The influence of young age and positive family history of breast cancer on the prognosis of ductal carcinoma in situ treated by excision with or without radiation therapy or by mastectomy.

BACKGROUND: Several recent studies have investigated the influence of family history on the progression of DCIS patients treated by tylectomy and radiation therapy. Since three treatment strategies have been used for DCIS at our institution, we evaluated the influence of family history and young age on outcome by treatment method. METHODS: Between 1/1/82 and 12/31/92, 128 patients were treated for DCIS by mastectomy (n = 50, 39%), tylectomy alone (n = 43, 34%), and tylectomy with radiation therapy (n = 35, 27%). Median follow-up is 8.7 years. Thirty-nine patients had a positive family history of breast cancer; 26 in a mother, sister, or daughter (first-degree relative); and 26 in a grandmother, aunt, or cousin (second-degree relative). Thirteen patients had a positive family history in both first- and second-degree relatives. RESULTS: Six women developed a recurrence in the treated breast; all of these were initially treated with tylectomy alone. There were no recurrences in the mastectomy group or the tylectomy patients treated with postoperative radiation therapy. Patients with a positive family history had a 10.3% local recurrence rate (LRR), vs. a 2.3% LRR in patients with a negative family history (p = 0.05). Four of 44 patients (9.1%) 50 years of age or younger recurred, compared to two of 84 patients (2.4%) over the age of 50 (p = 0.10). Fifteen patients had both a positive family history and were 50 years of age or younger. Among these women, the recurrence rate was 20%. Women in this group treated by lesionectomy alone had a LRR of 38% (3 of 8). CONCLUSION: The most important determinant of outcome was the selection of treatment modality, with all of the recurrences occurring in the tylectomy alone group. In addition to treatment method, a positive family history significantly influenced LRR in patients treated by tylectomy, especially in women 50 years of age or younger. These results suggest that DCIS patients, particularly premenopausal women with a positive family history, benefit from treatment of the entire breast, and raise concerns about treating patients with a possible genetic susceptibility to breast cancer with tylectomy alone.

Immunohistochemistry as a predictor of clinical outcome in patients given postoperative radiation for subtotally resected pituitary adenomas.

There is general agreement that postoperative radiation therapy is beneficial for patients with subtotally resected pituitary adenomas. We have identified 41 such patients treated during a 20-year period who received postoperative irradiation for a pituitary adenoma. The usual dose was 5040 cGy in 28 fractions. The mean follow-up time was 10.3 years. On routine hematoxylin and eosin (H&E) staining, there were thirty-three chromophobe, seven eosinophilic, and one basophilic adenoma. Tissue blocks were stained for growth hormone (GH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), prolactin (PRL), and/or adrenocorticotropin (ACTH) using the peroxidase-antiperoxidase immunohistochemistry (IHC) method. Routine H&E staining was a poor predictor of the IHC stain. While most patients with a known clinical endocrine syndrome stained positive on IHC for the suspected offending hormone, many patients without a clinical syndrome also stained positive indicating the presence of hormonally occult adenomas in this locally invasive group. The IHC stain results were compared to clinical outcome. The presence of positive GH IHC staining decreased the 15-year progression-free survival (PFS) from 100% to 64% compared to GH negative adenomas (p = 0.06). There was a trend toward decreased 15-year PFS in patients who did not stain for LH. Positive staining for prolactin, ACTH, or TSH had no influence on the progression-free survival. We conclude that additional prognostic information can be obtained in this subset of patients (by performing IHC analysis) that is not known by the clinical presentation or appearance on H&E stain.

Recurrent pituitary adenomas after surgical resection: the role of radiation therapy.

Postoperative radiation therapy for pituitary adenomas is usually reserved for extensive lesions or those that are incompletely resected. Nineteen patients who received external beam radiation as a salvage procedure after recurrence following surgery alone for pituitary adenomas were studied. At recurrence, nine patients underwent reexcision. All 19 patients underwent external beam irradiation for salvage. Within a median follow-up time of 11.8 years from the time of surgical failure, two patients have died of progressive adenoma, two are alive with disease progression, eight are alive without disease progression, and seven have died of intercurrent disease. The 5-, 10-, 15-, and 20-year overall actuarial (and progression-free) survival rates were 79% (90%), 62% (90%), 44% (80%), and 44% (53%), respectively. Dose of radiation, suprasellar extension at the time of surgical failure, and histologic findings had no bearing on prognosis. One patient developed a radiation-induced brain necrosis that was successfully resected. Radiation therapy can be an effective salvage modality for recurrent pituitary adenomas after surgical failure.

Radiation therapy for gliomas of the optic nerve and chiasm.

Thirty-three patients with optic glioma seen over a 30-year period were reviewed. Five patients (15%) had tumor confined to the optic nerve, 8 patients (24%) had optic nerve and chiasmal involvement, and the remaining 20 patients (61%) had invasion of contiguous structures as well as chiasmal involvement. Eleven patients (33%) had a history of neurofibromatosis. Two-thirds of the patients had either a biopsy or a partial resection of the tumor, with the remaining one-third being clinically diagnosed. All patients received irradiation to local fields. The median dose was 5040 cGy in 160 cGy fractions. Of patients alive at last follow-up, the median time of follow-up was 12.3 years. The 5-, 10-, and 15-year overall actuarial survivals were 94, 81, and 74%, respectively. Univariate and multivariate analysis were performed on the following clinical variables: extent of primary tumor, extent of surgery, dose of radiation, gender, race, age, and presence or absence of neurofibromatosis. Extension of the primary lesion to the optic chiasm and age less than or equal to 15 years were the only two variables to have statistically significantly inferior 15-year progression free survivals by multivariate analysis. Eighteen (55%) patients had treatment related complications with most involving the pituitary gland. We conclude that postoperative radiotherapy is beneficial in patients with chiasmal involvement and those with incomplete resections. A minimum tumor dose of 4000 cGy is recommended.

Inflammatory carcinoma of the breast: treatment results on 107 patients.

From 1958 to 1985, 107 patients with a clinical and/or histopathologic diagnosis of non-metastatic inflammatory breast cancer received radiotherapy as all or part of initial treatment. Therapy included definitive irradiation alone in 31 patients, irradiation with mastectomy in 16 patients, irradiation and combination chemotherapy in 23 patients, and irradiation with chemotherapy and surgery in 37 patients. Survivors have a median follow-up of 30 months. Overall median relapse-free survival (RFS) was 12 months (12% at 5 years). Local control and relapse-free survival were significantly improved for patients receiving surgery as part of initial treatment: 19% (10/52) of operated patients experienced locoregional failure vs. 70% (37/53) not operated (p less than 0.0001). The median overall actuarial survival was 24 months (17% at 5 years). Patients who received surgery showed improved survival (44 months vs. 18 months median; 37% vs. 7% at 5 years; p = 0.0004). Chemotherapy also was associated with improved relapse-free survival (18 months vs. 8 months median; 20% vs. 5% at 5 years; p = 0.02) and actuarial survival (32 months vs. 17 months median; 23% vs. 3% at 5 years; p less than 0.02). Patients treated with initial chemotherapy (usually 2-3 cycles of CAF), surgery, and postoperative irradiation followed by maintenance chemotherapy showed a 34 month median relapse-free survival (37% at 5 years RFS) and a 47 month median survival (48% at 5 years). Moderate to severe complications were seen in 25% of patients, the most frequent complication being fibrosis of the breast or chest wall. There were two fatalities secondary to Adriamycin-induced cardiomyopathy. This study suggests better local control, with fewer complications, when surgery and irradiation are combined with multiagent chemotherapy. Further prospective clinical trials are strongly recommended.

Prognostic factors and results of surgery and postoperative irradiation in the management of pituitary adenomas.

Prognostic factors and results of therapy were analyzed in a retrospective examination of 121 patients with pituitary adenomas treated with surgery and postoperative irradiation (RT) from January 1954 through December 1982 at the Radiation Oncology Center, Mallinckrodt Institute of Radiology. The 10-year overall and disease-free survival for all patients was 85.1 and 89.4%. The expected survival for an age-, gender-, and race-matched population was not significantly distinct at 85.3% (p = 0.72). Follow-up of 94 surviving patients ranged from 3.4 to 29.5 years (mean, 11.7). Statistical analysis was performed for multiple prognostic factors including age, race, gender, disease bulk, visual field symptoms, disease type, surgical approach, and irradiation dose and volume. The only prognostic variable identified by univariate analysis to significantly alter disease-free survival was irradiation dose. Patients receiving 5000-5400 cGy had a tumor control rate of 94.1% (64/68) compared to 85.0% (17/20) for 4000-4999 cGy, 75.0% (18/24) for 3000-3999 cGy, and 28.6% (2/7) for less than 3000 cGy (p = 0.000059). Factors evaluated but established to be insignificant were age, race, gender, disease bulk, visual field symptoms, disease type, surgical approach, and irradiated volume. The 10-year disease-free survival by classification was 93.3% for patients with amenorrhea/galactorrhea, 89.9% for non-functioning adenomas, and 76.4% for acromegaly (p = 0.21). Overall improvement in visual field defects subsequent to treatment occurred in 48.4% (44/91) of those with visual field defects before RT and was significantly correlated with RT dose. The median time to progression of disease was 10.2 years with the last failure occurring at 25 years following the fulfillment of RT. Severe complications related to RT were apparent in 1.7% (2/121). None were known to have endured brain radionecrosis. Serious surgical complications occurred in 9.9% (12/121).

Prognostic factors and results of therapy for adult thalamic and brainstem tumors.

This report is a retrospective analysis of 83 adults (greater than 16 years of age) with histologically proven or presumed primary neoplasms of the thalamus, hypothalamus, midbrain, pons, and medulla. Patients were treated with combined surgery and postoperative irradiation or with irradiation alone at the Washington University Medical Center (St. Louis, MO) from January 1950 through December 1984. Histologic analysis confirmed the diagnosis of tumor in 21, including nine with well-differentiated astrocytoma, four with astrocytoma with anaplasia, and eight with glioblastoma multiforme. Overall and disease-free survivals at 5 years were 28.7 and 23.2%, respectively. A statistical analysis was performed to ascertain the prognostic importance of the following variables: age, race, gender, duration of symptoms, cranial nerve paresis, primary site, extent of surgery, histology, and irradiation dose. The only factor identified by univariate analysis to be critical for survival was primary location of disease. Patients with supratentorial (thalamus/hypothalamus, midbrain) tumors had a 10-year disease-free survival of 15.4% compared to 29.6% for those with infratentorial (pons, medulla) tumors (P = 0.07). Patients with lesions of the pons had a 5-year disease-free survival of 35.8% compared to 13.8% for those with tumors of the thalamus (P = 0.05). Increasing irradiation dose was not correlated with superior survival. Factors evaluated but established to be insignificant were age (P = 0.27), race (P = 0.63), gender (P = 0.27), duration of symptoms (P = 0.19), cranial nerve paresis (P = 0.71), histologic type (P = 0.16), and extent of surgery (P = 0.94). Follow-up for 13 surviving patients ranged from 2.6 to 28.7 (mean, 12.0) years. Neurologic deficits in surviving patients were absent in 15% (two of 13), mild in 62% (eight of 23), and moderate in 23% (three of 13). One case of brain radionecrosis was identified (6000 cGy, 200 cGy daily).

Multivariate analysis of prognostic factors in pediatric and adult thalamic and brainstem tumors.

A multivariate analysis of prognostic variables was performed on a retrospective review of 136 patients with presumed or histologically proven primary lesions of the thalamus and brainstem treated by combined surgery and post-operative irradiation or by irradiation alone from January 1950 through December 1983. Overall survival for all patients at 5 and 10 years was 34.4 and 27.8%, respectively. Follow-up of 33 living patients ranged from 3 to 22 years. Prognostic variables analyzed by univariate analysis and found to be of significance (p less than 0.05) were race, duration of symptoms, extent of surgery (i.e. subtotal excision), and dose of irradiation. Further evaluation by Cox regression analysis revealed these same factors to be of prognostic significance (p less than 0.05). It is of importance to note that age and tumor site were not significant prognostic variables in the multivariate analysis but were significant by univariate analysis. The 5-year overall survival for patients with thalamic tumors was 59.5 and 20.9% for children and adults, respectively (p = 0.006). The 5-year overall survival for patients with pontine lesions was 46.6 and 16.0% for adults and children, respectively (p = 0.01). Only one patient was known to have expired due to a complication of therapy. Neurologic deficits and functional ability was normal or mild in 57.6% of the surviving patients.

Prognostic factors in inflammatory breast cancer. Univariate and multivariate analysis.

Between 1958 and 1985, 107 patients with nonmetastatic inflammatory breast cancer (IBC) received radiotherapy as all or part of initial treatment at the Mallinckrodt Institute of Radiology. For this review, the diagnosis of IBC was made on the basis of either clinical or histopathologic criteria. Fifteen factors of potential prognostic significance were evaluated, by both univariate and multivariate analysis. For relapse-free survival, univariate analysis suggested prognostic value for initial tumor size, discrete versus diffuse tumor mass, adjuvant chemotherapy, and mastectomy. In the multivariate analysis, the independent prognostic factors, in order of significance, were mastectomy, diffuse versus discrete tumor mass, and race (marginal). For survival, univariate analysis suggested prognostic value for initial tumor size, diffuse versus discrete tumor mass, nodal stage, year of treatment, adjuvant chemotherapy, and mastectomy. In the multivariate analysis, the prognostic factors in order of significance were mastectomy and chemotherapy (marginal). The diagnostic selection group showed no prognostic value, suggesting that either clinical or histopathologic criteria justify the diagnosis of IBC. Our results appear to support a role for surgery as part of the combined modality approach to this disease.

Long-term results of radiotherapy in the treatment of pituitary adenomas in children and adolescents.

A retrospective review was performed of 11 children and adolescents (less than 19 years of age) with diagnosed pituitary adenomas. The patients were treated with subtotal resection and postoperative irradiation (S + R) or with irradiation alone (RT) at the Radiation Oncology Center, Mallinckrodt Institute of Radiology, Washington University Medical Center, from January 1958 through December 1982. Patient conditions at diagnosis were acromegaly in one, Nelson's syndrome in one, prolactinoma in three, chromophobe adenoma in three, and Cushing's disease in three. Median follow-up was 15.6 years (range 6.3-29.5 years). Only two patients have had failure: one at 8.6 years and the other at 20.7 years following treatment. All four patients with visual field (VF) defects at diagnosis underwent S + R, with only one developing recurrent disease. The remaining seven patients, who did not have VF defects, received RT only, and there has been one failure in this group. None have suffered long-term visual complications. All have been able to continue school and/or work. Three of eight females have borne children. Hypopituitarism requiring medication occurred in all who received S + R and in four of seven who received RT only.

An analysis of neuroblastoma at a single institution.

Between 1949 and 1978, 119 children with the diagnosis of neuroblastoma or ganglioneuroblastoma were treated at the Washington University Medical Center. Of these, 50 (41%) were alive and disease-free 3 or more years after diagnosis. Important prognostic variables included stage of tumor (Evans staging), histology, age at diagnosis, and site of primary tumor. A stepwise logistic regression analysis of these data has shown that, in order of significance, stage, histology and age at diagnosis are independent prognostic variables. Sex of the patient and nodal status at diagnosis (where known) were not significant prognostic variables. No effects of individual treatment modalities could be detected. This study confirms the overwhelming influence of factors unrelated to treatment in determining the prognosis of neuroblastoma.

Late effects of treatment for Wilms' tumor.

Twenty-six out of a total of 49 patients who were treated for Wilms' tumor at the Mallinckrodt Institute of Radiology between January 1960 and December 1975 have survived at least five years. The median follow-up time is 153 months (12 years, 9 months). One girl, who received pelvic irradiation, has not reached puberty at age 14, but the other 25 patients are currently in good health and have no major complaints or functional impairments at present. Twenty-one patients have, however, developed some complication at some time since treatment. Serious side-effects requiring hospitalization included one case of pericarditis and one of esophageal varices secondary to portal hypertension. Both these patients, however, had advanced tumors requiring aggressive treatment and their complications should be seen in perspective. There has also been one case of temporary low grade renal failure and one of transient hypertension. More common complications were 14 instances of scoliosis (only three have had any symptoms, however), five of osseous hypoplasia, three of soft tissue hypoplasia, three of liver damage and three of lung damage. There was one case of osteochondroma within a radiotherapy field. The factors pertaining to these complications and the anticancer therapy which preceded them are discussed in detail. We conclude that, whereas structural changes following modern radiotherapy for Wilms' tumor are very common, severe dysfunctions are infrequent. Even more extended periods of observation will be required before the total number of abnormalities is ascertained. However, the striking observation from this study is the lack of late functional effects.

Alternative approaches to evaluating the impact of local control on survival.

An important aspect of evaluating treatments aimed at local tumor control is to assess the effect of local control on survival. A common approach to this problem is to compare all patients who have failed locally with those who have not using a logrank test. However, this method of analysis does not take into account the effect of time on a patient's local disease status. Since patients in the local failure group must survive long enough to fail, this group may be biased in favor of longer survival times. The Mantel-Byar extension of the logrank test avoids this source of bias by utilizing the data on time to local failure in defining the local control and local failure groups. In this paper, the application of this technique is illustrated using data from recurrent breast cancer patients and contrasted with the results obtained using the standard logrank test.

The risk of second primaries subsequent to irradiation for cervix cancer.

A review of 1048 patients with cancer of the cervix treated with radiation, either alone or combined with surgery, disclosed 32 cases of second primary malignancies occurring from 1 to 16 years subsequent to treatment. Using the person years approach, the incidence rate of second primaries was 5.49 per 1000 person years, which is not significantly different from population based rates. The anatomic locations of the new malignancies and the times from treatment of the cervix cancer to diagnosis of a new primary are presented; the possible carcinogenic effects of radiation are discussed. In this group of patients, it was concluded that under the period of observation irradiation administered at therapeutic doses did not increase the probability of second malignancy in the pelvis or at other sites.