Rita Abi-Raad

Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications.

PURPOSE It has been hypothesized that tumors with high interstitial fluid pressure (IFP) and/or hypoxia respond poorly to chemotherapy (CT) because of poor drug delivery. Preclinical studies have shown that paclitaxel reduces the IFP and improves the oxygenation (pO(2)) of tumors. Our aim is to evaluate the IFP and pO(2) before and after neoadjuvant CT using sequential paclitaxel and doxorubicin in patients with breast cancer tumors of >/= 3 cm. PATIENTS AND METHODS Patients were randomly assigned, according to an institutional review board-approved phase II protocol, to receive neoadjuvant sequential CT consisting of either four cycles of dose-dense doxorubicin at 60 mg/m(2) every 2 weeks followed by nine cycles of weekly paclitaxel at 80 mg/m(2) (group 1) or vice versa, with paclitaxel administered before doxorubicin (group 2). Patients were re-evaluated clinically and radiologically. The IFP (wick-in-needle technique) and pO(2) (Eppendorf) were measured in tumors at baseline and after completing the administration of the first and second drug. RESULTS IFP and pO(2) were measured in 54 patients at baseline and after the first CT. Twenty-nine and 25 patients were randomly assigned to groups 1 and 2, respectively. Paclitaxel, when administered first, decreased the mean IFP by 36% (P = .02) and improved the tumor pO(2) by almost 100% (P = .003). In contrast, doxorubicin did not have a significant effect on either parameter. This difference was independent of the tumor size or response measured by ultrasound. CONCLUSION Paclitaxel significantly decreased the IFP and increased the pO(2), whereas doxorubicin did not cause any significant changes. Tumor physiology could potentially be used to optimize the sequence of neoadjuvant CT in breast cancer.

Patterns and risk factors of locoregional recurrence in T1-T2 node negative breast cancer patients treated with mastectomy: implications for postmastectomy radiotherapy.

PURPOSE Postmastectomy radiation therapy (PMRT) can reduce locoregional recurrences (LRR) in high-risk patients, but its role in the treatment of lymph node negative (LN-) breast cancer remains unclear. The aim of this study was to identify a subgroup of T1-T2 breast cancer patients with LN- who might benefit from PMRT. METHODS AND MATERIALS We retrospectively reviewed 1,136 node-negative T1-T2 breast cancer cases treated with mastectomy without PMRT at the Massachusetts General Hospital between 1980 and 2004. We estimated cumulative incidence rates for LRR overall and in specific subgroups, and used Cox proportional hazards models to identify potential risk factors. RESULTS Median follow-up was 9 years. The 10-year cumulative incidence of LRR was 5.2% (95% CI: 3.9-6.7%). Chest wall was the most common (73%) site of LRR. Tumor size, margin, patient age, systemic therapy, and lymphovascular invasion (LVI) were significantly associated with LRR on multivariate analysis. These five variables were subsequently used as risk factors for stratified analysis. The 10-year cumulative incidence of LRR for patients with no risk factors was 2.0% (95% CI: 0.5-5.2%), whereas the incidence for patients with three or more risk factors was 19.7% (95% CI: 12.2-28.6%). CONCLUSION It has been suggested that patients with T1-T2N0 breast cancer who undergo mastectomy represent a favorable group for which PMRT renders little benefit. However, this study suggests that select patients with multiple risk factors including LVI, tumor size ≥2 cm, close or positive margin, age ≤50, and no systemic therapy are at higher risk of LRR and may benefit from PMRT.

CHEST WALL RADIOTHERAPY: MIDDLE GROUND FOR TREATMENT OF PATIENTS WITH ONE TO THREE POSITIVE LYMPH NODES AFTER MASTECTOMY

PURPOSE To evaluate the outcomes for patients with Stage II breast cancer and one to three positive lymph nodes after mastectomy who were treated with observation or adjuvant radiotherapy to the chest wall (CW) with or without the regional lymphatics. METHODS AND MATERIALS We retrospectively analyzed 238 patients with Stage II breast cancer (one to three positive lymph nodes) treated with mastectomy at the Massachusetts General Hospital between 1990 and 2004. The estimates of locoregional recurrence (LRR), disease-free survival (DFS), and overall survival were analyzed according to the delivery of radiotherapy and multiple prognostic factors. RESULTS LRR and DFS were significantly improved by postmastectomy radiotherapy (PMRT), with a 5- and 10-year LRR rate without PMRT of 6% and 11%, respectively and, with PMRT, of 0% at both 5 and 10 years (p = .02). The 5- and 10-year DFS rate without PMRT was 85% and 75%, respectively, and, with PMRT, was 93% at both 5 and 10 years (p = .03). A similar benefit was found for patients treated with RT to the CW alone. The LRR, DFS, and overall survival rate for patients treated to the CW only was 0%, 96%, and 95% at 10 years, respectively. CONCLUSION Our data suggest that adjuvant PMRT to the CW alone provides excellent disease control for patients with breast cancer <5 cm with one to three positive lymph nodes.

External Beam Accelerated Partial-Breast Irradiation Using 32 Gy in 8 Twice-Daily Fractions: 5-Year Results of a Prospective Study

PURPOSE External beam accelerated partial breast irradiation (APBI) is an increasingly popular technique for treatment of patients with early stage breast cancer following breast-conserving surgery. Here we present 5-year results of a prospective trial. METHODS AND MATERIALS From October 2003 through November 2005, 98 evaluable patients with stage I breast cancer were enrolled in the first dose step (32 Gy delivered in 8 twice-daily fractions) of a prospective, multi-institutional, dose escalation clinical trial of 3-dimensional conformal external beam APBI (3D-APBI). Median age was 61 years; median tumor size was 0.8 cm; 89% of tumors were estrogen receptor positive; 10% had a triple-negative phenotype; and 1% had a HER-2-positive subtype. Median follow-up was 71 months (range, 2-88 months; interquartile range, 64-75 months). RESULTS Five patients developed ipsilateral breast tumor recurrence (IBTR), for a 5-year actuarial IBTR rate of 5% (95% confidence interval [CI], 1%-10%). Three of these cases occurred in patients with triple-negative disease and 2 in non-triple-negative patients, for 5-year actuarial IBTR rates of 33% (95% CI, 0%-57%) and 2% (95% CI, 0%-6%; P<.0001), respectively. On multivariable analysis, triple-negative phenotype was the only predictor of IBTR, with borderline statistical significance after adjusting for tumor grade (P=.0537). CONCLUSIONS Overall outcomes were excellent, particularly for patients with estrogen receptor-positive disease. Patients in this study with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI. Larger, prospective 3D-APBI clinical trials should continue to evaluate the effect of hormone receptor phenotype on IBTR rates.

Does Lymphovascular Invasion Predict Regional Nodal Failure in Breast Cancer Patients With Zero to Three Positive Lymph Nodes Treated With Conserving Surgery and Radiotherapy? Implications for Regional Radiation

PURPOSE To examine the relationship between lymphovascular invasion (LVI) and regional nodal failure (RNF) in breast cancer patients with zero to three positive nodes treated with breast-conservation therapy (BCT). METHODS AND MATERIALS The records of 1,257 breast cancer patients with zero to three positive lymph nodes were reviewed. All patients were treated with BCT at Massachusetts General Hospital from 1980 to December 2003. Lymphovascular invasion was diagnosed by hematoxylin and eosin-stained sections and in some cases supported by immunohistochemical stains. Regional nodal failure was defined as recurrence in the ipsilateral supraclavicular, axillary, or internal mammary lymph nodes. Regional nodal failure was diagnosed by clinical and/or radiologic examination. RESULTS The median follow-up was 8 years (range, 0.1-21 years). Lymphovascular invasion was present in 211 patients (17%). In univariate analysis, patients with LVI had a higher rate of RNF (3.32% vs. 1.15%; p = 0.02). In multivariate analysis, only tumor size, grade, and local failure were significant predictors of RNF (p = 0.049, 0.013, and 0.0001, respectively), whereas LVI did not show a significant relationship with RNF (hazard ratio = 2.07; 95% CI, 0.8-5.5; p = 0.143). The presence of LVI in the T2/3 population did not increase the risk of RNF over that for those with no LVI (p = 0.15). In addition, patients with Grade 3 tumors and positive LVI did not have a higher risk of RNF than those without LVI (p = 0.96). CONCLUSION These results suggest that LVI can not be used as a sole indicator for regional nodal irradiation in breast cancer patients with zero to three positive lymph nodes treated with BCT.