastases at the time of first surgical intervention as determined by gross and histologic findings at surgery, whole-body radioiodine scans, chest radiographs, and other radiologic studies. This stratification system was established empirically before initiation of the registry by a group of experienced clinicians on the basis of information available in 1985. The criteria for categorization as high risk are noted in Table 1. Patients with preoperative vocal cord paresis or with postoperative hypocalcemia or vocal cord paresis that persisted 2 months or less were not designated as having these complications of surgery. The extent of initial surgery, use of postoperative radioiodine therapy, and application of external radiation therapy were analyzed for impact on outcome. With rare exceptions, all patients received thyroxine therapy.

    View this table:
    Table 1. Criteria for Stratification to High-Risk Groups

    Outcomes were death due to thyroid cancer or to complications of its treatment, progression (defined as a patient alive with progressive thyroid cancer or dead because of thyroid cancer or complications of its treatment at last follow-up), and disease-free survival (defined as a patient alive with no known residual thyroid cancer or free of thyroid cancer at the time of death from other causes).

    Statistical Analysis

    All data were extracted by using a computer-based integrated data management package (Med-log, Information Analysis Corporation, Incline Village, Nevada). Cox proportional-hazards models were performed to determine whether each predictor variable was associated on univariate analysis (Table 2) with survival, progression, and disease-free survival (SAS Institute, Cary, North Carolina). The hazard model was also used to identify the set of predictor variables that best explained the probabilities of overall survival, cancer-specific mortality, progression of disease, or disease-free survival (Table 3). A P value of 0.05 or less was considered statistically significant. Risk ratios obtained from the Cox proportional-hazards analyses are given with 95% CIs. Risk ratios less than 1 indicate improved outcome, and those greater than 1 indicate a worsened outcome.

    View this table:
    Table 2. Variables Associated with Mortality, Progression, and Disease-Free Survival (by Univariate Analysis)
    View this table:
    Table 3. Variables That Best Predict Overall Mortality, Cancer-Specific Mortality, Progression of Disease, or Disease-Free Survival (by Multivariate Analysis)
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    Results

    Follow-up

    Three hundred three patients with papillary carcinoma and 82 patients with follicular carcinoma were considered to have high-risk thyroid cancer. Twenty patients (5.2%) were lost to follow-up. An additional 64 patients were not included in the survival analyses because no information on patient status was available (n = 60), no cause of death was recorded (n = 2), or patients were alive with no cancer status reported (n = 2). Demographic characteristics of the two groups were similar regardless of whether these cases were included. Patients were followed for a mean of 3.1 years after the date of surgery; 35% were men. The mean (±SD) age at entry was 57 ± 15 years.

    Sex and Age

    Compared with men, women with papillary cancer had a lower risk for overall mortality (risk ratio [RR], 0.03 [95% CI, 0.23 to 0.92]) but not cancer-specific mortality. Older age did not affect outcome in patients with papillary carcinoma or those with follicular carcinoma, but an age effect might be masked by the fact that age was a factor in defining these high-risk patients.

    Histologic Type

    Only 18 patients with papillary cancer had the tall-cell variant (P not significant by multivariate analysis). By univariate analysis, radioiodine therapy was associated with reduced disease progression (risk ratio, 0.10 [CI, 0.01 to 0.72]; P = 0.02).

    Thyroid Surgery

    The first surgical procedure on the thyroid and any surgical therapy of the thyroid that occurred within the next 4 months were classified as initial thyroid surgery. Data were not sufficient to allow analysis of the effect of modified neck dissections on complication rates. Of 300 patients with papillary cancer, 256 (85.3%) had a total or near-total thyroidectomy as initial thyroid surgery, 10 (3.3%) had bilateral subtotal thyroidectomy, 26 (8.7%) had lobectomy, 1 (0.3%) had lumpectomy, 4 (1.3%) had biopsy only, and 3 (1.0%) had nonspecified surgery. Of 80 patients with follicular cancer, 57 (71.3%) had total or near-total thyroidectomy as initial thyroid surgery, 2 (2.5%) had bilateral subtotal thyroidectomy, 13 (16.3%) had lobectomy, 4 (5.0%) had lumpectomy, and 4 (5.0%) had biopsy only.

    The charts of all patients with reported surgical complications were reviewed. The complication rate of initial surgery varied among centers. The overall rate of some type of complication was 14.4% (52 of 360 patients). Specific data on complications were available for 286 of 303 patients with papillary cancer and 74 of 82 patients with follicular thyroid cancer. Hypoparathyroidism alone occurred in 19 of 286 (6.6%) patients with papillary cancer and 3 of 74 (4.0%) patients with follicular cancer. Vocal cord palsy alone was noted in 17 of 286 (5.9%) patients with papillary cancer and 6 of 74 (8.0%) patients with follicular cancer. Combined hypoparathyroidism and vocal cord palsy occurred in 4 of 286 (1.4%) patients with papillary cancer and no patients with follicular cancer. Data were not sufficient to allow analysis of any effect of modified neck dissections on complication rates.

    Overall mortality from papillary cancer improved with total or near-total thyroidectomy compared with other surgical procedures (RR, 0.41 [CI, 0.20 to 0.85]) (Table 2). Progression of disease and disease-free survival were not improved by more extensive surgery, and surgery did not affect mortality, progression, or disease-free survival in patients with follicular cancer by univariate (Table 2) or multivariate (Table 3) analyses.

    Radioiodine Therapy

    Postoperative radioiodine therapy with iodine-131 was administered to 258 of 302 (85.4%) patients with papillary cancer; the initial dose was 30 mCi or less in 15% of patients, 31 to 75 mCi in 9%, and more than 75 mCi in 76%. Among patients with follicular thyroid cancer, 79.3% (65 of 82) received postoperative radioiodine therapy; the initial dose was 30 mCi or less in 23% of patients, 31 to 75 mCi in 11%, and more than 75 mCi in 66%.

    Cancer-specific survival was slightly improved (RR, 0.30 [CI, 0.09 to 0.93] by multivariate analyses only) and disease progression was less (RR, 0.38 [CI, 0.17 to 0.87]) among patients with papillary cancer who received radioiodine therapy compared with those who did not receive this therapy. Radioiodine therapy did not improve disease-free survival in patients with papillary thyroid cancer.

    Radioiodine therapy was highly effective in improving outcome in patients with follicular thyroid cancer. Overall mortality (RR, 0.2 [CI, 0.08 to 0.56]) and cancer-specific survival (RR, 0.16 [CI, 0.06 to 0.49]) in this group improved significantly with radioiodine therapy. The likelihood of progression was lower in patients with high-risk follicular thyroid cancer who received radioiodine therapy (RR, 0.30 [CI, 0.12 to 0.77]). The likelihood of being disease-free after radioiodine therapy was of borderline significance in multivariate analysis (RR, 0.29 [CI, 0.08 to 1.01]). The number of adverse outcomes was not sufficient to permit analysis of the effect of administered activity on outcome.

    External-Beam Radiation and Control of Local Disease

    Forty-six of 248 (18.5%) patients who had high-risk papillary or follicular thyroid cancer without distant metastases were given external radiation to the neck or the thyroid bed. The mean dose of radiation was 46 Gy, the mean number of fractions was 18.5, and the mean fraction size was 2.5 Gy per fraction. Seventy-eight percent of the 46 patients had papillary thyroid cancer. The prevalence of lymph node metastases in the 46 patients who received external radiation (50%) was similar to that in the 202 patients who did not receive external radiation (47%). However, more patients receiving external radiation than patients not receiving external radiation had gross residual disease after initial surgery (20% [9 of 46 patients] and 9% [19 of 202 patients]; P = 0.05), and more patients who received external radiation had gross extrathyroid invasion (88% [36 of 41 patients] compared with 65% [49 of 73 patients]; P = 0.02). Patients receiving external radiation were older than those who did not receive it (mean age, 61 and 55 years; P = 0.02). All three variables (gross residual disease, gross extrathyroidal invasion, and older age) are poor prognostic factors.

    Among patients with high-risk papillary cancer, those who received local external radiation had higher overall mortality than those not receiving this therapy (RR, 2.38 [CI, 1.17 to 4.85]). Overall and cancer-specific mortality were also higher among patients with high-risk follicular cancer who received external radiation therapy (RR, 4.55 [CI, 1.79 to 11.6] and 8.41 [CI, 2.84 to 24.93]) than in those not receiving such therapy. The likelihood of progression (RR, 5.70 [CI, 2.4 to 13.3]) and disease-free survival (RR, 4.46 [CI, 1.5 to 13.0]) was poorer in patients with follicular cancer who received external-beam radiation.

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    Discussion

    Recommendations for the optimal extent of thyroid surgery range from extensive neck dissection to limited tumor resection [4, 5]. Common practice has been to perform total thyroidectomy on patients perceived as being at higher risk, such as those who have lymph node metastases, aggressive variants of disease, multifocal cancer, or a history of therapeutic radiation to the neck [2, 4]. The impact of the extent of surgery on outcome has been assessed in several retrospective studies. Mazzaferri and colleagues [2] showed that surgery that was more extensive than lobectomy improved survival in persons who had papillary and follicular cancers and no distant metastases. Rossi and associates [20] studied patients with surgically incurable thyroid cancer and found improved long-term survival after extensive resection of thyroid tissue, excision of soft-tissue spread, and removal of obvious lymph node metastases but not after radical neck dissection. A more thorough thyroidectomy was recommended by DeGroot and Kaplan [7], who noted that 40% of patients treated with initial lobectomy or partial lobectomy required a second operation. Other investigators have shown no improvement with more extensive surgery [21, 22]. Our prospective, multicenter study of patients with high-risk papillary thyroid cancer suggests that overall survival is improved with total or near-total thyroidectomy but that more extensive surgery is not associated with improvement of other outcomes. No effect of extent of surgery was seen in patients with follicular cancer.

    Hypoparathyroidism has been reported in 5% of all thyroid surgeries and is associated with extent of surgery [21]. Operations specific for thyroid cancer may increase this Figure to 14% [23]. In our study, surgical complications were noted in 14.4% of high-risk patients with thyroid cancer.

    Postoperative iodine-131 therapy has been advocated for several reasons, including treatment of possible residual disease and ablation of residual thyroid tissue to allow more accurate follow-up of the patient with whole-body iodine-131 scans and serum thyroglobulin measurements. The effectiveness of radiation therapy has been controversial. In one study, radioiodine therapy of papillary cancers larger than 1 cm with or without metastases or local invasion was shown to improve survival [11]. Radioiodine therapy in patients with differentiated thyroid cancer has resulted in decreased recurrences, regardless of whether patients had known residual disease [11] or no known residual disease [23, 24]. This prospective study confirms that radiation therapy with iodine-131 improves cancer-specific mortality rates and progression in patients with papillary cancer and improves cancer-specific mortality rates, progression, and disease-free survival in patients with follicular cancer.

    Reports on the use of external radiation to the thyroid bed or neck have had contradictory conclusions. Mazzaferri and Young [14] reported on a small group of patients who had external radiation therapy; these patients had a higher local relapse rate than patients who did not have the treatment. The lack of a beneficial effect of external radiation on local control or survival has also been reported by others [15-17]. In contrast, Simpson and coworkers [18] and others [19, 25] have shown that external radiation resulted in improved local control in patients considered to be at high risk for local relapse. Our data indicate that external radiation therapy was associated with poorer outcome.

    In summary, this prospective, multicenter study showed an association of total or near-total thyroidectomy with improved overall mortality among patients with papillary carcinoma but not those with follicular carcinoma. Postoperative radioiodine-131 therapy was associated with improved cancer-specific mortality rates and disease progression in patients with papillary or follicular cancer, and external-beam radiation was associated with worsened outcomes in these patients. Thus, in patients with high-risk papillary or follicular thyroid cancer, a more aggressive therapeutic approach may be warranted.

    From University of Cincinnati Medical Center, Cincinnati, Ohio; Georgetown University Medical Center, Washington, D.C.; National Institutes of Health, Bethesda, Maryland; University of Kentucky Medical Center, Lexington, Kentucky; Maine Medical Center, Scarborough, Maine; The Princess Margaret Hospital-Ontario Cancer Institute, Toronto, Canada; Sinai Hospital of Baltimore, Baltimore, Maryland; University of Colorado Health Sciences Center, Denver, Colorado; Mayo Clinic, Rochester, Minnesota; North Shore University Hospital, Manhassat, New York; Johns Hopkins Hospital, Baltimore, Maryland; Massachusetts General Hospital, Boston, Massachusetts; University of Texas M.D. Anderson Cancer Center, Houston, Texas; and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

    Dr. Specker: Ethel Austin Program, Box 2275A, South Dakota State University, Brookings, SD 57007.

    Dr. Robbins: National Institute of Diabetes and Digestive and Kidney Diseases, Genetics, and Biochemistry Branch, National Institutes of Health, Building 10, Room 6C201, Bethesda, MD 20892.

    Mr. Sperling: Radio Biology Laboratory, University Hospital, 234 Goodman Street, Cincinnati, OH 45267.

    Ms. Ho: Pediatric Bone Department, University Hospital, 341 Bethesda Avenue, Cincinnati, OH 45267.

    Dr. Ain: University of Kentucky Medical Center, Department of Medicine, 800 Rose Street, Room MN520, Lexington, KY 40536-0084.

    Dr. Bigos: Division of Endocrinology, Maine Medical Center, 100 U.S. Route One, Unit 116, Scarborough, ME 04074-9308.

    Dr. Brierley: The Princess Margaret Hospital-Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9.

    Dr. Cooper: Sinai Hospital of Baltimore, Endocrine Division, Suite 56, Hoffberger Professional Center, 2401 West Belvedere Avenue, Baltimore, MD 21215-5271.

    Dr. Haugen: Division of Endocrinology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Room B151, Denver, CO 80262.

    Dr. Hay: Division of Endocrinology (West 18), Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

    Dr. Hertzberg: Department of Biostatistics, Emory University, Rollin School of Public Health, 1518 Clifton Road, NE, Atlanta, GA 30322.

    Dr. I. Klein: North Shore University Hospital-Cornell University Medical College, Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, 300 Community Drive, Manhasset, NY 11030.

    Dr. H. Klein: University of Pittsburgh, School of Medicine, Presbyterian University Hospital, 200 Lothrop Street, Pittsburgh, PA 15213.

    Dr. Ladenson: Endocrinology and Metabolism, The Johns Hopkins Hospital, 600 North Wolfe Street, Blalock 904, Baltimore, MD 21287-4904.

    Dr. Nishiyama: Department of Pathology, Maine Medical Center, 100 U.S. Route One, Scarborough, ME 04074.

    Dr. Ross: Thyroid Associates, Thyroid Unit ACC-730, Massachusetts General Hospital, Boston, MA 02114.

    Dr. Sherman: The University of Texas M.D. Anderson Cancer Center, Endocrinology Box 15, 1515 Holcombe Boulevard, Houston, TX 77030-4095.

    Dr. Maxon: Nuclear Medicine, University of Cincinnati Medical Center, 234 Goodman Street, Mont Reid Pavilion, Suite G026, Cincinnati, OH 45267.

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