In 1976 we began a randomized trial to evaluate breast conservation by a segmental mastectomy in the treatment of Stage I and II breast tumors less than or equal to 4 cm in size. The operation removes only sufficient tissue to ensure that margins of resected specimens are free of tumor. Women were randomly assigned to total mastectomy, segmental mastectomy alone, or segmental mastectomy followed by breast irradiation. All patients had axillary dissections, and patients with positive nodes received chemotherapy. Life-table estimates based on data from 1843 women indicated that treatment by segmental mastectomy, with or without breast irradiation, resulted in disease-free, distant-disease-free, and overall survival at five years that was no worse than that after total breast removal. In fact, disease-free survival after segmental mastectomy plus radiation was better than disease-free survival after total mastectomy (P = 0.04), and overall survival after segmental mastectomy, with or without radiation, was better than overall survival after total mastectomy (P = 0.07, and 0.06, respectively). A total of 92.3 per cent of women treated with radiation remained free of breast tumor at five years, as compared with 72.1 per cent of those receiving no radiation (P less than 0.001). Among patients with positive nodes 97.9 per cent of women treated with radiation and 63.8 per cent of those receiving no radiation remained tumor-free (P less than 0.001), although both groups received chemotherapy. We conclude that segmental mastectomy, followed by breast irradiation in all patients and adjuvant chemotherapy in women with positive nodes, is appropriate therapy for Stage I and II breast tumors less than or equal to 4 cm, provided that margins of resected specimens are free of tumor.

In 1971 we began a randomized trial to compare alternative local and regional treatments of breast cancer, all of which employ breast removal. Life-table estimates were obtained for 1665 women enrolled in the study for a mean of 126 months. There were no significant differences among three groups of patients with clinically negative axillary nodes, with respect to disease-free survival, distant-disease--free survival, or overall survival (about 57 per cent) at 10 years. The patients were treated by radical mastectomy, total ("simple") mastectomy without axillary dissection but with regional irradiation, or total mastectomy without irradiation plus axillary dissection only if nodes were subsequently positive. Similarly, no differences were observed between patients with clinically positive nodes treated by radical mastectomy or by total mastectomy without axillary dissection but with regional irradiation. Survival at 10 years was about 38 per cent in both groups. Our findings indicate that the location of a breast tumor does not influence the prognosis and that irradiation of internal mammary nodes in patients with inner-quadrant lesions does not improve survival. The data also demonstrate that the results obtained at five years accurately predict the outcome at 10 years. We conclude that the variations of local and regional treatment used in this study are not important in determining survival of patients with breast cancer.

One hundred seventy-four evaluable patients with noninflammatory Stage III (both operable and inoperable) breast cancer were treated with a combined modality strategy between 1974 and 1985. All patients received combination chemotherapy with 5-fluorouracil, Adriamycin (doxorubicin), and cyclophosphamide (FAC) as their initial form of therapy. After three cycles of chemotherapy, local treatment in the form of a total mastectomy with axillary dissection, or radiotherapy, or both, was completed. Subsequently, adjuvant chemotherapy was continued. There were 48 patients with Stage IIIA, and 126 patients with Stage IIIB disease. A complete remission was achieved in 16.7% of the patients, and 70.7% achieved a partial remission after the initial three cycles of FAC. The complete response rate was higher for patients with Stage IIIA, than for patients with Stage IIIB disease. All but six of the 174 patients treated were rendered disease-free after induction chemotherapy and local treatment. The median follow-up of this group of patients is 59 months. The 5-year disease-free survival rates were 84% for patients with Stage IIIA, and 33% for patients with Stage IIIB disease. The 5-year survival rate for, patients with Stage IIIA was 84%, and for patients with Stage IIIB 44%. At 10 years, 56% of patients with Stage IIIA and 26% of patients with Stage IIIB disease are projected to be alive. Younger patients, and those with estrogen receptor-positive tumors, had a trend for better survival than older patients and those with estrogen receptor-negative tumors. The quality of response to induction chemotherapy correlated prominently with prognosis, as did compliance with treatment. Twenty-six patients (15.3%) had locoregional recurrence. This multidisciplinary approach to locally advanced breast cancer rendered most patients disease-free and produced an excellent local control rate. Modifications of this treatment strategy may result in further improvement of survival rates.

Fifty‐two patients with locally advanced primary breast cancer (T3, T4/N2, N3) without distant metastases were treated with three cycles of combination chemotherapy consisting of 5‐FU, Adriamycin and cyclophosphamide (FAC) and immunotherapy with Bacillus Calmette‐Guerin (BCG) followed by local therapy (simple mastectomy and/or radiotherapy to breast/chest wall and regional lymphatics) and adjuvant chemotherapy to complete two years of treatment. Forty‐nine of 52 (94%) patients were rendered free of clinically detectable disease. The median disease‐free interval was 24 months. At a median follow‐up time of 60 months, 40% of patients remained free of disease, off all therapy. Those patients who completed two years of therapy and started adjuvant chemotherapy promptly after local treatment had a 48% disease‐free survival at five years. Local recurrences were observed in 21% of patients. Distant metastases developed in 40% of patients. Despite good tolerance, treatment compliance was poor. The complete remission rate with this multimodal approach is high and long‐term disease‐free survival is achieved in a considerable number of patients.

The optimal treatment for squamous and cloacogenic tumors of the anorectum is controversial. Radical surgery, limited surgery, and radiotherapy (XRT) are all potentially curative. This study was undertaken to determine which patients are candidates for each type of treatment and which would benefit from combined treatment. The records of 192 patients treated at this institution between 1954 and 1979 with the diagnosis of squamous or cloacogenic carcinoma of the anorectum were retrospectively reviewed. A subgroup of 132 patients undergoing abdominal perineal resection (APR) was analyzed to determine prognostic factors for these tumors. No survival difference was observed between the two histologic types (P = 0.51). Prognostic variables significant at P = 0.05 or better were sex, size, nodal status, and level of invasion. A new staging system is proposed that utilizes tumor size, invasion, grade, and nodal status. Actuarial 10‐year survival was 100%, 76%, 29%, and 0% for Stages A, B, C and D, respectively (P values 0.22, 0.0007, and 0.01, respectively). Twelve patients undergoing APR received postoperative XRT; when compared by stage with APR alone no survival difference can be shown, although there is a trend towards fewer local recurrences. Of 26 patients (14 Stage B, 12 Stage C) receiving preoperative XRT (average 4000 R) before APR, 10 had inoperable tumors prior to XRT. All became operable. Eight patients had negative surgical margins and survival was equivalent stage for stage to the operable group (Stage B 78%, 5‐year survival; Stage C 43%, 5‐year survival). Eleven patients had no demonstrable primary tumor after XRT, although three had nodal metastasis. Five‐year survival was 83% for this group. Thirty‐one local recurrences were retreated for cure by surgery, XRT, or combination. Actuarial 5‐year survival after retreatment was 38%. Thirty metachronous inguinal metastases were seen, 20 were retreated for cure, 18 by inguinal lymphadenectomy. Actuarial 5‐year survival was 42%. Using a new staging system based on analysis of prognostic parameters for this disease, the outcome of combined surgery and XRT is compared. The efficacy of preoperative XRT for inoperable tumors is demonstrated. An appreciable salvage rate for local or inguinal recurrence was observed. Cancer 53:1285‐1293, 1984.

In 1971, the National Surgical Adjuvant Breast Project (NSABP) implemented a prospective randomized clinical trial to compare the worth of alternative treatments with radical mastectomy in women with primary operable breast cancer. Information has been obtained from 1,665 patients eligible for follow-up from 34 NSABP member institutions in Canada and the United States. Results from that trial, at present in its sixth year with patients on study for an average of 36 months, (26 to 62 months), fail to demonstrate an advantage for those who had a radical mastectomy. No significant difference in the treatment failure or survival has as yet been observed in clinically negative node patients who have been randomly managed by conventional radical mastectomy, total mastectomy with postoperative regional radiation or total mastectomy followed by axillary dissection of those patients who subsequently develop positive nodes. Similarly, there presently exists no difference between patients with clinically positive nodes treated by radical mastectomy o r by total mastectomy followed by radiation. Of particular interest is the observation that based upon findings from radical mastectomy patients, there may be as many as 40% of patients having a total mastectomy who had histologically positive nodes unremoved, to date only 15% have developed positive nodes requiring a n axillary dissection. The persistence of such a difference in incidence would have profound biological significance. The discovery that leaving behind positive axillary nodes has as yet not been influential in enhancing the incidence of distant metastases o r the overall proportion of treatment failures and that a disproportionate number of treatment failures in the total mastectomy group occurred in those patients who subsequently required axillary dissection provides reinforcement to the view that positive axillary lymph nodes are not the predecessor of distant tumor spread but are a manifestation of disseminated disease.comer 39:2827-2839,1977. HERE HAS EXISTED GREAT CONTROVERSYtional Surgical Adjuvant Breast Project T concerning the treatment of primary breast (NSABP), after almost a decade of planning cancer. Prompted by that uncertainty, the Na-initiated in August of 1971, a prospective ran-

Between 1971 and 1974, 1,665 women with primary operable breast cancer were entered into a prospective randomized clinical trial in order to compare the worth of radical mastectomy with alternative treatments. Six-hundred forty-six of the women, 352 clinically nodenegative and 294 node-positive, were randomized so that they were to have been treated with total mastectomy and postoperative radiation. Due to a meticulous comprehensive program of radiation monitoring involving close cooperation between the NSABP Headquarters, the NSABP Radiation Monitoring Committee, the Radiological Physics Center at M. D. Anderson Cancer Center and participating institutions, it has been possible to determine protocol compliance of the radiation administered and to correlate any variation of radiation employed with treatment outcome. At the onset of the study and prior to any evaluation of treatment results, the Radiation Monitoring Committee defined minor variations from the protocol which were acceptable and those variations which were more major and unacceptable. While it was found that 53% of the 543 evaluable patients had been treated by radiation having some degree of variation from the protocol, it was ascertained that 77% of the 2,172 irradiated fields of those patients (82% in clinically node-negative and 71% in clinically node-positive patients) received radiation per protocol. Only 6.7% of all sites were the recipients of a major (unacceptable) variation in radiation. Analysis of data demonstrated that there was a remarkable similarity in the incidence and rate of treatment failure (TF) or mortality between patients having some radiation variation, regardless of its degree or extent and those who were treated with no protocol variation.Results were similar when comparisons were made taking into consideration either the degree (minor or major low) or the extent (one or more than one field) of the radiation variation. A substantial number of clinically positive axillary node patients received only the radiation to the axillary field intended for those with clinically negative nodes, i.e., they failed to receive the specified radiation boost. Despite that deviation, there was no difference in TF or survival from those receiving the prescribed treatment. Moreover, findings were not different when the axilla was the only site of radiation deviation or there were deviations to other fields as well. Of singular importance was an inability to associate the localregional location of a recurrence with a low-dose radiation deviation at the site. Almost all recurrences in clinically node-negative patients were at sites treated per protocol. In positive-node patients, supraclavicular and chest wall recurrences occurred in patients having acceptable radiation to those sites and axillary recurrences were equivalent in patients treated with or without deviations at that site. The findings from these investigations are not presented in order to indicate that the quality and quantity of radiation may be unimportant. They have been obtai...

Two hundred and seventy-four consecutive patients with measurable metastatic breast cancer, without prior exposure to cytotoxic agents were treated with tamoxifen, 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). The initial 133 patients received doxorubicin by bolus IV administration and for the next group of 141 patients doxorubicin was administered via a central venous catheter over a 48-hour (79 patients) or 96-hour (62 patients) continuous infusion schedule. Patients treated with bolus doxorubicin had this agent discontinued usually when 450 mg/m2 were reached; for patients in the infusion group treatment was continued until evidence of progressive disease or clinical or subclinical cardiac dysfunction developed. The complete remission rate was 21% the partial remission rate, 59%. There were no differences in response rate, response duration, or survival duration between groups of patients treated with doxorubicin by bolus, 48-hour or 96-hour infusion FAC. The incidence of moderate and severe nausea and vomiting was lower in the group of patients treated with infusion FAC as compared to bolus FAC (P less than 0.001); however, the incidence of mucositis was higher in the infusion group than in the bolus group (P less than 0.001). Doxorubicin administered by continuous infusion schedules was less cardiotoxic than when administered by bolus, as shown by a greater than 75% decrease in the frequency of clinical congestive heart failure at cumulative dosages greater than or equal to 450 mg/m2 (P = 0.004). Doxorubicin administered as a 48-hour or 96-hour continuous IV infusion is safer, and better tolerated than doxorubicin administered by bolus.