John A. Charlson

Impact of chemotherapy on survival in surgically resected retroperitoneal sarcoma

BACKGROUND The role of systemic chemotherapy (CT) in the multimodality treatment strategy for retroperitoneal sarcomas (RPS) remains controversial. We hypothesized that chemotherapy does not improve overall survival for patients with surgically resected RPS. METHODS The National Cancer Database was used to identify all patients with RPS that underwent surgical resection from 1998 to 2011. Univariate and multivariable Cox proportional hazards modeling were used to assess overall survival (OS) and logistic regression was used for associations. Propensity score (PS) modeling was performed to create balanced cohorts for analysis. RESULTS A total of 8653 patients with surgically resected RPS were identified; 1525 (17.6%) received CT; 10.6% of patients (n = 163) in the neoadjuvant setting. Factors associated with receipt of CT included moderate (OR 2.3) to poorly differentiated (OR 4.3) tumors, leiomyosarcoma (OR 1.8) or undifferentiated pleomorphic sarcoma (OR 2.3) histology, and R2 resection status (OR 2.2) (all p < 0.05). Unadjusted median OS for patients receiving CT compared to surgery alone was 40 vs 68.2 months respectively (p < 0.01). Following propensity score matching, worse median OS persisted among the CT cohort (40 vs 52 months, p = 0.002). Receipt of chemotherapy was not associated with improved long term survival in adjusted models for the raw and propensity matched cohorts (HR 1.17, 95% CI: 1.04-1.31; p = 0.009). CONCLUSION Current available chemotherapy regimens for RPS do not confer a survival benefit. Routine use of chemotherapy for RPS should be discouraged until new effective systemic agents become available.

The Introduction of Generic Aromatase Inhibitors and Treatment Adherence Among Medicare D Enrollees

BACKGROUND Aromatase inhibitors (AIs) substantially reduce breast cancer mortality in clinical trials, but high rates of nonadherence to these long-term oral therapies have reduced their impact outside of trials. We examined the association of generic AI availability with AI adherence among a large national breast cancer cohort. METHODS Using a quasi-experimental prepost design, we examined the effect of generic AI introductions (7/2010 and 4/2011) on adherence among a national cohort of women with incident breast cancer in 2006 and 2007 who were enrolled in the Medicare D pharmaceutical coverage program. Medicare D claims were used to calculate AI adherence, defined as a medication possession ratio of 80% or more of eligible days, over 36 months. Multivariable logistic regression models estimated with generalized estimating equations were applied to longitudinal adherence data to control for possible confounders, including receipt of a Medicare D low-income subsidy, and to account for repeated measures. All statistical tests were two-sided. RESULTS Sixteen thousand four hundred sixty-two Medicare D enrollees were eligible. Adherence declined throughout the study. However, among women without a subsidy, the median quarterly out-of-pocket cost of anastrozole fell from

Multimodality management of metastatic patients with soft tissue sarcomas may prolong survival.

183 in the fourth quarter of 2009 to

Prognostic variables in patients with primary soft tissue sarcoma of the extremity and trunk treated with neoadjuvant radiotherapy or neoadjuvant sequential chemoradiotherapy

15 in 2011, and declines in adherence were attenuated with generic AI introductions. Regression-adjusted adherence probabilities were estimated to be 5.4% higher after generic anastrozole was introduced in 2010 and 11% higher after generic letrozole/exemestane was introduced in 2011. Subsidy recipients had higher adherence rates throughout the study. CONCLUSIONS The introduction of generic medications attenuated the decline in adherence to AIs over three years of treatment among breast cancer survivors not receiving low-income subsidies for Medicare D coverage.

Medicare D Subsidies and Racial Disparities in Persistence and Adherence With Hormonal Therapy

Objectives:Patients who develop metastatic disease from soft tissue sarcoma have a poor prognosis. The purpose of this study was to identify metastatic survival rates and identify prognostic variables that predict for these outcomes. Methods:Between 2000 and 2010, 182 patients with stage I to IV primary soft tissue sarcomas of the extremity and trunk were treated with multimodality treatment. Fifty-five patients developed or presented with metastasis. We retrospectively analyzed prognostic factors for metastatic survival. Metastatic survival between groups was compared with the log-rank test. Survival curves were estimated by Kaplan-Meier plots. Multivariate analysis was performed using the Cox proportional hazards model. Results:Median follow-up was 3.1 years. Median metastatic survival was 24.2 months. Median metastatic survival in those undergoing multimodality therapies was 40 versus 22 months in those receiving single modality treatments. In single predictor Cox models, age, stage, number of lung metastases, location of metastases, and primary disease were significant for metastatic survival. On multivariate analysis, number of pulmonary metastases, histology, stage, and location of primary disease predicted for metastatic survival. Patients who had pulmonary-only disease had improved metastatic survival versus those that had extrapulmonary with or without pulmonary metastatic disease (38 vs. 15 mo). Patients who had ⩽5 pulmonary metastasis had improved metastatic survival versus those that had >5 pulmonary lesions (55 vs. 22 mo). Conclusions:This analysis shows that >5 pulmonary metastasis, malignant fibrous histiocytoma histology, stage III disease, and proximal lower extremity sarcomas are associated with decreased metastatic survival. Moreover, aggressive multimodality management of metastatic disease may prolong metastatic survival.

A Phase II Study of Concurrent Docetaxel, Epirubicin and Cyclophosphamide as a Neoadjuvant Chemotherapy Regimen in Patients with Locally Advanced Breast Cancer

BackgroundNeoadjuvant radiotherapy (NRT) is an effective strategy to treat soft tissue sarcomas (STS). However, the role of neoadjuvant chemoradiotherapy (NCRT) remains to be determined.MethodsFrom May 1999 to July 2010, 112 patients with localized STS of the extremity and trunk who were treated with NRT or NCRT followed by surgery were retrospectively reviewed. Clinical outcomes including overall survival (OS), disease-free survival (DFS), and distant metastasis free survival (DMFS) were calculated using Kaplan-Meier survival analyses. Prognostic variables were determined by univariate (UVA) and multivariate analyses (MVA).ResultsMedian follow-up was 37 months. Median RT dose was 50 Gy. Forty-nine patients received NCRT. Overall limb-preservation rate was 99% and local control was 97%. The estimated 3-year OS, DFS, and DMFS were 86%, 68%, and 72%, respectively. Age was the only variable to predict for OS, DFS and DMFS on UVA. Age ≥ 70 predicted for poor OS, stage III disease predicted for poor DFS and DMFS, and the addition of chemotherapy predicted for improved DMFS on MVA.ConclusionsExcellent rates of local control and limb-preservation were observed in patients with primary STS treated with neoadjuvant therapy followed by surgery. Neoadjuvant sequential chemotherapy followed by radiotherapy may be considered for young patients with stage III STS.

Overall survival after resection of retroperitoneal sarcoma at academic cancer centers versus community cancer centers: An analysis of the National Cancer Data Base

Purpose To investigate the role of out-of-pocket cost supports through the Medicare Part D Low-Income Subsidy on disparities in breast cancer hormonal therapy persistence and adherence by race or ethnicity. Methods A nationwide cohort of women age ≥ 65 years with a breast cancer operation between 2006 and 2007 and at least one prescription filled for oral breast cancer hormonal therapy was identified from all Medicare D enrollees. The association of race or ethnicity with nonpersistence (90 consecutive days with no claims for a hormonal therapy prescription) and nonadherence (medication possession rate < 80%) was examined. Survival analyses were used to account for potential differences in age, comorbidity, or intensity of other treatments. Results Among the 25,111 women in the study sample, 77% of the Hispanic and 70% of the black women received a subsidy compared with 21% of the white women. By 2 years, 69% of black and 70% of Hispanic patients were persistent compared with 61% of white patients. In adjusted analyses, patients in all three unsubsidized race or ethnicity groups had greater discontinuation than subsidized groups (white patients: hazard ratio [HR], 1.83; 95% CI, 1.70 to 1.95; black patients: HR, 2.09; 95% CI, 1.73 to 2.51; Hispanic patients: HR, 3.00; 95% CI, 2.37 to 3.89). Racial or ethnic persistence disparities that were present for unsubsidized patients were not present or reversed among subsidized patients. All three subsidized race or ethnicity groups also had higher adherence than all three unsubsidized groups, although with the smallest difference occurring in black women. Conclusion Receipt of a prescription subsidy was associated with substantially improved persistence to breast cancer hormonal therapy among white, black, and Hispanic women and lack of racial or ethnic disparities in persistence. Given high subsidy enrollment among black and Hispanic women, policies targeted at low-income patients have the potential to also substantially reduce racial and ethnic disparities.

Is long-term survival possible after margin-positive resection of retroperitoneal sarcoma (RPS)?

Background: Neoadjuvant chemotherapy with concurrent docetaxel, doxorubicin and cyclophosphamide is commonly used for patients with locally advanced breast cancer. Epirubicin is another anthracycline used in breast cancer but the concurrent use of epirubicin and taxane is not well-established. We conducted a single institution, phase II study to assess the efficacy and safety of concurrent docetaxel, epirubicin and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen in breast cancer. Methods: Patients with newly diagnosed locally advanced breast cancer defined as T2 >3 cm, T3, T4 with any N, or any T with N1-3 were eligible. A chemotherapy regimen of docetaxel 75mg/m2, epirubicin 75mg/m2 and cyclophosphamide 600mg/m2 was given with filgrastim support every 3 weeks for 6 cycles. The primary end-point was pathologic complete response rate. Results: Twenty patients were enrolled from 2003 to 2006. The median age was 51 (29-70) year-old. Eight patients were premenopausal. Ten patients had positive hormone receptors. Four patients had HER2 positive receptor. Nineteen patients completed six cycles of TEC chemotherapy. The pathologic complete response rate was 25%. Eight of sixteen patients with N1-3 disease had pathological negative lymph nodes. With a median follow up of 57.5 (16-71) months, four patients relapsed including one death from recurrence. The estimated 5 year relapse-free survival was 79.3% and the 5-year overall survival was 94.7%. No patient had cardiac failure or death during treatment. The most common grade 3-4 toxicity was neutropenia (35%). Conclusion: TEC regimen is a well- tolerated and effective neoadjuvant chemotherapy regimen for locally advanced breast cancer that results in a pathologic complete response rate of 25%.

Erratum to: Patient costs of breast cancer endocrine therapy agents under Medicare Part D vs with generic formulations.

Background Operative resection remains the definitive curative therapy for retroperitoneal sarcoma. Data published recently show a correlation between improved outcomes for complex oncologic operations and treatment at academic centers. For large retroperitoneal sarcomas, operative resection can be complex and require multidisciplinary care. We hypothesized that survival rates vary between type of treating center for patients undergoing resection for retroperitoneal sarcoma. Methods Patients with stage I to III nonmetastatic retroperitoneal sarcomas who underwent operative resection were identified from the National Cancer Database during the years 2004–2013. Treating centers were categorized as academic cancer centers or community cancer centers. Overall survival was analyzed by log‐rank test and graphed using Kaplan‐Meier method. Results A total of 2,762 patients were identified. A majority of patients (59.4%, n = 1,642) underwent resection at an academic cancer centers. Median age at diagnosis was 63 years old. Neoadjuvant radiotherapy was more common at academic cancer centers, while adjuvant radiotherapy was more common at community cancer centers. Improved overall survival was seen at academic cancer centers across all stages compared with community cancer centers (P = .014) but, after multivariable Cox regression analysis, was not a significant independent predictor of survival (hazard ratio = 0.91, 95% confidence interval, 0.79–1.04, P = .171). Academic cancer centers exhibited a greater rate of R0 resection (55.9% vs 47.0%, P < .001) and a lesser odds of positive margins (odds ratio 0.83, 95% confidence interval, 0.69–0.99, P = .044) after multivariable logistic regression. Conclusion Resection for retroperitoneal sarcoma performed at academic cancer centers was an independent predictor of margin‐negative resection but was not a statistically significant factor for survival. This observation suggests that site of care may contribute to some aspect of improved oncologic resection for retroperitoneal sarcoma.

The effect of smoking and major vein resection on post-therapy lymphedema in soft tissue sarcomas treated with neoadjuvant radiation and limb-salvage surgery.

For various reasons, some patients undergo a gross margin positive resection (R2) leading to a dilemma in care. We hypothesized that there is a subset of patients who have long‐term survival (LTS, ≥5 years) after R2 resection for retroperitoneal sarcoma (RPS).