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PURPOSE: The purpose of this study was to determine the clinical, pathological, and treatment factors that are predictive of local-regional recurrence and overall survival for patients with breast cancer that is refractory to neoadjuvant chemotherapy. PATIENTS AND METHODS: This study analyzed the data of the 177 breast cancer patients treated on our institutional protocols who had less than a partial response to neoadjuvant chemotherapy. The initial clinical stage of disease was II in 27%, III in 69%, and IV (supraclavicular lymph node involvement) in 4%. Surgery was performed in 94% of the patients, and 77% of these patients also received adjuvant chemotherapy. RESULTS: After a median follow-up of 5.2 years, 106 patients experienced disease recurrence, with 98 of these having distant metastases and 45 having local-regional recurrence. The 5- and 10-year overall survivals for the entire group were 56% and 33%, respectively. The factors that were independently associated with a statistically significant poorer overall survival in a Cox regression analysis were pathologically involved lymph nodes after surgery, estrogen receptor-negative disease, and progressive disease during neoadjuvant chemotherapy. The 5-year overall survival for patients with pathologically negative lymph nodes ranged from 84% (estrogen receptor-positive disease) to 75% (estrogen re-ceptor-negative disease), compared with rates for patients with pathologically positive lymph nodes of 66% (estrogen receptor-positive disease) and 40% (estrogen receptor-negative disease). The 5-year survival of patients with progressive disease was only 19%. The 5- and 10-year local-regional recurrence rates for the 177 patients were 27% and 34%, respectively. Significant factors on Cox analysis that predicted for local-regional recurrence were four or more pathologically involved lymph nodes and estrogen receptor-negative disease. For the 105 patients treated with surgery and postoperative radiation therapy, the 10-year local-regional recurrence rates for the subgroups with 0, 1, or 2 of these factors were 12%, 25%, and 44%, respectively. CONCLUSIONS: For patients with a poor response to neoadjuvant chemotherapy, conventional treatments achieve reasonable outcomes in those with lymph node-negative disease or estrogen receptor-positive disease. However, more active systemic and local therapies are needed for patients with estrogen receptor-negative disease and positive lymph nodes and for those with clinical evidence of progressive disease during neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

PURPOSE: To conduct a retrospective analysis of chemotherapy and radiation sequencing in lymph node-negative breast cancer patients treated with breast-conserving surgery. PATIENTS AND METHODS: Between February 1982 and January 1996, 124 patients with lymph node-negative breast cancer underwent breast-conserving surgery with axillary dissection followed by chemotherapy and radiation therapy. The outcome of 68 patients who received chemotherapy first was compared with that of 56 patients who received radiation first. The two groups were balanced with respect to patient age, tumor stage, margin status, and estrogen and progesterone receptor status. Sixty-two percent of the patients had T1 primary disease. The median follow-up among surviving patients was 44 months for the chemotherapy-first group and 61 months for the radiation-first group. RESULTS: There were no statistically significant differences in local control, disease-free survival, or overall survival between the two groups. Five-year actuarial rates for local control for the chemotherapy-first and the radiation-first groups were 100% and 94%, respectively. Five-year recurrence-free rates for the chemotherapy-first and radiation-first groups were 92% and 77%, respectively. The 5-year overall survival rate was 89% for both groups. DISCUSSION: Giving chemotherapy before radiation in lymph node-negative breast cancer did not compromise local control. Given the concerns about increased distant metastases if radiation is given first, the chemotherapy-radiation sequence is recommended. [ABSTRACT FROM AUTHOR]

Purpose: To describe and evaluate the modified lateral decubitus boost, a breast irradiation technique. Patients are repositioned and resimulated for electron boost to minimize the necessary depth for the electron beam and optimize target volume coverage., Methods and Materials: A total of 2,606 patients were treated with post-lumpectomy radiation at our institution between January 1, 2000, and February 1, 2008. Of these, 231 patients underwent resimulation in the lateral decubitus position with electron boost. Distance from skin to the maximal depth of target volume was measured in both the original and boost plans. Age, body mass index (BMI), boost electron energy, and skin reaction were evaluated., Results: Resimulation in the lateral decubitus position reduced the distance from skin to maximal target volume depth in all patients. Average depth reduction by repositioning was 2.12 cm, allowing for an average electron energy reduction of approximately 7 MeV. Mean skin entrance dose was reduced from about 90% to about 85% (p < 0.001). Only 14 patients (6%) experienced moist desquamation in the boost field at the end of treatment. Average BMI of these patients was 30.4 (range, 17.8-50.7). BMI greater than 30 was associated with more depth reduction by repositioning and increased risk of moist desquamation., Conclusions: The lateral decubitus position allows for a decrease in the distance from the skin to the target volume depth, improving electron coverage of the tumor bed while reducing skin entrance dose. This is a well-tolerated regimen for a patient population with a high BMI or deep tumor location.

Purpose: Static multileaf collimated field-in-field forward-planned intensity-modulated radiation treatment (FiF-IMRT) has been shown to improve dose homogeneity compared to conventional wedged fields. However, a direct comparison of the scattered dose to the contralateral breast resulting from wedged and FiF-IMRT plans remains to be documented., Methods: The contralateral scattered breast dose was measured in a custom-designed anthropomorphic breast phantom in which 108 thermoluminescent dosimeters (TLDs) were volumetrically placed every 1-2cm. The target phantom breast was treated to a dose of 50Gy using three dose compensation techniques: No medial wedge and a 30-degree lateral wedge (M0-L30), 15-degree lateral and medial wedges (M15-L15), and FiF-IMRT. TLD measurements were compared using analysis of variance., Results: For FiF-IMRT, the mean doses to the medial and lateral quadrants of the contralateral breast were 112cGy (range 65-226cGy) and 40cGy (range 18-91 cGy), respectively. The contralateral breast doses with FiF-IMRT were on average 65% and 82% of the doses obtained with the M15-L15 and M0-L30 techniques, respectively (p<0.001). Compared to the M15-L15 technique, the maximum dose reduction obtained with FiF-IMRT was 115cGy (range 13-115cGy)., Conclusions: The dose to the contralateral breast is significantly reduced with FiF-IMRT compared to wedge-compensated techniques. Although long-term follow-up is needed to establish the clinical relevance of this finding, these results, along with the previously reported improvement in ipsilateral dose homogeneity, support the use of FiF-IMRT if resources permit.

Background: African-American (AA) race has been associated with a worse outcome in breast cancer. It is unclear whether this is due to biological factors, socioeconomic factors, or both., Methods: The records from 2 independent cohorts of breast cancer patients treated on institutional protocols with mastectomy and adjuvant (n = 1456) or neoadjuvant (n = 684) doxorubicin-based chemotherapy were retrospectively reviewed., Results: The adjuvant (Adj) chemotherapy cohort included 1142 Caucasian (CA), 186 Hispanic (HI), and 128 (AA) patients. The neoadjuvant (Neo) chemotherapy protocols included 448 CA, 114 HI, and 122 AA patients. In both groups, AA patients had later-stage tumors (Adj P = .017; Neo P = .051), a higher rate of estrogen receptor (ER)-negative disease (Adj P = .054; Neo P = .039), and a worse 10-year actuarial overall survival rate than CA or HI patients (Adj, 52%, 62%, and 62%, respectively, P = .009; Neo, 40%, 50%, and 56%, respectively, P = .015). In multivariate analyses, AA race remained independently associated with a poorer overall survival rate in both cohorts (Adj, hazard ratio = 1.39, P = .018; Neo, hazard ratio = 1.37, P = .02)., Conclusions: The data suggest that AA race is associated with less favorable biological tumor features, such as an increased likelihood of ER-negative disease, than those found in CA and HI patients. Such differences in tumor biology, as well as previously described socioeconomic factors, likely contribute to the lower rate of survival in the AA breast cancer population., ((c) 2006 American Cancer Society.)

Purpose: To analyze the results of a Phase III clinical trial that investigated whether a hyperfractionated radiotherapy (RT) schedule could reduce the risk of locoregional recurrence in patients with locally advanced breast cancer treated with chemotherapy and mastectomy., Methods and Materials: Between 1985 and 1989, 200 patients with clinical Stage III noninflammatory breast cancer were enrolled in a prospective study investigating neoadjuvant and adjuvant chemotherapy. Of the 179 patients treated with mastectomy after neoadjuvant chemotherapy, 108 participated in a randomized component of the trial that compared a dose-escalated, hyperfractionated (twice-daily, b.i.d.) chest wall RT schedule (72 Gy in 1.2-Gy b.i.d. fractions) with a once-daily (q.d.) schedule (60 Gy in 2-Gy q.d. fractions). In both arms of the study, the supraclavicular fossa and axillary apex were treated once daily to 50 Gy. The median follow-up period was 15 years., Results: The 15-year actuarial locoregional recurrence rate was 7% for the q.d. arm and 12% for the b.i.d. arm (p=0.36). The rates of severe acute toxicity were similar (4% for q.d. vs. 5% for b.i.d.), but moist desquamation developed in 42% of patients in the b.i.d. arm compared with 28% of the patients in the q.d. arm (p=0.16). The 15-year actuarial rate of severe late RT complications did not differ between the two arms (6% for q.d. vs. 11% for b.i.d., p=0.54)., Conclusion: Although the sample size of this study was small, we found no evidence that this hyperfractionation schedule of postmastectomy RT offered a clinical advantage. Therefore, we have concluded that it should not be further studied in this cohort of patients.

Purpose: The purpose of this study was to describe regional nodal failure patterns in patients who had undergone mastectomy with axillary dissection to define subgroups of patients who might benefit from supplemental regional nodal radiation to the axilla or supraclavicular fossa/axillary apex., Methods and Materials: The cohort consisted of 1031 patients treated with mastectomy (including a level I-II axillary dissection) and doxorubicin-based systemic therapy without radiation on five clinical trials at M.D. Anderson Cancer Center. Patient records, including pathology reports, were retrospectively reviewed. All regional recurrences (with or without distant metastasis) were recorded. Median follow-up was 116 months (range, 6-262 months)., Results: Twenty-one patients recurred within the low-mid axilla (10-year actuarial rate 3%). Of these, 16 were isolated regional failures (no chest wall failure). The risk of failure in the low-mid axilla was not significantly higher for patients with increasing numbers of involved nodes, increasing percentage of involved nodes, larger nodal size or gross extranodal extension. Only 3 of 100 patients with <10 nodes examined recurred in the low-mid axilla. Seventy-seven patients had a recurrence in the supraclavicular fossa/axillary apex (10-year actuarial rate 8%). Forty-nine were isolated regional recurrences. Significant predictors of failures in this region included > or = 4 involved axillary lymph nodes, >20% involved axillary nodes, and the presence of gross extranodal extension (10-year actuarial rates 15%, 14%, and 19%, respectively, p < 0.0005). The extent of axillary dissection and the size of the largest involved node were not predictive of failure within the supraclavicular fossa/axillary apex., Conclusions: These results suggest that failure in the level I-II axilla is an uncommon occurrence after modified radical mastectomy and chemotherapy. Therefore, supplemental radiotherapy to the dissected axilla is not warranted for most patients. However, patients with > or = 4 involved axillary lymph nodes, >20% involved axillary nodes, or gross extranodal extension are at increased risk of failure in the supraclavicular fossa/axillary apex and should receive radiation to undissected regions in addition to the chest wall.

Objective: Immediate breast reconstruction is an attractive option for patients who undergo mastectomy. The purpose of this study was to qualitatively assess the effect of immediate reconstruction on the design of postmastectomy radiotherapy fields at our institution., Methods: We retrospectively reviewed the records of 152 patients treated at our institution with postmastectomy radiotherapy over a 1-year period. We identified 18 postmastectomy radiotherapy plans in the setting of prior reconstruction. By consensus, 2 board-certified radiation oncologists scored the 18 plans in terms of 4 outcomes: coverage of the chest wall breadth, coverage of the ipsilateral internal mammary chain (IMC) region, minimization of lung exposure, and avoidance of the heart., Results: Only 4 of the 18 plans resulted in optimal treatment of the chest wall breadth and IMC region while well avoiding the heart and lung. Of the remaining 14 plans, 12 compromised coverage of the chest wall breadth medially and/or laterally, and 9 provided no IMC coverage., Conclusion: Immediate breast reconstruction may impose limitations on the treatment planning of postmastectomy radiotherapy, particularly in regard to providing broad coverage of the chest wall and IMC region while avoiding excess exposure of the heart and lung.

The present study evaluated the outcome of salvage treatment for women with local or local-regional recurrence after initial breast conservation treatment with radiation for mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast. The study cohort consisted of 90 women with local only first failure (n=85) or local-regional only first failure (n=5). The histology at the time of recurrence was invasive carcinoma for 53 patients (59%), non-invasive carcinoma for 34 patients (38%), angiosarcoma for one patient (1%), and unknown for two patients (2%). The median follow-up after salvage treatment was 5.5 years (mean=5.8 years; range=0.2-14.2 years). The 10-year rates of overall survival, cause-specific survival, and freedom from distant metastases after salvage treatment were 83%, 95%, and 91%, respectively. Adverse prognostic factors for the development of subsequent distant metastases after salvage treatment were invasive histology of the local recurrence and pathologically positive axillary lymph nodes. These results demonstrate that local and local-regional recurrences can be salvaged with high rates of survival and freedom from distant metastases. Close follow-up after initial breast conservation treatment with radiation is warranted for the early detection of potentially salvageable local and local-regional recurrences.

Purpose: To identify the clinical and pathologic factors predictive of locoregional recurrence (LRR) after neoadjuvant chemotherapy, mastectomy, and radiotherapy., Methods and Materials: We retrospectively reviewed the hospital records of 542 patients treated on six consecutive institutional prospective trials using neoadjuvant chemotherapy and postmastectomy radiotherapy. The clinical stage (American Joint Committee on Cancer, 1988) was Stage II in 17%, Stage IIIA in 30%, Stage IIIB in 43%, and Stage IV (ipsilateral supraclavicular disease) in 10%. All LRRs were considered events, irrespective of the timing to distant metastases., Results: The median follow-up was 70 months. The 5-year and 10-year actuarial LRR rate was 9% and 11%, respectively. The clinical factors associated with LRR included combined clinical stage, clinical T stage, ipsilateral supraclavicular nodal disease, chemotherapy response, physical examination size after chemotherapy, and no tamoxifen use (p < or = 0.04 for all factors). The pathologic predictors of LRR included the number of positive nodes, dissection of <10 nodes, multifocal/multicentric disease, lymphovascular space invasion, extracapsular extension, skin/nipple involvement, and estrogen receptor-negative disease (p

Background: Ductal carcinoma in situ (DCIS) is detected most commonly on routine screening mammography in the asymptomatic patient, and has a long natural history. The objective of the current study was to determine the long-term outcome after breast-conservation surgery followed by definitive breast irradiation for women with mammographically detected DCIS of the breast., Methods: In total, 1003 women with unilateral, mammographically detected DCIS of the breast underwent breast-conserving surgery followed by definitive breast irradiation. These women were treated in 10 institutions in North America and Europe. The median follow-up was 8.5 years (mean, 9.0 years; range, 0.2-24.6 years)., Results: The 15-year overall survival rate was 89%, and the 15-year cause-specific survival rate was 98%. The 15-year rate of freedom from distant metastases was 97%. In total, there were 100 local failures (10%) in the treated breast. The 15-year rate of any local failure was 19%, and the 15-year rate of local only first failure was 16%. Patient age > or = 50 years at the time of treatment and negative final pathology margins from the primary tumor excision both were associated independently with a lower risk of local failure in univariate analysis (P = 0.00062 and P = 0.024, respectively) and in multivariate analysis (P = 0.00057 and P = 0.0026, respectively). For favorable subgroups of patients age > or = 50 years or with negative resection margins, the 10-year risk of local failure was < or = 8%., Conclusions: The current results support the use of breast-conserving surgery followed by definitive breast irradiation for the treatment of patients with mammographically detected DCIS of the breast. Patient age > or = 50 years at the time of treatment and negative resection margins both were associated independently with a decreased risk of local failure.

Background: The appropriate selection criteria for breast-conserving therapy (BCT) after neoadjuvant chemotherapy are poorly defined. The purpose of the current report was to develop a prognostic index to help refine selection criteria and to serve as a general framework for clinical decision-making for patients treated by this multimodality approach., Methods: From a group of 340 patients treated with BCT after neoadjuvant chemotherapy, the authors previously determined 4 statistically significant predictors of ipsilateral breast tumor recurrence (IBTR) and locoregional recurrence (LRR): clinical N2 or N3 disease, residual pathologic tumor size > than 2 cm, a multifocal pattern of residual disease, and lymphovascular space invasion in the specimen. The M. D. Anderson Prognostic Index (MDAPI) was developed by assigning scores of 0 (favorable) or 1 (unfavorable) for each of these 4 variables and using the total to give an overall MDAPI score of 0-4., Results: The MDAPI stratified the 340 patients into 3 subsets with statistically different levels of risk for IBTR and LRR after neoadjuvant chemotherapy and BCT. Actuarial 5-year IBTR-free survival rates were 97%, 88%, and 82% for patients in the low (MDAPI overall score 0 or 1, n=276), intermediate (MDAPI score 2, n=43), and high (MDAPI score 3 or 4, n=12) risk groups, respectively (P<0.001). Corresponding actuarial 5-year LRR-free survival rates were 94%, 83%, and 58%, respectively (P<0.001)., Conclusions: Patients with an MDAPI score of 0 or 1, which made up 81% of the study population, had very low rates of IBTR and LRR. The MDAPI enabled the identification of a small group (4%) of patients who are at high risk for IBTR and LRR and who may benefit from alternative locoregional treatment strategies., (Copyright (c) 2005 American Cancer Society.)

Purpose: To evaluate the efficacy of radiation in patients treated with neoadjuvant chemotherapy and mastectomy., Patients and Methods: We retrospectively analyzed the outcomes of 542 patients treated on six consecutive institutional prospective trials with neoadjuvant chemotherapy, mastectomy, and radiation. These data were compared to those of 134 patients who received similar treatment in these same trials but without radiation., Results: Irradiated patients had a lower rate of local-regional recurrence (LRR) (10-year rates: 11% v 22%, P = .0001). Radiation reduced LRR for patients with clinical T3 or T4 tumors, stage > or = IIB disease (AJCC 1988), pathological tumor size >2 cm, or four or more positive nodes (P < or = .002 for all comparisons). Patients who presented with clinically advanced stage III or IV disease but subsequently achieved a pathological complete response to neoadjuvant chemotherapy still had a high rate of LRR, which was significantly reduced with radiation (10-year rates: 33% v 3%, P = .006). Radiation improved cause-specific survival (CSS) in the following subsets: stage > or = IIIB disease, clinical T4 tumors, and four or more positive nodes (P < or = .007 for all comparisons). On multivariate analyses of LRR and CSS, the hazard ratios for lack of radiation were 4.7 (95% CI, 2.7 to 8.1; P < .0001) and 2.0 (95% CI, 1.4 to 2.9; P < .0001), respectively., Conclusion: After neoadjuvant chemotherapy and mastectomy, comprehensive radiation was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage III-IV (ipsilateral supraclavicular nodal) disease and for patients with four or more positive nodes. Radiation should be considered for these patients regardless of their response to initial chemotherapy.

Background: Taxane-based chemotherapy has been associated with an increased risk of radiation pneumonitis in patients with breast cancer. To obtain additional information about this association, we investigated the association between paclitaxel chemotherapy and radiation pneumonitis in patients participating in a phase III randomized study., Methods: Five hundred and twenty-four breast cancer patients were prospectively and randomly assigned to receive either four cycles of paclitaxel followed by four cycles of 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) or eight cycles of FAC. One hundred and eighty-nine of these patients (100 in the paclitaxel-FAC group and 89 in the FAC group) subsequently underwent radiation therapy in our institution and had medical records available to review for pulmonary symptoms. In addition, a radiologist who was unaware of the type of treatment scored chest x-ray changes after radiation treatment. Crude rates of radiation pneumonitis were compared with chi-square or Fisher's exact test, and actuarial rates were assessed with Kaplan-Meier and log-rank tests. All statistical tests were two-sided., Results: No difference in the rate of clinically relevant radiation pneumonitis was observed between the two groups (5.0% in the paclitaxel-FAC group versus 4.5% in the FAC group; difference = 0.5%, 95% CI = -6.6% to 5.5%; P = 1.00). Oral steroids for pneumonitis were taken by two patients in the paclitaxel-FAC group but by none in the FAC group, and no patient was hospitalized for or died of radiation pneumonitis. The paclitaxel-FAC group (39.3%) had a higher rate of radiographic changes after irradiation than the FAC group (23.7%; difference = 15.6%, 95% CI = -0.11% to 28.8%; P = .034)., Conclusion: Patients with breast cancer treated with sequential paclitaxel, FAC, and radiation therapy appeared to have a very low rate of clinically relevant radiation pneumonitis that was no different from that of patients treated with FAC alone.

Purpose: Preclinical data suggest that overexpression of Her2/neu confers cellular radioresistance. We retrospectively studied whether Her2/neu-positive disease was associated with locoregional recurrence (LRR) after postmastectomy radiotherapy (RT) for breast cancer., Methods and Materials: Data from 337 patients treated in four institutional prospective clinical trials neoadjuvant doxorubicin-based chemotherapy, mastectomy, and RT were reviewed. The trials were conducted between 1989 and 2000. Of the 337 patients, 108 (32%) had tumors that were tested for Her2/neu, with positivity defined by 3+ immunohistochemistry staining or gene amplification detected by fluorescence in situ hybridization. RT was delivered to the chest wall and draining lymphatics (median dose, 50 Gy) followed by a chest wall boost (median dose, 10 Gy)., Results: Thirty-two patients had Her2/neu-positive disease and 76 patients had Her2/neu-negative disease. The Her2/neu-positive tumors were associated with a greater rate of estrogen receptor-negative disease (p = 0.03), the presence of supraclavicular disease at diagnosis (p = 0.027), and a greater number of positive lymph nodes after chemotherapy (p = 0.026). Despite these adverse features, the actuarial overall LRR rate was roughly equivalent for the patients with Her2/neu-positive tumors vs. those with Her2/neu-negative tumors (5-year rate 17.5% vs. 13.9%, respectively; 10-year rate 17.5% vs. 18.9%, respectively; p = 0.757). On Cox regression analysis of LRR adjusted for N stage and estrogen receptor status, the hazard ratio for Her2/neu positivity was 0.89 (95% confidence interval, 0.31-2.59; p = 0.83)., Conclusion: Her2/neu overexpression does not appear to predispose to LRR after neoadjuvant doxorubicin-based chemotherapy, mastectomy, and RT.

Purpose: The optimal design of radiation fields for patients with positive sentinel lymph nodes (SLNs) who do not undergo axillary dissection is unknown. We have previously shown that modified breast tangent fields can include most axillary Level I-II lymph nodes. We have also reported that irradiation of the axillary apex/supraclavicular fossa is indicated for patients with four or more positive axillary lymph nodes. To determine the optimal arrangement for patients with positive SLNs, we studied what factors predicted for having four or more positive lymph nodes., Methods and Materials: We reviewed the records of 339 consecutive patients with one to three positive SLNs who underwent complete axillary dissection at our institution between 1995 and 2002. We separately analyzed the outcome for those initially treated with surgery (n = 265) and those receiving neoadjuvant chemotherapy (n = 74). A logistic regression model was used to identify independent factors predictive for four or more positive lymph nodes., Results: A total of 28 of 265 patients in the initial surgery group and 20 of 74 patients in the neoadjuvant group had four or more positive lymph nodes. In the initial surgery group, the independent factors associated with four or more positive lymph nodes were no drainage seen on lymphoscintigraphy (rate, 38%, odds ratio [OR] = 5.4, p = 0.03), more than one positive SLN (rate, 24-42%, OR = 2.9, p = 0.02), and lymphovascular space invasion (LVSI; rate, 25%, OR = 4.8, p = 0.01). Of the 106 patients without any of these factors, only 2 had four or more positive lymph nodes. For the patients treated with neoadjuvant chemotherapy, the independent factors were clinical Stage III (rate, 48%, OR = 3.1, p = 0.03), more than one positive SLN (rate, 37-67%, OR = 4.8, p = 0.03), and LVSI (rate, 62%, OR = 8.1, p = 0.02). Of the 28 patients without any of these factors, only 1 had four or more positive lymph nodes., Conclusion: It is reasonable to treat with modified tangents fields that include most axillary Level I-II nodes for patients with one positive SLN who do not undergo axillary dissection if drainage is seen on lymphoscintigraphy and no LVSI is present. This approach is also reasonable for patients treated with neoadjuvant chemotherapy who have Stage II disease, no LVSI, and only one positive SLN. The remaining patients have a greater risk of having four or more positive lymph nodes, and, therefore, the high axilla/supraclavicular fossa should also be included in the radiation fields.

Purpose: To evaluate the use of an alternate, non-cross-resistant adjuvant chemotherapy regimen in women with a poor pathologic response to a preoperative doxorubicin-based regimen., Patients and Methods: Patients with locally advanced breast cancer received three cycles of vincristine, doxorubicin, cyclophosphamide, and prednisone (VACP) every 21 days followed by surgery. Patients with less than 1 cm(3) residual tumor at mastectomy received an additional five cycles of VACP. Those with more than 1 cm(3) residual tumor were randomly assigned to receive an additional five cycles of VACP or five cycles of vinblastine, methotrexate with calcium leucovorin rescue, and fluorouracil (VbMF)., Results: One hundred ninety-three patients were evaluable. Overall clinical response was seen in 83.4% after three cycles of VACP, whereas the pathologic complete response was 12.2%. One hundred six patients were randomly assigned to VACP or VbMF. Those receiving VbMF achieved higher relapse-free survival (RFS) and overall survival (OS) than those who received additional VACP, although the differences did not reach statistical significance. Initial stage of tumor, clinical complete response, and pathologic complete response were all associated with statistically superior survival rates., Conclusion: Clinical and pathologic response to preoperative doxorubicin-based chemotherapy predicted for improved survival in women with operable breast cancer. For those with a poor response to initial neoadjuvant chemotherapy, treatment with VbMF was associated with a trend toward improved RFS and OS compared with those continuing with the doxorubicin regimen.

Purpose: To determine patterns of local-regional recurrence (LRR) and ipsilateral breast tumor recurrence (IBTR) among patients treated with breast conservation therapy after neoadjuvant chemotherapy., Patients and Methods: Between 1987 and 2000, 340 cases of breast cancer were treated with neoadjuvant chemotherapy followed by conservative surgery and radiation therapy. Clinical stage at diagnosis (according to the 2003 American Joint Committee on Cancer system) was I in 4%, II in 58%, and III in 38% of patients. Only 4% had positive surgical margins., Results: At a median follow-up period of 60 months (range, 10 to 180 months), 29 patients had developed LRR, 16 of which were IBTRs. Five-year actuarial rates of IBTR-free and LRR-free survival were 95% and 91%, respectively. Variables that positively correlated with IBTR and LRR were clinical N2 or N3 disease, pathologic residual tumor larger than 2 cm, a multifocal pattern of residual disease, and lymphovascular space invasion in the specimen. The presence of any one of these factors was associated with 5-year actuarial IBTR-free and LRR-free survival rates of 87% to 91% and 77% to 84%, respectively. Initial T category (T1-2 v T3-4) correlated with LRR but did not correlate with IBTR (5-year IBTR-free rates of 96% v 92%, respectively, P =.19)., Conclusion: Breast conservation therapy after neoadjuvant chemotherapy results in acceptably low rates of LRR and IBTR in appropriately selected patients, even those with T3 or T4 disease. Advanced nodal involvement at diagnosis, residual tumor larger than 2 cm, multifocal residual disease, and lymphovascular space invasion predict higher rates of LRR and IBTR.

Purpose: To help define the clinical and pathologic predictors of locoregional recurrence (LRR) in breast cancer patients treated with neoadjuvant chemotherapy and mastectomy without radiotherapy for early-stage disease., Methods and Materials: We retrospectively reviewed the outcomes of all 132 patients with Stage I or II breast cancer treated in prospective institutional trials with neoadjuvant chemotherapy and mastectomy without radiotherapy between 1974 and 2001. The clinical stage (American Joint Committee on Cancer 1988) at diagnosis was I in 5%, IIA in 46%, and IIB in 49% of patients. The median age at diagnosis was 49 years. All patients were treated with either a doxorubicin-based neoadjuvant regimen or single-agent paclitaxel. The total LRR rates were calculated by the Kaplan-Meier method, and comparisons were made with two-sided log-rank tests. The median follow-up was 46 months., Results: The actuarial LRR rate at both 5 and 10 years was 10%. Factors that correlated positively with LRR included clinical Stage T3N0 (p = 0.0057), four or more positive lymph nodes at surgery (p = 0.0001), age < or =40 years at diagnosis (p = 0.0001), and no use of tamoxifen. In the patients who did not receive tamoxifen, estrogen receptor-positive disease correlated positively with LRR (p = 0.0067). The 5-year LRR rate for the 42 patients with clinical Stage T1 or T2 disease and one to three positive lymph nodes at surgery was 5% (only two events)., Conclusions: For patients with clinical Stage II breast cancer, T3 primary disease, four or more positive lymph nodes after chemotherapy, and age < or =40 years old predicted for LRR. For most patients with clinical T1 or T2 disease and one to three positive lymph nodes, the 5-year risk for LRR was low, and the routine inclusion of postmastectomy radiotherapy does not appear to be justified.

In patients with early-stage breast cancer who are scheduled to undergo mastectomy and desire breast reconstruction, the optimal timing of reconstruction depends on whether postmastectomy radiation therapy will be needed. Immediate reconstruction offers the best aesthetic outcomes if postmastectomy radiation therapy is not needed, but if postmastectomy radiation therapy is required, delayed reconstruction is preferable to avoid potential aesthetic and radiation-delivery problems. Unfortunately, the need for postmastectomy radiation therapy cannot be reliably determined until review of the permanent tissue sections. The authors recently implemented a two-stage approach, delayed-immediate breast reconstruction, to optimize reconstruction in patients at risk for requiring postmastectomy radiation therapy when the need for postmastectomy radiation therapy is not known at the time of mastectomy. Stage 1 consists of skin-sparing mastectomy with insertion of a completely filled textured saline tissue expander. After review of permanent sections, patients who did not require post-mastectomy radiation therapy underwent immediate reconstruction (stage 2) and patients who required postmastectomy radiation therapy completed postmastectomy radiation therapy and then underwent standard delayed reconstruction. In this study, the feasibility and outcomes of this approach were reviewed. Fourteen patients were treated with delayed-immediate reconstruction between May of 2002 and June of 2003. Twelve patients had unilateral reconstruction and two patients had bilateral reconstruction, for a total of 16 treated breasts. All patients completed stage 1. Tissue expanders were inserted subpectorally in 15 breasts and subcutaneously in one breast. The mean intraoperative expander fill volume was 475 cc (range, 250 to 750 cc). Three patients required postmastectomy radiation therapy and underwent delayed reconstruction. Eleven patients did not require postmastectomy radiation therapy. Nine patients had 11 breast reconstructions (stage 2), six with free transverse rectus abdominis musculocutaneous (TRAM) flaps, one with a superior gluteal artery perforator flap, and four with a latissimus dorsi flap plus an implant. The median interval between stages was 13 days (range, 11 to 22 days). Two patients who did not require postmastectomy radiation therapy have not yet had stage 2 reconstruction, one because she wished to delay reconstruction and the other because she required additional tissue expansion before permanent implant placement. Six complications occurred. The stage 1 complications involved two cases of mastectomy skin necrosis in patients who required post-mastectomy radiation therapy; one patient required removal of the subcutaneously placed expander before postmastectomy radiation therapy and the other patient had a subpectorally placed expander that only required local wound care. The stage 2 complications were a recipient-site seroma in a patient with a latissimus dorsi flap, a recipient-site hematoma in the patient with the superior gluteal artery perforator flap, and two arterial thromboses in patients with TRAM flaps. Both TRAM flaps were salvaged. Delayed-immediate reconstruction is technically feasible and safe in patients with early-stage breast cancer who may require postmastectomy radiation therapy. With this approach, patients who do not require postmastectomy radiation therapy can achieve aesthetic outcomes essentially the same as those with immediate reconstruction, and patients who require postmastectomy radiation therapy can avoid the aesthetic and radiation-delivery problems that can occur after an immediate breast reconstruction.

Background: Mothers of children who have ataxia telangiectasia have been reported to be at increased risk for development of breast carcinoma. To test whether sequence variants in the ataxia telangiectasia, mutated, gene (ATM) are associated with breast carcinoma, the authors compared the frequency of ATM cDNA sequence changes in patients with breast carcinoma with the corresponding frequency in control patients., Methods: The authors sequenced ATM cDNA from 91 patients with breast carcinoma and compared the frequencies of sequence changes in these patients with the corresponding frequencies in a control sample of 940 individuals with no history of malignant disease., Results: Thirty-five patients with breast carcinoma had one or more single-base changes in ATM. Three genetic variants were found in at least two patients. These variants resulted in Asp1853Asn, Pro1054Arg, or Ser49Cys amino acid substitutions in the ATM protein. The Ser49Cys variant was more common in patients with breast carcinoma than in the control patients, with respective frequencies of 6.7% (5 of 75 patients) and 1.3% (12 of 940 patients; P=0.006; Fisher two-sided exact test). The subgroup of patients with bilateral breast carcinoma had a Ser49Cys frequency of 11.8% (2 of 17 patients), which again was significantly different from what was observed in the control group (P=0.024; Fisher two-sided exact test). The allele frequencies of the other two variants were not different between case patients and control patients., Conclusions: Patients with breast carcinoma, particularly those with bilateral disease, were more likely to have a variant in the ATM gene that resulted in a Ser49Cys substitution in the gene product. Additional studies are needed to evaluate the potential functional consequences of the Ser49Cys substitution and confirm the relevance of this variant in the development of breast carcinoma., (Copyright 2004 American Cancer Society.)

During the past decade, improvements in treatment-planning tools, computer and imaging technologies, and new therapeutic modalities have allowed radiation to be delivered in a conformal fashion while minimizing treatment toxicity. It is important that physicians involved in breast cancer treatment recognize the numerous advances that have occurred in the delivery of radiation therapy. Changes in 3 specific areas in treatment planning and delivery have revolutionized the way we approach breast cancer treatment: the design of radiation fields using computed tomography (CT) data sets, the development of 3-dimensional dose-calculation algorithms, and the development of new methods to modulate the delivery of radiation dose. With the advent of CT simulators, individual patient anatomy and pathology can be readily visualized and reconstructed in axial, coronal, and sagittal views. With an improved anatomic delineation between the target volumes and critical organ structures, the treatment fields can be designed to be more congruous to the areas at highest risk. In the past few years, new 3-dimensional dose-calculation algorithms have been generated that more accurately calculate dose distributions throughout the treatment-planning volume. Finally, modern linear accelerators allow for modulation of the dose intensity of the radiation beam, which may lead to improved aesthetics and decreased side effects while ensuring that the volumes at high risk receive the prescribed dose. Radiation therapy can be delivered safely and effectively to patients with breast cancer.

Purpose: To compare rates of locoregional recurrence (LRR) after mastectomy, doxorubicin-based chemotherapy, and radiation with those of patients receiving mastectomy and doxorubicin-based chemotherapy without radiation and to determine predictors of LRR after postmastectomy radiation., Methods: Kaplan-Meier freedom-from-LRR rates were calculated for 470 patients treated with mastectomy, doxorubicin-based chemotherapy, and postmastectomy radiation in five single-institution clinical trials. The LRR rates in these patients were compared to previously reported rates in 1031 patients treated without radiation in the same trials., Results: Median follow-up was 14 years. Irradiated patients had significantly less favorable prognostic factors for LRR than did unirradiated patients. Despite this, in all subsets of node-positive patients, postmastectomy radiation led to lower rates of LRR. This included patients with T1 or T2 tumors and one to three positive nodes (10-year LRR rates of 3% vs. 13%, p = 0.003). Multivariate analysis of LRR for patients with this stage of disease revealed that no radiation, close/positive margins, gross extracapsular extension, and dissection of <10 nodes predicted for increased LRR (hazard ratios 6.25, 4.61, 3.27, and 2.66, respectively). Significant predictors of LRR for patients treated with postmastectomy radiation were higher number and >or=20% positive nodes, larger tumor size, lymphovascular space invasion, and estrogen receptor (ER)-negative disease. Recursive partitioning analysis revealed ER-negative status to be the most powerful discriminator of LRR in irradiated patients., Conclusions: Postmastectomy radiation decreases LRR for patients with breast cancer, including those with Stage II breast cancer and one to three positive lymph nodes.

Purpose: To assess the incidence of long-term toxicity after postmastectomy radiation and doxorubicin-based adjuvant chemotherapy., Methods: Records of 470 patients treated with mastectomy, doxorubicin-based chemotherapy, and postmastectomy radiation in five institutional prospective trials were retrospectively reviewed. Actuarial toxicity rates were compared with those of 1031 patients treated with mastectomy and doxorubicin-based chemotherapy who did not receive postmastectomy radiation. For those treated with radiation, the chest wall received a median dose of 55 Gy with Co-60 (42%) or electrons (51%). Adjuvant chemotherapy consisted of a doxorubicin-based regimen, often followed by 2 years of cyclophosphamide, methotrexate, and fluorouracil., Results: Median follow-up was 10 years. The overall 10-year actuarial rates of RTOG toxicity Grade >1 and >or=3 after radiation were 4% and 2%, respectively. The overall 10- and 15-year actuarial rates of second non-breast cancer malignancy were 3.8% and 7%, respectively. There was no statistical difference between the rates of non-breast cancer second malignancy in the radiated and unirradiated cohorts (3.4% vs. 4.7% 10-year actuarial rates). Increasing age and treatment with >10 cycles of chemotherapy were associated with higher rates of second malignancy (p = 0.025, p = 0.016). The 10-year actuarial rate of death from myocardial infarction (MI) was 2.4% (eight events) and 0.5% (five events) in the radiated and unirradiated groups, respectively (p = 0.058). Of the 8 irradiated patients who died of MI, 2 patients had left-sided breast cancer., Conclusions: We found very low rates of serious sequelae after postmastectomy radiation, including death from myocardial infarction and non-breast cancer second malignancy. The rate of second non-breast cancer malignancy was increased among patients treated with >10 cycles of cyclophosphamide-containing chemotherapy.

Purpose: To evaluate how implementation of the 2003 American Joint Committee on Cancer (AJCC) staging system will affect stage-specific survival of breast cancer patients., Patients and Methods: Records of 1,350 patients treated on sequential institutional protocols with mastectomy and adjuvant doxorubicin-based chemotherapy were reviewed. Pathologic stage was assigned retrospectively according to the 1988 and the 2003 AJCC staging criteria. Overall stage-specific survival (OS) was calculated using the Kaplan-Meier method, and hypothetical differences were compared by the log-rank test., Results: Six hundred five of 1,087 patients with stage II disease according to the 1988 classification system had stage II disease according to the 2003 system. The 10-year OS for patients with stage II disease was significantly improved using the 2003 system (76% [2003] v 65% [1988]; P <.0001). Two hundred eighty-nine of 633 patients with stage IIb disease using the 1988 system were stage IIb with the 2003 system, and 10-year OS was 58% (1988) versus 70% (2003; P =.003). The number of patients with stage III disease increased from 207 (1988) to 443 (2003), and the 10-year OS changed from 45% (1988) to 50% (2003; P =.077). Most of this difference resulted from changes within stage IIIa: OS, 45% (1988) versus 59% (2003; P <.0001)., Conclusion: Stage reclassification using the new AJCC staging system for breast cancer will result in significant changes in reported outcome by stage. It is imperative that careful attention is devoted to this effect so that accurate conclusions regarding the efficacy of new treatment strategies can be drawn.

Radiation therapy is an effective treatment of micrometastatic disease involving lymph nodes. Correspondingly, radiation may be an important adjuvant treatment for selected patients who undergo sentinel lymph node surgery. The specific cohorts for whom radiation maybe of benefit include those at risk for a false-negative surgery, patients with a positive sentinel lymph node who elect to forgo an axillary dissection, and patients with drainage to the internal mammary lymph nodes. For these patients, radiation treatment fields must be specifically designed to include the appropriate nodal regions within the target treatment volumes.

Background: The current study identified determinants of systemic recurrence and disease-specific survival (DSS) in patients with early-stage breast carcinoma treated with breast-conserving surgery and radiation therapy (breast-conserving therapy, or BCT)., Methods: The study population consisted of 1,043 consecutive women with Stages I or II breast carcinoma who underwent BCT between 1970 and 1994. Clinical and pathologic characteristics evaluated included age, tumor size, tumor grade, estrogen and progesterone receptor status, surgical margins, axillary lymph node involvement, and use of adjuvant therapy., Results: At a median follow-up time of 8.4 years, 127 patients (12%) had developed an ipsilateral breast tumor recurrence (IBTR), and 184 patients (18%) had developed a systemic recurrence. On multivariate logistic regression analysis, tumor size greater than 2 cm, positive lymph nodes, lack of adjuvant tamoxifen therapy, and positive margins (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.1-12.3; P = 0.034) were predictors of systemic recurrence. When IBTR was added into the model, adjuvant therapy and surgical margins were not independent predictors; however, IBTR was an independent predictor of systemic recurrence (IBTR vs. no IBTR; OR, 6.2; 95% CI, 3.1-12.3; P < 0.001). The 10 year DSS rate after BCT was 87%. On multivariate Cox proportional hazards model analysis, the following factors were independent predictors of poor DSS: tumor size greater than 2 cm (vs. < or = 2 cm; relative risk [RR], 2.3; 95% CI, 1.2-4.3; P = 0.010), negative progesterone receptor status (vs. positive; RR, 2.7; 95% CI, 1.4-5.1; P = 0.003), positive margins (vs. negative; RR, 3.9; 95% CI, 1.4-11.5; P = 0.011), and IBTR (vs. no IBTR; RR, 5.5; 95% CI, 2.8-11.0; P < 0.001)., Conclusions: Positive surgical margins and IBTR are predictors of systemic recurrence and disease-specific survival after BCT. Aggressive local therapy is necessary to ensure adequate surgical margins and to minimize IBTR., (Copyright 2003 American Cancer Society)

Background: To distinguish true local recurrences (TR) from new primary tumors (NP) and to assess whether this distinction has prognostic value in patients who develop ipsilateral breast tumor recurrences (IBTR) after breast-conserving surgery and radiotherapy., Methods: Between 1970 and 1994, 1339 patients underwent breast-conserving surgery at The University of Texas M. D. Anderson Cancer Center for ductal carcinoma in situ or invasive carcinoma. Of these patients, 139 (10.4%) had an IBTR as the first site of failure. For the 126 patients with clinical data available for retrospective review, we classified the IBTR as a TR if it was located within 3 cm of the primary tumor bed and was of the same histologic subtype. All other IBTRs were designated NP., Results: Of the 126 patients, 48 (38%) patients were classified as NP and 78 (62%) as TR. Mean time to disease recurrence was 7.3 years for NP versus 5.6 years for TR (P = 0.0669). The patients with NP had improved 10-year rates of overall survival (NP 77% vs. TR 46%, P = 0.0002), cause-specific survival (NP 83% vs. TR 49%, P = 0.0001), and distant disease-free survival (NP 77% vs. TR 26%, P < 0.0001). Patients with NP more often developed contralateral breast carcinoma (10-year rate: NP 29% vs. TR 8%, P = 0.0043), but were less likely to develop a second local recurrence after salvage treatment of the first IBTR (NP 2% vs. TR 18%, P = 0.008)., Conclusions: Patients with NP had significantly better survival rates than those with TR, but were more likely to develop contralateral breast carcinoma. Distinguishing new breast carcinomas from local disease recurrences may have importance in therapeutic decisions and chemoprevention strategies. This is because patients with new carcinomas had significantly lower rates of metastasis than those with local disease recurrence, but were more likely to develop contralateral breast carcinomas., (Copyright 2002 American Cancer Society.)

Purpose: To analyze the long-term outcome of breast conservation therapy in patients with ductal carcinoma in situ (DCIS) in a single institution and to analyze the prognostic importance, if any, of young patient age., Methods and Materials: The hospital records of 150 patients with DCIS treated with surgical excision and radiotherapy at our institution between 1980 and 1997 were retrospectively reviewed. For most of the patients, intraoperative specimen radiographs or postoperative mammograms were available for use in assessing that an adequate surgical resection had been performed. The median patient age was 53 years (range 32-81), with 13% of patients or=40 years, p = 0.39). In all cases of local recurrence, patients underwent surgery with or without chemotherapy, and disease control was achieved., Conclusion: The results of this study demonstrate high rates of long-term overall survival, disease-specific survival, and local control in patients with DCIS of the breast treated conservatively with segmental mastectomy and radiotherapy. On the basis of the excellent long-term local control and 100% disease-specific survival rates, we found that patient age does not affect the outcome if the margins are clear. Continued studies in young patients treated with breast conservative therapy for DCIS are needed.

Purpose: To assess the therapeutic outcomes and treatment-related morbidity of patients treated with radiation for inoperable breast cancer resistant to anthracycline-containing primary chemotherapy., Methods and Materials: We analyzed the medical records of breast cancer patients treated on five consecutive institutional trials who had been designated as having inoperable locoregional disease after completion of primary chemotherapy, without evidence of distant metastases at diagnosis. The cohort for this analysis was 38 (4.4%) of 867 patients enrolled in these trials. Kaplan-Meier statistics were used for survival analysis, and prognostic factors were compared using log-rank tests. The median follow-up of surviving patients was 6.1 years., Results: Thirty-two (84%) of the 38 patients were able to undergo mastectomy after radiotherapy. For the whole group, the overall survival rate at 5 years was 46%, with a distant disease-free survival rate of 32%. The 5-year survival rate for patients who were inoperable because of primary disease extent was 64% compared with 30% for those who were inoperable because of nodal disease extent (p = 0.0266). The 5-year rate of locoregional control was 73% for the surgically treated patients and 64% for the overall group. Of the 32 who underwent mastectomy, the 5-year rate of significant postoperative complications was 53%, with 4 (13%) requiring subsequent hospitalization and additional surgical revision. Preoperative radiation doses of >or=54 Gy were significantly associated with the development of complications requiring surgical treatment (70% vs. 9% for doses <54 Gy, p = 0.0257)., Conclusion: Despite the poorer prognosis of patients with inoperable disease after primary chemotherapy, almost one-half remained alive at 5 years and one-third were free of distant disease after multidisciplinary locoregional management. These patients have high rates of locoregional recurrence after preoperative radiotherapy and mastectomy, and the morbidity associated with this approach may limit dose-escalation strategies. Alternative therapeutic strategies such as novel systemic agents, use of planned myocutaneous repair for closure, or radiation combined with radiosensitizing agents, should be considered in this class of patients.

Purpose: Conformal electron beam therapy can be delivered using shaped bolus, which varies the penetration of the electrons across the incident beam so that the 90% isodose surface conforms to the distal surface of the planning target volume (PTV). Previous use of this modality has shown that the irregular proximal surface of the bolus causes the dose heterogeneity in the PTV to increase from 10%, the typical dose spread of a flat-water surface to approximately 20%. The present work evaluates the ability to restore dose homogeneity by varying the incident electron intensity., Methods and Materials: Three patients, one each with chest wall, thorax, and head-and-neck cancer, were planned using electron conformal therapy with bolus, with and without intensity modulation. Resulting dose distributions and dose-volume histograms were compared with non-intensity-modulated bolus plans., Results: In all cases, the DeltaD(90%-10%) for the PTV was reduced; for example, for the head-and-neck case, the DeltaD(90%-10%) for the PTV was reduced from 14.9% to 9.2%. This reduction in dose spread is a direct result of intensity modulation., Conclusions: The results showed that intensity-modulated electron beams could significantly improve the dose homogeneity in the PTV for patients treated with electron conformal therapy using shaped bolus.

Purpose: To compare the pathologic factors associated with postmastectomy locoregional recurrence (LRR) in breast cancer patients not receiving radiation who were treated with neoadjuvant chemotherapy (NEO) vs. adjuvant chemotherapy (ADJ)., Methods and Materials: We retrospectively analyzed the rates of LRR of subsets of women treated in prospective trials who underwent mastectomy and received chemotherapy but not radiation. These trials were designed to answer chemotherapy questions. There were 150 patients in the NEO group and 1031 patients in the ADJ group. In the NEO group, 55% had clinical Stage IIIA or higher vs. 9% in the ADJ group (p <0.001, chi-square test)., Results: Despite the more advanced clinical stage in the NEO group, the pathologic size of the primary tumor and the number of positive lymph nodes (+LNs) were significantly less in the NEO group than in the ADJ group (p <0.001 for both comparisons). However, the 5-year actuarial LRR rate was 27% for the NEO group vs. 15% for the ADJ group (p = 0.001, log-rank). The 5-year risk for LRR was higher in the NEO patients for all pathologic tumor sizes: 0-2 cm (18% vs. 8%, p = 0.011), 2.1-5 cm (36% vs. 15%, p <0.001), and >5 cm (46% vs. 28%, p = 0.028). The risk of LRR by the number of +LNs was similar in the NEO and ADJ groups, except for the subset of patients with > or =4 +LNs (53% vs. 23%, p <0.001). The rates of LRR in the patients with primary tumors measuring < or =2.0 cm and 1-3 +LNs were similar in both groups. However, for the patients with a pathologic tumor size of 2.1-5.0 cm and 1-3 +LNs, the LRR was higher in the NEO group than in the ADJ group (30% vs. 15%, p = 0.016). Most failures in this NEO subgroup had clinical Stage III disease. In a subset of NEO and ADJ patients matched for clinical stage, no significant differences were found in the rates of LRR according to primary tumor size and number of +LNs when these variables were analyzed independently. Again, however, differences were found in the subgroup of patients with tumors pathologically measuring 2.1-5.0 cm with 1-3 +LNs (32% NEO vs. 8% ADJ, p = 0.030)., Conclusion: The rates of postmastectomy LRR for any pathologic tumor size are higher for patients treated with initial chemotherapy than for patients treated with initial surgery. Radiotherapy should be offered to all patients with > or =4 +LNs, tumor size >5 cm, or clinical Stage IIIA or greater disease, regardless of whether they receive neoadjuvant or postoperative chemotherapy. The information assessing LRR rates in patients with clinical Stage II disease who receive neoadjuvant chemotherapy, particularly if 1-3 lymph nodes remain pathologically involved, is insufficient to determine whether these patients should receive radiotherapy.

Background: Breast-conservation surgery plus radiotherapy has become the standard of care for early-stage breast cancer; we evaluated its long-term complications., Methods: We selected patients treated with surgery and radiotherapy between January 1990 and December 1992 (an era in which standard radiation dosages were used) with follow-up for at least 1 year. Patients were prospectively monitored for treatment-related complications. Median follow-up time was 89 months., Results: A total of 294 patients met the selection criteria. Grade 2 or higher late complications were identified in 29 patients and included arm edema in 13 patients, breast skin fibrosis in 12, decreased range of motion in 4, pneumonitis in 2, neuropathy in 2, fat necrosis in 1, and rib fracture in 1. Arm edema was more common after lumpectomy plus axillary node dissection than after lumpectomy alone. Arm edema occurred in 18% of patients who underwent surgery plus irradiation of the lymph nodes and 10% who underwent surgery without nodal irradiation., Conclusions: Breast-conservation surgery plus radiotherapy was associated with grade 2 or higher complications in only 9.9% of patients. Half of these complications were attributable to axillary dissection, it is hoped that lower complication rates can be achieved with sentinel lymph node biopsy. Breast-conservation surgery and radiotherapy is associated with grade 2 or greater complications in only 9.9% of patients. Nearly half of these complications are attributable to axillary dissection.

Purpose: Paclitaxel has significant antitumor activity in patients with metastaticbreast cancer who have been previously treated with or exposed to anthracycline-containing chemotherapy. In this prospective randomized trial, the role of paclitaxel was evaluated in an adjuvant setting to determine its impact on reducing the risk of recurrence in patients with operable breast cancer., Experimental Design: Five hundred twenty-four patients were randomized to be treated either with 4 cycles of paclitaxel followed by 4 cycles of combination therapy with 5-fluorouracil, Adriamycin, and cyclophosphamide (Pac/FAC) or with 8 cycles of FAC alone. Patients with intact primary breast cancer received the initial 4 cycles of paclitaxel or 4 cycles of FAC in a neoadjuvant setting. Planned duration of therapy was the same in all patients. After completion of 8 cycles of chemotherapy, those patients who were > or =50 years and whose tumors were positive for estrogen receptors received tamoxifen for 5 years., Results: Ninety-two patients have had a recurrence after a median follow-up of 60 months with a range of 5-89 months. Estimated disease-free survival at 48 months was 0.83 for FAC and 0.86 for Pac/FAC group. The difference between the two groups was not statistically significant (P = 0.09). The overall estimated hazard ratio for Pac/FAC compared with FAC derived by fitting the Cox regression model and incorporating terms for prognostic factors was 0.66., Conclusion: Preliminary results suggest that the addition of paclitaxel to a FAC regimen of adjuvant or neoadjuvant therapy may further reduce the risk of disease recurrence; however, differences were not statistically significant. At the time of this analysis, there have been 47 deaths. The survival data are too preliminary to permit meaningful evaluation of the impact of paclitaxel on mortality.

Despite years of clinical study, there are still many unanswered questions regarding postmastectomy radiation. It is clear that radiation therapy plays a critical role in the multidisciplinary management of patients with locally advanced or inflammatory breast cancer. It is also accepted that postmastectomy radiation is not required for most women with noninvasive disease or stage I disease. Randomized clinical trials studying radiation treatments for women with stage II or III breast cancer have shown that the addition of radiation after mastectomy can reduce local-regional recurrence rates, which then improves survival. However, other data have indicated that the risk of local-regional recurrence after mastectomy and chemotherapy is low for patients with small tumors and one to three positive lymph nodes, leading some to question whether postmastectomy radiation is useful for this group. A second controversy regards the sequencing of postmastectomy radiation and breast reconstruction. In this article we discuss these controversies, review the data that are relevant, and provide our institutional approaches to these issues.

Purpose: To define clinical and pathologic predictors of local-regional recurrence (LRR) for patients treated with neoadjuvant chemotherapy and mastectomy without radiation., Patients and Methods: We analyzed the outcome of the 150 breast cancer cases treated on prospective institutional trials with neoadjuvant chemotherapy and mastectomy without postmastectomy radiation. Clinical stage at diagnosis was I in 1%, II in 43%, IIIA in 23%, IIIB in 25%, and IV in 7%. No patient had inflammatory breast cancer., Results: The median follow-up period of surviving patients was 4.1 years. The 5- and 10-year actuarial rates of LRR were both 27%. Pretreatment factors that positively correlated with LRR were increasing T stage (P <.0001) and increasing combined clinical stage (P <.0001). Pathologic and treatment factors that positively correlated with LRR were size of the residual primary tumor (P =.0048), increasing number of involved lymph nodes (P <.0001), and no use of tamoxifen (P =.0013). The LRR rate for the 18 patients with a pathologic complete response of both the primary tumor and lymph nodes (pCR) was 19% (95% confidence interval, 6% to 48%). In a forward stepwise Cox logistic regression analysis, clinical stage IIIB or greater (hazard ratio of 4.5, P <.001), pathologic involvement of four or more lymph nodes (hazard ratio of 2.7, P =.008), and no use of tamoxifen (hazard ratio of 3.9, P =.027) independently predicted for LRR., Conclusion: Advanced disease at presentation and positive lymph nodes after chemotherapy predict for clinically significant rates of LRR. Achievement of pCR does not preclude the need for postmastectomy radiation if warranted by the pretreatment stage of the disease.

Purpose: Postmastectomy irradiation (PMI) is a technically complex treatment requiring consideration of the primary tumor location, possible risk of internal mammary node involvement, varying chest wall thicknesses secondary to surgical defects or body habitus, and risk of damaging normal underlying structures. In this report, we describe the application of a customized three-dimensional (3D) electron bolus technique for delivering PMI., Methods and Materials: A customized electron bolus was designed using a 3D planning system. Computed tomography (CT) images of each patient were obtained in treatment position and the volume to be treated was identified. The distal surface of the wax bolus matched the skin surface, and the proximal surface was designed to conform to the 90% isodose surface to the distal surface of the planning target volume (PTV). Dose was calculated with a pencil-beam algorithm correcting for patient heterogeneity. The bolus was then fabricated from modeling wax using a computer-controlled milling device. To aid in quality assurance, CT images with the bolus in place were generated and the dose distribution was computed using these images., Results: This technique optimized the dose distribution while minimizing irradiation of normal tissues. The use of a single anterior field eliminated field junction sites. Two patients who benefited from this option are described: one with altered chest wall geometry (congenital pectus excavatum), and one with recurrent disease in the medial chest wall and internal mammary chain (IMC) area., Conclusion: The use of custom 3D electron bolus for PMI is an effective method for optimizing dose delivery. The radiation dose distribution is highly conformal, dose heterogeneity is reduced compared to standard techniques in certain suboptimal settings, and excellent immediate outcome is obtained.

Purpose: The purpose of this article is to report dose-volume histograms of coronary vessels from irradiation of the intact left breast., Patients and Methods: Fifteen women with cancer of the left breast underwent computed tomographic treatment planning for radiation treatments of an intact left breast. Images through the heart were reconstructed at 1-mm increments to permit contouring of the coronary vessels. Five treatment plans were created for each patient; one plan from the simulated treatment fields and four additional plans that were generated from virtual treatment fields created by shifting the isocenter 5 mm and 10 mm both superficially and deep. The radiation dose was calculated using a three-dimensional treatment planning system that incorporated heterogeneity correction factors., Results: With no adjustment to the perpendicular lung distance, a mean volume of 12% of the left anterior descending coronary artery received 20 Gy, 6% received 30 Gy, and 3% received 40 Gy. The dose to the left anterior descending coronary artery varied significantly with changes in the perpendicular lung distance. From the mean perpendicular lung distance of 1.87 for the simulated fields, a 5-mm increase in the perpendicular lung distance resulted in an increase of 20%, 15%, and 12% in the percentage of the left anterior descending coronary artery treated to 20 Gy, 30 Gy, and 40 Gy, respectively. With a 10-mm increase, the respective volumes were increased to 49%, 41%, and 34%, respectively. A 5-mm reduction of lung distance in the original plan resulted in a decrease of 10%, 5%, and 3% in the percentage treated to 20 Gy, 30 Gy, and 40 Gy, respectively. The dose to the left main coronary artery, the right main coronary artery, and the left circumflex coronary artery was limited to scatter and was less than 7 Gy. Changes in the perpendicular lung distance did not significantly affect the dose administered to these vessels., Discussion: The left anterior descending coronary artery is anatomically located at the edge of the cardiac silhouette on traditional treatment films. Small changes in the perpendicular lung distance can significantly change the dose delivered to this vessel. A fundamental change in the shape of the dose-volume histogram occurs at a perpendicular lung distance of 2.3 cm, whereas the dose is very low when the perpendicular lung distance is less than 1.3 cm. These points may serve as clinically important values in the treatment planning for cancer of an intact breast.

Purpose: To evaluate the volume of nodal irradiation associated with breast-conserving therapy, we defined the anatomic relationship of sentinel lymph nodes and axillary level I and II lymph nodes in patients receiving tangential breast irradiation., Methods and Materials: A retrospective analysis of 65 simulation fields in women with breast cancer treated with sentinel lymph node surgery and 39 women in whom radiopaque clips demarcated the extent of axillary lymph node dissection was performed. We measured the relationship of the surgical clips to the anatomic landmarks and calculated the percentage of prescribed dose delivered to the sentinel lymph node region., Results: A cranial field edge 2.0 cm below the humeral head the sentinel lymph node region was included or at the field edge in 95% of the cases and the entire extent of axillary I and II dissection in 43% of the axillary dissection cases. In the remaining 57%, this field border encompassed an average of 80% of cranial/caudal extent of axillary level I and II dissection. In 98.5% of the cases, all sentinel lymph nodes were anterior to the deep field edge and 71% were anterior to the chest wall-interface, whereas 61% of the axillary dissection cohort had extension deep to the chest wall-lung interface. If the deep field edge had been set 2 cm below the chest wall-lung interface, the entire axillary dissection would have been included in 82% of the cases, and the entire sentinel lymph node would have been covered with a 0.5-cm margin. The median dose to the sentinel lymph node region was 98% of the prescribed dose., Conclusions: By extending the cranial border to 2 cm below the humeral head and 2 cm deep to the chest wall-lung interface, the radiotherapy fields used to treat the breast can include the sentinel lymph node region and most of axillary levels I and II.

Purpose: The objective of this study was to evaluate the influence of pathologic factors other than tumor size and number of involved axillary nodes on the risk of locoregional recurrence (LRR) following mastectomy., Patients and Methods: We reviewed the medical records of 1031 patients treated with mastectomy and doxorubicin-based chemotherapy without radiation on 5 prospective clinical trials. Median follow-up was 116 months (range, 6-262 months)., Results: Patients with gross multicentric disease were at increased risk of LRR (37% at 10 years). However, patients with multifocal disease and those with microscopic multicentric disease did not experience higher rates of LRR than those with single lesions (17% at 10 years). Patients with lymph-vascular space invasion (LVSI) or involvement of the skin or nipple also experienced high rates of LRR (25%, 32%, and 50%, respectively). The presence of close (<5 mm) or positive margins was associated with an increased risk of LRR (45%). The increased risk of LRR observed for patients with pectoral fascial invasion (33%) was not reduced when negative deep margins were obtained. On multivariate analysis, the presence of 4 or more involved axillary nodes, tumor size of greater than 5 cm, close or positive surgical margins, and gross multicentric disease were found to be independent predictors of LRR (all, p < 0.01). In a separate analysis including only patients with 1-3 involved axillary nodes, microscopic invasion of the skin or nipple, pectoral fascial invasion, and the presence of close or positive margins were significant predictors of LRR., Conclusion: In addition to the extent of primary and nodal disease, other factors that predict for high rates of LRR include the presence of LVSI, involvement of the skin, nipple or pectoral fascia, close or positive margins, or gross multicentric disease. These factors predict for high LRR rates regardless of the number of involved axillary nodes.

Purpose: Postmastectomy irradiation improves overall survival for breast cancer patients at high risk for locoregional recurrence (LRR). The objective of this study was to use recursive partitioning analysis (RPA) to define patient subgroups at high risk for LRR following mastectomy., Patients and Methods: A cohort of 1031 patients treated on prospective trials with mastectomy and doxorubicin-based chemotherapy without irradiation was analyzed. The variables considered in the RPA were tumor size, number of involved nodes, number of nodes examined, and percentage of nodes involved (nodes involved/nodes examined). The endpoint was LRR +/- distant metastasis. Only patients with complete data were analyzed (n = 913). Median follow-up was 8 years (range, 0.7-22 years)., Results: Involvement of 20% or more of the lymph nodes examined was the most significant variable predicting LRR. Three risk categories were defined. Patients with 20% or more involved nodes and tumors of 3.5 cm or more were at greatest risk for LRR (41% at 8 years). An intermediate-risk group included patients with 20% or more involved nodes and tumors of less than 3.5 cm as well as those with less than 20% involved nodes and tumor size of 5 cm or greater (18% at 8 years). Patients with less than 20% involved nodes and tumor size of less than 5 cm were at lowest risk for LRR (10% at 8 years)., Conclusion: Tumor size and extent of nodal involvement play interrelated roles in predicting LRR following mastectomy and systemic therapy. Patients with 20% or greater involved nodes and those with less than 20% nodes and tumors of 5.0 cm or greater are at significant risk of LRR and should be considered for postoperative irradiation.

Purpose: To determine the impact of tamoxifen and chemotherapy on local control for breast cancer patients treated with breast-conservation therapy., Patients and Methods: The data from 484 breast cancer patients who were treated with breast-conserving surgery and radiation were analyzed. Only patients with lymph node-negative disease were studied to provide comparative groups with a similar stage of disease and a similar competing risk for distant metastases. Actuarial local control rates of the 277 patients treated with systemic therapy (128, chemotherapy with or without tamoxifen; 149, tamoxifen alone) were compared with the rates for the 207 patients who received no systemic treatment. Only 10% of the patients had positive (2%), close (3%), or unknown margin status (5%)., Results: Patients treated with systemic therapy had improved 5-year (97.5% v 89.8%) and 8-year (95.6% v 85.2%) local control rates compared with those that did not receive systemic treatment (P =.004, log-rank test). There was no statistical difference in local control between patients treated with chemotherapy and patients treated with tamoxifen alone (P =.219). Systemic treatment, margin status, young patient age, estrogen and progesterone receptor status, and primary tumor size were analyzed in a Cox regression analysis. The use of systemic treatment was the most powerful predictor of local control: patients who did not receive systemic treatment had a relative risk of local recurrence of 3.3 (95% confidence interval, 1.5 to 7.5; P =.004)., Conclusion: In this retrospective analysis, systemic therapy appears to contribute to long-term local control in patients with lymph node-negative breast cancer treated with breast-conservation therapy.

Background: Macromastia has been considered a contraindication to breast conservation therapy because of difficulties with radiation therapy. This study evaluates the feasibility of bilateral reduction mammoplasty as a component of breast conservation therapy for breast cancer patients with pendulous breasts., Methods: Of 153 patients undergoing reduction mammoplasty at the University of Texas M. D. Anderson Cancer Center, 28 were identified as breast cancer patients with macromastia receiving breast conservation therapy. Median follow-up was 23.8 months., Results: Median patient age was 55 years. Nearly all patients were described as obese. Median weight of the reduction mammoplasty specimen on the cancerous side was 766 g. One patient (4%) required completion mastectomy for inadequate margin control. Major postoperative complications occurred in 2 patients (7%). There were no major postradiation complications. Patient survey revealed a satisfaction rate of 86%., Conclusion: Bilateral reduction mammoplasty is a reasonable and safe option for breast cancer patients with macromastia who desire breast conservation therapy.

Purpose: Local control rates for breast cancer in genetically predisposed women are poorly defined. Because such a small percentage of breast cancer patients have proven germline mutations, surrogates, such as a family history for breast cancer, have been used to examine this issue. The purpose of this study was to evaluate local-regional control following breast conservation therapy (BCT) in patients with bilateral breast cancer and a breast cancer family history., Methods and Materials: We retrospectively reviewed records of all 58 patients with bilateral breast cancer and a breast cancer family history treated in our institution between 1959 and 1998. The primary surgical treatment was a breast-conserving procedure in 55 of the 116 breast cancer cases and a mastectomy in 61. The median follow-up was 68 months for the BCT patients and 57 months for the mastectomy-treated patients., Results: Eight local-regional recurrences occurred in the 55 cases treated with BCT, resulting in 5- and 10-year actuarial local-regional control rates of 86% and 76%, respectively. In the nine cases that did not receive radiation as a component of their BCT, four developed local-regional recurrences (5- and 10-year local-regional control rates of BCT without radiation: 49% and 49%). The 5- and 10-year actuarial local-regional control rates for the 46 cases treated with BCT and radiation were 94% and 83%, respectively. In these cases, there were two late local recurrences, developing at 8 years and 9 years, respectively. A log rank comparison of radiation versus no radiation actuarial data was significant at p = 0.009. In the cases treated with BCT, a multivariate analysis of radiation use, patient age, degree of family history, margin status, and stage revealed that only the use of radiation was associated with improved local control (Cox regression analysis p = 0.021). The 10-year actuarial rates of local-regional control following mastectomy with and without radiation were 91% and 89%, respectively., Conclusions: Patients with a possible genetic predisposition to breast cancer had low 5-year rates of local recurrence when treated with breast conserving surgery and radiation, but the local failure rate exceeded 50% when radiation was omitted. Our data are consistent with the hypothesis that patients with an underlying genetic predisposition develop cancers with radiosensitive phenotypes.

Background: Cystosarcoma phyllodes is a rare sarcoma of the breast. Although surgical removal is the mainstay of treatment, the extent of surgery required (excision vs. mastectomy) and the need for additional local therapy, such as radiotherapy, are unclear. The current study evaluated the rate of local and distant failure, as well as potential prognostic factors, to better define appropriate treatment strategies., Methods: One hundred one patients treated primarily for cystosarcoma phyllodes of the breast were evaluated. These tumors were classified histologically into benign (58%), indeterminate (12%), and malignant (30%) based on well defined criteria. Stromal overgrowth (29%) was considered separately. Surgery was comprised of local excision with breast conservation (47%) or mastectomy (53%). Microscopic surgical margins were negative in 99% of cases. Six patients received adjuvant radiotherapy., Results: Overall survival for the 101 patients was 88%, 79%, and 62% at 5, 10, and 15 years, respectively. For patients with nonmalignant (benign or indeterminate) and malignant cystosarcoma phyllodes, the overall survival was 91% and 82%, respectively, at 5 years, and 79% and 42%, respectively, at 10 years. Similar rates were observed based on the presence or absence of stromal overgrowth. Local recurrence occurred in 4 patients, with an actuarial 10-year rate of 8%. Eight patients developed distant metastases, with an actuarial 10-year rate of 13%. Multivariate analysis using Cox proportional hazards regression revealed stromal overgrowth to be the only independent predictor of distant failure., Conclusions: Local failure in this group of largely margin negative patients with cystosarcoma phyllodes of the breast was low, showing that breast-conserving surgery with appropriate margins is the preferred primary therapy. The current study data do not support the use of adjuvant radiotherapy for patients with adequately resected disease. Patients with stromal overgrowth, particularly when the tumor size was > 5 cm, were found to have a high rate of distant failure; such patients merit consideration of a trial that examines the efficacy of systemic therapy.

Background: The role of breast-conserving therapy (BCT) in the management of ductal carcinoma-in-situ (DCIS) is controversial because of reported high recurrence rates. We reviewed our experience to determine whether the rate and pattern of locoregional recurrence after BCT were similar in patients with DCIS and patients with early-stage (T1) invasive breast tumors and whether local recurrence affected survival., Methods: Between 1973 and 1994, 87 patients with DCIS alone, 22 patients with DCIS with microinvasion (DCIS-M), and 646 patients with invasive breast cancer 2 cm or smaller in diameter were treated with BCT (wide local excision with radiotherapy) at The University of Texas M. D. Anderson Cancer Center. Survival was calculated by the Kaplan-Meier method. The median follow-up times were 11 years for patients with DCIS alone, 12 years for patients with DCIS-M, and 8 years for patients with invasive breast cancer., Results: Eleven (13%) of 87 patients with DCIS and 5 (23%) of 22 patients with DCIS-M had developed locoregional recurrences at follow-up. Two patients with DCIS with locoregional recurrence died of breast cancer. Of the 646 patients with invasive breast cancer, 56 (9%) had a locoregional recurrence, and 16 (2%) died of breast cancer. The median time to locoregional recurrence was significantly longer in patients with DCIS or DCIS-M (9-10 years) than patients with invasive tumors (5 years)., Conclusions: DCIS is a favorable disease with an excellent long-term survival. The locoregional recurrence rate in patients with DCIS treated with BCT is similar to that in patients with early-stage invasive breast cancer treated with BCT, but time to locoregional recurrence is significantly longer in patients with DCIS. In patients with DCIS treated with BCT, intense surveillance for locoregional recurrence needs to be maintained for the patient's lifetime.

Purpose: The objective of this study was to determine locoregional recurrence (LRR) patterns after mastectomy and doxorubicin-based chemotherapy to define subgroups of patients who might benefit from adjuvant irradiation., Patients and Methods: A total of 1,031 patients were treated with mastectomy and doxorubicin-based chemotherapy without irradiation on five prospective trials. Median follow-up time was 116 months. Rates of isolated and total LRR (+/- distant metastasis) were calculated by Kaplan-Meier analysis., Results: The 10-year actuarial rates of isolated LRR were 4%, 10%, 21%, and 22% for patients with zero, one to three, four to nine, or >/= 10 involved nodes, respectively (P <.0001). Chest wall (68%) and supraclavicular nodes (41%) were the most common sites of LRR. T stage (P <.001), tumor size (P <.001), and >/= 2-mm extranodal extension (P <.001) were also predictive of LRR. Separate analysis was performed for patients with T1 or T2 primary disease and one to three involved nodes (n = 404). Those with fewer than 10 nodes examined were at increased risk of LRR compared with those with >/= 10 nodes examined (24% v 11%; P =.02). Patients with tumor size greater than 4.0 cm or extranodal extension >/= 2 mm experienced rates of isolated LRR in excess of 20%. Each of these factors continued to significantly predict for LRR in multivariate analysis by Cox logistic regression., Conclusion: Patients with tumors >/= 4 cm or at least four involved nodes experience LRR rates in excess of 20% and should be offered adjuvant irradiation. Additionally, patients with one to three involved nodes and large tumors, extranodal extension >/= 2 mm, or inadequate axillary dissections experience high rates of LRR and may benefit from postmastectomy irradiation.

Purpose: To evaluate the effect of radiation dose escalation on locoregional control, overall survival, and long-term complication in patients with inflammatory breast cancer., Patients and Methods: From September 1977 to December 1993, 115 patients with nonmetastatic inflammatory breast cancer were treated with curative intent at The University of Texas M. D. Anderson Cancer Center. The usual sequence of multimodal treatment consisted of induction FAC or FACVP chemotherapy, mastectomy (if the tumor was operable), further chemotherapy, and radiation therapy to the chest wall and draining lymphatics. Sixty-one patients treated from September 1977 to September 1985 received a maximal radiation dose of 60 Gy to the chest wall and 45-50 Gy to the regional lymph nodes, 22 treated once a day at 2 Gy per fraction, and 35 were treated b.i.d. (32 after mastectomy and all chemotherapy was completed, and 2 immediately after mastectomy; one patient had distant metastases discovered during b.i.d. irradiation, and treatment was stopped). Four additional patients received preoperative radiation with standard fractionation. Based on the analysis of the failure patterns of the patients, the dose was increased for the b.i.d. patients in the new series, with 51 Gy delivered to the chest wall and regional nodes, followed by a 15-Gy boost to the chest wall with electrons. From January 1986 to December 1993, 39 patients were treated b.i.d. to this higher dose after mastectomy and all the chemotherapy was completed; and 8 additional patients received preoperative irradiation with b.i.d. fractionation to 51 Gy. During this period, another 7 patients were treated using standard daily doses of 2 Gy per fraction to a total of 60 Gy, either because they had a complete response or minimal residual disease at mastectomy or because their work schedule did not permit the b.i.d. regimen. Comparison was made between the groups for locoregional control, disease-free and overall survival, and complication rates., Results: The median follow-up time was 5.7 years (range, 1.8-17.6 years). For the entire patient group, the 5- and 10-year local control rates were 73.2% and 67.1%, respectively. The 5- and 10-year disease-free survival rates were 32.0% and 28.8%, respectively, and the overall survival rates for the entire group were 40.5% and 31.3%, respectively. To evaluate the effectiveness of dose escalation, a specific comparison of patients who received b.i.d. radiation after mastectomy and completion of adjuvant chemotherapy was performed. There were 32 patients treated b.i.d. to 60 Gy in the old series versus 39 patients treated b.i.d. to 66 Gy in the new series. There was an significant improvement in the rate of locoregional control for the b.i.d. patients for the old vs. new series, from 57.8% to 84.3% and from 57.8% to 77.0% (p = 0.028) at 5 and 10 years, respectively. Chemotherapy regimens did not change significantly during this time period.Long-term complications of radiation, such as arm edema more than 3 cm (7 patients), rib fracture (10 patients), severe chest wall fibrosis (4 patients), and symptomatic pneumonitis (5 patients), were comparable in the two groups, indicating that the dose escalation did not result in increased morbidity. Significant differences in the rates of locoregional control (p = 0.03) and overall survival (p = 0.03), and a trend of better disease-free survival (p = 0.06) were also observed that favored the recently treated patients receiving the higher doses of irradiation., Conclusion: Twice-daily postmastectomy radiation to a total of 66 Gy for patients with inflammatory breast cancer resulted in improved locoregional control, disease free survival, and overall survival, and was well tolerated.