Results of mastectomy and postoperative irradiation in the management of locoregionally advanced carcinoma of the breast.

Between 1955 and 1984, 376 patients with locoregionally advanced breast carcinoma were treated at The University of Texas M. D. Anderson Cancer Center with mastectomy and irradiation and without adjuvant chemotherapy. Patients with inflammatory carcinoma or synchronous bilateral primary tumors were excluded. There were 202 patients with Stage IIIA disease and 174 patients with Stage IIIB disease (AJC Staging--1983). In 124 patients the surgical management was confined to the breast only--total mastectomy (BR) and in 252 dissection of the axilla was performed--extended total, modified radical, or classic radical mastectomy (BR + AX). All patients had postoperative irradiation. The follow-up period ranged between 8 and 34 years. At 10 years, the actuarial disease-specific, relapse-free survival (DSRFS) rate for the entire group was 40%, and the actuarial locoregional control rate was 82%. For patients with Stage IIIA disease the DSRFS was 48% and locoregional control rate was 88%. For those with Stage IIIB disease, the figures were 30% and 74%, respectively. Most of the failures occurred within 5 years of the mastectomy and essentially all occurred within 10 years. When analyzed by type of surgery, both the locoregional control and DSRFS rates were improved by the axillary dissection, the difference being largely caused by fewer axillary node recurrences after dissection of both the breast and axilla than after removal of the breast alone. In the 252 patients in whom the axilla was assessed, the number of positive nodes was a powerful predictor of both locoregional control and survival. The DSRFS rates at 10 years for patients with 0, 1-3, and greater than or equal to 4 positive nodes were 63%, 48%, and 30%, respectively. The actuarial locoregional control rates at 10 years exceeded 95% for patients with 0-3 positive nodes and 75% for those with greater than or equal to 4 nodes. These results show that locoregionally advanced breast cancer is not a uniformly fatal disease when treated without chemotherapy and provide a baseline upon which to assess the value of adjuvant systemic therapy for this stage of disease.

Prognostic implications of age in breast cancer patients treated with tumorectomy and irradiation or with mastectomy.

Conservation breast treatment is of particular interest to young women, but whether saving the breast carries a penalty in shorter survival or local-regional recurrent disease has not been well-established. At The University of Texas M.D. Anderson Hospital and Tumor Institute at Houston, 1161 patients treated prior to 1983 with Stage I or II breast cancer were reviewed. Of these patients, 378 were treated with tumorectomy plus irradiation, and 783 were treated with radical or modified radical mastectomy. The two patient groups were compared relative to local-regional disease recurrence and overall and disease-free survivals. Local recurrences in the breast appear to be more frequent in patients less than or equal to 35 years of age treated with tumorectomy and irradiation than in patients older than 35 years, but in patients aged less than or equal to 50 or greater than 50 or less than or equal to 35 or greater than 35 years, there was no significant statistical difference between tumorectomy and irradiation or mastectomy nor was there a difference in disease-free survival. Overall survival rates favored patients treated by tumorectomy and irradiation.

Lack of concordance of growth rates of primary and recurrent breast cancer.

The degree of concordance of growth rates of primary tumors with corresponding recurrences was investigated by using data from 184 patients with breast cancer with measurable recurrences. For conduction of this examination, the detection processes of both the primary tumor and the recurrence were explored. The probability of detection of a recurrence per unit time was found to be nearly proportional to the tumor's diameter. Approximately 60,000 cells initiated the recurrence, and the distribution of doubling times of the recurrences was exponential, with a mean of 2.1 months. The probability of detection of the primary tumor per unit time was approximately proportional to its volume. The distribution of doubling times of primary tumors was nearly exponential; from other evidence, we inferred that the mean doubling time was also close to 2.1 months. Several techniques to measure growth rate agreement between the primary and recurrent tumors within individuals were developed, and all of them yielded the result that the growth rates are nearly unrelated.

Management of locoregional recurrent breast cancer.

The influence of radiation and/or chemotherapy on locoregional tumor control and survival in patients treated for recurrent breast cancer after radical or modified radical mastectomy is retrospectively evaluated in 164 patients treated between 1972 and 1983 at the University of Texas M. D. Anderson Hospital. Treatment consisted of radiation alone in 57 patients, chemotherapy alone in 50 patients, and a combination of radiation and chemotherapy in 57 patients. Important differences in the composition of these three groups include a preponderance of postmenopausal women (44% vs. 32%) and more patients with four or more positive axillary nodes at the time of initial mastectomy (32% vs. 18%) in the radiotherapy group. Locoregional control of recurrent cancer was achieved in 65% of patients with radiotherapy compared to 46% of patients with chemotherapy (P = 0.049) and 67% with chemotherapy and radiotherapy. The addition of chemotherapy produced a trend toward improved disease-free survival rates. The two prognostic factors affecting tumor control and survival in this study are the tumor burden of the recurrence and the histologic axillary node status at the time of the initial mastectomy.

Tumor volume, nodal status, and metastasis in breast cancer in women.

The relationship between primary tumor volume at detection, number of positive nodes, and probability of and time until first distant metastasis was examined for a group of 2,663 women with breast cancer. Time until metastasis was shown to decrease and probability of metastasis to increase as tumor volume and number of nodes increased. Either factor remained significant after correction for the other. Simple proportional hazards models were shown to be inadequate to describe the data. Graphic techniques were used to obtain nonparametric estimates of the forms of the relationships between tumor volume, nodal status, and the time course of the occurrence of metastasis. A simple calculation demonstrated that the average contribution per cell to the probability of metastasis decreased with increasing volume.

Radiation therapy and breast cancer. Past, present, and future.

After radical mastectomy, postoperative irradiation unquestionably diminishes the incidence of local-regional failures, and there are series in which the survival rates are improved for a subset of patients. The comparative survival rates shown in Table 6 suggest that adjuvant postoperative irradiation produces survival benefits. For more advanced tumors, simple mastectomy and axillary dissection with chemotherapy and irradiation is effective, with the optimal sequence still to be determined. In selected patients, tumorectomy and irradiation produce survival rates equivalent to radical mastectomy with very satisfactory cosmetic results. In all situations, gross masses in the breast and axilla should be removed leaving for irradiation only subclinical disease that is controlled with doses that do not produce significant sequelae.

Results of irradiation in the treatment of locoregional breast cancer recurrence.

A retrospective review is presented of 255 patients with chest wall and/or regional nodal recurrent breast cancer treated between January 1956 through December 1981 at the University of Texas M. D. Anderson Hospital; 61 patients had such massive or diffuse disease that only palliative irradiation was given, and 194 patients were treated with curative intent and form the basis of this report. All patients treated with radical irradiation received greater than or equal to 4500 rad, and 65% of the patients received boost therapy through reduced fields. Thirty-two percent of patients were treated only to a single recurrent site, 11% of two sites, and 57% to the chest wall and regional nodes. Failure to control recurrent disease within or on the border of the irradiated field occurred in 27% of patients. Of 62 patients treated to the local recurrence site, 27% had further recurrences in adjacent unirradiated sites. The patients with the greatest success for tumor control (78%) and survival at 5 years (48% disease-free) are those patients with histologically negative nodes at time of mastectomy and a single chest wall recurrence. Possible prognostic factors are discussed: initial clinical stage, age of the patient, axillary histology at the time of mastectomy, disease-free interval between mastectomy and recurrence, number and size of recurrences, and prior chest wall recurrence.

Local regional effectiveness of surgery and radiation therapy in the treatment of breast cancer.

Although gross tumor can be controlled with high doses of radiation therapy, control is achieved at the expense of severe radiation sequelae. In order to improve tumor control with minimum complications, the field of treatment should contain only subclinical disease. This article reviews the successful combination of surgery for the removal of gross cancer and radiation of moderate dose for the treatment of subclinical disease in patients with breast cancer. In patients with clinically favorable and operable disease, the combination of a radical or modified radical mastectomy and postoperative radiation therapy of 5000 rad to the peripheral lymphatics and chest wall can secure 90% of the treated areas. For patients with locally and regionally advanced breast cancer, the combination of a simple mastectomy and dissection of the lateral axilla followed by postoperative irradiation of 5000 rad in 5 weeks to the chest wall, axilla, and peripheral lymphatic areas will control more than 85% of the patients treated as compared with approximately 70% control when surgery or radiotherapy alone is used, even with chemotherapy. Yet another clinical application of the subclinical disease concept is the successful combination of conservation surgery (whether segmental mastectomy, quadrantectomy, or wide excision) for gross tumor in the breast and axilla and irradiation for residual microscopic and multiple foci of tumor, yielding more than 90% control of locoregional disease with survival rates equal to those patients treated with radical or modified radical mastectomy. Results of multiple clinical trials and reported series are reviewed.

Management of inflammatory carcinoma of the breast. A combined modality approach.

From May 1973 to December 1981, 63 patients with inflammatory carcinoma of the breast were treated with a doxorubicin-containing chemotherapy regimen (FAC). After a median of three cycles of FAC, 41 patients received primary therapy with irradiation; more recently, 21 had mastectomy as primary therapy. One patient relapsed following a treatment delay and did not receive local therapy. Fourteen of 21 patients who underwent mastectomy had subsequent consolidation therapy with irradiation. At median follow-up of 60 months, median relapse-free survival (RFS) and survival were 24 and 43 months, respectively. The initial site of recurrence was locoregional in eight patients (20%). In addition, two of seven uncensored patients (18%) who suffered initial recurrence in the contralateral breast remained disease-free at 28 and 55 months with further surgery. While no locoregional recurrences were seen in the 14 mastectomy patients who completed comprehensive irradiation, no RFS nor survival advantage was noted for either initial local therapy. Sixteen patients with dermal lymphatic carcinomatosis and 10 patients with negative skin biopsies had median RFS of 31 and 46 months, respectively (p = 0.45). Median RFS was 36 months in patients greater than or equal to 50 years of age and 19 months in patients less than 50 (p = 0.05). Response to FAC was the most significant predictor of RFS and survival. Patients who achieved complete or partial remission (PR) with induction FAC as compared to patients who achieved less than PR had median RFS of 31 vs. 19 months (p = 0.01) and median survivals of 60 vs. 27 months (p = 0.05), respectively. Categorization of patients according to clinical, mammographic, and pathologic criteria facilitated identification of potential long-term responders. With combined modality approach to inflammatory carcinoma of the breast, we can expect an estimated 31% of patients to be relapse-free at 5 years after treatment.

Conservation surgery and irradiation as an alternative to mastectomy in the treatment of clinically favorable breast cancer.

The combination of conservation surgery and radiation therapy for early breast cancer is gaining acceptance as an alternative to radical mastectomy. This article reviews the results of randomized trials showing that there is no advantage to a radical mastectomy in patients with early breast cancer. In addition, the article will review multiple reports concerning the local and regional tumor control and survival of patients treated with conservation surgery and irradiation as well as a comparison of 1073 patients with TIS T1 T2 N0 N1 breast cancer treated at University of Texas (UT) M. D. Anderson Hospital between 1955 and 1980, of whom 345 were treated with conservation surgery and irradiation and 728 were treated with radical or modified radical mastectomy alone. The locoregional recurrence in the patients treated with an intact breast is 4.9%, and 5.6% in patients treated with radical or modified radical mastectomy. There is no significant difference in the 10-year disease-free survival rates between the two groups of patients. In addition, a comparison of 2467 patients with Stage I and Stage II breast cancer treated at the UT M. D. Anderson Hospital shows no significant difference in the incidence of consecutive second breast carcinoma as a result of the use of radiation therapy in the treatment of the first breast cancer.

Epidermoid cancer of the anorectum.

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.

Conservation surgery and radiation therapy in the treatment of operable breast cancer.

The combination of conservation surgery and radiation therapy for favorable breast cancer is gaining acceptance as an alternative to radical mastectomy. Presented here is a review of the local and regional tumor control and survival results of several authors, as well as a comparison of 1073 patients with clinically favorable breast cancer treated at the University of Texas M. D. Anderson Hospital between 1955 and 1980, 345 of whom have been treated with conservation surgery and irradiation and 728 of whom have been treated with radical or modified radical mastectomy alone. The locoregional recurrence in the patients treated with an intact breast is 4.9%, and 5.6% in patients treated with radical or modified radical mastectomy; there is no significant difference in the 10-year disease-free survival rates between the two groups. A detailed analysis of the location and timing of recurrences and the incidence of contralateral breast cancer is presented.

Combined modality approach in breast cancer with isolated or multiple metastases.

One hundred thirty-six patients with isolated recurrence of breast cancer received regional therapy (surgery and/or irradiation) followed by combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC). The disease-free survival of the group receiving FAC was compared to that of a historical control group treated with only regional therapy. The median disease-free interval between the first and second recurrence for the control group was 9 months and for the patients receiving FAC, 38 months (p less than 0.01). The median survivals from first recurrence for the control and the FAC groups were 40 months and 60 months, respectively (p less than 0.02). In addition, 20 selected patients with multiple sites of metastasis or bulky isolated recurrence were initially treated with FAC chemotherapy; following complete or partial response with chemotherapy, these patients had regional therapy at the known sites of metastases. At a median follow-up time of 54 months, 9/20 patients (45%) have remained in complete remission. Combined modality approach significantly prolongs the disease-free survival of patients with isolated recurrences of breast cancer, and in selected patients with multiple metastases, this approach results in extended complete remissions.

Estimation of human tumor growth rate from distribution of tumor size at detection.

Methods are presented for estimating the growth curve of a tumor (up to an unknown scale factor of time) from the distribution of volumes at detection on the basis of two assumptions: 1) the existence of a common growth curve and 2) the assumption that the probability of detecting a tumor in a period of time is proportional to the tumor volume. These methods can accommodate variation between individuals in speed of traversal of the growth curve. The methods are applied to volumes of tumor at detection of a large series of breast cancers. The simplest, adequate description is exponential growth with great individual-to-individual variation in tumor doubling time. The data are consistent with bounded growth (Gompertzian or logistic form) as well as exponential growth. However, there is no evidence that the bound on growth is within the range of the data. The shape of the distribution of volumes does not yield an effective lower limit on such a bound.

Treatment of locoregionally advanced breast cancer with surgery, radiotherapy, and combination chemoimmunotherapy.

Fifty-two patients with locally advanced primary breast cancer (T3, T4, N2, N3) but no evidence of distant metastases were treated with three cycles of combination chemotherapy. The regimen consisted of 5-fluorouracil, Adriamycin, cyclophosphamide, and Bacillus Calmette-Guerin (FAC-BCG), followed by local therapy (simple mastectomy and/or radiotherapy to the breast/chest wall and the regional lymphatic system) and adjuvant chemotherapy for two full years. The results were compared with those in an historical control group of 52 patients matched for initial stage of disease who were treated by a simple mastectomy and postoperative radiotherapy only. Forty-nine (94%) of 52 FAC-treated patients and 48 (92%) of the control patients became free of clinically detectable disease. At the median follow-up time of 56 months, 37.5% of the FAC-treated patients and 19.5% of the control patients had remained free of disease. FAC-treated patients who completed 2 years of therapy and in whom adjuvant chemotherapy was started promptly after local treatment had a 48% disease-free survival rate of 4 years. In those in whom the initial manifestation was supraclavicular involvement, the estimated 5-year disease-free survival rate was 42% for patients treated with FAC and 9% for control patients. There were local recurrences in 25% of FAC-treated patients and 23% of control patients (not significant). Distant metastases developed in 50% of FAC-treated patients and 77% of control patients (p less than 0.01). The median disease-free interval was 25 months in the FAC-treated group and 11 months in the control group (p = 0.025). The greatest improvement in prognosis was in patients with supraclavicular involvement; the median disease-free survival was 26 months in FAC-treated patients and 6 months in the control group (p = 0.007). This multimodal approach effectively renders the majority of patients with locoregionally advanced breast cancer free of disease and prolongs the disease-free survival period.

Conservation surgery and irradiation as treatment for early breast cancer.

Conservation surgery and irradiation were compared with radical or modified radical mastectomy, without irradiation, in the treatment of clinically favorable breast cancer. Patients with minimal breast cancer, stage I (T1 N0), and stage II (T1 N1, T2 N0, or T2 N1) were found to have similar five- and ten-year survival rates for the two types of primary treatment. Local recurrence rates were also similar: 0.8%, 4.4% and 8.4% for radical mastectomy, and 2.5%, 6.8%, and 4.9% for conservation surgery and irradiation, respectively, in each successive stage of disease. Cosmetic and functional results were deemed satisfactory and supported consideration and examination of this alternative to radical mastectomy for selected patients with early breast cancer.

Preoperative or postoperative irradiation as adjunctive treatment with radical mastectomy in breast cancer.

Results from the standpoint of survival rates and locoregional failures are compared in three series of patients having had a radical mastectomy for breast cancer: (1) radical mastectomy alone for the patients who had essentially outer quadrant lesions and a negative axilla; (2) postoperative irradiation when the axillary nodes were positive and/or the tumor was centrally located or in the inner quadrants; and (3) preoperative irradiation for patients with an outside biopsy presenting with a very disturbed breast with edema and ecchymosis, and in a small group of patients with a lesion of clinically borderline operability. The ten-year survival rates are identical in the three groups. In the radical mastectomy alone group, 14% of the patients had positive axillary nodes, in the preoperative irradiation group 30% (probably one half of the true incidence without preoperative irradiation), and in the postoperative group, 71%. This data is indicative that irradiation, either pre- or postoperatively, has survival benefits since there is direct relationship between the percentage of patients with positive axillary nodes and the survival rates. However, there is no evidence that preoperative irradiation is superior to postoperative irradiation.

Multimodal treatment of locoregionally advanced breast cancer.

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.