A Canadian national guideline on the neoadjuvant treatment of invasive breast cancer, including patient assessment, systemic therapy, and local management principles.

PURPOSE: The neoadjuvant treatment of breast cancer (NABC) is a rapidly changing area that benefits from guidelines integrating evidence with expert consensus to help direct practice. This can optimize patient outcomes by ensuring the appropriate use of evolving neoadjuvant principles. METHODS: An expert panel formulated evidence-based practice recommendations spanning the entire neoadjuvant breast cancer treatment journey. These were sent for practice-based consensus across Canada using the modified Delphi methodology, through a secure online survey. Final recommendations were graded using the GRADE criteria for guidelines. The evidence was reviewed over the course of guideline development to ensure recommendations remained aligned with current relevant data. RESULTS: Response rate to the online survey was almost 30%; representation was achieved from various medical specialties from both community and academic centres in various Canadian provinces. Two rounds of consensus were required to achieve 80% or higher consensus on 59 final statements. Five additional statements were added to reflect updated evidence but not sent for consensus. CONCLUSIONS: Key highlights of this comprehensive Canadian guideline on NABC include the use of neoadjuvant therapy for early stage triple negative and HER2 positive breast cancer, with subsequent adjuvant treatments for patients with residual disease. The use of molecular signatures, other targeted adjuvant therapies, and optimal response-based local regional management remain actively evolving areas. Many statements had evolving or limited data but still achieved high consensus, demonstrating the utility of such a guideline in helping to unify practice while further evidence evolves in this important area of breast cancer management.

DUCHESS: an evaluation of the ductal carcinoma in situ score for decisions on radiotherapy in patients with low/intermediate-risk DCIS.

BACKGROUND: Identification of women with DCIS who have a very low risk of local recurrence risk (LRR) after breast-conserving surgery (BCS) is needed to de-escalate therapy. We evaluated the impact of 10-year LRR estimates after BCS, calculated by the integration of a 12-gene molecular expression assay (Oncotype Breast DCIS Score®) and clinicopathological features (CPFs), on its ability to change radiation oncologists' recommendations for RT after BCS for DCIS. METHODS: Prospective cohort study of women with DCIS treated with BCS. Eligibility criteria were as follows: age > 45 years, tumor ≤ 2.5 cm, and margins ≥ 1 mm. Radiation oncologists provided 10-year LRR estimates without RT and recommendation for RT pre- and post-assay. Primary outcome was change in RT recommendation. RESULTS: 217 patients were evaluable, with mean age = 63 years, mean tumor size = 1.1 cm, and mean DCIS Score = 32; 140 (64%) were in the low-risk (<39), 32 (15%) were in the intermediate-risk (39-54), and 45 (21%) were in the high-risk groups (≥55). The assay led to a change in treatment recommendation in 76 (35.2%) (95%CI 29.1-41.8%) patients. RT recommendations decreased from 79% pre-assay to 50% post-assay (difference = 29%; 95%CI 22-35%) due to a significant increase in the proportion of patients with a predicted low LRR (< 10%) post-assay and recommendations to omit RT for those with a low predicted risk. The assay was associated with improved patient satisfaction and reduced decisional conflict. CONCLUSION: The DCIS Score assay combined with CPFs identified more women with an estimated low (<10%) 10-yr LR risk after BCS, leading to a significant decrease in recommendations for RT compared to estimates based on CPFs alone.

External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.

BACKGROUND: Whole breast irradiation delivered once per day over 3-5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. METHODS: We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5-8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035. FINDINGS: Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3-9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9-4·0) in the APBI group and 2·8% (1·8-3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84-1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3). INTERPRETATION: External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. FUNDING: Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

Genetic and clinical predictors of arthralgia during letrozole or anastrozole therapy in breast cancer patients.

PURPOSE: Female patients with breast cancer frequently develop arthralgia when treated with aromatase inhibitors (AI). Although the mechanism of AI-induced arthralgia is unknown, potential biomarkers have been identified. The purpose of this study was to investigate the clinical and genetic predictors of AI-induced arthralgia in a prospective cohort of patients with estrogen receptor-positive breast cancer. METHODS: One hundred and ninety-six patients were enrolled at initiation of AI therapy with either letrozole or anastrozole. Patients completed two validated self-report questionnaires assessing pain, stiffness, and physical function at baseline, and repeated the questionnaires at two and at six months after the initiation of treatment with an AI. Germline DNA of all patients was genotyped for seven single-nucleotide polymorphisms (SNPs) previously identified by genetic screens and genome-wide association studies as associated with AI-induced arthralgia. RESULTS: More than 50% of the study group experienced arthralgia symptoms. Genetic analysis revealed that four SNPs, in CYP19A1 (rs4775936) and ESR1 (rs9322336, rs2234693, rs9340799), were associated with the development of arthralgia (adjusted P = 0.016, 0.018, 0.017, 0.047). High body mass index (BMI) was also associated with the development of arthralgia symptoms (adjusted P = 0.001). Patients prescribed letrozole were significantly more likely to develop arthralgia than patients on anastrozole (P = 0.018), and also more likely to discontinue AI therapy due to arthralgia. The CYP19A1 (rs4775936) SNP was significantly associated with discontinuation of therapy due to intolerable arthralgia. CONCLUSIONS: Our results suggested that BMI and AI drug (letrozole versus anastrozole) were clinical predictors of arthralgia, while genetic variants rs4775936, rs9322336, rs2234693, and rs9340799 were genetic predictors of AI-induced arthralgia. Significantly, rs4775936 was also a predictor of discontinuation of therapy.

Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer.

PURPOSE: The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia. METHODS: We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms. RESULTS: More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline. CONCLUSIONS: CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

Long-term results of hypofractionated radiation therapy for breast cancer.

BACKGROUND: The optimal fractionation schedule for whole-breast irradiation after breast-conserving surgery is unknown. METHODS: We conducted a study to determine whether a hypofractionated 3-week schedule of whole-breast irradiation is as effective as a 5-week schedule. Women with invasive breast cancer who had undergone breast-conserving surgery and in whom resection margins were clear and axillary lymph nodes were negative were randomly assigned to receive whole-breast irradiation either at a standard dose of 50.0 Gy in 25 fractions over a period of 35 days (the control group) or at a dose of 42.5 Gy in 16 fractions over a period of 22 days (the hypofractionated-radiation group). RESULTS: The risk of local recurrence at 10 years was 6.7% among the 612 women assigned to standard irradiation as compared with 6.2% among the 622 women assigned to the hypofractionated regimen (absolute difference, 0.5 percentage points; 95% confidence interval [CI], -2.5 to 3.5). At 10 years, 71.3% of women in the control group as compared with 69.8% of the women in the hypofractionated-radiation group had a good or excellent cosmetic outcome (absolute difference, 1.5 percentage points; 95% CI, -6.9 to 9.8). CONCLUSIONS: Ten years after treatment, accelerated, hypofractionated whole-breast irradiation was not inferior to standard radiation treatment in women who had undergone breast-conserving surgery for invasive breast cancer with clear surgical margins and negative axillary nodes. (ClinicalTrials.gov number, NCT00156052.)

CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy.

Tamoxifen is a widely utilized adjuvant anti-estrogen agent for hormone receptor-positive breast cancer, known to undergo CYP2D6-mediated bioactivation to endoxifen. However, little is known regarding additional genetic and non-genetic determinants of optimal endoxifen plasma concentration. Therefore, 196 breast cancer patients on tamoxifen were enrolled in this prospective study over a 24-month period. Blood samples were collected for pharmacogenetic and drug-level analysis of tamoxifen and metabolites. Regression analysis indicated that besides CYP2D6, the recently described CYP3A4*22 genotype, seasonal variation, and concomitant use of CYP2D6-inhibiting antidepressants were significant predictors of endoxifen concentration. Of note, genetic variation explained 33 % of the variability while non-genetic variables accounted for 13 %. Given the proposed notion of a sub-therapeutic endoxifen concentration for predicting breast cancer recurrence, we set the therapeutic threshold at 18 nM, the 20th percentile for endoxifen level among enrolled patients in this cohort. Nearly 70 % of CYP2D6 poor metabolizers as well as extensive metabolizers on potent CYP2D6-inhibiting antidepressants exhibited endoxifen levels below 18 nM, while carriers of CYP3A4*22 were twofold less likely to be in sub-therapeutic range. Unexpectedly, endoxifen levels were 20 % lower during winter months than mean levels across seasons, which was also associated with lower vitamin D levels. CYP3A4*22 genotype along with sunshine exposure and vitamin D status may be unappreciated contributors of tamoxifen efficacy. The identified covariates along with demographic variables were integrated to create an endoxifen concentration prediction algorithm to pre-emptively evaluate the likelihood of individual patients falling below the optimal endoxifen concentration.

Long-term outcomes and effects of hypofractionated radiotherapy in microinvasive breast cancer: Analysis from a randomized trial.

PURPOSE: The natural history of microinvasive (T1mi) breast cancer is uncertain. The objective was to evaluate long-term local and distant recurrence rates following breast conserving surgery (BCS) in a prospective cohort of patients with T1mi compared to T1a-2 disease who received whole breast irradiation (WBI) in the context of a randomized trial of hypofractionation. METHODS: 1234 patients with T1-2 N0 breast cancer were randomized to receive adjuvant WBI of 42.5Gy in 16 daily fractions, or 50Gy in 25 daily fractions after BCS. An analysis of patients with T1mi tumors compared with T1a-2 disease was performed. Kaplan-Meier estimates of local recurrence (LR), distant recurrence, and overall survival (OS) were compared using the log-rank test. RESULTS: Median follow-up was 12 years. T1mi was found in 3% (n = 38) of patients. The 10-year LR rate was 22.6% in T1mi vs. 6.9% in T1a-2 breast cancer [hazard ratio (HR) = 3.73; 95% confidence interval (CI): 1.93, 7.19; p < 0.001]. The 10-year risk of distant recurrence was 5.1% for T1mi, and 12.1% for T1a-2 disease (HR = 0.56; 95% CI: 0.19, 1.84; p = 0.36). Ten-year OS was 91.5% in T1mi and 84.4% in T1a-2 disease, (HR = 0.48; 95% CI: 0.18, 1.30; p = 0.14). Rates of LR did not differ whether treated by hypofractionation or conventional fractionation (HR = 1.21; 95% CI: 0.35, 4.18; p = 0.77). CONCLUSIONS: The risk of LR was considerably higher in patients with T1mi compared to T1a-2 tumors, but OS remained very good. Future research should evaluate the utility of wider local excision and boost radiation to optimize local control for microinvasive breast cancer.

Dosimetric Planning Comparison for Left-Sided Breast Cancer Radiotherapy: The Clinical Feasibility of Four-Dimensional-Computed Tomography-Based Treatment Planning Optimization.

BACKGROUND: Adjuvant whole-breast radiotherapy (RT) is a significant part of the standard of care treatment after breast cancer (BC) conserving surgery. Modern techniques including intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) have constituted to better target coverage and critical organs sparing. However, BC survivors are at risk of developing radiation-induced cardiac toxicity. Hence, deep-inspiration breath-hold (DIBH) techniques have been implemented at many centers to further reduce cardiac exposure but require compliance. 4D-CT robust optimization can account for heart intrafractional motion per breathing phase. The optimization has been explored in cardiac sparing of breast IMRT compared to DIBH in a small sample size but has not been evaluated in substructures sparing, nor in VMAT. To provide patients who are not compliant to breath-hold with an optimal treatment approach, various heart sparing techniques need to be evaluated for statistical significance and clinical feasibility. AIM: This retrospective study aimed to provide an extensive dosimetric heart sparing comparison of free-breathing, 4D-CT-based treatment planning, including robust optimization with DIBH-based treatment planning. Combinations of forward and inverse IMRT and VMAT are also considered. METHODS: Fifteen early stage left-sided BC standard treatment plans were selected. Breast, lung, left anterior descending artery (LAD), left ventricle (LV), and the whole heart were contoured on each 4D-CT phase and DIBH CT dataset. Each treatment plan was optimized using forward/inverse IMRT and VMAT on the following CT datasets: DIBH, average 4D-CT, and the complete 4D-CT dataset needed for robust optimization. Dose-volume histograms were used to compare V5GyHeart, mean heart dose, mean and max LAD dose, mean LV dose, and V50%Lung. RESULTS: All RT techniques assessed including 4D robust optimization were clinically feasible. Statistically significant differences in mean heart, LAD and LV dose, max LAD dose, and V5GyHeart (p < 0.01) but no difference in V50%Lung (p = 0.29) were found between different techniques. IMRT DIBH achieved the optimal cardiac and substructure sparing among treatment plans. 4D robust IMRT had significantly greater mean heart and LV dose than DIBH IMRT (p ≤ 0.01), except LAD dose. Among free-breathing methods, no difference in all cardiac and substructure dose parameters was observed (p > 0.2) in comparing forward and inverse IMRT with average 4D-CT, inverse average 4D-CT, and 4D robust with IMRT, and between average 4D-CT VMAT and 4D robust VMAT. Only V5GyHeart and mean LV dose were significantly greater in 4D robust VMAT (p < 0.01) compared to DIBH VMAT. Mean heart and LV doses were significantly reduced (p < 0.01) in DIBH IMRT compared to DIBH VMAT. Moreover, mean heart and LV dose, V5GyHeart were significantly reduced in inverse IMRT average 4D-CT compared to average 4D-CT VMAT (p < 0.02) and in 4D robust IMRT compared to 4D robust VMAT (p < 0.04). CONCLUSION: This study demonstrated the clinical feasibility of 4D robust optimization in limiting the cardiac and substructures dose during free-breathing RT with both IMRT/VMAT for patients who are not compliant with breath-hold RT. However, this study also presents that 4D robust optimization can reduce LAD dose but not fully outperform DIBH or conventional 4D-CT-based planning with IMRT/VMAT in heart sparing in treating early staged left-sided BC patients.

Redefining postmastectomy radiation contouring in the era of immediate breast reconstruction: An accurate assessment of local recurrence risk.

INTRODUCTION: Most studies report post-mastectomy local recurrences as chest wall recurrences without clarifying whether the recurrence is in the subcutaneous tissue, muscle or underlying rib. Post-mastectomy chest wall radiation is recommended in patients at increased risk of locoregional recurrence. Chest wall radiation-related fibrosis has become an important clinical consideration in the era of immediate implant-based breast reconstruction. In patients with commonly performed subpectoral implant-based reconstruction, the pectoralis major becomes relocated anterior to the implant and just deep to skin, therefore raising the question of value in radiating deep chest wall structures. This study assessed the rate of recurrence in each anatomical region of chest wall in post-mastectomy patients. METHODS: A comprehensive breast cancer database of 4287 patients at a single regional cancer center from 2006 to 2018 was retrospectively analyzed to identify 1571 mastectomy patients. Recurrences were classified as local skin/subcutaneous, pectoralis muscle (pectoralis major), deep chest wall (pectoralis minor, intercostal muscle or rib) or regional axillary recurrence. RESULTS: A total of 26 patients with locoregional recurrence were identified. Most recurrences were in the skin/subcutaneous level. Of 1571 mastectomy patients, only one patient developed a local recurrence posterior to pectoralis major. Our literature search and meta-analysis revealed that local recurrences post-mastectomy are much more likely to be in subcutaneous tissues/pectoralis major versus deeper chest wall. CONCLUSION: A reduced clinical target volume which encompasses skin/subcutaneous and pectoralis muscle layers without treating deep chest wall may be more appropriate to reduce radiation-associated toxicity since avoiding circumferential radiation of an implant may prevent capsular contracture without compromising treatment benefit.

Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline.

PURPOSE: To provide recommendations on the best strategies for the management and on the best timing and treatment (surgical and radiotherapeutic) of the axilla for patients with early-stage breast cancer. METHODS: Ontario Health (Cancer Care Ontario) and ASCO convened a Working Group and Expert Panel to develop evidence-based recommendations informed by a systematic review of the literature. RESULTS: This guideline endorsed two recommendations of the ASCO 2017 guideline for the use of sentinel lymph node biopsy in patients with early-stage breast cancer and expanded on that guideline with recommendations for radiotherapy interventions, timing of staging after neoadjuvant chemotherapy (NAC), and mapping modalities. Overall, the ASCO 2017 guideline, seven high-quality systematic reviews, 54 unique studies, and 65 corollary trials formed the evidentiary basis of this guideline. RECOMMENDATIONS: Recommendations are issued for each of the objectives of this guideline: (1) To determine which patients with early-stage breast cancer require axillary staging, (2) to determine whether any further axillary treatment is indicated for women with early-stage breast cancer who did not receive NAC and are sentinel lymph node-negative at diagnosis, (3) to determine which axillary strategy is indicated for women with early-stage breast cancer who did not receive NAC and are pathologically sentinel lymph node-positive at diagnosis (after a clinically node-negative presentation), (4) to determine what axillary treatment is indicated and what the best timing of axillary treatment for women with early-stage breast cancer is when NAC is used, and (5) to determine which are the best methods for identifying sentinel nodes.Additional information is available at www.asco.org/breast-cancer-guidelines.

Changes over time of extracellular domain of HER2 (ECD/HER2) serum levels have prognostic value in metastatic breast cancer.

BACKGROUND: Blood levels of the extracellular domain of HER-2/neu (ECD/HER2) have been suggested to have potential as a tumor marker in breast cancer. Our aim was to assess the prognostic value of baseline levels of ECD/HER2, but more importantly changes in levels over time, in women with metastatic breast cancer. METHODS: Baseline and serial levels of ECD/HER2 were measured in 158 women with newly-diagnosed metastatic breast cancer, in whom we previously performed serial measurement of plasma osteopontin. ECD/HER2 was measured in 1,282 serum samples using a validated ELISA at baseline and every 3-12 weeks during and after therapy until death (median, n=8 samples per patient). Multivariate time-dependent survival analyses were conducted using models that right-censored patient outcomes 3, 6 and 12 months after last known ECD/HER2 measurement. RESULTS: Thirty-four patients (22%) had elevated baseline ECD/HER2 (median 10.2 ng/ml: range 4.1-40.4 ng/ml). In univariate analysis, elevated baseline ECD/HER2 was associated with short survival (P=0.001). In a multivariate model incorporating standard clinical prognostic factors, baseline ECD/HER2 was significantly associated with survival duration (RR 1.029; P=0.020). Presence of visceral metastases and ECOG status 2-4 also retained significance. In a multivariate model incorporating standard prognostic factors and changes in sequential ECD/HER2 levels, an ECD/HER2 increase of >12 ng/ml at any time was the variable with most prognostic value for poor survival (RR 6.10; P=0.0003); poor ECOG status also retained significance. CONCLUSION: Increases over time of ECD/HER2 levels were strongly associated with poor survival in this cohort of women with metastatic breast cancer.

The number of axillary nodes removed as a predictor of regional recurrence in node negative breast cancer.

PURPOSE: To determine if the number of axillary nodes removed is a predictor of recurrence in node negative breast cancer. MATERIALS AND METHODS: Five hundred thirty-six patients with T1-T2, N0 invasive breast cancer, treated with lumpectomy and axillary node dissection (AND), were reviewed from January 1, 1986 to December 31, 1992. Patients received radiation to whole breast only, without regional nodal radiation. There was no adjuvant chemotherapy or Tamoxifen given. Patients were grouped according to the number of axillary nodes dissected as follows: 1-5 nodes (91 patients), 6-10 nodes (225 patients) and > 10 nodes (220 patients). Hazard ratios and p-values were determined for time to local recurrence, regional recurrence and for disease specific survival. RESULTS: Median follow-up was 11.2 years. The overall local recurrence and regional recurrence rates for the three groups were: 1-5 nodes, 9.9% and 8.8%, respectively, 6-10 nodes, 10.2% and 2.2%, respectively, and > 10 nodes, 11.8% and 2.7%, respectively. The effect of number of axillary nodes removed was statistically significant only for regional recurrence (p = 0.017). There was no adverse effect on disease specific survival (p = 0.363). CONCLUSION: The number of axillary nodes removed predicts only for regional recurrence in node negative breast cancer patients, with less than 6 nodes removed associated with higher regional recurrence. This may have clinical implications with the current practice of sentinel node biopsy (SNB) replacing axillary node dissection in early stage breast cancer.

Palmar-plantar Erythrodysesthesia with Genital Involvement Secondary to Capecitabine Chemoradiotherapy: A Case Report.

Palmar-plantar erythrodysesthesia (PPE) is a common dermatologic adverse reaction secondary to capecitabine use, but the skin toxicity rarely involves the genitals. We describe a case of PPE with scrotal and penile involvement secondary to capecitabine chemotherapy concurrent with radiotherapy. The patient presented with pain and erythema involving the penis and scrotum during the fifth week of neoadjuvant chemoradiotherapy with capecitabine for T3c N2b M0 low rectal adenocarcinoma. The onset and severity of symptoms in the genitals were loosely associated with the symptoms in the hands and feet. The pain and erythema were self-limiting and improved 11 days after capecitabine discontinuation and local supportive care.

A prospective evaluation of helical tomotherapy.

PURPOSE: To report results from two clinical trials evaluating helical tomotherapy (HT). METHODS AND MATERIALS: Patients were enrolled in one of two prospective trials of HT (one for palliative and one for radical treatment). Both an HT plan and a companion three-dimensional conformal radiotherapy (3D-CRT) plan were generated. Pretreatment megavoltage computed tomography was used for daily image guidance. RESULTS: From September 2004 to January 2006, a total of 61 sites in 60 patients were treated. In all but one case, a clinically acceptable tomotherapy plan for treatment was generated. Helical tomotherapy plans were subjectively equivalent or superior to 3D-CRT in 95% of plans. Helical tomotherapy was deemed equivalent or superior in two thirds of dose-volume point comparisons. In cases of inferiority, differences were either clinically insignificant and/or reflected deliberate tradeoffs to optimize the HT plan. Overall imaging and treatment time (median) was 27 min (range, 16-91 min). According to a patient questionnaire, 78% of patients were satisfied to very satisfied with the treatment process. CONCLUSIONS: Helical tomotherapy demonstrated clear advantages over conventional 3D-CRT in this diverse patient group. The prospective trials were helpful in deploying this technology in a busy clinical setting.

A treatment planning study comparing whole breast radiation therapy against conformal, IMRT and tomotherapy for accelerated partial breast irradiation.

PURPOSE AND BACKGROUND: Conventional early breast cancer treatment consists of a lumpectomy followed by whole breast radiation therapy. Accelerated partial breast irradiation (APBI) is an investigational approach to post-lumpectomy radiation for early breast cancer. The purpose of this study is to compare four external beam APBI techniques, including tomotherapy, with conventional whole breast irradiation for their radiation conformity index, dose homogeneity index, and dose to organs at risk. METHODS AND MATERIALS: Small-field tangents, three-dimensional conformal radiation therapy, intensity-modulated radiation therapy and helical tomotherapy were compared for each of 15 patients (7 right, 8 left). One radiation conformity and two dose homogeneity indices were used to evaluate the dose to the target. The mean dose to organs at risk was also evaluated. RESULTS: All proposed APBI techniques improved the conformity index significantly over whole breast tangents while maintaining dose homogeneity and without a significant increase in dose to organs at risk. CONCLUSION: The four-field IMRT plan produced the best dosimetric results; however this technique would require appropriate respiratory motion management. An alternative would be to use a four-field conformal technique that is less sensitive to the effects of respiratory motion.

Oxybutynin for refractory hot flashes in cancer patients.

OBJECTIVE: There is little information available on the treatment of hot flashes in patients refractory to pharmaceutical interventions. Anecdotal evidence led to the use of oxybutynin for the management of hot flashes in refractory cancer patients; therefore, we performed a retrospective chart review of such patients to determine the effect of oxybutynin in treating hot flashes and to observe the side effects of the drug in these patients. DESIGN: A prospective database of all patients treated for hot flashes was started in July 2004 and was retrospectively analyzed as of March 2006. Also included were individual charts preceding July 2004. Fifty-two patient charts were examined. Demographic information was obtained along with baseline severity and frequency of hot flashes, dose and duration of treatment with oxybutynin, patient response to oxybutynin, and side effects. RESULTS: More than 90% of patients analyzed were refractory to hot flash treatments before starting oxybutynin. Seventy percent of patients showed a partial or excellent response to oxybutynin. The duration of oxybutynin use ranged from 2 weeks to 5 years with more than half of patients currently on oxybutynin or taking oxybutynin for longer than 6 months. Of those patients who experienced an excellent or partial response to treatment, 12% stopped because of documented oxybutynin-related side effects within 4 weeks. CONCLUSION: Oxybutynin seems promising in the management of hot flashes with tolerable side effects in the majority of refractory patients. A placebo-controlled, randomized study is being developed to look more closely at the effectiveness of oxybutynin in reducing hot flashes.

Serial plasma osteopontin levels have prognostic value in metastatic breast cancer.

PURPOSE: Osteopontin is a malignancy-associated protein measurable in blood and tumor tissue. To evaluate its prognostic value in advanced disease, we conducted a prospective clinical study measuring serial osteopontin plasma levels in women with metastatic breast cancer throughout the course of their disease. EXPERIMENTAL DESIGN: One hundred fifty-eight women with newly diagnosed metastatic breast cancer were enrolled in the study. Plasma osteopontin was measured using our validated ELISA, at baseline and every 3 to 12 weeks during and after therapy until death. Multivariate time-dependent survival analyses were conducted using models that right censored patient outcomes 3, 6, and 12 months after the last known osteopontin measurement. RESULTS: Osteopontin was measured in 1,378 samples (median, 9 per patient). Ninety-nine patients had elevated baseline osteopontin (median, 177 ng/mL; range, 1-2,648 ng/mL). In univariate analysis, elevated baseline osteopontin was associated with short survival (P = 0.02). In a multivariate model incorporating standard prognostic factors, baseline osteopontin was significantly associated with survival duration (relative risk, 1.001; P = 0.038). Metastasis-free interval, visceral metastases, and Eastern Cooperative Oncology Group status 2 to 4 also retained significance. In a multivariate model incorporating standard prognostic factors and changes in sequential osteopontin levels, an osteopontin increase of >250 ng/mL at any time was the variable with the most prognostic value for poor survival (relative risk, 3.26; P = 0.0003), and poor Eastern Cooperative Oncology Group status also retained significance. CONCLUSIONS: This is the first study to show that in women with metastatic breast cancer, increases in osteopontin levels over time are strongly associated with poor survival. Sequential monitoring of osteopontin may have use in making treatment decisions for these patients.