Pathologic complete response to neoadjuvant chemotherapy with trastuzumab predicts for improved survival in women with HER2-overexpressing breast cancer.

BACKGROUND: We sought to determine the prognostic value of pathologic response to neoadjuvant chemotherapy with concurrent trastuzumab. PATIENTS AND METHODS: Two hundred and twenty-nine women with HER2/neu (HER2)-overexpressing breast cancer were treated with neoadjuvant chemotherapy plus trastuzumab between 2001 and 2008. Patients were grouped based on pathologic complete response (pCR, n = 114) or less than pCR (

Identifying factors that impact survival among women with inflammatory breast cancer.

BACKGROUND: The objective of this retrospective study was to determine factors impacting survival among women with inflammatory breast cancer (IBC). METHODS: The Surveillance, Epidemiology and End Results Registry (SEER) was searched to identify women with stage III/IV IBC diagnosed between 2004 and 2007. IBC was identified within SEER as T4d disease as defined by the sixth edition of the American Joint Committee on Cancer. The Kaplan-Meier product-limit method was used to describe inflammatory breast cancer-specific survival (IBCS). Cox models were fitted to assess the multivariable relationship of various patient and tumor characteristics and IBCS. RESULTS: Two thousand three hundred and eighty-four women with stage IIIB/C and IV IBC were identified. Two-year IBCS among women with stage IIIB, IIIC and IV disease was 81%, 67% and 42%, respectively (P < 0.0001). In the multivariable model, patients with stage IIIB disease and those with stage IIIC disease had a 63% [hazard ratio (HR) 0.373, 95% confidence interval (CI) 0.296-0.470, P < 0.001] and 31% (HR 0.691, 95% CI 0.512-0.933, P = 0.016) decreased risk of death from IBC, respectively, compared with women with stage IV disease. Other factors significantly associated with decreased risk of death from IBC included low-grade tumors, being of white/other race, undergoing surgery, receiving radiation therapy and hormone receptor-positive disease. Among women with stage IV disease, those who underwent surgery of their primary had a 51% decreased risk of death compared with those who did not undergo surgery (HR = 0.489, 95% CI 0.339-0.704, P < 0.0001). CONCLUSIONS: Although IBC is an aggressive subtype of locally advanced breast cancer, it is heterogeneous with various factors affecting survival. Furthermore, our results indicate that a subgroup of women with stage IV IBC may benefit from aggressive combined modality management.

Multifocality and multicentricity in breast cancer and survival outcomes.

BACKGROUND: The clinicopathological characteristics and the prognostic significance of multifocal (MF) and multicentric (MC) breast cancers are not well established. PATIENTS AND METHODS: MF and MC were defined as more than one lesion in the same quadrant or in separate quadrants, respectively. The Kaplan-Meier product limit was used to calculate recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes. RESULTS: Of 3924 patients, 942 (24%) had MF (n = 695) or MC (n = 247) disease. MF/MC disease was associated with higher T stages (T2: 26% versus 21.6%; T3: 7.4% versus 2.3%, P < 0.001), grade 3 disease (44% versus 38.2%, P < 0.001), lymphovascular invasion (26.2% versus 19.3%, P < 0.001), and lymph node metastases (43.1% versus 27.3%, P < 0.001). MC, but not MF, breast cancers were associated with a worse 5-year RFS (90% versus 95%, P = 0.02) and BCSS (95% versus 97%, P = 0.01). Multivariate analysis shows that MF or MC did not have an independent impact on RFS, BCSS, or OS. CONCLUSIONS: MF/MC breast cancers were associated with poor prognostic factors, but were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T stage.

Risk factors and incidence of thromboembolic events (TEEs) in older men and women with breast cancer.

BACKGROUND: The purpose of this study is to evaluate the risk factors and the prevalence of thromboembolic events (TEEs) in breast cancer patients. PATIENTS AND METHODS: This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare database. Breast cancer patients diagnosed from 1992 to 2005 ≥66 years old were identified. International Classification of Diseases, Ninth Revision, and Healthcare Common Procedure Coding System codes were used to identify TEEs within 1 year of the breast cancer diagnosis. Analyses were conducted using descriptive statistics and logistic regression. RESULTS: A total of 89 841 patients were included, of them 2658 (2.96%) developed a TEE. In the multivariable analysis, males had higher risk of a TEE than women [odd ratio (OR) = 1.57; confidence interval (CI) 1.10-2.25] and blacks had higher risk than whites (OR = 1.20; CI 1.04-1.40). Compared with stage I patients, patients with stage II, III and IV had 22%, 39% and 98% increase, respectively, in risk. Placement of central catheters (OR = 2.71; CI 2.43-3.02), chemotherapy treatment (OR = 1.66; CI 1.48-1.86) or treatment with erythropoiesis-stimulating agents (ESAs) (OR = 1.33; CI 1.33-1.52) increase the risk. Other significant predictors included comorbidities, age, receptor status, marital status and year of diagnosis. Similar estimates were seen for pulmonary embolism, deep vein thromboembolism and other TEEs. CONCLUSIONS: In total, 2.96% of patients in this cohort developed a TEE within 1 year from breast cancer diagnosis. Stage, gender, race, use of chemotherapy and ESAs, comorbidities, receptor status and catheter placement were associated with the development of TEEs.

International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment.

BACKGROUND: Inflammatory breast cancer (IBC) represents the most aggressive presentation of breast cancer. Women diagnosed with IBC typically have a poorer prognosis compared with those diagnosed with non-IBC tumors. Recommendations and guidelines published to date on the diagnosis, management, and follow-up of women with breast cancer have focused primarily on non-IBC tumors. Establishing a minimum standard for clinical diagnosis and treatment of IBC is needed. METHODS: Recognizing IBC to be a distinct entity, a group of international experts met in December 2008 at the First International Conference on Inflammatory Breast Cancer to develop guidelines for the management of IBC. RESULTS: The panel of leading IBC experts formed a consensus on the minimum requirements to accurately diagnose IBC, supported by pathological confirmation. In addition, the panel emphasized a multimodality approach of systemic chemotherapy, surgery, and radiation therapy. CONCLUSIONS: The goal of these guidelines, based on an expert consensus after careful review of published data, is to help the clinical diagnosis of this rare disease and to standardize management of IBC among treating physicians in both the academic and community settings.

Incidence of and survival following brain metastases among women with inflammatory breast cancer.

BACKGROUND: The purpose of this study was to determine the incidence of and survival following brain metastases among women with inflammatory breast cancer (IBC). PATIENTS AND METHODS: Two hundred and three women with newly diagnosed stage III/IV IBC diagnosed from 2003 to 2008, with known Human epidermal growth factor receptor 2 (HER2) and hormone receptor status, were identified. Cumulative incidence of brain metastases was computed. Survival estimates were computed using the Kaplan-Meier product limit method. Multivariable Cox proportional hazards models were fitted to explore the relationship between breast tumor subtype and time to brain metastases. RESULTS: Median follow-up was 20 months. Thirty-two (15.8%) patients developed brain metastases with a cumulative incidence at 1 and 2 years of 2.7% and 18.7%, respectively. Eleven (5.3%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 1 and 2 years of 1.6% and 5.7%, respectively. Compared with women with triple receptor-negative IBC, those with hormone receptor-positive/HER2-negative disease [hazard ratio (HR) = 0.55, 95% confidence interval (CI) 0.19-1.51, P = 0.24] had a decreased risk of developing brain metastases, and those with HER2-positive disease (HR = 1.02, 95% CI 0.43-2.40, P = 0.97) had an increased risk of developing brain metastases, although these associations were not statistically significant. Median survival following a diagnosis of brain metastases was 6 months. CONCLUSION: Women with newly diagnosed IBC have a high early incidence of brain metastases associated with poor survival and may be an ideal cohort to target for site-specific screening.

TRIP12 as a mediator of human papillomavirus/p16-related radiation enhancement effects.

Patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) have better responses to radiotherapy and higher overall survival rates than do patients with HPV-negative HNSCC, but the mechanisms underlying this phenomenon are unknown. p16 is used as a surrogate marker for HPV infection. Our goal was to examine the role of p16 in HPV-related favorable treatment outcomes and to investigate the mechanisms by which p16 may regulate radiosensitivity. HNSCC cells and xenografts (HPV/p16-positive and -negative) were used. p16-overexpressing and small hairpin RNA-knockdown cells were generated, and the effect of p16 on radiosensitivity was determined by clonogenic cell survival and tumor growth delay assays. DNA double-strand breaks (DSBs) were assessed by immunofluorescence analysis of 53BP1 foci; DSB levels were determined by neutral comet assay; western blotting was used to evaluate protein changes; changes in protein half-life were tested with a cycloheximide assay; gene expression was examined by real-time polymerase chain reaction; and data from The Cancer Genome Atlas HNSCC project were analyzed. p16 overexpression led to downregulation of TRIP12, which in turn led to increased RNF168 levels, repressed DNA damage repair (DDR), increased 53BP1 foci and enhanced radioresponsiveness. Inhibition of TRIP12 expression further led to radiosensitization, and overexpression of TRIP12 was associated with poor survival in patients with HPV-positive HNSCC. These findings reveal that p16 participates in radiosensitization through influencing DDR and support the rationale of blocking TRIP12 to improve radiotherapy outcomes.

High-dose chemotherapy and autologous peripheral blood stem cell transplantation for primary breast cancer refractory to neoadjuvant chemotherapy.

The role of high-dose chemotherapy (HDCT) in patients with refractory breast cancer is not well established. Forty-two female patients (median age of 46 years) with breast cancer refractory to neoadjuvant chemotherapy received HDCT (cyclophosphamide, carmustine and thiotepa) supported by an autologous peripheral blood stem cells transplant. Their disease had been refractory (defined as less than partial response) to one (18 patients) or two (24 patients) regimens of neoadjuvant chemotherapy. Twenty-nine patients had surgery before HDCT. The best response after surgery, HDCT, and radiation therapy was assessed 60 days after transplantation. Thirty patients had complete remission, eight had a PR, one had a minor response, and three had progressive disease. In seven of 13 patients whose disease was inoperable before HDCT, it became operable. After a median follow-up of 42 months, 21 patients were alive, and 15 remained disease free. Five-year overall survival (OS) was 57% (CI, 50-64%), and the estimated 5-year progression-free survival was 40% (CI, 32-48%). Both OS and PFS were better in patients whose disease became operable after chemotherapy than in those whose disease remained inoperable. A randomized study is warranted in this patient population.

Frequency of first metastatic events in breast cancer: implications for sequencing of systemic and local-regional treatment.

PURPOSE: The sequencing of treatment for early breast cancer is controversial. The purpose of this study was to quantify the risk of delaying surgery, using estimates of the frequency of first metastases from breast primary tumors. PATIENTS AND METHODS: The probability that 560 (node-negative), 657 (with one to three positive nodes), and 505 (with more than three positive nodes) women treated without adjuvant chemotherapy would be free of distant disease at presentation was fit to a mathematical model of the seeding of distant metastases and combined with estimates of the growth rate to calculate the frequency of first distant disseminations per month. RESULTS: Frequencies of first distant metastases were approximately 1% to 2% per month, 2% to 4% per month, and 3% to 6% per month in T1 patients who were node-negative, had one to three positive nodes, or more than three positive nodes, respectively. As a result, the typical patient with T1 disease, who has a 70% to 80% chance of being free of distant disease, runs a 1% to 4% risk of distant dissemination for each month surgery is delayed. Assuming a 30% reduction in mortality caused by adjuvant chemotherapy, the model predicts that T1 patients treated with neoadjuvant chemotherapy would potentially have a higher rate of distant metastasis development than those treated with an initial surgical resection followed by adjuvant chemotherapy. CONCLUSION: We formulate the hypothesis that optimal sequencing of surgery and systemic treatment of breast cancer may be size-dependent, with a disadvantage or no benefit from neoadjuvant treatment for T1 patients but an increasing benefit with increasing size of the primary tumor.

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.

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.

Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy.

PURPOSE: To assess patient and tumor characteristics associated with a complete pathologic response (pCR) in both the breast and axillary lymph node specimens and the outcome of patients found to have a pCR after neoadjuvant chemotherapy for locally advanced breast cancer (LABC). PATIENTS AND METHODS: Three hundred seventy-two LABC patients received treatment in two prospective neoadjuvant trials using four cycles of doxorubicin-containing chemotherapy. Patients had a total mastectomy with axillary dissection or segmental mastectomy and axillary dissection followed by four or more cycles of additional chemotherapy. Patients then received irradiation treatment of the chest-wall or breast and regional lymphatics. Median follow-up was 58 months (range, 8 to 99 months). RESULTS: The initial nodal status, age, and stage distribution of patients with a pCR were not significantly different from those of patients with less than a pCR (P>.05). Patients with a pCR had initial tumors that were more likely to be estrogen receptor (ER)-negative (P<.01), and anaplastic (P = .01) but of smaller size (P<.01) than those of patients with less than a pCR. Upon multivariate analysis, the effects of ER status and nuclear grade were independent of initial tumor size. Sixteen percent of the patients in this study (n = 60) had a pathologic complete primary tumor response. Twelve percent of patients (n = 43) had no microscopic evidence of invasive cancer in their breast and axillary specimens. A pathologic complete primary tumor response was predictive of a complete axillary lymph node response (P<.01 ). The 5-year overall and disease-free survival rates were significantly higher in the group who had a pCR (89% and 87%, respectively) than in the group who had less than a pCR (64% and 58%, respectively; P<.01). CONCLUSION: Neoadjuvant chemotherapy has the capacity to completely clear the breast and axillary lymph nodes of invasive tumor before surgery. Patients with LABC who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival rate. However, a pCR does not entirely eliminate recurrence. Further efforts should focus on elucidating the molecular mechanisms associated with this response.

Radiation-induced chromatid breaks as a predictor of breast cancer risk.

PURPOSE: In in vivo models, radiation-induced genomic instability correlates with the risk of breast cancer development. In addition, homozygous mutations in tumor suppressor genes associated with breast cancer development adversely affects the processing and repair of radiation-induced DNA damage. We performed a case-control study to determine whether an assay measuring radiation-induced chromatid breaks correlated with the risk of having bilateral breast cancer. METHODS AND MATERIALS: Patients were prospectively studied on an institutional review board-approved protocol. We included only women with bilateral breast cancer as cases to obtain patients with a presumed genetic susceptibility for breast cancer. Controls were healthy women without a previous cancer history. A mutagen sensitivity assay using gamma-radiation was performed on lymphocytes obtained from 26 cases and 18 controls. One milliliter of whole blood was cultured with 9 mL of blood medium for 91 h and then treated with 125 cGy using a Cs-137 irradiator. Following an additional 4 h in culture, cells were treated with Colcemid for 1 h to arrest cells in metaphase. The number of chromatid breaks per cell was counted using a minimum of 50 metaphase spreads for each sample. RESULTS: Cases had a statistically higher number of gamma-radiation-induced chromatid breaks per cell than controls, with mean values of 0.61 +/- 0.24 vs. 0.45 +/- 0.14, respectively (p = 0.034, Wilcoxon rank sum test). Using the 75th percentile value in the control group as a definition of radiation sensitivity, the radiation-sensitive individuals had a 2.83-fold increased odds ratio for breast cancer development compared with individuals who were not radiation sensitive (95% confidence intervals of 0.83 and 9.67). CONCLUSIONS: These preliminary data suggest that sensitivity to radiation-induced chromatid breaks in lymphocytes correlates with the risk of bilateral breast cancer. Although the differences between cases and controls were statistically significant, the small sample size necessitates that this finding be validated in a larger study. More data are also needed to determine whether this sensitivity is limited to breast cancer patients with a genetic susceptibility for the disease or also applies to the general breast cancer population.

Dosimetric analysis of intact breast irradiation in off-axis planes.

PURPOSE/OBJECTIVE: The purpose of this investigation is to quantify dose inhomogeneity of intact breast irradiation in off-axis planes, and determine how dose inhomogeneity varies according to patient breast size and anatomical region of the breast. METHODS AND MATERIALS: Eleven patients treated with intact breast radiation underwent a treatment-planning computer tomography (CT) scan with 1-cm slices through the entire breast. The area of breast tissue was defined on each CT slice. Treatment planning with lung correction factors was performed using a two-dimensional treatment-planning system that calculates off-axis dose distributions on a slice-by-slice basis. Each plan utilized tangential beams with matched nondivergent posterior borders and with collimator rotation to match the chest wall slope. Dose inhomogeneity within the central plane was minimized during treatment planning by the use of a wedge on the lateral tangent field and by the differential weighting of fields. Dose was normalized at the breast and pectoralis major interface at midseparation in the central plane. Off-axis dose inhomogeneity was not considered in the optimization of the treatment plan. Dose distributions were plotted for each 1-cm slice, and the area of each isodose curve within the breast on each CT slice was calculated. The results of each slice were summed to give an approximation of dose-volume relationships. RESULTS: For the entire population, an average of 10% of the breast volume (range 1-40%) received 110% or greater of the prescribed dose. Increasing dose inhomogeneity was positively correlated with increasing breast sizes (r = 0.72, p = 0.01--Spearmen rank test). Analysis of dose as a function of location within the breast, revealed that the greatest dose inhomogeneity occurred in the lower anatomical quadrants of the breast (p = 0.003-Kruskal-Wallis test). For the group, the mean breast volume that received a 110% or greater dose was: 30% at 6 cm below central axis, 14% at 4 cm below central axis, 6% at central axis, 5% at 4 cm above central axis, and 7% at 6 cm above central axis. CONCLUSION: Our study demonstrates that a significant volume of breast tissue receives 110% or greater of the prescribed dose. This inhomogeneity is greatest in women with larger breast sizes, providing a possible explanation for the poorer cosmetic result seen in this subset of patients compared to women with small breast sizes. In addition, our results show the greatest dose inhomogeneity in the lower quadrants of the breast. Off-axis dose inhomogeneity should be considered in the planning of tumor bed boosts in women with lower quadrant tumors.

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.

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.

Effect of delay in radiation in the combined modality treatment of breast cancer.

PURPOSE: To study how the timing of radiation influences local control, overall survival, and disease-free survival in patients being treated with chemotherapy and radiation for a local-regional carcinoma of the breast. METHODS AND MATERIALS: Over a ten year period, 105 patients received chemotherapy and radiation treatments for a local-regional breast cancer. The population was divided into two groups based on the timing of their radiation treatments. Forty-eight patients began their radiation within 6 months of their diagnosis (early radiation group). Fifty-seven patients had a delay in their radiation for 6 or greater months in order to first maximize chemotherapy treatments (delayed radiation group). There were no significant differences between the two groups with respect to nodal status, stage of the primary, estrogen receptor status, patient age, or type of surgery performed. The only prognostic parameter that was imbalanced was that of a greater percentage of patients with close or positive margins in the early radiation group compared to the delayed radiation group (69% versus 38%, p < 0.02). RESULTS: Comparisons of local control, overall survival, and disease-free survival between the early radiation patients and delayed radiation patients all favored the early radiation group. Respective 8-year actuarial rates were: local control--98% vs. 76%, p = 0.004; overall survival--80% vs. 52%, p = 0.016; disease-free survival--71% vs. 48%, p = 0.008. The differences continued to be significant in a multivariate Cox regression model comparison: p = 0.011, p = 0.050, p = 0.009. There was only one death from intercurrent disease, so that overall survival approximated cause-specific survival to an accurate degree. CONCLUSIONS: In patients requiring chemotherapy and radiation treatments for a local-regional breast cancer, a delay in the initiation of radiation for a period of 6 months or greater from diagnosis resulted in a higher local failure rate. Furthermore, this higher local failure rate was associated with an increased rate of distant metastases and a decreased overall survival rate.

Boron neutron capture therapy: a mechanism for achieving a concomitant tumor boost in fast neutron radiotherapy.

PURPOSE: For many years neutron radiation has been used to treat malignant disease both as fast neutron radiotherapy and as thermal neutron induced boron neutron capture therapy (BNCT). To date, these two approaches have been used independently of one another due to the large difference in neutron energies each employs. In this paper we discuss the potential application of BNCT to enhance the therapeutic effectiveness of a fast neutron radiotherapy beam. METHODS AND MATERIALS: Measurements are presented for the thermal neutron component that is spontaneously developed as the University of Washington fast neutron radiotherapy beam penetrates a water phantom. The biological effect of this thermalized component on cells "tagged" with boron-10 (10B) is modeled mathematically and the expected change in cell survival calculated. The model is then extended to estimate the effect this enhanced cell killing would have for increased tumor control. RESULTS: The basic predictions of the model on changes in cell survival are verified with in vitro measurements using the V-79 cell line. An additional factor of 10-100 in tumor cell killing appears achievable with currently available 10B carriers using our present neutron beam. A Poisson model is then used to estimate the change in tumor control this enhanced cell killing would produce in various clinical situations and the effect is sufficiently large so as to be clinically relevant. It is also demonstrated that the magnitude of the thermalized component can be increased by a factor of 2-3 with relatively simple changes in the beam generating conditions. CONCLUSION: BNCT may provide a means of enhancing the therapeutic effectiveness of fast neutron radiotherapy in a wide variety of clinical situations and is an area of research that should be aggressively pursued.

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.

A survey of current clinical practice of permanent prostate brachytherapy in the United States.

PURPOSE: To help establish standards of care for transperineal interstitial permanent prostate brachytherapy (TIPPB) by obtaining data regarding current clinical practice among the most experienced TIPPB brachytherapists in the United States. METHODS AND MATERIALS: The 70 brachytherapists who performed the greatest number of TIPPB cases in 1995 in the U.S. were surveyed. Each received a comprehensive four page questionnaire that included sections on training and experience, patient and isotope selection criteria, manpower, technique, and follow-up. Thirty-five (50%) surveys were ultimately returned after three mailings and follow-up phone calls. The cumulative experience of the 35 respondents represented approximately 45% of the total TIPPB volume in the U.S. for 1995. Respondents included 29 from the private sector and six from academic programs. RESULTS: The median physician experience with TIPPB was reported as 4.9 years. Each performed an average of 73 TIPPB procedures in 1995 (range 40-300). This represented an increase in volume for most (74%) of the respondents. Sixty-three percent of the respondents attended a formal training course, 54% had TIPPB-specific residency training, and 31% had been proctored (16 had received two or more types of training experience). The most commonly reported selection criteria for implant alone was on Gleason score < or = 7, PSA < 15, < or = Stage T2a, and gland size < or = 60 cc, although no clear consensus was found. Fifty-four percent considered a history of TURP to be a relative contraindication, while 34% considered TURP to have no impact on patient selection. Eighty-six percent of respondents combine brachytherapy with external beam radiation in an average of 32% of their patients. Boosts were given with both 125I prescribed to 120 Gy (75%) or 103Pd to 90 Gy (50%). Sixty percent reported using a Mick applicator, 46% prefer using preloaded needles, and (11%) use both techniques. Real-time imaging was usually performed with ultrasound (94%); most included fluoroscopy (60%). Definitions of PSA control varied widely. CONCLUSIONS: TIPPB clinical practice in the U.S. demonstrates similarities in technique, but differences in patient selection and definitions of biochemical control. It is, therefore, incumbent on those beginning TIPPB programs to carefully review the specific practice details of those institutions with a broad experience.