Assessing the relative impact of lupus nephritis on mortality in a population-based systemic lupus erythematosus cohort.

OBJECTIVE: There is limited knowledge on the relative impact of lupus nephritis (LN) on morbidity and mortality in population-based systemic lupus erythematous (SLE) cohorts. Here, the primary aim was to compare mortality rates between patients with and without LN in a population-based SLE cohort. METHODS: The study cohort included all SLE patients resident in the city of Oslo during 1999-2008. Follow-up time was median 14 (0-15) years. Presence of LN was defined according to the 1987 American College of Rheumatology classification criteria for SLE. LN class was determined by renal biopsy. Data on kidney function, including presence of end-stage renal disease (ESRD), were obtained from patient charts. Standardized mortality ratios (SMRs) were estimated by comparing deaths in the SLE cohort with age- and gender-matched population controls. RESULTS: We found that 98/325 SLE patients (30%) developed LN, 92% of whom had occurrence within the first five years from disease onset. Incidence rate of ESRD was 2.3 per 1000 patient-years. A total of 56 deaths occurred during the study period, corresponding to an overall SMR in the SLE cohort of 2.1 (95% confidence interval (CI) 1.2-3.4). Estimated SMR for LN patients was 3.8 (95% CI 2.1-6.2), and for SLE patients without LN it was 1.7 (95% CI 0.9-2.7). CONCLUSION: In this population-based SLE cohort, we found that LN was associated with increased morbidity and mortality, whereas SLE patients who did not develop LN had good overall prognoses regarding survival.

Single organ metastatic sites in non-small cell lung cancer: Patient characteristics, treatment patterns and outcomes from a large retrospective Canadian cohort.

BACKGROUND: There is a paucity of information about the characteristics, treatment patterns, and outcomes of non-small cell lung cancer (NSCLC) patients with single organ metastasis (SOM). METHODS: This retrospective cohort study includes all patients with a diagnosis of stage IV NSCLC diagnosed from 2014 to 2016 and treated at Princess Margaret Cancer Centre. We compared baseline characteristics and patterns of metastatic sites between patients with SOM versus multiple (M)OM. Additionally, we identified treatment modalities and outcomes for patients with SOM. Cox multivariable models (MVA) were utilized to evaluate differences in overall survival (OS) between the SOM and MOM cohorts. RESULTS: Of 893 pts analyzed, 457 (51 %) had SOM, while 436 (49 %) had MOM at initial diagnosis. Demographics were comparable between the two groups. Brain was the most common site of metastasis for SOM patients. When compared to the MOM group, the SOM group had lower percentages of liver and adrenal metastases. Amongst SOM patients, 54 % received single modality treatment, and 20 % did not receive any treatment for their SOM. In MVA, patients with liver (HR 2.4), bone (HR 1.8), and pleural (HR 1.7) metastasis as their SOM site had the worst outcomes, with median OS of 6.8 months, 12.1 months, and 13.0 months respectively. Patients with SOM had a significantly improved median OS compared to those with MOM (15.9 months vs. 10.6 months; HR 0.56, 95 % CI 0.47-0.66, p < 0.001). CONCLUSION: In NSCLC patients who presented with SOM, survival correlated with the initial organ involved and was better overall compared to patients with MOM. SOM NSCLC may benefit from specific management strategies and SOM patients could be considered as a specific subgroup for survival analyses in observational and non-randomized interventional studies. In clinical trials, SOM can be considered as a stratification factor in the future.

Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway.

Identification of unique features of cancer cells is important for defining specific and efficient therapeutic targets. Mutant p53 is present in nearly half of all cancer cases, forming a promising target for pharmacological reactivation. In addition to being defective for the tumor-suppressor function, mutant p53 contributes to malignancy by blocking a p53 family member p73. Here, we describe a small-molecule RETRA that activates a set of p53-regulated genes and specifically suppresses mutant p53-bearing tumor cells in vitro and in mouse xenografts. Although the effect is strictly limited to the cells expressing mutant p53, it is abrogated by inhibition with RNAi to p73. Treatment of mutant p53-expressing cancer cells with RETRA results in a substantial increase in the expression level of p73, and a release of p73 from the blocking complex with mutant p53, which produces tumor-suppressor effects similar to the functional reactivation of p53. RETRA is active against tumor cells expressing a variety of p53 mutants and does not affect normal cells. The results validate the mutant p53-p73 complex as a promising and highly specific potential target for cancer therapy.

[Transcriptional inhibition of human papilloma virus in cervical carcinoma cells reactivates functions of the tumor suppressor p53].

Inactivation of tumor suppressor p53 accompanies the majority of malignant diseases in humans. Restoration of p53 functions in tumor results in death of cancer cells, which can be used in cancer therapy. In cervical cancer a product of E6 gene of the human papilloma virus promotes accelerated degradation of p53 in proteasome system. Therefore, one of the approaches to reactivation of p53 in cervical carcinoma cells could be the use of small molecules that inhibit functions of viral proteins. By using as a test system human cervical carcinoma cells (HeLa cell line bearing human papilloma virus type 18, HPV-18) with introduced reporter construct that expresses beta-galactosidase under control of a p53-dependent promoter we carried out screening of a library of small molecules to select small molecules capable of reactivating transcriptional activity of p53. We then characterized the effects of two most active compounds in cell lines that differ in the status of p53-dependent signaling pathway. Both of the compounds caused specific activation of p53 in the cell lines expressing HPV-18, to a lesser extent--HPV-16, and do not cause any effect in control p53 negative cells, or in the cells with undisrupted p53 pathway. Activation of p53 in cervical carcinoma cells was accompanied by the induction of the p53-dependent gene CDKN1 (p21), by inhibition of proliferation, and by the induction of apoptosis. Both of the compounds were capable of deep inhibition of transcription from the HPV genome, which apparently was the cause for p53 reactivation in response to decreased expression of the E6 protein. The observed low toxicity for normal cells allows considering these chemical compounds as prototypes for future anticancer drugs.

Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma.

BACKGROUND: Uncontrolled studies have reported encouraging outcomes for patients with high-risk primary breast cancer treated with high-dose chemotherapy and autologous hematopoietic stem cell support. We conducted a prospective randomized trial to compare standard-dose chemotherapy with the same therapy followed by high-dose chemotherapy. PATIENTS AND METHODS: Patients with 10 or more positive axillary lymph nodes after primary breast surgery or patients with four or more positive lymph nodes after four cycles of primary (neoadjuvant) chemotherapy were eligible. All patients were to receive eight cycles of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC). Patients were stratified by stage and randomly assigned to receive two cycles of high-dose cyclophosphamide, etoposide, and cisplatin with autologous hematopoietic stem cell support or no additional chemotherapy. Tamoxifen was planned for postmenopausal patients with estrogen receptor-positive tumors and chest wall radiotherapy was planned for all. All P values are from two-sided tests. RESULTS: Seventy-eight patients (48 after primary surgery and 30 after primary chemotherapy) were registered. Thirty-nine patients were randomly assigned to FAC and 39 to FAC followed by high-dose chemotherapy. After a median follow-up of 6.5 years, there have been 41 relapses. In intention-to-treat analyses, estimated 3-year relapse-free survival rates were 62% and 48% for FAC and FAC/high-dose chemotherapy, respectively (P =.35), and 3-year survival rates were 77% and 58%, respectively (P =.23). Overall, there was greater and more frequent morbidity associated with high-dose chemotherapy than with FAC; there was one septic death associated with high-dose chemotherapy. CONCLUSIONS: No relapse-free or overall survival advantage was associated with the use of high-dose chemotherapy, and morbidity was increased with its use. Thus, high-dose chemotherapy is not indicated outside a clinical trial.

Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience.

PURPOSE: To determine outcomes in local-regional control, disease-free survival, and overall survival in patients with locally advanced breast cancer (LABC) who present with ipsilateral supraclavicular metastases and who are treated with combined-modality therapy. PATIENTS AND METHODS: Seventy patients with regional stage IV LABC, which is defined by our institution as LABC with ipsilateral supraclavicular adenopathy without evidence of distant disease, received treatment on three prospective trials of neoadjuvant chemotherapy. All patients received neoadjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil, or cyclophosphamide, doxorubicin, vincristine, and prednisone. Patients then received local therapy that consisted of either total mastectomy and axillary lymph node dissection (ALND) or segmental mastectomy and ALND before or after irradiation. Patients with no response to neoadjuvant chemotherapy were treated with surgery and/or radiotherapy. After completion of local therapy, chemotherapy was continued for four to 15 cycles, followed by radiotherapy. Patients older than 50 years who had estrogen receptor-positive tumors received tamoxifen for 5 years. RESULTS: Median follow-up was 11.6 years (range, 4.8 to 22.6 years). Disease-free survival rates at 5 and 10 years were 34% and 32%, respectively. The median disease-free survival was 1.9 years. Overall survival rates at 5 and 10 years were 41% and 31%, respectively. The median overall survival was 3.5 years. The overall response rate (partial and complete responses) to induction chemotherapy was 89%. No treatment-related deaths occurred. CONCLUSION: Patients with ipsilateral supraclavicular metastases but no other evidence of distant metastases warrant therapy administered with curative intent, ie, combined-modality therapy consisting of chemotherapy, surgery, and radiotherapy. Patients with ipsilateral supraclavicular metastases should be included in the stage IIIB category of the tumor-node-metastasis classification because their clinical course and prognosis are similar to those of patients with stage IIIB LABC.

Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: implications for postoperative irradiation.

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.

Impact of systemic treatment on local control for patients with lymph node-negative breast cancer treated with breast-conservation therapy.

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.

Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer.

PURPOSE: To compare prospectively the antitumor activity of single-agent paclitaxel to the three-drug combination of fluorouracil, doxorubicin, and cyclophosphamide (FAC) as neoadjuvant therapy in patients with operable breast cancer. PATIENTS AND METHODS: Patients with T1-3N0-1M0 disease were randomized to receive either paclitaxel (250 mg/m(2)) as 24-hour infusion or FAC in standard doses at every-3-week intervals. Each patient was treated with four cycles of preoperative chemotherapy. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after four cycles of induction chemotherapy. RESULTS: A total of 174 patients were registered, and 87 were randomized to each arm of the study. Clinical response, ie, complete and partial responses, was similar in both arms of the study. Three patients in the FAC arm and one patient in the paclitaxel subgroup had progressive disease. The extent of residual disease by intent-to-treat analysis at the time of surgery was similar between the two arms of the study. CONCLUSION: The results of this prospective study demonstrated that single-agent paclitaxel as neoadjuvant therapy has significant antitumor activity, and this was clinically comparable to FAC. Similar fractions of patients had clinical complete and partial responses, and very few patients had no response to either therapy. The value of alternate non-cross-resistant therapies as used in this protocol on the clinical course of this disease would require longer follow-up.

Methylobacillus flagellatus KT contains a novel cbo-type cytochrome oxidase.

The o-type oxidase from the methanol-grown obligate methylotroph Methylobacillus flagellatus KT has been purified to homogeneity. The complex is composed of four subunits (57, 40, 35 and 30 kDa). It contains six haems (4C:1B:1O) and one copper atom per molecule. It is proposed that the haem O-Cu(B) binuclear centre and a low-spin haem B are located in subunit I (57 kDa), two haems C reside in the cytochrome c homodimer (35 kDa), two haems C belong to the dihaem cytochrome c (30 kDa). The presented data provide evidence that cytochrome cbo is a novel representative of the haem-copper oxidase superfamily.

Postmastectomy irradiation: rationale for treatment field selection.

The goal of postmastectomy irradiation is to eliminate residual viable tumor in tissue remaining after standard mastectomy. Because this subclinical disease is, by definition, not detectable by current technology, the choice of patients and treatment volumes for postmastectomy irradiation must be inferred from a variety of data sources. The absolute risk of locoregional recurrence is related to the stage of disease, the extent of lymphatic involvement, and other treatment received. Patterns of failure analyses consistently identify the chest wall as the most important target for treatment with radiation therapy in high-risk patients. When patients with multiple locoregional sites of recurrence are included, the chest wall may be involved in as many as 60% to 80% of patients. The second most common place for locoregional failure is the undissected lymphatics of the paraclavicular region. The cumulative probability of failure in this region ranges from 10% to 35% of the patients treated for locoregional recurrence. Microscopic tumor metastases in the internal mammary chain are theorized to represent a potential source for distant metastases. Each of the prospective trials of postmastectomy irradiation that have shown survival benefit included the internal mammary chain within their target volume. Nonetheless, local failure in the internal mammary nodes is an uncommon finding. Similarly, after a level I and II axillary dissection, axillary failure is a minor component of local recurrence risk, and it is probable that only a subset of patients may benefit from axillary irradiation.

Whole brain irradiation for patients with metastatic melanoma: a review of 87 cases.

PURPOSE: We have conducted a retrospective study of the use of whole brain irradiation (WBI) for melanoma patients with brain metastases. The purpose of the study was to obtain a description of the population offered this form of treatment, an overview of radiation doses and schedules, an assessment of palliative effect, and survival. METHODS AND MATERIALS: A database of melanoma patients diagnosed with brain metastases was searched to identify patients who had received WBI and for whom adequate documentation existed. Data regarding demographics, treatment, and survival were compiled. RESULTS: Information was obtained for 87 patients. Ninety-five percent of the patients received total doses of at least 30 Gy. The frequent use of corticosteroids during treatment made it difficult to assess palliative effect. However, 52% of all patients and 48% of symptomatic patients were able to discontinue corticosteroid therapy upon completion of irradiation, suggesting that some degree of control or palliation had been obtained. In the small number of patients with postradiotherapy imaging studies, it was not uncommon to see stability or shrinkage of tumors. The median survival of the entire group was 19 weeks. Improved survival was noted for patients who underwent resection of all brain metastases (45 weeks) and for those with no extracranial disease (54 weeks). CONCLUSION: WBI may provide palliation for a portion of melanoma patients with brain metastasis. The outcome of these patients, however, is dominated by the aggressive nature of their systemic disease. These data serve as a baseline for comparison of new approaches for management of brain metastases from melanoma.

The influence of pathologic tumor characteristics on locoregional recurrence rates following mastectomy.

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.

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.

A custom three-dimensional electron bolus technique for optimization of postmastectomy irradiation.

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.

Recursive partitioning analysis of locoregional recurrence patterns following mastectomy: implications for adjuvant irradiation.

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.

Locoregional irradiation for inflammatory breast cancer: effectiveness of dose escalation in decreasing recurrence.

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.

Local-regional control of recurrent breast carcinoma after mastectomy: does hyperfractionated accelerated radiotherapy improve local control?

PURPOSE: Hyperfractionated, accelerated radiotherapy (HART) has been advocated for patients with local-regionally recurrent breast cancer because it is believed to enhance treatment effects in rapidly proliferating or chemoresistant tumors. This report examines the value of HART in patients with local-regionally recurrent breast cancer treated with multimodality therapy. METHODS AND MATERIALS: The study included 148 patients with local-regionally recurrent breast cancer after mastectomy, who were treated with definitive local irradiation and systemic therapy consisting of either tamoxifen, cytotoxic chemotherapy, or both, along with excision of the recurrent tumor when possible. Patients with distant metastases were excluded, except for two patients with ipsilateral supraclavicular nodal metastases. Patients received comprehensive irradiation to the chest wall and regional lymphatics to a median dose of 45 Gy, with a boost to 60 Gy to areas of recurrence. Sixty-eight patients (46%) were treated once daily at 2 Gy/fraction (fx), and 80 (54%) were treated twice daily at 1.5 Gy/fx. Forty-eight patients (32%), who had palpable gross disease that was unresponsive to systemic therapy and/or unresectable, were irradiated. The median follow-up time of surviving patients was 78 months. RESULTS: Overall actuarial local-regional control (LRC) rates at 5 and 10 years were 68% and 55%, respectively. Five- and ten-year actuarial overall survival (OS) and disease-free survival (DFS) rates were 50% and 35%, 39% and 29%, respectively. Univariate analysis revealed that LRC was adversely affected by 1. advanced initial American Joint Committee on Cancer (AJCC) stage (p = 0.001), 2. clinically evident residual disease at time of treatment (p < 0.0001), 3. more than three positive nodes at initial mastectomy (p = 0.014), 4. short interval from mastectomy to recurrence (< 24 months, p = 0.0007), 5. nuclear grade (III vs. I or II, p = 0.045), and 6. number of recurrent nodules (1 vs. > 1, p = 0.02). Patient age at time of recurrence (< 40 vs. > or = 40 years), recurrence location on the chest wall, estrogen receptor status, progesterone receptor status or menopausal status did not adversely affect LRC. On multivariate analysis, only clinically evident residual disease at the time of treatment and short interval from mastectomy to recurrence remained significant. When once-a-day irradiation was compared to the twice-a-day schedule, no significant differences were seen in LRC (67% vs. 68%), OS (47% vs. 52%), or DFS (42% vs. 36%) for the entire group of patients at 5 years. Pairwise comparison of the two fractionation schedules in each of the adverse outcome subgroups identified above showed no clinically significant differences in LRC at 5 years. For the 48 patients who began radiotherapy with measurable gross local recurrence, the complete response rate to radiotherapy was 73%, with no difference seen between the two fractionation schedules. The incidence of acute and chronic radiation-related complications was similar in both treatment groups. CONCLUSIONS: Hyperfractionated accelerated radiotherapy, although well tolerated by patients with local-regionally recurrent breast cancer, did not result in superior local-regional control rates when compared to daily fractionated regimens. Alternative strategies, such as dose escalation or chemoradiation, may be required to improve control.

Local-regional control in breast cancer patients with a possible genetic predisposition.

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.