Susan Kesmodel

Preoperative Bevacizumab Does Not Significantly Increase Postoperative Complication Rates in Patients Undergoing Hepatic Surgery for Colorectal Cancer Liver Metastases

PURPOSE Although bevacizumab (BV) increases survival rates when used with chemotherapy (CTX) in patients who have metastatic colorectal cancer (CRC), an increase in wound complications has been observed in patients who undergo surgery while receiving BV. We therefore evaluated whether neoadjuvant BV is associated with an increase in postoperative complications in patients undergoing surgery for CRC liver metastases. PATIENTS AND METHODS Two subgroups of patients who received neoadjuvant CTX + BV (n = 81) or CTX alone (n = 44) were identified from a database of patients who underwent surgery for CRC liver metastases. Univariate and multivariate logistic regression models were used to evaluate the association of patient and tumor characteristics, neoadjuvant therapy, and operative factors with postoperative complications. RESULTS Postoperative complications developed in 40 patients (49%) who received CTX + BV and 19 patients (43%) who received CTX. The median time from BV discontinuation to surgery was 58 days (range, 31 to 117 days). No significant associations were identified between BV use and timing of BV discontinuation and postoperative complications. On multivariate analysis, lower serum albumin and concomitant surgical procedures were associated with an increased risk of developing any complication (P = .035 and .023, respectively), and lower serum albumin was associated with hepatobiliary complications (P = .016). CONCLUSION Neither the use of BV nor timing of BV administration was associated with an increase in complication rates. These data suggest that the combination of BV with neoadjuvant CTX in patients who have CRC liver metastases does not increase surgical complications. To determine the optimal timing of surgery in patients receiving neoadjuvant BV, confirmatory prospective studies are required.

Similar survival with breast conservation therapy or mastectomy in the management of young women with early-stage breast cancer

PURPOSE To evaluate survival outcomes of young women with early-stage breast cancer treated with breast conservation therapy (BCT) or mastectomy, using a large, population-based database. METHODS AND MATERIALS Using the Surveillance, Epidemiology, and End Results (SEER) database, information was obtained for all female patients, ages 20 to 39 years old, diagnosed with T1-2 N0-1 M0 breast cancer between 1990 and 2007, who underwent either BCT (lumpectomy and radiation treatment) or mastectomy. Multivariable and matched pair analyses were performed to compare overall survival (OS) and cause-specific survival (CSS) of patients undergoing BCT and mastectomy. RESULTS A total of 14,764 women were identified, of whom 45% received BCT and 55% received mastectomy. Median follow-up was 5.7 years (range, 0.5-17.9 years). After we accounted for all patient and tumor characteristics, multivariable analysis found that BCT resulted in OS (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.83-1.04; p = 0.16) and CSS (HR, 0.93; CI, 0.83-1.05; p = 0.26) similar to that of mastectomy. Matched pair analysis, including 4,644 BCT and mastectomy patients, confirmed no difference in OS or CSS: the 5-, 10-, and 15-year OS rates for BCT and mastectomy were 92.5%, 83.5%, and 77.0% and 91.9%, 83.6%, and 79.1%, respectively (p = 0.99), and the 5-, 10-, and 15-year CSS rates for BCT and mastectomy were 93.3%, 85.5%, and 79.9% and 92.5%, 85.5%, and 81.9%, respectively (p = 0.88). CONCLUSIONS Our analysis of this population-based database suggests that young women with early-stage breast cancer have similar survival rates whether treated with BCT or mastectomy. These patients should be counseled appropriately regarding their treatment options and should not choose a mastectomy based on the assumption of improved survival.

Preoperative radiation therapy significantly increases patient eligibility for accelerated partial breast irradiation using 3D-conformal radiotherapy.

Introduction:Three-dimensional-conformal radiation (3D-CRT) is the most common approach used in National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39 for accelerated partial breast irradiation (APBI). Administration of APBI-3D-CRT in the preoperative (preop) setting has been shown to decrease the planning target volume. The impact of this decrease on patient eligibility for APBI has not been evaluated in a comparative manner. Materials and Methods:Forty patients with 41 previously treated breast cancers (⩽4 cm) were analyzed. A spherical preop tumor volume was created using the largest reported radiographic dimension and centered within the contoured lumpectomy cavity. Plans were created and optimized using the preop tumor volume and postoperative lumpectomy cavity using NSABP B-39 guidelines. The primary end point was to evaluate for differences in patient eligibility and normal tissue exposure. Results:Thirty-five tumors (85%) in the preop versus 19 tumors (46%) in the postoperative setting were eligible for 3D-CRT-APBI using NSABP B-39 criteria (P=0.0002). The most common reason for ineligibility was due to >60% of the ipsilateral breast volume receiving 50% of the dose. Other reasons included dose to the contralateral breast, heart, and ipsilateral lung. Preop 3D-CRT-APBI was associated with statistically significant improvements in dose sparing to the heart, ipsilateral normal breast tissue, contralateral breast, chest wall, ipsilateral lung, and skin. Conclusions:Dosimetrically, the use of preop radiation would increase patient eligibility for 3D-CRT-APBI and decrease dose to normal tissues, which will potentially decrease toxicity and improve cosmesis. These results provide the basis for a recently activated prospective study of preop 3D-CRT-APBI.

Isolated hepatic perfusion for patients with liver metastases.

Up to 80% of colorectal, melanoma, and neuroendocrine liver metastases are unresectable due to excessive tumor burden. Isolated hepatic perfusion (IHP) administers intensive therapy to the liver while limiting systemic toxicity and thus may have an important role in the management of unresectable liver metastases. This review s describes the development of IHP, initial clinical results, open and percutaneous IHP techniques, and contemporary long-term treatment outcomes. IHP with melphalan or tumor necrosis factor α (TNFα) has been shown to achieve hepatic response rates of greater than 50% with progression-free survival of greater than 12 months among patients with refractory ocular melanoma liver metastases. The only series describing outcomes of IHP for neuroendocrine liver metastases notes an overall response rate of 50% and a median actuarial overall survival of 48 months after IHP treatment with melphalan or TNFα. The majority of studies that have evaluated IHP have been performed in patients with colorectal cancer liver metastases (CRCLM). In aggregate, survival results from retrospective studies and phase I/II clinical trials suggest that IHP demonstrated no significant survival benefit compared with systemic chemotherapy alone as first-line therapy. In contrast, IHP does improve outcomes relative to that provided by second-line chemotherapy for CRCLM, with overall response rates of 60% and median duration of liver response of 12 months. Continued evaluation of IHP for unresectable liver metastases is necessary to establish its role in multidisciplinary treatment approaches.

Invariant natural killer T cells generated from human adult hematopoietic stem-progenitor cells are poly-functional

Invariant natural killer T (iNKT) cells constitute an important subset of T cells that can both directly and indirectly mediate anti-tumor immunity. However, cancer patients have a reduction in both iNKT cell number and function, and these deficits limit the potential clinical application of iNKT cells for cancer therapy. To overcome the problem of limited iNKT cell numbers, we investigated whether iNKT cells can be generated in vitro from bone marrow-derived adult hematopoietic stem-progenitor cells (HSPC). Our data demonstrate that co-culture of HSPC with OP9-DL1 stromal cells, results in a functional CD3(+) T cell population. These T cells can be further differentiated into iNKT cells by secondary culture with CD1d-Ig-based artificial antigen-presenting cells (aAPC). Importantly, these in vitro-generated iNKT cells are functional, as demonstrated by their ability to proliferate and secrete IFN-γ and GM-CSF following stimulation.

Combined Cancer Therapy: Strategies to Overcome Acquired Aromatase Inhibitor Resistance

Aromatase inhibitors (AIs) have become one of the mainstays of treatment of postmenopausal women with hormone receptorpositive breast cancer. However, acquired resistance to treatment continues to be a significant clinical challenge. There is increasing evidence from preclinical studies that activation of growth factor signaling pathways, as well as cross-talk between these pathways and estrogen receptor-alpha signaling pathways are important mechanisms that contribute to AI resistance. These preclinical studies have been the foundation for multiple randomized clinical trials that have evaluated combination targeted therapy in patients with advanced breast cancer. While the clinical benefit observed in these trials has been variable, the preclinical studies were successful in predicting clinical outcomes. This review focuses on mechanisms of acquired AI resistance and describes preclinical studies that have evaluated combination targeted therapy to overcome AI resistance, as well as clinical trials that have translated this information to the clinical setting.

Outcomes and chemotherapy-related toxicity in HIV-infected patients with breast cancer

In the era of combination antiretroviral therapy (ART), there has been a shift in the type of malignancies affecting patients with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS).1 Incidence of the three AIDS-defining malignancies (ADCs) (Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer) has significantly declined. Non-AIDS defining malignancies (NADCs) now account for a larger fraction of malignancies compared with the pre-ART era.2,3 In a recent review of the cancer burden in the HIV-infected population in the United States between 1991 and 2005,4 certain NADCs, including breast cancer, had significantly increased in incidence over time. This increase likely reflects the aging of the HIV-infected population as well as an expansion of HIV/AIDS prevalence among women in the U.S. From a global perspective, breast cancer is the most frequently diagnosed malignancy in women, representing 23% of all cancer cases and 14% of cancer deaths.5 It is the leading cause of cancer death in females in the developing world.5 In the past, the incidence of breast cancer has been lower in the AIDS population compared to the general population,6,7 with little variation in incidence by CD4 count or duration of HIV infection.8 However, the incidence of breast cancer in HIV-infected patients is increasing over time and now approaches the general population risk.9 African-Americans account for nearly half of new HIV infections in the U.S. despite comprising a minority of the general U.S. population.10 Eighty-five percent of HIV/AIDS patients are African-American in Baltimore city.11 For some cancers, including breast cancer, inferior treatment outcomes have been reported both for African-Americans12–15 and for HIV-infected patients.16 The impact of cancer on urban, predominantly African-American, HIV-infected patients in the late ART era is understudied. Given these shifts in cancer incidence and the changing face of the HIV epidemic in this country, we sought to better understand the characteristics and outcomes of breast cancer in HIV-infected patients at our large, urban, academic medical center in Baltimore, Maryland.

Expansion of Screening Mammography in the Veterans Health Administration: Implications for Breast Cancer Treatment

IMPORTANCE Women represent the fastest-growing demographic in the Veterans Health Administration. In 2008, we implemented programmatic changes to expand screening mammography, develop on-site breast care resources, and better coordinate care with non-Veterans Affairs (VA) facilities. OBJECTIVE To determine whether the programmatic changes would increase patient volumes, decrease time to definitive treatment, and increase the rate of breast conservation therapy (BCT). DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective cohort study of all breast cancer cases treated from January 1, 2000, to May 31, 2012, at the Baltimore VA Medical Center. MAIN OUTCOMES AND MEASURES We compared process-of-care metrics before and after 2008, when programmatic changes were implemented. Metrics evaluated included the number of mammograms performed annually, sex shift, the interval from clinical suspicion to tissue diagnosis and definitive treatment, and the rate of BCT. RESULTS From 2000 to 2012, a total of 7355 mammograms were performed and 76 patients with breast cancer received treatment. Most mammograms (n = 6720) were performed after 2008. A median of 1453 (interquartile range [IQR], 592-1458) mammograms were performed and 6.33 patients received cancer treatment annually after 2008, representing 1200% and 49% increases, respectively, compared with the 2000 to 2007 interval. Most patients (86.7%) received screening and diagnostic imaging, biopsy, and surgery between multiple institutions. The interval between screening mammography and tissue diagnosis was 34 days (IQR, 20-52), with no significant difference between study intervals (P = .18). Time from tissue diagnosis to initiation of definitive treatment increased from 33 days (IQR, 26-51) to 51 days (IQR, 36-75) (P = .03) between 2008 and 2012. Thirty-three patients eligible for BCT (67.3%) received it, while 16 patients (32.7%) underwent mastectomy. CONCLUSIONS AND RELEVANCE Our institution has rapidly and successfully expanded screening mammography. Higher mammography volumes have been associated with increased use of non-VA breast care services and increased time to definitive treatment. Appropriate counseling regarding BCT was consistently documented, and mastectomy in BCT-eligible patients was largely the result of patient preference or clinical/social factors. Our data suggest that as patient volumes increase with intensified screening, VA hospitals may benefit from acquiring a full complement of on-site breast care services rather than improving flow between VA hospitals and non-VA breast care centers having specialized resources.

Patient-reported Adherence to Adjuvant Aromatase Inhibitor Therapy Using the Morisky Medication Adherence Scale: An Evaluation of Predictors.

Objectives: Endocrine therapy is part of standard adjuvant therapy for patients with hormone receptor-positive breast cancer and has been shown to improve recurrence-free and overall survival. However, adherence to endocrine therapy is suboptimal and is difficult to measure. In this study we evaluate the feasibility of using the Morisky Medication Adherence Scale (MMAS) to assess patient adherence to aromatase inhibitor (AI) therapy. Methods: Patients with stage 1 to 3, hormone receptor-positive breast cancer receiving adjuvant AI therapy were prospectively enrolled on an Institutional Review Board approved protocol. The MMAS questionnaire was administered to each patient and adherence was measured. Information on duration of AI therapy, patient and tumor characteristics, and treatment was collected. A multivariable logit model approach was utilized to evaluate potential barriers to adherence. Results: Between 2011 and 2014, 100 patients were enrolled. The distribution of adherence levels was 13% low, 37% medium, and 50% high. High adherence was reported more frequently in white women (58%), patients with stage 2 and 3 disease (54%), and patients who did not receive chemotherapy (62%). Multivariable analysis demonstrated that higher adherence was more likely in white women compared with African American women (estimated odds ratio=2.8). Conclusions: Using the MMAS, only 50% of women with stage 1 to 3 breast cancer reported high adherence to AI therapy, consistent with other reports showing suboptimal adherence to adjuvant endocrine therapy. The MMAS allows for the rapid assessment of adherence to oral adjuvant endocrine therapy and is valuable in a busy clinical setting.

Effect of reduction mammoplasty on acute radiation side effects and use of lumpectomy cavity boosts

PURPOSE Reduction mammoplasty (RM) during breast-conserving surgery is popular among women with large-volume breasts because it reduces redundant breast folds and may decrease skin-related morbidity from radiation therapy. However, RM may obscure the lumpectomy cavity (LC) and pose challenges to administering an LC boost, potentially affecting local control. We investigated the impact of RM on acute side effects and use of LC boosts. METHODS AND MATERIALS The records of 645 consecutive women treated with whole-breast irradiation at an urban university and 2 community practices between January 2012 and December 2014 were reviewed on an institutional review board-approved study. The primary endpoint was grade ≥3 radiation dermatitis; the secondary endpoint was use of LC boost. Student 2-sample t tests, Pearson χ2 tests, Fisher exact tests, and univariate and multivariable logistic regression analyses were performed. RESULTS Forty-three (7%) RMs were performed in 650 treated breasts. No significant differences in grade 3 toxicities were identified among RM and non-RM patients. LC boost was delivered to 474 breasts. Fewer (16/43) RM patients received LC boosts compared with non-RM patients (458/607), P = .0001. RM patients were more likely to have neoadjuvant chemotherapy, stage III or multifocal disease, higher body mass index, larger planning treatment volumes, and conventional fractionation (P < .05). CONCLUSIONS RM was associated with decreased use of LC boost without significant differences in acute toxicities. Further investigation to delineate LCs in patients undergoing RM or identify alternative strategies for delivering LC dose is needed.