Susan A. Higgins

Locoregional Relapse and Distant Metastasis in Conservatively Managed Triple Negative Early-Stage Breast Cancer

PURPOSE To determine the prognostic significance of triple negative breast cancers with respect to locoregional relapse and distant metastasis in conservatively managed breast cancer patients. PATIENTS AND METHODS A database of conservative managed (conservative surgery followed by radiation) patients, in whom all three markers (estrogen receptor, progesterone receptor, and HER2/neu) were available, was reviewed. Patients were classified as triple negative if they tested negative for all three markers. Of 482 patients with all three markers available, 117 were classified as triple negative. RESULTS As of September 2005, with a median follow-up time of 7.9 years, of the 482 patients in the study, there have been 53 in-breast relapses, 10 nodal relapses, 77 distant relapses, and 69 deaths. At 5 years, the triple negative cohort had a poorer distant metastasis-free rate compared with the other subtypes (67% v 82%, respectively; P = .002). Triple negative subtype was an independent predictor of distant metastasis (hazard ratio = 2.14; 95% CI, 1.31 to 3.53; P = .002) and cause-specific survival (hazard ratio = 1.79; 95% CI, 1.03 to 3.22; P = .047). There was no significant difference in local control between the triple negative and other subtypes (83% v 83%, respectively). Of 99 BRCA-tested patients in this cohort, 10 had deleterious mutations in BRCA1, and seven had mutations in BRCA2. Of 10 BRCA1 patients, eight were triple negative, whereas only one of seven BRCA2 patients was triple negative (P < .001). CONCLUSION Patients classified as triple negative have a poor prognosis. However, there was no evidence that these patients are at higher risk for local relapse after conservative surgery and radiation. Patients with BRCA1 mutations develop predominantly triple negative tumors.

Chemoradiation as primary or adjuvant treatment for locally advanced carcinoma of the vulva

PURPOSE To determine the impact of primary or adjuvant chemotherapy and radiation (CRT) on the survival rates of patients with locally advanced vulvar carcinoma. METHODS AND MATERIALS Between 1973 and 1998, 54 patients with vulvar cancer were treated with radiation therapy, among which 20 received CRT, while 34 patients received radiation therapy (RT) alone. Of the 20 patients, 14 were treated for primary or recurrent disease (pCRT), and 6 after radical vulvectomy for high-risk disease (aCRT). Of the 34 patients, 12 were treated primarily (pRT) and 22 received adjuvant treatment (aRT). Chemotherapy consisted of 2 courses of 5-fluorouracil (5-FU) and mitomycin C administered during RT. Six patients received cisplatin in place of mitomycin C. In CRT groups, radiation was administered to the vulva, pelvic, and inguinal lymph nodes to a median dose of 45 Gy with additional 6-17 Gy to gross disease. In RT groups, the median dose to the microscopic diseases was 45 Gy. Nine patients received external beam boost and 16 patients received supplementary brachytherapy in the forms of (226)Ra or (241)Am plaques to sites of macroscopic disease. RESULTS Overall survival was superior in the patients treated with pCRT versus pRT with statistical significance (p = 0.04). There was also a statistically significant improvement in disease-specific (p = 0.03) and relapse-free survival (p = 0.01) favoring pCRT. No statistically significant trends of improved survival rates favoring aCRT over aRT were observed. CONCLUSION Concurrent radiation therapy and chemotherapy decreases local relapse rate, improves disease-specific and overall survival over RT alone as primary treatment for locally advanced vulvar cancer.

Alteration of the effects of cancer therapy agents on breast cancer cells by the herbal medicine black cohosh.

SummaryRecent studies have revealed that many, perhaps most, patients receiving cancer therapy are simultaneously self-medicating with one or several complementary and alternative medicines, often without discussing the use of these agents with their physicians. The effects of these agents on the efficacy and toxicity of standard anticancer therapy have not been studied. The experiments described in this report used a well characterized mouse breast cancer cell line to ask whether commercially available extracts of black cohosh, an herb widely used by breast cancer patients, altered the response of cancer cells to radiation and to four drugs commonly used in cancer therapy. The black cohosh extracts increased the cytotoxicity of doxorubicin and docetaxel and decreased the cytotoxicity of cisplatin, but did not alter the effects of radiation or 4-hydroperoxycyclophosphamide (4-HC), an analog of cyclophosphamide which is active in cell culture. These data sound a warning that the herbal medicines being used by patients undergoing cancer therapy can have effects on cancer cells that alter their response to the agents commonly used to treat breast cancer.

Effects of breast-conserving therapy on lactation after pregnancy

BACKGROUNDAs the incidence of breast-conserving therapy in women of childbearing years increases, patient concerns regarding subsequent pregnancies and lactation have become more prevalent. There is a paucity of data regarding lactation outcomes in women who have undergone breast-conserving therapy and then sustained full-term pregnancies. Our objective was to evaluate lactation outcomes in patients with early-stage breast cancer treated with breast-conserving therapy. METHODSWe reviewed a database of over 3,000 patients treated from 1965 to 2003 to identify our cohort of premenopausal women who underwent breast-conserving therapy and subsequently sustained full-term pregnancies. Lactation outcome parameters (breast swelling, ability to lactate, and volume of lactation in the treated and untreated breasts) were the main outcome measures. RESULTSWe identified 28 pregnancies in 21 patients. The median age at diagnosis was 32 years. One patient underwent bilateral breast treatment; therefore, a total of 22 breasts were irradiated. All patients interviewed reported little or no swelling of the treated breast during pregnancy. Of the patients studied, 4 (18.2%) elected pharmacological suppression of lactation. Of the remaining 18 breasts, lactation occurred in 10 (55.6%), did not occur in 7 (38.9%) and was unknown for 1 (5.5%). The volume was reported as significantly diminished in 80% of breasts treated. Lactation in the contralateral breast occurred in all patients who did not undergo pharmacological suppression. CONCLUSIONPatients can experience successful lactation in the contralateral, untreated breast after breast-conserving therapy. In the treated breast, functional lactation is possible but is significantly diminished in the majority of patients.

American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part III: Low-dose-rate and pulsed-dose-rate brachytherapy

PURPOSE To develop a guideline for quality practice of low-dose-rate (LDR) and pulsed-dose-rate (PDR) brachytherapy for locally advanced cervical cancer. METHODS Members of the American Brachytherapy Society (ABS) with expertise in cervical cancer brachytherapy formulated updated guidelines for LDR and PDR brachytherapy for locally advanced (International Federation of Gynecology and Obstetrics [FIGO] Stages IB2-IVA) cervical cancer based on literature review and clinical experience. RESULTS The ABS strongly recommends the use of brachytherapy as a component of the definitive treatment of locally advanced cervical carcinoma. Precise applicator placement is necessary to maximize the probability of achieving local control without major side effects. The ABS recommends a cumulative delivered dose of approximately 80-90Gy for definitive treatment. Dosimetry must be performed after each insertion before treatment delivery. The dose delivered to point A should be reported for all intracavitary brachytherapy applications regardless of treatment planning technique. The ABS also recommends adoption of the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology guidelines for contouring, image-based treatment planning and dose reporting. Interstitial brachytherapy may be considered for a small proportion of patients whose disease cannot be adequately encompassed by intracavitary application and should be performed by practitioners with special expertise in these procedures. Quality management measures must be performed, and follow-up information should also be obtained. CONCLUSIONS Updated ABS guidelines are provided for LDR and PDR brachytherapy for locally advanced cervical cancer. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their clinical practices and to adopt dose-reporting policies that are critical for outcome analysis.

Patterns of reduced nipple aspirate fluid production and ductal lavage cellularity in women at high risk for breast cancer

IntroductionNipple aspiration is a noninvasive technique for obtaining breast fluids from the duct openings of the nipple for the evaluation of abnormalities associated with breast cancer. Nipple aspirate fluid (NAF) can be elicited from 48 to 94% of healthy women, and its production has been linked to an increased relative risk for breast cancer development. NAF production has been used in studies to guide the selection of ducts for ductal lavage, a procedure in which ducts are cannulated and flushed with saline to collect cells. In a previous multicenter trial to evaluate intraductal approaches in women at high-risk for breast cancer, NAF production was observed in 84% of the subjects. However, we observed a significantly lower proportion of fluid-yielding subjects in a similar series of high-risk women. The purpose of the present study was to identify variables associated with this reduction.MethodNipple aspiration was performed on 33 high-risk women (defined as having a 5-year Gail model index of more than 1.7, a personal or family history of breast cancer, and/or a BRCA1 or BRCA2 germline mutation) to identify ductal orifices for lavage procedures. Lavage was performed on all fluid-yielding ducts and on nine non-fluid-yielding ducts.ResultsFluid-yielding ducts were identified in 12 of 33 (36%) of the subjects in the present series, compared with 16 of 19 (84%) of the subjects undergoing identical procedures at our facility during a multicenter trial (P = 0.001). Reduced NAF yields were associated with postmenopausal status (P = 0.02), BRCA germline mutations (P = 0.004), and risk reduction therapies, including bilateral salpingo-oophorectomy (BSO) and/or selective estrogen receptor modulators (SERMs; P = 0.009). All nine (100%) of the ductal lavage specimens collected from non-fluidyielding ducts were acellular, in comparison with 3 of 13 specimens from fluid-yielding ducts (P < .001).ConclusionAnalysis of high-risk women in the present series revealed patterns of reduced NAF production and ductal lavage cellularity compared with a previous multicenter trial. The present series included more BRCA-positive women, many of whom had undergone BSO and/or were using SERMs. Our data suggest that endocrine mechanisms associated with these risk-reducing therapies may be related to patterns of diminished breast fluid production.

Radiation therapy and expander-implant breast reconstruction: an analysis of timing and comparison of complications.

BackgroundThe optimal timing of expander-implant exchange in the setting of postmastectomy radiation therapy (PMRT) remains unclear with prior reports yielding inconsistent and variable results. The purpose of this study was to characterize complications associated with the sequencing of expander-implant breast reconstruction before or after PMRT and to compare the outcomes between early (<4 months) and late (>4 months) expander-implant exchange in the subset of patients who received PMRT before exchange. Materials and MethodsThe medical records of all patients PMRT in the setting of tissue expander-implant breast reconstruction between June 2004 and June 2011 at our institution were reviewed retrospectively. Patients were first classified as having undergone expander-implant exchange before the initiation of PMRT or after the completion of PMRT. Patients who underwent expander-implant exchange after PMRT were then classified as having undergone exchange early (<4 months after PMRT) or late (>4 months after PMRT). All complications requiring additional surgery or hospitalization were recorded. ResultsFifty-five eligible patients were identified as having undergone 56 two-stage tissue expander-implant breast reconstructions. Twenty-two reconstructions underwent exchange before PMRT and 34 reconstructions underwent exchange after PMRT. There was no significant difference in overall complication rate (54.55% vs 47.06%, P = 0.785) or reconstruction failure rate (13.64% vs 20.59%, P = 0.724) between the 2 cohorts. Twenty reconstructions underwent exchange less than 4 months after PMRT and 14 underwent exchange more than 4 months after PMRT. There was no significant difference in overall complication rate (40% vs 57.14%, P = 0.487) or failure rate (25% vs 14.29%, P = 0.672) between the 2 groups. Trends suggest a higher rate of infection in patients who underwent exchange earlier (30% vs 14.29%, P = 0.422) and a higher rate of capsular contracture in patients who underwent exchange later (5% vs 21.43%, P = 0.283); however, statistical significance was not reached. ConclusionsOur findings suggest that neither the sequencing nor timing of expander-implant exchange in the setting of PMRT affects overall complication or reconstruction failure rate. However, the timing of exchange may impact the type of complication encountered. Further investigation is necessary to determine an optimal time for expander-implant exchange.

A prospective, multicenter study of complementary/alternative medicine (CAM) utilization during definitive radiation for breast cancer.

PURPOSE Although complementary and alternative medicine (CAM) utilization in breast cancer patients is reported to be high, there are few data on CAM practices in breast patients specifically during radiation. This prospective, multi-institutional study was conducted to define CAM utilization in breast cancer during definitive radiation. MATERIALS/METHODS A validated CAM instrument with a self-skin assessment was administered to 360 Stage 0-III breast cancer patients from 5 centers during the last week of radiation. All data were analyzed to detect significant differences between users/nonusers. RESULTS CAM usage was reported in 54% of the study cohort (n=194/360). Of CAM users, 71% reported activity-based CAM (eg, Reiki, meditation), 26% topical CAM, and 45% oral CAM. Only 16% received advice/counseling from naturopathic/homeopathic/medical professionals before initiating CAM. CAM use significantly correlated with higher education level (P<.001), inversely correlated with concomitant hormone/radiation therapy use (P=.010), with a trend toward greater use in younger patients (P=.066). On multivariate analysis, level of education (OR: 6.821, 95% CI: 2.307-20.168, P<.001) and hormones/radiation therapy (OR: 0.573, 95% CI: 0.347-0.949, P=.031) independently predicted for CAM use. Significantly lower skin toxicity scores were reported in CAM users vs nonusers, respectively (mild: 34% vs 25%, severe: 17% vs 29%, P=.017). CONCLUSION This is the first prospective study to assess CAM practices in breast patients during radiation, with definition of these practices as the first step for future investigation of CAM/radiation interactions. These results should alert radiation oncologists that a large percentage of breast cancer patients use CAM during radiation without disclosure or consideration for potential interactions, and should encourage increased awareness, communication, and documentation of CAM practices in patients undergoing radiation treatment for breast cancer.

Breast sentinel lymph node dissection before preoperative chemotherapy

HYPOTHESIS Timing of sentinel lymph node dissection (SLND), before or after preoperative chemotherapy (PC), for breast cancer is controversial. DESIGN Single-institution experience with SLND before PC. SETTING Data from prospectively collected Yale-New Haven Breast Center Database. PATIENTS Fifty-five SLNDs were performed before PC for invasive breast cancer in clinically node-negative patients between October 1, 2003, and September 30, 2007. The results are compared with patients who underwent SLND and definitive breast and axillary surgery before chemotherapy (control group; n = 463 SLNDs). INTERVENTIONS If sentinel nodes (SNs) were negative before PC, no axillary lymph node dissection (ALND) was performed. If SNs were positive, ALND was performed after PC at the time of definitive breast surgery. MAIN OUTCOME MEASURES Sentinel node identification rate, false-negative rate, rate of positivity, and rate of residual disease in axilla. RESULTS Of the 55 SLNDs performed before PC, 30 (55%) had a positive SN. The SN identification rate was 100% and the clinical false-negative rate was 0%. In the control group of those with a positive SN, 55% (56 of 101 patients) had no additional positive nodes, 25% (25 of 101) had 1 to 3 positive nodes, and 20% (20 of 101) had 4 or more positive nodes. In the group with a positive SN before PC, 69% (18 of 26 patients) had no additional positive nodes after PC, 27% (7 of 26) had 1 to 3 nodes, and 4% (1 of 26) had 4 or more nodes. Among the SN-positive patients, a pathologic complete response in the breast was found in 4 of 18 patients who had a tumor-free axilla after PC. CONCLUSIONS Sentinel lymph node dissection before PC allows accurate staging of the axilla for prognosis and treatment decisions. Despite downstaging by PC, a significant percentage of patients had residual nodal disease in the axillary dissection.

Brain metastases in epithelial ovarian and primary peritoneal carcinoma.

Objectives: Central nervous system metastases are believed to be becoming more clinically evident as long-term survival for epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC) has improved. Our objective was to report our experience with managing brain metastatic disease (BMD) in patients with EOC and PPC. Methods: A retrospective review was performed on patients with EOC and PPC diagnosed with BMD from 1983 to 2007 at our institution. Results: Twenty-four patients were identified. Patients with multiple brain lesions (n = 16) had a shorter median time to diagnosis of BMD than patients with single lesions (n = 8; 22.5 vs 39 months). Radiation therapy was included in the treatment of BMD for 19 patients (78%). Fourteen patients received whole-brain radiation therapy (WBRT) only (survival, 6 months [range, 1-51 months]). Three patients received a combination of gamma knife radiosurgery and WBRT (survival, 20 months [range, 17-67 months]), and 1 patient received gamma knife radiosurgery alone (survival, 10 months). Four patients underwent craniotomy with 3 receiving postoperative WBRT (survival, 8.5 months [range, 2-97 months]). Two patients elected for palliative care only. The median survival from the diagnosis of BMD was 8.5 months (range, 1-97 months) with a 42% 1-year survival and 16% 2-year survival. Patients with single lesions had a significantly longer survival than patients with multiple lesions (17 months [range, 3-97 months] vs 6 months [range, 3-67 months], respectively). Conclusions: Our report provides the largest single-institution experience of brain metastasis from EOC and PPC in patients receiving predominantly platinum and paclitaxel therapy. Patients with BMD from EOC and PPC have a poor prognosis overall; however, prolonged survival is possible in a small subset of patients.