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Introduction: Quality of life has become an important measure of treatment success and is currently being explored not only for patients on active treatment, but also for long-term breast cancer survivors. The long-term quality of life breast cancer scale (LTQOL-BC) is a tool to assess QOL in breast cancer survivors. This study aimed to validate the tool with health care professionals (HCPs)., Methods: Six HCPs with extensive experience working with breast cancer survivors were selected. HCPs completed the LTQOL-BC and were asked to assess the relevance of each included item to the disease-free breast cancer population. They were also instructed to identify items that could be upsetting for patients, irrelevant to this population, and to assess the tool's breadth of coverage., Results: Feedback indicated that some items such as the body image and sexual functioning questions were potentially upsetting to patients and should be rephrased or removed. The overall breadth of coverage of the tool was inadequate, with employment status, economic situation, ability to meet needs of family, health care insurance coverage, and overall sense of well-being not being addressed by the LTQOL-BC. HCPs also identified that certain items should be edited including those specifying pain in the lower body and the item containing the term "homemaker"., Conclusion: The LTQOL-BC may need to be modified to take into the recommendations provided by HCPs.

Purpose: The Radiation Therapy Oncology Group 9804 study identified good-risk patients with ductal carcinoma in situ (DCIS), a breast cancer diagnosis found frequently in mammographically detected cancers, to test the benefit of radiotherapy (RT) after breast-conserving surgery compared with observation., Patients and Methods: This prospective randomized trial (1998 to 2006) in women with mammographically detected low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins ≥ 3 mm, compared RT with observation after surgery. The study was designed for 1,790 patients but was closed early because of lower than projected accrual. Six hundred thirty-six patients from the United States and Canada were entered; tamoxifen use (62%) was optional. Ipsilateral local failure (LF) was the primary end point; LF and contralateral failure were estimated using cumulative incidence, and overall and disease-free survival were estimated using the Kaplan-Meier method., Results: Median follow-up time was 7.17 years (range, 0.01 to 11.33 years). Two LFs occurred in the RT arm, and 19 occurred in the observation arm. At 7 years, the LF rate was 0.9% (95% CI, 0.0% to 2.2%) in the RT arm versus 6.7% (95% CI, 3.2% to 9.6%) in the observation arm (hazard ratio, 0.11; 95% CI, 0.03 to 0.47; P < .001). Grade 1 to 2 acute toxicities occurred in 30% and 76% of patients in the observation and RT arms, respectively; grade 3 or 4 toxicities occurred in 4.0% and 4.2% of patients, respectively. Late RT toxicity was grade 1 in 30%, grade 2 in 4.6%, and grade 3 in 0.7% of patients., Conclusion: In this good-risk subset of patients with DCIS, with a median follow-up of 7 years, the LF rate was low with observation but was decreased significantly with the addition of RT. Longer follow-up is planned because the timeline for LF in this setting seems protracted., (© 2015 by American Society of Clinical Oncology.)

Purpose: Whole-breast radiation therapy (XRT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) may decrease the risk of local recurrence, but the optimal dose regimen remains unclear. Past studies administered 50 Gy in 25 fractions (conventional); however, treatment pattern studies report that hypofractionated (HF) regimens (42.4 Gy in 16 fractions) are frequently used. We report the impact of HF (vs conventional) on the risk of local recurrence after BCS for DCIS., Methods and Materials: All women with DCIS treated with BCS and XRT in Ontario, Canada from 1994 to 2003 were identified. Treatment and outcomes were assessed through administrative databases and validated by chart review. Survival analyses were performed. To account for systematic differences between women treated with alternate regimens, we used a propensity score adjustment approach., Results: We identified 1609 women, of whom 971 (60%) received conventional regimens and 638 (40%) received HF. A total of 489 patients (30%) received a boost dose, of whom 143 (15%) received conventional radiation therapy and 346 (54%) received HF. The median follow-up time was 9.2 years. The median age at diagnosis was 56 years (interquartile range [IQR], 49-65 years). On univariate analyses, the 10-year actuarial local recurrence-free survival was 86% for conventional radiation therapy and 89% for HF (P=.03). On multivariable analyses, age <45 years (hazard ratio [HR] = 2.4; 95% CI: 1.6-3.4; P<.0001), high (HR=2.9; 95% CI: 1.2-7.3; P=.02) or intermediate nuclear grade (HR=2.7; 95% CI: 1.1-6.6; P=.04), and positive resection margins (HR=1.4; 95% CI: 1.0-2.1; P=.05) were associated with an increased risk of local recurrence. HF was not significantly associated with an increased risk of local recurrence compared with conventional radiation therapy on multivariate analysis (HR=0.8; 95% CI: 0.5-1.2; P=.34)., Conclusions: The risk of local recurrence among individuals treated with HF regimens after BCS for DCIS was similar to that among individuals treated with conventional radiation therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: Radiation Therapy Oncology Group 98-04 sought to identify women with ‘good risk’ ductal carcinoma in situ (DCIS) who receive no significant benefit from radiation. Enrolment criteria excluded close or positive margins and grade 3 disease. To ensure reproducibility in identifying good risk pathology, an optional web based teaching tool was developed and a random sampling of 10% of submitted slides were reviewed by a central pathologist., Methods: Submitting pathologists were asked to use the web based teaching tool and submit an assessment of the tool along with the pathology specimen form and DCIS H&E stained slide. Per protocol pathology was centrally reviewed for 10% of the cases., Results: Of the 55 DCIS cases reviewed, three had close or positive margins and three were assessed to include grade 3 DCIS, therefore 95% of DCIS cases reviewed were correctly graded, and 89% reviewed were pathologically appropriate for enrolment. Regarding the teaching tool, 13% of DCIS cases included forms that indicated the website was used. One of these seven who used the website submitted DCIS of grade 3., Conclusions: Central review demonstrates high pathological concordance with enrolment eligibility, particularly with regard to accurate grading. The teaching tool appeared to be underused.

Aims: Tissue microarrays (TMAs) are effective tools for performing high-throughput standardization analyses of biomarkers, but evidence indicating the core number required to be representative of the whole tumour is lacking. Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. The number and size of cores that can best represent a DCIS lesion are unknown. Rather than performing extensive experiments using several variants of physical TMAs, the aim of this study was to develop a 'virtual TMA' approach that is effective at optimizing biomarker discovery and validation., Methods and Results: Whole DCIS sections from 95 patients were evaluated by immunohistochemistry for oestrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67. Histoscores were generated manually for ER, PgR, and HER2, as well as percentage positivity for Ki67. Slides were scanned using the FDA-approved Ariol SL50 Image Analysis system, and the virtual array (V-Array) module was used. Virtual cores created virtual TMAs, and our validated scoring classifiers were applied. Automated histoscores and percentage positivity were determined, and compared against increasing numbers of cores. The optimal number of cores was based on concordant results between virtual TMAs and corresponding whole sections., Conclusions: We have shown that virtual arrays constitute an important tool in digital pathology in both research and clinical settings., (© 2013 John Wiley & Sons Ltd.)

Purpose: The main goal of treating ductal carcinoma in situ (dcis) is to prevent the development of invasive breast cancer. Most women are treated with breast-conserving surgery (bcs) and radiotherapy. Age at diagnosis may be a risk factor for recurrence, leading to concerns that additional treatment may be necessary for younger women. We report a population-based study of women with dcis treated with bcs and radiotherapy and an evaluation of the effect of age on local recurrence (lr)., Methods: All women diagnosed with dcis in Ontario from 1994 to 2003 were identified. Treatments and outcomes were collected through administrative databases and validated by chart review. Women treated with bcs and radiotherapy were included. Survival analyses were performed to evaluate the effect of age on outcomes., Results: We identified 5752 cases of dcis; 1607 women received bcs and radiotherapy. The median follow-up was 10.0 years. The 10-year cumulative lr rate was 27% for women younger than 45 years, 14% for women 45-50 years, and 11% for women more than 50 years of age (p < 0.0001). The 10-year cumulative invasive lr rate was 22% for women younger than 45 years, 10% for women 45-50 years, and 7% for women more than 50 years of age (p < 0.0001). On multivariate analyses, young age (<45 years) was significantly associated with lr and invasive lr [hazard ratio (hr) for lr: 2.6; 95% confidence interval (ci): 1.9 to 3.7; p < 0.0001; hr for invasive lr: 3.0; 95% ci: 2.0 to 4.4; p < 0.0001]. An age of 45-50 years was also significantly associated with invasive lr (hr: 1.6; 95% ci: 1.0 to 2.4; p = 0.04)., Conclusions: Age at diagnosis is a strong predictor of lr in women with dcis after treatment with bcs and radiotherapy.

Background: Screening for invasive cancer has led to a marked increase in the detection of ductal carcinoma in situ (DCIS). DCIS is, if appropriately managed, a low-risk disease which has a small chance of impacting on patient life expectancy. However, despite significant advances in prognostic marker development in invasive breast cancer, there are no validated diagnostic assays to inform treatment choice for women with DCIS. Therefore we are unable to target effective treatment strategies to women at high risk and avoid over-treatment of women at low risk of progression to invasive breast cancer. Paradoxically, one effect of this uncertainty is undertreatment of some women., Content: We review current practice and research in the field to identify key challenges in the management of DCIS. The impact of clinical research, particularly on the over and undertreatment of women with DCIS is assessed. We note slow progress toward development of diagnostic biomarkers and highlight key opportunities to accelerate advances in this area., Summary: DCIS is a low-risk disease, its incidence is increasing, and current treatment is effective. However, many women are either over- or undertreated. Despite repeated calls for development of diagnostic biomarkers, progress in this area has been slow, reflecting a relative lack of investment of research effort and funding. Given the low event rate in treated patients and the lateness of recurrences, many previous studies have only limited power to identify independent prognostic and predictive biomarkers. However, the potential for such biomarkers to personalize treatment for DCIS is extremely high.

Purpose: To report the outcomes of a population of women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and radiation and to evaluate the independent effect of boost radiation on the development of local recurrence., Methods and Materials: All women diagnosed with DCIS and treated with breast-conserving surgery and radiation therapy in Ontario from 1994 to 2003 were identified. Treatments and outcomes were identified through administrative databases and validated by chart review. The impact of boost radiation on the development of local recurrence was determined using survival analyses., Results: We identified 1895 cases of DCIS that were treated by breast-conserving surgery and radiation therapy; 561 patients received boost radiation. The cumulative 10-year rate of local recurrence was 13% for women who received boost radiation and 12% for those who did not (P=.3). The 10-year local recurrence-free survival (LRFS) rate among women who did and who did not receive boost radiation was 88% and 87%, respectively (P=.27), 94% and 93% for invasive LRFS (P=.58), and was 95% and 93% for DCIS LRFS (P=.31). On multivariable analyses, boost radiation was not associated with a lower risk of local recurrence (hazard ratio = 0.82, 95% confidence interval 0.59-1.15) (P=.25)., Conclusions: Among a population of women treated with breast-conserving surgery and radiation for DCIS, additional (boost) radiation was not associated with a lower risk of local or invasive recurrence., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Ductal carcinoma in situ (DCIS), a non-invasive breast cancer, is usually treated by breast-conserving surgery (BCS). Randomized trials prove that the addition of radiotherapy (XRT) leads to lower rates of recurrence. Despite the evidence, half of women do not receive XRT after BCS. It is unknown how well clinicians identify women with low risk DCIS for treatment by BCS alone or to what extent women with DCIS develop recurrent cancer due to the omission of radiotherapy. We report the outcomes of a population of women with DCIS treated with BCS, alone or with radiotherapy, and evaluate the effectiveness of each therapeutic approach. All women diagnosed with DCIS and treated with BCS, alone or with radiotherapy in Ontario from 1994 to 2003 were identified. Treatments and outcomes were validated by chart review. Survival analyses were used to study the development of local recurrence (LR) in relation to patient and tumor characteristics and the use of radiotherapy. The cohort included 3,762 women treated with breast-conserving therapy; 1,895 of whom (50 %) also received radiation. At 10 years median follow-up, LR developed in 233 (12 %) women who received radiotherapy and in 363 (19 %) of women who did not (p < 0.0001). The 10-year actuarial LR rate for women who did and did not receive radiotherapy was 12.7 and 20.0 % (p < 0.0001). Differences were significant for both for invasive LR (7.0 vs. 10.0 %, p < 0.0001) and for DCIS recurrence (6.1 vs. 10.8 %, p < 0.0001). We estimate that 22 % of recurrences diagnosed in Ontario women treated for DCIS between 1994 and 2003 would have been prevented if all patients had received radiotherapy. The omission of radiotherapy after BCS for DCIS resulted in substantive recurrences that might have been avoided with treatment. Additional markers are needed to identify a low risk group in whom radiation can be safely omitted.

Purpose: Ultrasound elastography is a new imaging technique that can be used to assess tissue stiffness. The aim of this study was to investigate the potential of ultrasound elastography for monitoring treatment response of locally advanced breast cancer patients undergoing neoadjuvant therapy., Methods: Fifteen women receiving neoadjuvant chemotherapy had the affected breast scanned before, 1, 4, and 8 weeks following therapy initiation, and then before surgery. Changes in elastographic parameters related to tissue biomechanical properties were then determined and compared to clinical and pathologic tumor response after mastectomy., Results: Patients who responded to therapy demonstrated a significant decrease (P < .05) in strain ratios and strain differences 4 weeks after treatment initiation compared to non-responding patients. Mean strain ratio and mean strain difference for responders was 81 ± 3% and 1 ± 17% for static regions of interest (ROIs) and 81 ± 3% and 6 ± 18% for dynamic ROIs, respectively. In contrast, these parameters were 102±2%, 110±17%, 101±4%, and 109±30% for non-responding patients, respectively. Strain ratio using static ROIs was found to be the best predictor of treatment response, with 100% sensitivity and 100% specificity obtained 4 weeks after starting treatment., Conclusions: These results suggest that ultrasound elastography can be potentially used as an early predictor of tumor therapy response in breast cancer patients.

Background: Brain metastases represent a significant healthcare problem. It is estimated that 20% to 40% of patients with cancer will develop metastatic cancer to the brain during the course of their illness. The burden of brain metastases impacts on quality and length of survival. Presenting symptoms include headache (49%), focal weakness (30%), mental disturbances (32%), gait ataxia (21%), seizures (18%), speech difficulty (12%), visual disturbance (6%), sensory disturbance (6%) and limb ataxia (6%).Brain metastases may spread from any primary site. The most common primary site is the lung, followed by the breast then gastrointestinal sites. Eighty-five per cent of brain metastases are found in the cerebral hemispheres, 10% to 15% in the cerebellum and 1% to 3% in the brainstem. Brain radiotherapy is used to treat cancer participants who have brain metastases from various primary malignancies.This is an update to the original review published in Issue 3, 2006., Objectives: To assess the effectiveness and adverse effects of whole brain radiotherapy (WBRT) in adult participants with multiple metastases to the brain., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2011), MEDLINE and EMBASE to July 2011., Selection Criteria: Randomized controlled trials (RCTs) comparing WBRT either alone or with other treatments in adults with newly diagnosed multiple metastases to the brain from any primary cancer. Trials of prophylactic WBRT were excluded as well as trials that dealt with surgery or WBRT, or both, for the treatment of single brain metastasis., Data Collection and Analysis: Two review authors independently assessed trial quality and abstracted information. Adverse effects information was also collected from the trials., Main Results: Nine RCTs involving 1420 participants were added in this updated review. This updated review now includes a total of 39 trials involving 10,835 participants.Eight published reports (nine RCTs) showed no benefit of altered dose-fractionation schedules as compared to the control fractionation (3000 cGy in 10 fractions daily) of WBRT for overall survival. These studies also showed no improvement in symptom control nor neurologic improvement among the different dose-fractionation schemes as compared to 3000 cGy in 10 daily fractions of WBRT. This updated review includes two trials comparing 4000 cGy in 20 fractions given twice daily versus 2000 cGy in 4 or 5 daily fractions. Overall, there was no survival advantage (hazard ratio (HR) 1.18, 95% confidence interval (CI) 0.89 to 1.56, P = 0.25) with the use of 4000 cGy in 20 fractions given twice daily compared to 2000 cGy in 4 or 5 daily fractions.The addition of radiosensitizers in six RCTs did not confer additional benefit to WBRT in either the overall survival times (HR 1.08, 95% CI 0.98 to 1.18, P = 0.11) or brain tumour response rates (HR 0.87, 95% CI 0.60 to 1.26, P = 0.46).Two RCTs found no benefit in overall survival (HR 0.61, 95% CI 0.27 to 1.39, P = 0.24) with the use of WBRT and radiosurgery boost as compared to WBRT alone for selected participants with multiple brain metastases (up to four brain metastases). Overall, there was a statistically significant improvement in local brain control (HR 0.35, 95% CI 0.20 to 0.61, P = 0.0003) favouring the WBRT and radiosurgery boost arm. Only one trial of radiosurgery boost with WBRT reported an improved Karnofsky performance score outcome and improved ability to reduce the dexamethasone dose.In this updated review, a total of three RCTs reported on selected patients (with up to three or four brain metastases) treated with radiosurgery alone versus WBRT and radiosurgery. Based on two trials, there was no difference in overall survival (HR 0.98, 95% CI 0.71 to 1.35, P = 0.88). The addition of WBRT when added to radiosurgery significantly improved locally treated brain metasatases control (HR 2.61, 95% CI 1.68 to 4.06, P < 0.0001) and distant brain control (HR 2.15, 95% CI 1.55 to 2.99, P < 0.00001). On the other hand, one trial concluded that patients treated with WBRT and radiosurgery boost were significantly more likely to show a decline in learning and memory function as compared to those treated with radiosurgery alone.One RCT examined the use of WBRT and prednisone versus prednisone alone and produced inconclusive results., Authors' Conclusions: None of the RCTs with altered WBRT dose-fractionation schemes as compared to standard (3000 cGy in 10 daily fractions or 2000 cGy in 4 or 5 daily fractions) found a benefit in terms of overall survival, neurologic function, or symptom control.The use of radiosensitizers or chemotherapy in conjunction with WBRT remains experimental.Radiosurgery boost with WBRT may improve local disease control in selected participants as compared to WBRT alone, although survival remains unchanged for participants with multiple brain metastases.This updated review now includes a total of three RCTs examining the use of radiosurgery alone versus WBRT and radiosurgery. The addition of WBRT to radiosurgery improves local and distant brain control but there is no difference in overall survival. Patients treated with radiosurgery alone were found to have better neurocognitive outcomes in one trial as compared to patients treated with WBRT and radiosurgery.The benefit of WBRT as compared to supportive care alone has not been studied in RCTs. It may be that supportive care alone, without WBRT, is appropriate for some participants, particularly those with advanced disease and poor performance status.

Purpose: To test, in a prospective Phase I/II trial, a partial breast irradiation technique using a 103Pd permanent breast seed implant (PBSI) realized in a single 1-h procedure under sedation and local freezing., Methods and Materials: Eligible patients had infiltrating ductal carcinoma < or = 3 cm in diameter, surgical margin > or = 2 mm, no extensive intraductal component, no lymphovascular invasion, and negative lymph nodes. Patients received a permanent seed implant, and a minimal peripheral dose of 90 Gy was prescribed to the clinical target volume, with a margin of 1.5 cm., Results: From May 2004 to April 2007, 67 patients received the PBSI treatment. The procedure was well tolerated, with 17% of patients having significant pain after the procedure. Only 1 patient (1.5%) had an acute skin reaction (Grade 3 according to the National Cancer Institute Common Toxicity Criteria). The rates of acute moist desquamation, erythema, and indurations were 10.4%, 42%, and 27%, respectively. At 1 year the rate of Grade 1 telangiectasia was 14%. The rate of skin reaction decreased from 65% to 28% when skin received less than the 85% isodose. According to a Radiation Therapy Oncology Group questionnaire, 80-90% of patients were very satisfied with their treatment, and the remainder were satisfied. One patient (1.5%) developed an abscess, which resolved after the use of antibiotics. There was no recurrence after a median follow-up of 32 months (range, 11-49 months)., Conclusions: The feasibility, safety, and tolerability of PBSI compares favorably with that of external beam and other partial breast irradiation techniques.

DCIS is a heterogeneous group of non-invasive cancers of the breast characterized by various degrees of differentiation and unpredictable propensity for transformation into invasive carcinoma. We examined the expression and prognostic value of 9 biological markers with a potential role in tumor progression in 133 patients with pure DCIS treated with breast conserving surgery alone, between 1982-2000. Histology was reviewed and immunohistochemical staining was performed. Pearson correlation coefficient was used to determine the associations between markers and histopathological features. Univariate and multivariate analysis examined associations between time to recurrence and clinicopathologic features and biological markers.Median age at diagnosis was 55 years (25-85). With a median follow up of 8.91 years, 41/133 patients recurred (21 as invasive recurrence). In this cohort 13.5% had low, 43% intermediate and 42% high nuclear grade. Comedo necrosis was found in 65% of cases. Expression of ER (62.4%), PR (55.6%), HER2/neu (31.6%), MIB1 (39.8%), p53 (22.6%), p21 (39.8%), Cyclin D1 (95.5%) calgranulin (20.5%), psoriasin (12%), was found in DCIS. HER2/neu was overexpressed in 45% that recurred as DCIS and 42.9% that recurred as invasive cancer, and only in 26.1% in cases that never recurred. On univariate analysis, HER2/neu overexpression was the only marker associated with an increased risk for any recurrence (p = 0.044). The hazard ratio for recurrence for HER2/neu positive DCIS was 1.927 (confidence interval 1.016-3.653) compared to HER2 negative DCIS. On multivariate analysis, HER2/neu overexpression remained the only independent variable significantly associated with any recurrence (p = 0.014) and with invasive recurrence (p = 0.044).This data suggest that HER2/neu testing may become an important parameter in the management of DCIS and the treatment of cases with positive HER2/neu status could be modified accordingly, similar to the current approach for HER2/neu positive invasive disease.

Background: A recent SEER study identified significant variations in the care of women with DCIS, yet several potential confounding variables were not included. We report a patterns of care study of women with DCIS to better understand the gap between evidence-based knowledge and the management of DCIS., Methods: We studied all cases of DCIS diagnosed through the Ontario Breast Screening Program from 1991 to 2000. Data was obtained by database linkage and chart abstraction. A logistic regression model using generalized estimating equations to adjust for clustering was used., Results: About 320,236 women were screened and 727 individuals were diagnosed with DCIS. The rate of mastectomy was 30% and was associated with multifocality (OR: 3.5 [1.7, 7.1], P = 0.0005), tumor size (OR: >2 cm vs. 1 cm (OR: 2.4 [1.3, 4.4], P = 0.006). Half of cases with margins <1 cm did not receive XRT., Conclusions: Our study corroborates previous reports on the persistent rates of mastectomy and axillary nodal dissection and the limited use of XRT in the treatment of DCIS.

Background: Brain radiotherapy is used to treat cancer patients who have brain metastases resulting from various primary malignancies., Objectives: To assess the effectiveness and adverse effects of whole brain radiotherapy (WBRT) in adult patients with multiple metastases to the brain., Search Strategy: CENTRAL (The Cochrane Library), MEDLINE, EMBASE, CANCERLIT, and CINAHL were searched., Selection Criteria: Randomized controlled trials (RCTs) in which adult patients with multiple metastases to the brain from any primary cancer and treated with WBRT were included. Trials of prophylactic WBRT were excluded as well as trials that dealt with surgery or WBRT, or both, for the treatment of a single brain metastasis., Data Collection and Analysis: Two review authors independently abstracted information for each predetermined outcome: overall survival at six months, intracranial progression-free duration, local brain response, local brain control, quality of life, symptom control, neurological function, and the proportion of patients able to reduce the daily dexamethasone dose. Adverse effects were also collected., Main Results: Eight published reports (nine trials) showed no benefit of altered dose-fractionation schedules as compared to control fractionation (3000 cGy in 10 fractions) of WBRT on the probability of survival at six months. These studies also showed no difference in symptom control nor neurologic improvement among the different dose-fractionation schemes. The addition of radiosensitizers, in five RCTs, did not confer additional benefit to WBRT in either overall median survival times or brain tumor response rates. The addition of the radiosensitizer motexafin gadolinium did not improve quality of life nor time to neurologic progression overall. For the radiosensitizer misonidazole, there was no improvement in Karnofsky performance score outcomes. Three RCTs found no benefit in overall survival with the use of WBRT and a radiosurgery boost as compared to WBRT alone for selected patients with multiple brain metastases (up to four brain metastases). Overall, however, there was a statistically significant improvement in local brain control favoring the whole brain radiotherapy and radiosurgery boost arm. Only one trial of radiosurgery boost with WBRT reported an improved Karnofsky performance score outcome and improved ability to reduce dexamethasone dose. One RCT examined the use of WBRT and prednisone versus prednisone alone and produced inconclusive results., Authors' Conclusions: None of the RCTs with altered dose-fractionation schemes as compared to standard delivery (3000 cGy in ten fractions) found a benefit in terms of overall survival, neurologic function, or symptom control. The use of radiosensitizers or chemotherapy in conjunction with WBRT remains experimental. A radiosurgery boost with WBRT may improve local disease control in selected patients, although survival remains unchanged. The benefit of WBRT as compared to supportive care alone has not been studied in RCTs. It may be that supportive care alone, without WBRT, may be appropriate for some patients, particularly those with advanced disease and poor performance status.

Purpose: Recent reports demonstrate a dramatically increased rate of secondary leukemia for breast cancer patients receiving adjuvant high-dose anthracycline and radiotherapy, and that radiation is an independent factor for the development of leukemia. This study aimed to evaluate the radiation body exposure during breast radiotherapy and to characterize the factors associated with an increased exposure., Patients and Methods: In a prospective cohort of 120 women, radiation measurements were taken from four sites on the body at the time of adjuvant breast radiotherapy. Multiple regression analysis was performed to analyze patient and treatment factors associated with the amount of scattered radiation., Results: For standard 50 Gy breast radiotherapy, the minimal dose received by abdominal organs is on average 0.45 Gy, ranging from 0.06 to 1.55 Gy. The use of physical wedges as a compensation technique was the most significant factor associated with increased scattered dose (p < 0.001), resulting in approximately three times more exposure compared with breast intensity-modulated radiation therapy (IMRT) and dynamic wedge., Conclusions: The amount of radiation that is scattered to a patient's body is consistent with exposure reported to be associated with excess of leukemia. In accordance with the As Low As Reasonably Achievable (ALARA) principle, we recommend using breast IMRT or virtual wedging for the radiotherapy of breast cancer receiving high-dose anthracycline chemotherapy.

Purpose: A new technique of adjuvant partial breast irradiation using 103Pd permanent breast seed implants (PBSI) is presented. The procedure is performed in a single 1-hour session under local anesthesia., Methods and Materials: Patients referred to a single institution for adjuvant radiotherapy after lumpectomy for an infiltrating ductal carcinoma < or = 3 cm in diameter, surgical margin > or = 2 mm, no extensive in situ carcinoma, no lymphovascular invasion, and minimal or negative lymph node involvement were offered a PBSI., Results: Between May and December 2004, 31 eligible patients underwent CT scan and ultrasound simulations assessing PBSI feasibility. Fifteen were excluded because of feasibility issues, and 16 received PBSI. A minimal peripheral dose of 90 Gy was prescribed to the planning target volume corresponding to the clinical target volume identified on the CT scan plus a margin of 1 cm. The procedure was well tolerated; 56% of the patients reported no pain during the procedure, and 46% of the patients developed National Cancer Institute Common Toxicity Criteria Grade 1 acute reaction. None experienced toxicity Grade 2 or 3., Conclusions: Permanent breast seed implantation seems feasible and well tolerated on these preliminary clinical data and represents an ultimate step in the reduction of treatment fraction for partial breast irradiation.

Eighteen percent of all new breast cancers detected on screening mammography are ductal carcinoma in situ (DCIS), a preinvasive lesion that is highly curable. However, some women with DCIS will develop life-threatening invasive breast cancer. Because the determinants of invasive recurrence are unknown, all women with DCIS require the same treatment (usually with surgery and radiation). Therefore, there is a need to identify biologic markers and create a profile that will provide prognostic information that is more accurate than the currently used van Nuys Index to predict invasive recurrence. In the present review, we examined the many biologic markers studied in breast cancer, describe their main biologic role and their expression in DCIS, and review the various studies regarding their ability to serve as prognostic factors in breast cancer with an emphasis on predicting invasive recurrence in patients with DCIS. This review covers established markers, namely, ER, PR and HER2/neu, that are used routinely to make treatment decisions as well as investigative biologic factors involved in cell proliferation, cell cycle regulation, extracellular molecules, factors involved in extracellular matrix degradation, and angiogenesis. However, controversies exist regarding the value of these prognostic factors, their interrelationship, and their advantages over morphologic evaluation.

Breast intensity-modulated radiation therapy (IMRT) improves dose distribution homogeneity within the whole breast. Previous publications report the use of inverse or forward dose optimization algorithms. Because the inverse technique is not widely available in commercial treatment planning systems, it is important to compare the 2 algorithms. The goal of this work is to compare them on a prospective cohort of 30 patients. Dose distributions were evaluated on differential dose-volume histograms using the volumes receiving more than 105% (V(105)) and 110% (V(110)) of the prescribed dose, and on the maximum dose (D(max)) or hot spot and the sagittal dose gradient (SDG) being the gradient between the dose on inframammary crease and the dose prescribed. The data were analyzed using Wilcoxon signed rank test. The inverse planning significantly improves the V(105) (mean value 9.7% vs. 14.5%, p=0.002), and the V(110) (mean value 1.4% vs. 3.2%, p=0.006). However, the SDG is not statistically significantly different for either algorithm. Looking at the potential impact on skin acute reaction, although there is a significant reduction of V(110) using an inverse algorithm, it is unlikely this 1.6% volume reduction will present a significant clinical advantage over a forward algorithm. Both algorithms are equivalent in removing the hot spots on the inframammary fold, where acute skin reactions occur more frequently using a conventional wedge technique. Based on these results, we recommend that both forward and inverse algorithms should be considered for breast IMRT planning.

Purpose: A permanent breast seed implant (PBSI) technique has been developed as a new form of partial adjuvant radiation therapy for early-stage breast cancer. This study compares iodine-125 ((125)I) and palladium-103 ((103)Pd) isotopes by examining the exposure and effective dose (ED) to a patient's partner., Methods and Materials: A low-energy survey meter was used to measure exposure rates as a function of bolus thickness placed over (103)Pd or (125)I seeds. A general mathematical expression for the initial exposure rate at 1 m (x(o,1m)) from the skin surface as a function of the implant size, R, and the distance between the skin surface and the implant, d, was derived. Also, a second general equation is proposed to calculate the ED to the patient's partner., Results: The initial exposure rate at 1 meter and the ED are calculated as follows: x(o,1m) = 3alpha2R(3) ; ;beta(3) [e(-beta(2R+d))(betaR + 1) + e(-betad)(betaR - 1)], and ED = aR(b) [e(-c(2R+d)) (cR + 1) + e(-cd) (cR - 1)]. For (125)I, the parameters are: alpha = 0.154409, beta = 0.388460, a = 197, b = -0.95, and c = 0.38846. For (103)Pd, they are: alpha = 0.06877, beta = 0.421098, a = 18.6, b = -0.78, and c = 0.421098. For implant diameters varying from 2 to 6 cm and skin-to-implant distances varying from 0.7 to 4 cm, the ED is consistently below 2.6 mSv using the (103)Pd isotope, but more than 5 mSv in many instances and possibly up to 20 mSv using (125)I., Conclusions: PBSI using (103)Pd seeds appears safe because the patient's partner ED is consistently below 5 mSv. The(125)I isotope is not recommended for PBSI.

Background: The management of brain metastases is a significant health care problem. An estimated 20-40% of cancer patients will develop metastatic cancer to the brain during the course of their illness., Methods: A systematic review of randomized trials on adult cancer patients with single or multiple brain metastases from cancer of any histology was conducted. Eligible studies investigated external beam radiotherapy or radiosurgery in one of the study arms. Outcomes of interest included survival, intracranial progression-free duration, response of brain metastases to therapy, quality of life, symptom control, neurological function, and toxicity., Results: Twenty-seven trials were included in this systematic review of the evidence. Pooled results from three randomized trials of surgical excision combined with whole brain radiotherapy (WBRT) showed no improvement in overall survival as compared to WBRT alone in patients with single brain metastasis. One randomized study of postoperative WBRT following excision of a single brain metastasis versus surgery alone detected a significant reduction in intracranial tumour recurrence rates but no corresponding difference in overall survival. Nine trials of altered dose-fractionation schedules compared to a standard control fractionation schedule (3000 cGy in 10 fractions) of WBRT showed no difference in probability of survival at 6 months. The addition of radiosensitizers, as assessed in five trials, did not confer additional benefit to WBRT in terms of overall survival or the frequency of brain metastases response. Three trials examined the use of WBRT and radiosurgery boost versus WBRT alone in selected patients with brain metastases. Overall survival did not improve for patients with multiple brain metastases. However, one trial reported an improvement in survival for patients with single brain metastasis treated with WBRT and radiosurgery boost. One older randomized trial examined the use of WBRT versus supportive care alone (using oral prednisone). Results were not conclusive., Conclusion: For patients with a single brain metastasis, good performance status, and minimal or no evidence of extracranial disease, surgical excision and postoperative WBRT improves survival (as compared to WBRT alone). There may be a small survival advantage associated with the use of radiosurgery boost and WBRT as compared to WBRT alone in selected patients with a single brain metastasis. There is no difference in overall survival or in neurologic function improvement with the use of altered whole brain dose-fractionation schedules as compared to standard fractionation schedules (3000 cGy in 10 fractions or 2000 cGy in 5 fractions). There is no survival benefit associated with the use of radiosurgery boost and WBRT versus WBRT alone in patients with multiple brain metastases. Currently, neither chemotherapy nor radiosensitizers show a clear benefit in the objective parameters of survival and progression-free survival. For patients with poor performance status and active extracranial disease, steroids and supportive care are an option.

Purpose: Complementary and alternative medicines (CAMS) are frequently used by patients with breast cancer and their use may be related to the presence of psychosocial distress. The objective of this study is to assess the presence of anxiety and depression in breast cancer patients who use CAM and assess how they perceive their risks of recurrence and dying from breast cancer compared to non-users., Methods: Breast cancer patients attending ambulatory clinics at a single cancer center were approached by their oncologist. Participants completed a self-administered survey regarding CAM usage, beliefs associated with CAM, views of their risks of developing recurrent cancer, and of dying of breast cancer. The presence of anxiety and depression was scored using the Hospital Anxiety and Depression Scale (HADS). Responses were scored and compared between CAM users and non-users., Results: A total of 251 patients completed the survey. CAM usage was reported by 43% of patients. Individuals who used CAM were younger [53.1 versus 63.0 year (p < 0.001)], had higher education (p < 0.001), were more likely to have full time employment [25.7 versus 16.3% (p < 0.001)] and have private insurance for medications (76 versus 60%, p = 0.007) compared to non-users. CAM users perceived their risk of recurrence (p = 0.011) and death from breast cancer (p = 0.0001) as being significantly greater than non-users. There were no significant differences in anxiety or depression scores between CAM and non-users., Conclusion: CAM use is associated with an increased perception of breast cancer recurrence and of breast cancer-related death. There was no association between the presence of anxiety or depression and CAM use. Improved patient understanding of actual risks of recurrence and death are required such that women will be able to make more informed decisions about using CAMs.

Background: Current guidelines include a recommendation that a pathologist with expertise in breast disease review all ductal carcinoma in situ (DCIS) specimens due to the presence of significant variability in pathologic reporting of DCIS. The objective of this study was to evaluate the completeness and accuracy of pathologic reporting of DCIS over the past decade and to determine the current impact of expert breast pathology assessment on the management of DCIS., Methods: All patients with a diagnosis of DCIS referred to a single regional cancer centre between 1982 and 2000 have been reviewed. Inter-observer variability between initial and secondary reports has been evaluated using kappa statistics. For each case, the Van Nuys Prognostic Index (VNPI) using pathologic data obtained from the initial and reviewed pathology reports were compared. The impact of expert breast pathology on risk assessment and treatment was determined., Results: 481 individuals with DCIS were referred and pathology review was performed on 350 patients (73%). Inter-observer agreement was high for the main pathologic features of DCIS. From 1996 to 2000, secondary pathology assessments lead to a change in the assessment of local recurrence risk in 100 cases (29%) and contributed to a change in treatment recommendation in 93 (43%) cases., Conclusion: Expert breast pathology assessments continue to be necessary in the management of DCIS.

Purpose: Recent studies have reported improved survival with concurrent chemoradiotherapy (ChRT) for inoperable non-small-cell lung cancer (NSCLC). ChRT includes the delivery of low-dose chemotherapy given daily during radiotherapy (RT) or higher doses administered weekly. It remains unknown whether a difference in efficacy or toxicity exists between these approaches. A systematic review was performed to compare the efficacy and toxicity of weekly vs. daily ChRT., Methods and Materials: The results from randomized studies comparing ChRT to RT for NSCLC were pooled using meta-analyses. The relative risk (RR) of death at 1, 2, and 3 years and of acute esophagitis, pneumonitis, or neutropenia (World Health Organization Grade 3 or greater) were determined., Results: Ten studies involving 1802 patients were included. No significant difference in mortality or toxicity was observed between the weekly and daily regimens: RR of death at 2 years-weekly 0.93, 95% confidence interval [CI] 0.87-0.99; daily 0.92, 95% CI 0.85-1.00; RR of death at 3 years-weekly 0.93, 95% CI 0.89-0.98; daily 0.90, 95% CI 0.81-1.01; RR of esophagitis-weekly 2.07, 95% CI 0.96-4.46; daily 1.70, 95% CI 1.17-2.48; RR of pneumonitis-weekly 1.52, 95% CI 0.93-2.48; daily 1.17, 95% CI 0.65-2.09; and RR of neutropenia-weekly 8.57, 95% CI 3.75-19.58; daily 11.93, 95% CI 1.55-92.12., Conclusion: No statistically significant difference in efficacy or acute toxicity was observed to suggest the superiority of daily vs. weekly ChRT regimens for NSCLC.

Purpose: Halogenated pyrimidines (iododeoxyuridine [IUdR] and bromodeoxyuridine [BUdR]), platinum salts, and gadolinium porphyrins are heavy atom compounds used as radiosensitizers. For IUdR, it has been hypothesized that iodine inner shell ionizations (ISI) and Auger cascades could be one of the primary radiosensitization mechanisms. The purpose of this paper is to estimate the number of ISI produced per tumor cell and per 2 Gy irradiation in clinically relevant modelings., Materials and Methods: ISI were evaluated using a two-step method. Photon-induced ISI were calculated using the MCNP-4C Monte Carlo code, heavy atom concentrations from clinical data published in the literature, and at various depths in a water phantom irradiated with 6-MV, (60)Co, (137)Cs, or (192)Ir sources. Electron knock-on induced ISI on K, L, and M atomic shells were evaluated with an hybrid method, using simulated electron spectra and cross-sections derived from the Møller formalism. Using a biological dose equivalence of 0.05 Gy per cell ISI, relative biological effectiveness (RBE) values were calculated for each situation., Results: For platinum and gadolinium, ISI occurs in far less than 0.1% of the cell, whichever is the configuration. For IUdR and BUdR, ISI occurs in between 45% to 483% of the cell. Due to spectrum degradation, about 3 times more photoelectric ISI are generated at greater than shallower depths, and 10 times more for (192)Ir compared with (60)Co or 6-MV X-rays. Photoelectric ISI are about 3 times more frequent for iodine than bromine, but electron knock-on ISI are more frequent on bromine, and at the end about the same number of ISI are generated for both elements. RBEs were found to be between 1.01 and 1.12 for clinically relevant irradiation settings., Conclusions: The mechanisms of radiosensitization for platinum and gadolinium are clearly not related to an Auger cascade. For halogenated pyrimidines, however, clinically relevant numbers of ISI are generated within each cell. For IUdR, ISI appears to be strongly tied to the photon spectra. Halogenated pyrimidines should be evaluated again clinically, but using lower energy photons like a (192)Ir implant.

Purpose: To assess how women with ductal carcinoma in situ (DCIS) perceive their risks of recurrence, dying from breast cancer, and psychological distress compared to women with early stage invasive breast cancer (EIBC)., Patients and Methods: Eligible patients included those with DCIS or EIBC (T1 or T2, N0) referred to one cancer center between November 1998 and June 1999. Participants completed a self-administered survey regarding their views of their risks of developing recurrent cancer, of dying of breast cancer and the presence of psychological symptoms of distress. Responses were scored and compared between the two groups., Results: In total, 495 patients were screened, 240 found ineligible, 228 patients who agreed to participate. No significant difference between the two groups was observed in perceptions of risk related to the likelihood of developing local recurrence (DCIS: 53%, EIBC 45%, P = 0.14), distant recurrence (DCIS: 36%; EIBC: 39%, P = 0.35) or dying of breast cancer (DCIS: 27%, EIBC 27%, P = 0.5). Both groups expressed similar levels of psychological distress (anxiety, DCIS: 56%, EIBC 54%, P = 0.38; depression, DCIS: 41%, EIBC, 48%, P = 0.17)., Conclusions: Despite the excellent prognosis, women with DCIS express serious concerns and report similar psychological morbidity as women with invasive cancer.

Purpose: We examine differences in screening, detection, staging and treatment of prostate cancer between urologists in the United States and Canada., Materials and Methods: An anonymous questionnaire was developed and mailed to 700 randomly selected American and 350 Canadian urologists. The 7 domains of prostate cancer management comprised screening/case identification, radical prostatectomy indications, staging evaluations, neoadjuvant therapy, nerve sparing techniques, postoperative management and treatment of biochemical recurrence. The Dillman method of questionnaire administration was used. All data were stratified by country and analyzed using the generalized chi-square test., Results: Surveys were adequately completed by 45% and 79% of American and Canadian urologists, respectively. Practice experience and clinical volumes were not significantly different between the 2 cohorts. Overall, there were few differences in prostate cancer screening, staging, postoperative management, biochemical failure and use of neoadjuvant therapy. However, practicing American urologists tended to pursue more aggressive case finding practices, such as a higher age cutoff for prostate specific antigen testing (p = 0.0001) and more frequent use of transition zone biopsies (p = 0.0001). American urologists also displayed a tendency toward more liberal indication for extirpative surgery. They were more likely to perform radical prostatectomy in men older than 70 years, those with higher prostate specific antigen and those with node positive disease. Among both national cohorts there was considerable variation in management patterns for all domains of prostate cancer. Variation was most common among treatment of patients with adverse pathological conditions (positive margins, seminal vesicle involvement) and postoperative biochemical failure. Even when credible evidence exists (biopsy technique, preoperative staging) significant proportions of urologists in both countries continued to practice contrary to existing data., Conclusions: American and Canadian practice patterns for prostate cancer differ significantly only in the domains of case identification and surgical indications. In addition, considerable intra-national variation in practice patterns exists. These data highlight the necessity to support randomized clinical trials in prostate cancer.

Purpose: We determine the prevalence and patterns of the use of complementary therapies among patients with and those at high risk for prostate cancer., Materials and Methods: A cross-sectional survey was performed of men presenting to 2 urban tertiary urology clinics for prostate cancer evaluation or followup, and those attending a prostate cancer support group. All men diagnosed with and those at high risk (positive family history or abnormal prostate specific antigen) for prostate cancer were eligible for study. A 9-item self-administered, anonymous questionnaire about complementary therapies was administered., Results: Of 357 patients who received the survey 155 from the urology clinics and 113 from the support group responded, for a total response rate of 75%. Of the patients presenting to urology clinics and the support group 27.4 and 38.9% with and 25.8 and 80% at high risk for prostate cancer, respectively, used some form of complementary therapy. The use significantly differed according to disease status (p = 0.001), and was highest among men who were clinically disease-free after radical therapy. Of the patients 24% did not inform the urologist of using alternative therapy., Conclusions: The prevalence of the use of complementary therapy among patients with or at increased risk for prostate cancer was high and dependent on the disease state. Urologists should be aware of this pattern of use, and consider the potential effects when assessing patients for and with prostate cancer.

Penclomedine, a synthetic pyridine derivative, has documented antitumor activity and is being investigated in clinical trials. Its mechanism of action is unknown although it may be metabolized to a free radical, DNA-reactive species. We previously reported that telomerase positive colorectal carcinoma (RKO) cells with abrogated p53 function were more sensitive to penclomedine than were telomerase positive cells with wild-type p53. The present study demonstrates that significant differences in DNA fragmentation in response to penclomedine were observed in RKO cells lacking functional p53 compared with RKO cells with normal p53 function. No differences in DNA fragmentation in response to ionizing radiation were seen in RKO cells with normal or abrogated p53 function. RKO cells with functional p53 respond to penclomedine treatment with a dose-dependent increase in p53 protein levels. However, RKO cells with abrogated p53 function did not show any such change in p53 protein levels. Further, p53-independent increase of p21 was observed, although the significance of this response remains uncertain. These studies suggest that penclomedine may have a therapeutic advantage in killing cells that have abrogated p53 function.

Purpose: To determine if the inclusion of mitomycin C (MMC) in chemoradiation protocols for locally advanced cervical cancer (LACC) significantly enhances the development of serious (Grade 3) late bowel toxicity (SLBT)., Methods and Materials: The incidence of SLBT in 154 patients with LACC entered in six consecutive chemoradiotherapy protocols between February 1982 and June 1987 was determined. Fifty-four patients who were treated with MMC, 5-fluorouracil (5-FU), and radiation were compared to 100 patients who received similar treatment without MMC. Univariate and multivariate analyses assessed the effect of the following parameters on the development of SLBT: (a) external beam dose, (b) rectal and rectosigmoid dose, (c) paraaortic radiation, (d) intracavitary dose and dose rate, (e) volume of tissue irradiated to a total dose of 60 Gy, (f) International Federation of Gynecology and Obstetrics stage, (g) age, (h) number of courses of 5-FU, (i) previous abdominopelvic surgery, (j) split versus continuous radiation, and (k) administration of MMC., Results: The overall incidence of SLBT was 15.6%: 14 of 54 (26%) versus 10 of 100 (10%) for patients who did or did not receive MMC, respectively (p = 0.009). Multivariate analysis revealed the administration of MMC as the only factor predictive for the development of SLBT (p = 0.012, odds ratio = 3.15; 95% confidence interval 1.3-7.7). A significant reduction in SLBT was observed with the elimination of MMC from the chemoradiation protocols despite dose escalation of both radiation and 5-FU. No increase in overall survival was observed in patients receiving MMC, 5-FU, and radiation compared with 5-FU and radiation alone., Conclusion: The inclusion of MMC in these chemoradiation protocols for LACC is associated with significant enhancement in serious late bowel toxicity.