Matched pair analyses of stage IV breast cancer with or without resection of primary breast site.

BACKGROUND: Reports demonstrate improved survival of stage IV breast cancer patients with primary cancer resection. This may result from selection for surgery, rather than biological processes. METHODS: We performed matched-pair analysis that minimized potential bias in selecting surgery for primary cancer. Chart review was also performed of 5-year survivors to assess selection bias affecting breast surgery. RESULTS: 19,464 breast cancer patients were identified; 808 (4.2%) were stage IV: 622 were analyzed after eliminating wrong diagnoses or staging, and limiting patients to Massachusetts residents. Matched-pair analysis narrowed or eliminated apparent survival benefit associated with primary site surgery in several comparisons. When the impact of the sequence of systemic and surgical treatments was studied in stage IV patients, 90% 2-year survival occurred in patients receiving chemotherapy first, in contrast to receiving chemotherapy simultaneously with or after surgery, suggesting selection for delayed surgery after excellent response to initial chemotherapy. In bone metastases, the 2-year survival advantage occurred with chemotherapy before surgery; no difference in survival with or without surgery occurred when these treatments were simultaneous. Among 5-year survivors, frequency of primary site surgery after excellent response to systemic therapy, breast surgery in stage III patients incorrectly classified as stage IV, and frequency of oligo metastases all indicated selection bias. CONCLUSIONS: Case selection bias in primary breast cancer resection in state IV patients may explain most, if not all, the apparent survival advantage of such surgery.

Role of the Cdc25A phosphatase in human breast cancer.

The phosphatase Cdc25A plays an important role in cell cycle regulation by removing inhibitory phosphates from tyrosine and threonine residues of cyclin-dependent kinases, and it has been shown to transform diploid murine fibroblasts in cooperation with activated Ras. Here we show that Cdc25A is overexpressed in primary breast tumors and that such overexpression is correlated with higher levels of cyclin-dependent kinase 2 (Cdk2) enzymatic activity in vivo. Furthermore, in the breast cancer cell line MCF-7, Cdc25A activity is necessary for both the activation of Cdk2 and the subsequent induction of S-phase entry. Finally, in a series of small (< 1 cm) breast carcinomas, overexpression of Cdc25A was found in 47% of patients and was associated with poor survival. These data suggest that overexpression of Cdc25A contributes to the biological behavior of primary breast tumors and that both Cdc25A and Cdk2 are suitable therapeutic targets in early-stage breast cancer.

The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a,b) invasive breast carcinomas.

Breast carcinomas < or = 1 cm in size (T1a,b) are being detected more frequently as a result of screening. Because traditional prognostic parameters are either lacking (tumor size) or rare (nodal metastases), a marker(s) is needed to identify the subset of patients who could benefit from adjuvant therapy. A retrospective series of 202 patients with stage T1a,b invasive breast carcinomas was evaluated. The clinicopathological features (age, histological grade, extensive in situ carcinoma, hormone receptor status, and nodal metastasis) as well as microvessel density and the expression of c-erb-B2, p53, MIB-1/Ki-67, and cdc25B were assessed. In addition, expression of the cell cycle inhibitor p27 was evaluated. Nineteen patients (18% of patients who had axillary dissection) had locoregional lymph node metastases. Forty-two % of them died of disease (median survival, 112 months), whereas mortality was 11% in node-negative patients (median survival, 168 months; P = 0.0055). Patients with low p27 expression had a median survival of 139 months (17% mortality) versus 174 months (9% mortality) in the group with high p27 expression (P = 0.0233). Lack of p27 was associated with poor prognosis when node-positive patients were excluded (P = 0.0252). Nodal status and low p27 were found to be the only independent prognostic parameters by both univariate and multivariate analysis, with relative risks of dying of disease of 4.9 (P = 0.001) and 3.4 (P = 0.0306), respectively. Assessment of p27, which yields prognostic information in node-negative patients, could be useful to identify patients with small, invasive breast carcinomas who might benefit from adjuvant therapy.

Recurrence in the breast following conservative surgery and radiation therapy for early-stage breast cancer.

This report summarizes the experience of the Joint Center for Radiation Therapy (JCRT) in treating patients with clinical stage I and II breast cancer with conservative surgery and radiation therapy. The study population consisted of 1396 patients treated between 1968 and 1985. All patients underwent a gross excision of the tumor and received breast irradiation (with or without nodal irradiation) including a "boost" to bring the primary tumor site to a total dose of at least 60 Gy. The method of treatment evolved over the study-time period. During the interval from 1968 to 1982, patients typically underwent a limited gross excision of the tumor without regard to the microscopic margins of resection. During the period 1983 to 1985, film-screen mammography, inking of specimen margins, and reexcisions for inevaluable or involved margins were more commonly performed. With a median follow-up of 80 months, the 5-year crude rate of failure in the breast (as the first site of failure) was 8% (106/1396) and the crude rate of regional nodal/distant failure (as the first site of failure) was 16% (228/1396). The time-course of failures in the breast was protracted, occurring at a fairly constant rate over the first 7 years after treatment, but still seen beyond that point. Most recurrences in the breast (75%) developed at or near the original tumor site. The most important risk factor for developing a breast recurrence was the presence of an extensive intraductal component in the tumor. The cosmetic results following treatment were excellent or good in the majority of patients (87%) and were most adversely affected by extensive surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of surgical resection of liver metastases in colorectal carcinoma.

While hepatic resection of colorectal carcinoma, metastatic to the liver, is a suitable and effective treatment, it nevertheless remains applicable only to a highly selective group of patients. Even within this highly selective group of patients only a minority will survive 5 years disease-free indicating the increased sophistication needed to understand the biological factors that control outcome. It is clear that the good results come from biological suitability and not temporal acceleration of the detection process. Appropriate patients after careful selection and sophisticated diagnostic studies should be subjected to exploration and attempted hepatic resection. A preliminary prognostic scoring system has been presented to illustrate the usefulness of this approach.

Orthovoltage intraoperative radiotherapy: a new look at an old idea.

A 300 kvp orthovoltage machine has been permanently installed in an operating room for delivering intraoperative radiation therapy (IORT). A historical review of orthovoltage IORT and our present approach are described. The preliminary experience with 38 patients treated with orthovoltage IORT indicates that this technique is feasible, has low acute morbidity, and can be useful for palliation. "Radical" radiation therapy consisting of IORT "boost" treatment combined with external beam was used in 24 patients with primary or recurrent cancer. Local failure in 27 patients treated with IORT +/- external beam radiation therapy was 56%, but varied from 11% (1/9) for patients with resected disease to 78% (14/18) for patients with unresected disease. Complications occurred in nine patients (24%) and have been acceptable. There are 17 patients alive and six are NED, with follow-up of 4-18 months. There appears to be a role for orthovoltage IORT especially when combined with surgical resection for local control of advanced cancer arising in the abdomen where the use of high doses of external radiation therapy are hazardous.

Edema of the arm as a function of the extent of axillary surgery in patients with stage I-II carcinoma of the breast treated with primary radiotherapy.

Edema of the arm can be a significant complication following treatment of breast cancer. To determine the risk of arm edema and factors associated with this risk in patients treated with primary radiotherapy, we reviewed the records of 475 women with early breast cancer treated between 1968 and 1980. During this period, the use of axillary surgery prior to radiation gradually increased, and all patients received full axillary irradiation until late in the series. Based on the surgeon's report, the extent of axillary surgery was classified as either a sampling, a lower dissection, or a full dissection. Edema of the arm was scored on clinical grounds and ranged from mild hand swelling to an increased arm circumference of 8 cm. At 6 years, the actuarial risk of developing arm edema was 8% for the entire study population. This risk was 13% for 240 patients who had axillary surgery and 4% for 235 patients not undergoing axillary surgery (p = 0.006). For patients undergoing axillary surgery, the risk of arm edema was 37% with full dissection compared to 5% with sampling (p = 0.0003), and 8% with lower dissection (p = 0.03). The risk of arm edema at 6 years was 28% if more than ten nodes were removed, and 9% if one to ten nodes were removed (p = 0.03). However, the extent of axillary dissection was stronger predictor of subsequent edema than was the number of nodes obtained. The role of axillary irradiation could not be evaluated since 91% of patients received axillary irradiation. The use of chemotherapy, the site or size of the primary tumor, clinical nodal status, patient age and weight, type of suture, the use of a drain, and subsequent local or distant failure did not appear to be significant risk factors. We conclude that the combination of full dissection and full axillary irradiation results in an unacceptably high risk of arm edema.

Locally advanced rectal carcinoma: pelvic control and morbidity following preoperative radiation therapy, resection, and intraoperative radiation therapy.

PURPOSE: To determine the impact of intraoperative radiation therapy (IORT) combined with preoperative external beam irradiation and surgical resection in patients with locally advanced, unresectable rectal carcinoma. METHODS AND MATERIALS: Between 1982 and 1993, 40 patients with locally advanced colorectal cancer unresectable at initial presentation were treated with preoperative external beam radiation therapy (median dose 50.4 Gy). Thirty patients received concurrent 5-fluorouracil. Twenty-seven patients had primary tumors and 13 had recurrent disease; 1 patient had a solitary hepatic metastasis at the time of surgery. Four to 6 weeks after radiation, surgical resection was undertaken, and if microscopic or gross residual disease was encountered, IORT was delivered to the tumor bed. Patients with an unevaluable or high-risk margin were also considered for IORT. IORT was delivered through a dedicated 300-kVp orthovoltage unit. The median dose of IORT was 12.5 Gy (range 8-20). The dose was typically prescribed to a depth of 1-2 cm. The median follow-up was 33 months (range 5-100). RESULTS: Thirty-three patients were able to undergo a curative resection (83%). Five patients had gross residual disease despite aggressive surgery. Seven patients did not receive IORT: six because of clear margins, and one with gross disease that could not be treated for technical reasons. The remainder of the patients (26) received IORT to the site of pelvic adherence. The crude local control rates for patients following complete resection with negative margins were 92% for patients treated with IORT and 33% for patients without IORT. IORT was ineffective for gross residual disease. Pelvic control was none of four in this setting. The crude local control rate of patients with primary cancer was 73% (16 of 22), as opposed to 27% (3 of 11) for these with recurrent cancer. The 5-year actuarial overall survival and local control rates for patients undergoing gross complete resection and IORT were 64% and 75%, respectively. Seventeen of the 26 patients (65%) who received IORT experienced pelvic complications, as opposed to two patients (28%) who did not receive IORT. The incidence of complications was similar in the patients with primary versus recurrent disease. All cases were successfully treated with the placement of a posterior thigh myocutaneous flap. Of note, no pelvic osteoradionecrosis was seen in this series. CONCLUSION: Patients with locally advanced carcinoma of the rectum were aggressively treated with combined modality therapy consisting of preoperative external beam radiotherapy, surgery, and IORT. The pelvic control rate was 82% for patients with minimal residual disease. IORT failed to control gross residual disease. The incidence of pelvic wound healing problems was 65% in this series; however, a reconstructive procedure which replaced irradiated tissue with a vascularized myocutaneous flap was successful in treating this complication. We believe that IORT has therapeutic merit in the treatment of locally advanced rectal cancer, particularly in the setting of minimal residual disease.

Late cosmetic outcome after conservative surgery and radiotherapy: analysis of causes of cosmetic failure.

Although the majority of patients with early breast cancer treated with conservative surgery and radiotherapy have acceptable cosmetic outcomes, the specific causes of a less-than-acceptable result are not well known. To assess the technical factors associated with late cosmetic failure, we reviewed the records of 593 patients treated with conservative surgery and radiotherapy at the Joint Center for Radiation Therapy, Boston, between 1968 and 1981. Median follow-up was 76 months with a range of 37-186 months. Using a 4-point scoring system (excellent, good, fair, poor) patients were noted to have cosmetic "failure" if scored as either fair or poor. Cosmetic results were similar at 3, 5, and 7 years with excellent or good scores seen in 88%, 90%, and 78% of patients, respectively. Three technical factors were associated with a significant worsening of the cosmetic results. The resection of 70 cm3 or more of breast tissue was more common among the failed patients than among matched patients with good or excellent results (p = 0.03). Eighty-nine percent of patients treated with a tangent pair technique had excellent results at 5 years compared to 69% of patients treated with a three-field technique (p = 0.004). The use of a larger volume implant was associated with a greater risk of a fair or poor cosmetic result compared to the use of a smaller volume implant. We conclude that overall cosmesis has been acceptable in this series, but there are technical (surgery and radiotherapy) factors which can be modified to optimize the cosmetic result without compromising local tumor control.

Treatment outcome after tangential radiation therapy without axillary dissection in patients with early-stage breast cancer and clinically negative axillary nodes.

PURPOSE: To determine the risk of nodal failure in patients with early-stage invasive breast cancer with clinically negative axillary lymph nodes treated with two-field tangential breast irradiation alone, without axillary lymph node dissection or use of a third nodal field. METHODS AND MATERIALS: Between 1988 and 1993, 986 evaluable women with clinical Stage I or II invasive breast cancer were treated with breast-conserving surgery and radiation therapy. Of these, 92 patients with clinically negative nodes received tangential breast irradiation (median dose, 45 Gy) followed by a boost, without axillary dissection. The median age was 69 years (range, 49-87). Eighty-three percent had T1 tumors. Fifty-three patients received tamoxifen, 1 received chemotherapy, and 2 patients received both. Median follow-up time for the 79 survivors was 50 months (range, 15-96). Three patients (3%) have been lost to follow-up after 20-32 months. RESULTS: No isolated regional nodal failures were identified. Two patients developed recurrence in the breast only (one of whom had a single positive axillary node found pathologically after mastectomy). One patient developed simultaneous local and distant failures, and six patients developed distant failures only. One patient developed a contralateral ductal carcinoma in situ, and two patients developed other cancers. CONCLUSION: Among a group of 92 patients with early-stage breast cancer (typically T1 and also typically elderly) treated with tangential breast irradiation alone without axillary dissection, with or without systemic therapy, there were no isolated axillary or supraclavicular regional failures. These results suggest that it is feasible to treat selected clinically node-negative patients with tangential fields alone. Prospective studies of this approach are warranted.

Early breast cancer: predictors of breast recurrence for patients treated with conservative surgery and radiation therapy.

The identification of factors associated with breast recurrence following conservative surgery (CS) and radiation therapy (RT) is of potential use in refining patient selection criteria and treatment technique. In an attempt to define such factors we examined the relationship between various clinical, pathologic and treatment characteristics and the likelihood of breast recurrence in 783 patients with clinical stage I or II breast cancer treated between July 1968 and December 1982. Treatment consisted of complete gross excision of the primary tumor and RT to a total dose of at least 60 Gy to the primary site. During this period, pre-treatment mammograms and detailed histologic assessment of the margins of resection were not routinely performed. Median follow-up for surviving patients was 80 months. Thirteen patients (1.6%) were lost to follow-up. Ninety-one patients (12%) have developed a breast recurrence, corresponding to 5- and 10-year actuarial rates of 10 and 18%, respectively. The major feature associated with breast recurrence was the presence of an "extensive intraductal component" (EIC+). An EIC+ tumor was seen in 28% of evaluable cases with infiltrating ductal carcinoma and accounted for 60% of breast recurrences. Forty-three of 166 patients (26%) with EIC+ tumors developed a breast recurrence compared with 29 of 418 patients (7%) without an EIC (EIC-) (p = 0.0001). The 5-year actuarial rates of breast relapse were 24 and 6%, respectively (p = 0.0001). Very young age (defined as 34 years of age or younger) was also a significant factor associated with the risk of breast recurrence. Very young patients comprised 8% of the patient population and accounted for 16% of breast recurrences. Fifteen of 61 very young patients (25%) developed a breast recurrence compared with 76 of 722 older patients (11%) (p = 0.001). The corresponding 5-year actuarial rates of breast recurrence were 21 and 9% (p = 0.005). None of the other clinical or pathological factors examined by univariate analysis were significantly correlated with recurrence in the breast. A multivariate model of site of first failure (polychotomous logistic regression) also showed that EIC+ tumors and very young age were the main factors associated with a high relative risk of breast recurrence. We conclude that EIC+ tumors and very young age are associated with a high risk of breast recurrence for patients treated with limited excision prior to RT.

An expanded view of risk-group definition in differentiated thyroid carcinoma.

There continues to be controversy about every aspect of management of differentiated thyroid carcinoma. In an age-based risk group previously described, low-risk patients made up 62% of cases and had a death rate of only 1%. Recent reports from the Mayo Clinic have expanded the concept of the low-risk group to include 86% of all cases with a 2% death rate by utilizing several anatomic and pathologic criteria of risk. We offer here another multifactorial system for the identification of low-risk patients who made up 89.4% of all patient seen between 1961 and 1980 and who have a death rate of only 1.8%. The resultant high-risk group constitutes 11% of cases but carries a 46% mortality rate. The risk-group definition is completely clinical and is based on age, presence of distant metastases, and the size and extent of primary cancer. It can be used confidently at the operating table to select conservative surgical procedures in patients with negligible risk of death. Through the succeeding decades analyzed, from 1941 to 1980, the effectiveness of this clinical categorization has increased substantially in separating patients at high and low risk, so that a mortality rate ratio of 26:1 now exists between high- and low-risk groups, respectively.

Further evidence of the validity of risk group definition in differentiated thyroid carcinoma.

Three hundred nine consecutive patients primarily treated at the Lahey Clinic Foundation for differentiated thyroid carcinoma between the years 1961 and 1980 were followed for a median of 13 years and a minimum of 5 years. The recurrence and survival rates of these patients are strikingly different in the low-risk group (men 40 years of age and under and women 50 years and under) compared with the high-risk group (all older patients). Only two patients died and eight others had recurrences but survived in 192 low-risk patients, whereas 18 died and 23 had recurrences in 117 high-risk patients. Thus 20% of patients with recurrence in the low-risk group died but 78% of patients with recurrence in the high-risk group died. Follicular carcinoma and major capsular invasion carries a poor prognosis, but only 22% of low-risk in contrast to 55% of high-risk patients died. The fact that low- and high-risk patients have a separate biology is emphasized by unique sex ratio differences. Low-risk patients have a constant male to female ratio of about 5:1, whereas high-risk patients have progressively increased from 1:3 to a male predominance during the past 5 decades. This study showing unique differences in results by age reemphasizes the concept of basic risk groups in differentiated thyroid cancer. The effect of this basic risk group, as in our previous report, supercedes the effect of pathologic type, extent of local disease, or aspects of therapy and exerts principal control over biologic behavior.

Ultrasound-guided catheter localization of intrahepatic abscesses--an aid in open surgical drainage.

A catheter placed by the radiologist in a hepatic abscess before operation affords many luxuries to the surgeon. Percutaneous aspiration of the abscess provides material for Gram stain and culture, thereby allowing appropriate perioperative selection of antibiotics. The decompression provided gives the surgeon time to prepare the patient adequately for operation. Most important, use of the catheter as a guide to the abscess allows the surgeon to select the optimal approach to the liver and then proceed directly to the involved area. In this way operating time, blood loss, damage to uninvolved areas of the liver, and unnecessary contamination are kept to a minimum.

Management problems in coexisting parathyroid crisis and florid thyrotoxicosis.

The etiologic relationship between parathyroid and thyroid disease is controversial and still not well defined. An increased incidence of parathyroid adenomas with thyroid disease has been suggested by some researchers. Other authors are unable to confirm this and maintain that the major factor contributing to the coexistence of parathyroid adenomas and thyroid disease is the prevalence of these conditions, independently, in middle-aged women. Serum parathyroid hormone levels are generally lower in patients with thyrotoxicosis and higher in patients with hypothyroidism. The simultaneous occurrence of thyrotoxicosis and symptomatic hyperparathyroid crisis has been reported previously only once in the American literature. We report a case of a 32-year-old woman with documented uncontrolled Graves' disease (T4 = 20 micrograms/dl [normal = 4.5 to 11.5 micrograms/dl], total T3 = 361 ng/dl [normal = 115 to 190 ng/dl], T3RU = 53% [normal = 35% to 45%]), who developed parathyroid crisis (serum calcium = 15 mg/dl [normal = 9 to 11 mg/dl], N-terminal parathyroid hormone = 121 pg/ml [normal = 11 to 24 pg/ml], C-terminal parathyroid hormone = 9416 pg/ml [normal = 60 to 450 pg/ml]). After a turbulent 10-day period to achieve a euthyroid state with propranolol, propylthiouracil, and a saturated solution of potassium iodide, operation revealed a large parathyroid adenoma (2 by 2 by 3 cm) and a diffusely hyperplastic thyroid gland. Adenoma excision and bilateral subtotal thyroidectomy were performed. This case illustrates management guidelines of a true endocrine emergency in which prompt operation for acute hyperparathyroidism could not be undertaken until a euthyroid state and reduction in serum calcium levels were achieved with aggressive medical management.

Intraoperative radiation therapy for biliary tract carcinoma: results of a 5-year experience.

The results of a 5-year experience with use of intraoperative radiation therapy (IORT) in the management of locally advanced bile duct carcinoma are presented. Fifteen patients received IORT doses between 5 and 20 Gy for localized disease, which was either primary and resected with microscopic residual (2 patients), primary and unresected (10 patients), or recurrent (3 patients). Thirteen patients also received postoperative radiation therapy. The median survival of the 12 patients with primary disease was 14 months, with disease controlled in the porta hepatis in 5 of 10 evaluable patients. The three patients with recurrent disease survived 2, 9, and 11 months. There were two operative deaths, for an operative mortality of 13%. Acute and chronic complications are reviewed. Cholangitis is the most frequent in both categories. This aggressive approach in the therapy for advanced disease has an acceptable level of morbidity and may warrant the use of IORT as part of the management of biliary tract cancer.

Biologic considerations and operative strategy in papillary thyroid carcinoma: arguments against the routine performance of total thyroidectomy.

Reasons cited for the routine performance of total thyroidectomy in patients with papillary thyroid carcinoma include: fear of multicentric neoplastic foci causing local recurrence and death; risk of anaplastic transformation of unresected multifocal microscopic carcinoma; toxicity of high-dose radioactive iodine to ablate normal thyroid remnants; and lack of reliable criteria for grading malignancy and identifying patients at high risk. However, autopsy studies have detected microscopic foci of papillary thyroid cancer as incidental findings in up to 24% of patients dead of other diseases. The prevalence of anaplastic transformation of papillary thyroid carcinoma as determined from reports in the literature is less than 1%. A retrospective investigation of 90 patients with papillary thyroid carcinoma derived from the Swedish National Cancer Registry showed no complications from radioiodine ablation of postoperative thyroid remnants in 45 patients. Retrospective analysis of the DNA content of tumors at the time of the initial operation showed a significant difference between a group of 10 patients who died of recurrent and metastatic papillary thyroid carcinoma and a group of 16 patients alive at least 10 years after operation despite distant metastases or recurrent cancer in the thyroid bed and/or cervical lymph nodes. The risk of permanent hypoparathyroidism is higher in patients after total thyroidectomy without apparent improvement in survival rates when compared with less extensive resections. Therefore it is proposed that the criteria for total thyroidectomy in patients with papillary thyroid carcinoma be limited to: tumors that clinically involve both lobes of the thyroid gland, extracapsular spread of cancer requiring enbloc resection, and reoperations where scarring prevents accurate delineation of the extent of the tumor. By differentiating patients at high risk for death from papillary thyroid carcinoma from patients at low risk, the measurement of DNA content may decrease the need for routine total thyroidectomy.

The effect of thyroid hormone administration upon survival in patients with differentiated thyroid carcinoma.

Seven hundred sixty-one patients with operable differentiated thyroid carcinoma were treated between 1931 and 1970. Median follow-up time was 18 years and ranged from 5 to 40 years. Sixty-three percent of the patients were followed more than 15 years, and 46% were followed more than 20 years. Because resections usually spared sufficient thyroid tissue for homeostasis, thyroid hormone was not routinely prescribed after operations performed before 1960. Altogether 244 patients with papillary carcinoma and 76 patients with follicular carcinoma received thyroid hormone, while 296 patients with papillary carcinoma and 45 patients with follicular carcinoma did not receive thyroid hormone after operation. With papillary carcinoma, 14% of men greater than 40 and women greater than 50 years of age (high risk) but only 2% of men less than or equal to 40 years of age and women less than or equal to 50 years of age (low risk) died of disease (P 0.0001). Twenty-six percent of high-risk but only 4% of patients with low-risk follicular cancer died (P 0.0001). However, there was no statistically significant improvement in survival times with use of thyroid hormone when patients were categorized by risk group and pathology. These data support the importance of age and sex in previously described risk groups; these factors supersede the effects of adjuvant treatment. This absence of effect on survival times calls into question current recommendations for routine use of thyroid hormone after surgical therapy. Conceptually, such absence of adjunctive hormone effect on survival time after operation is similar to hormonal effects in other endocrine cancers, which may nevertheless provide good palliation in some cases.

Lymph node metastases. Indicators, but not governors of survival.

Regional lymph node filter function has traditionally been assumed to be critical in the prevention of the systemic spread of malignant cells shed from the primary cancer. However, in a multitude of clinical studies involving a variety of cancers, prophylactic removal of such regional lymph nodes, with or without metastases, does not improve cure rates compared with the observation of these lymph nodes. Furthermore, laboratory studies indicate that lymph node filter function may not be either complete or effective, and that many lymphatic and lymphaticovenous shunts exists that bypass regional lymph nodes and allow both lymphatic and hematogenous dissemination of malignant cells. These facts emphasize that regional lymph node metastases are indicators, but not governors, of survival in cancer. The timing of the clinical appearance of regional lymph node metastases and their number are, with few exceptions, excellent indicators of the biologic behavior of the primary cancer and the cells that are shed from it. This shedding of cells into the vascular and lymphatic vessels undoubtedly occurs simultaneously in the vast majority of cancers, but the later progressive growth of cells and micrometastases distributed hematogenously to vital organs is the ultimate governor of survival.

Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment.

OBJECTIVE: To reexamine the age, metastases, extent, and size (AMES) risk criteria for well-differentiated thyroid cancer with the effect of therapy on outcome. DESIGN: Review of patient medical records and direct-contact follow-up. SETTING: Two tertiary referral centers. MAIN OUTCOME MEASURES: Recurrence or death. PATIENTS: One thousand nineteen patients with well-differentiated thyroid cancer treated between 1940 and 1990. RESULTS: One thousand nineteen patients with well-differentiated thyroid cancer were treated between 1940 and 1990, with a mean follow-up of 13 years, including a recent group of 264 patients treated from 1980 to 1990 at 2 different institutions with a mean follow-up of 8 years. The AMES criteria were used to designate high- and low-risk patients. The entire group had 229 high- and 790 low-risk patients; the percentage of high-risk patients decreased slightly after 1960. From 1940 to 1960, 1960 to 1979, and 1980 to 1990, the high-risk groups had survival rates of 48%, 62%, and 47%, respectively. For the low-risk patients, survival rates were 96%, 98%, and 98%, respectively. Recurrences occurred in 5% of low-risk patients and were usually curable; in high-risk patients, recurrence was associated with a 75% mortality. In low-risk patients, there was no significant difference in recurrence or death according to type of operation (unilateral or bilateral) or use of radioactive iodine. In high-risk patients, there were trends toward but no significant improvement in survival with bilateral surgery and radioactive iodine therapy; thyroid replacement was associated with a significant improvement in survival. CONCLUSIONS: The AMES risk criteria remain highly valid predictors of risk. They define most low-risk patients for whom radical treatment may add excess morbidity but not improve already excellent prognoses.