Southwest Oncology Group Research Articles

Predictive markers in colorectal cancer: where are we now?

Heinz-Josef Lenz speaks to Ruth Williamson, Commissioning Editor: Heinz-Josef Lenz is Professor of Medicine and Professor of Preventive Medicine, and holds the Kathryn Balakrishnan Chair for Cancer Research. He is associate director of clinical research and co-chair of the Gastrointestinal Oncology Program at the University of Southern California (USC) Center for Molecular Pathways and Drug Discovery at the University of Southern California Keck School of Medicine and USC/Norris Comprehensive Cancer Center in Los Angeles (CA, USA). Dr Lenz received his medical degree from Johannes-Gutenberg Universität in Mainz, Germany, and went on to complete a residency in hematology and oncology at the Eberhard-Karls Universität Tübingen, Germany, before completing clerkships in oncology and hematology at George Washington University (WA, USA) and the Beth Israel Hospital of Harvard Medical School (MA, USA), respectively. He completed a postdoctoral fellowship in the Department of Biochemistry and Molecular Biology at the USC Keck School of Medicine. Dr Lenz’s research focus is in the identification of biomarkers in gastrointestinal cancers, early drug development and novel clinical trials. He is co-chair of Southwest Oncology Group Gastrointestinal Committee, co-chair of Southwest Oncology Group Gastrointestinal Translational Medicine and a member of the NCI Gastrointestinal Steering Committee, NCI Gastroesophageal Task Force and NCI Correlative Science Committee. He is the USC principal investigator on the U01, N01 and U10 NIH grants and NIH contract with City of Hope and the University of California Davis.

Effectiveness of first line treatment with bortezomib prior to autologous stem cell transplantation for multiple myeloma

Background: In this retrospective study we evaluated effectiveness and safety of first- line treatment with bortezomib and dexamethasone in multiple myeloma patients, comparing our results with already published clinical studies. Methods: Patients received bortezomib as part of everyday clinical practice and according to the latest guidelines of the Združenje hematologov Slovenije . Patients who were previously treated with first-line VAD (vincristine, doxorubicin modified with farmarubicine, dexamethasone), but due to uneffectiveness changed the treatment to bortezomib, were also included in the study. In 30 patients effectiveness was evaluated after average 3–4 cycles of bortezomib and dexamethasone according to the modified Southwest Oncology Group criteria. Treatment effectiveness was evaluated according to the previous VAD treatment, renal function and cytogenetic analysis. Side effects and reasons for early treatment discontinuation were described. Results: Patients received 2 to 8 cycles (median 4 cycles) of bortezomib and dexamethasone treatment. After average 3–4 cycles, 80 % of patients acheived good treatment response (56.7 % very good partial response, 23.3 % partial response). We observed that the treatment effectiveness was not influenced by previous VAD treatment, renal insufficiency and negative cytogenetic analisys, since we observed similar rates of very good partial response and partial response in patients without previous VAD treatment (82.3 % vs. 76.9 %), normal renal function (85.7 % vs. 75 % ) and normal cytogenetics (77.8 % vs. 80 %), although statistical evaluation was not possible due to small number of patients. The most common side effect was neuropathy (40 %) and in 5 patients (16.6 %), due to grade 3 or more, the treatment was discontinued. Other side effects were: anemia (26.6 %), infection (166 %), thrombocytopenia (10 %), neutropenia (6.6 %), gastrointestinal problems (23.3 %) and herpes zooster (6.6 %). Conclusions: Bortezomib (Velcade) in combination with dexamethasone is an effective and safe first-line multiple myeloma treatment and is not influenced by renal insuficience, unfavourable cytogenetic analysis or previous uneffective VAD treatment.

Impact of disease progression date determination on progression‐free survival estimates in advanced lung cancer

In patients with advanced lung cancer, overall survival is largely influenced by progression status. Because progression-free survival (PFS)-based endpoints are controversial, the authors evaluated the impact of the progression date (PD) determination approach on PFS estimates. Individual patient data from 21 trials (14 North Central Cancer Treatment Group trials and 7 Southwest Oncology Group trials) were used. The reported PD (RPD) was defined as either the radiographic scan date or the clinical deterioration date. PD was determined using Method 1 (M1), the RPD; M2, 1 day after the last progression-free scan; M3, midpoint between the last progression-free scan and the RPD; and M4, an interval-censoring approach. PFS was estimated using Kaplan-Meier (M1-M3), and maximum-likelihood (M4) methods. Simulation studies were performed to understand the impact of the length of time elapsed between the last progression-free scan and the PD on time-to-progression estimates. PFS estimates using the RPD were the highest, and M2 was the most conservative. M3 and M4 were similar because the majority of progressions occurred during treatment (ie, frequent disease assessments). M3 was influenced less by the length of the assessment schedules (percentage difference from the true time-to-progression, <1.5%) compared with M1 (11% to 30%) and M2 (-8% to -29%). The overall study conclusion was unaffected by the method used for randomized trials. The magnitude of difference in the PFS estimates was large enough to alter trial conclusions in patients with advanced lung cancer. The results indicate that standards for PD determination, the use of sensitivity analyses, and randomized trials are critical when designing trials and reporting efficacy using PFS-based endpoints.

Ten-year Follow-up of Neoadjuvant Therapy with Goserelin Acetate and Flutamide Before Radical Prostatectomy for Clinical T3 and T4 Prostate Cancer: Update on Southwest Oncology Group Study 9109

To update the results with 10-year data of a phase II prospective trial of neoadjuvant hormonal therapy with goserelin acetate and flutamide followed by radical prostatectomy for locally advanced prostate cancer (SWOG 9109). The optimal management for clinical stage T3 and T4 N0,M0 prostate cancer is uncertain. Sixty-two patients with clinical stage T3 and T4 N0,M0 prostate cancer were enrolled. Cases were classified by stage T3 vs T4 and by volume of disease (bulky >4 cm and nonbulky ≤ 4 cm). Fifty-five of 61 eligible patients completed the trial with radical prostatectomy after neoadjuvant androgen deprivation therapy (ADT). The median preoperative prostate-specific antigen value was 19.8 ng/mL, and 67% of patients had a Gleason score of ≥ 7. Among 41 patients last known to be alive, median follow-up is 10.6 years (range 5.1-12.6). In all, 38 patients have had disease progression (30/55, 55%) or died without progression (8/55, 15%) for a 10-year progression-free survival (PFS) estimate of 40% (95% CI 27-53). Median PFS was 7.5 years, and median survival has not been reached. The 10-year overall survival (OS) estimate is 68% (95% CI 56-80). In this small, prospective phase II study, neoadjuvant hormonal therapy with goserelin acetate and flutamide followed by radical prostatectomy achieves long-term PFS and OS comparable with alternative treatments. This approach is feasible and may be an alternative to a strategy of combined radiation and ADT.

Costs of early adjuvant radiation therapy after radical prostatectomy: a decision analysis

This analysis was carried out to evaluate the cost-effectiveness of adjuvant radiation therapy (ART) versus observation, using a decision analysis model based primarily upon the published results of the Southwest Oncology Group prospective trial (SWOG 8794). A decision analysis model was designed to compare ART versus observation over a 10-year time horizon. Probabilities of treatment success, utilization of salvage treatments, and rates of adverse events were taken from published results of SWOG 8794. Cost inputs were based on 2010 Medicare reimbursement rates. Primary outcome measure was incremental cost per prostate-specific antigen (PSA) success (i.e. serum PSA level <0.4 ng/ml). ART results in a higher PSA success rate than observation with probability of 0.43 versus 0.22. The mean incremental cost per patient for ART versus observation was $6023. The mean incremental cost-effectiveness ratio was $26,983 over the 10-year period. ART appears cost effective compared with observation based upon this decision analysis model. Future research should consider more costly radiation therapy (RT) approaches, such as intensity-modulated RT, and should evaluate the cost-effectiveness of ART versus early salvage RT.

Clinical research progression in chemoradiation therapy for resectable gastric cancer

In recent years, based on the phase III clinical study, postoperative chemoradiation, perioperative chemotherapy with ECF regimen and postoperative adjuvant chemotherapy with oral S-1 have become the standard adjuvant treatment of resectable gastric adenocarcinoma in the United States, Europe, and Japan, respectively. Since the Southwest Oncology Group in 2001 reported a large phase III randomized clinical trial INT0116, adjuvant chemoradiotherapy has become a standard treatment for gastric adenocarcinoma. With the rapid development of chemoradiotherapy technique, clinical researches for using operation combined with chemoradiotherapy to treat gastric adenocarcinoma emerged one after another, including adjuvant postoperative chemoradiation, preoperative chemoradiation, and chemoradiation combined with intraoperative radiotherapy and so on. This review will summarize the recent treatment protocol using chemoradiotherapy for resectable gastric adenocarcinoma, and comprehensively evaluate the clinical value and significance of chemoradiotherapy for resectable gastric adenocarcinoma.

Use of Fluorescence In Situ Hybridization to Predict Response to Bacillus Calmette-Guérin Therapy for Bladder Cancer: Results of a Prospective Trial

No reliable methods currently exist to predict patient response to intravesical immunotherapy with bacillus Calmette-Guérin given after transurethral resection for high risk nonmuscle invasive bladder cancer. We initiated a prospective clinical trial to determine whether fluorescence in situ hybridization results during bacillus Calmette-Guérin immunotherapy can predict therapy failure. Candidates for standard of care bacillus Calmette-Guérin were offered participation in a clinical trial. Fluorescence in situ hybridization was performed before bacillus Calmette-Guérin, and at 6 weeks, 3 months and 6 months during bacillus Calmette-Guérin therapy with maintenance. Cox proportional hazards regression was used to assess the relationship between fluorescence in situ hybridization results and tumor recurrence or progression. The Kaplan-Meier product limit method was used to estimate recurrence-free and progression-free survival. A total of 126 patients participated in the study. At a median followup of 24 months 31% of patients had recurrent tumors and 14% experienced disease progression. Patients who had positive fluorescence in situ hybridization results during bacillus Calmette-Guérin therapy were 3 to 5 times more likely than those who had negative fluorescence in situ hybridization results to experience recurrent tumors and 5 to 13 times more likely to have disease progression (p <0.01). The timing of positive fluorescence in situ hybridization results also affected outcomes. For example, patients with a negative fluorescence in situ hybridization result at baseline, 6 weeks and 3 months demonstrated an 8.3% recurrence rate compared to 48.1% for those with a positive result at all 3 points. Fluorescence in situ hybridization results can identify patients at risk for tumor recurrence and progression during bacillus Calmette-Guérin immunotherapy. This information may be used to counsel patients about alternative treatment strategies.

High-Dose Chemotherapy As Adjuvant Therapy in Breast Cancer: Could There Be a Survival Benefit?

TO THE EDITOR: Results of the recent meta-analysis by Berry et al provide evidence that high-dose chemotherapy (HDC) with hematopoietic stem-cell support prolongs relapse-free survival but does not improve overall survival in patients with high-risk primary breast cancer. In my opinion, a clinical point that needs to be stressed further is the striking 6% rate of death resulting from toxicity in the HDC group (procedure related, in most cases). The high mortality rate is attributable, at least in part, to the use of bone marrow as a source of stem cells in some patients and the highly toxic high-dose regimens (ie, carmustine containing) used in early studies. When patients whose deaths were attributed to toxicity were excluded, an HDC advantage in terms of overall survival was also observed. These data are clinically relevant, because HDC with peripheral-blood stem-cell support is today a safe procedure with a mortality rate and quality-adjusted survival parameters similar to those of conventional therapies. Furthermore, as pointed out by Berry et al, the control arms of some studies (eg, those by the Scandinavian Breast Group and Southwest Oncology Group) have involved nonconventional treatment with increased dose intensity. It would be interesting to know the survival data of only those studies—the vast majority—in which real, conventional control arms have been used. Mauro Moroni San Carlo Borromeo Hospital, Milan, Italy

Economic Evaluation of Genomic Test–Directed Chemotherapy for Early-Stage Lymph Node–Positive Breast Cancer

Multi-parameter genomic tests identify patients with early-stage breast cancer who are likely to derive little benefit from adjuvant chemotherapy. These tests can potentially spare patients the morbidity from unnecessary chemotherapy and reduce costs. However, the costs of the test must be balanced against the health benefits and cost savings produced. This economic evaluation compared genomic test-directed chemotherapy using the Oncotype DX 21-gene assay with chemotherapy for all eligible patients with lymph node-positive, estrogen receptor-positive early-stage breast cancer. We performed a cost-utility analysis using a state transition model to calculate expected costs and benefits over the lifetime of a cohort of women with estrogen receptor-positive lymph node-positive breast cancer from a UK perspective. Recurrence rates for Oncotype DX-selected risk groups were derived from parametric survival models fitted to data from the Southwest Oncology Group 8814 trial. The primary outcome was the incremental cost-effectiveness ratio, expressed as the cost (in 2011 GBP) per quality-adjusted life-year (QALY). Confidence in the incremental cost-effectiveness ratio was expressed as a probability of cost-effectiveness and was calculated using Monte Carlo simulation. Model parameters were varied deterministically and probabilistically in sensitivity analysis. Value of information analysis was used to rank priorities for further research. The incremental cost-effectiveness ratio for Oncotype DX-directed chemotherapy using a recurrence score cutoff of 18 was £5529 (US $8852) per QALY. The probability that test-directed chemotherapy is cost-effective was 0.61 at a willingness-to-pay threshold of £30 000 per QALY. Results were sensitive to the recurrence rate, long-term anthracycline-related cardiac toxicity, quality of life, test cost, and the time horizon. The highest priority for further research identified by value of information analysis is the recurrence rate in test-selected subgroups. There is substantial uncertainty regarding the cost-effectiveness of Oncotype DX-directed chemotherapy. It is particularly important that future research studies to inform cost-effectiveness-based decisions collect long-term outcome data.

Identifiability and Estimation of Causal Effects by Principal Stratification With Outcomes Truncated by Death

In medical studies, there are many situations where the final outcomes are truncated by death, in which patients die before outcomes of interest are measured. In this article we consider identifiability and estimation of causal effects by principal stratification when some outcomes are truncated by death. Previous studies mostly focused on large sample bounds, Bayesian analysis, sensitivity analysis. In this article, we propose a new method for identifying the causal parameter of interest under a nonparametric and semiparametric model. We show that the causal parameter of interest is identifiable under some regularity assumptions and the assumption that there exists a pretreatment covariate whose conditional distributions among two principal strata are not the same, but our approach does not need the assumption of a mixture normal distribution for outcomes as required by Zhang, Rubin, and Mealli (2009). Hence, the proposed method is applicable not only to a continuous outcome but also to a binary outcome. When some of the assumptions are violated, we discuss biases of estimators and propose methods to reduce these biases. We conduct several simulation studies to evaluate the finite-sample performance of the proposed approach. Finally, we apply the proposed approach to a real dataset from a Southwest Oncology Group (SWOG) clinical trial.

Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer

BackgroundLapatinib (GW572016) is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/ErbB2), which are reported as overexpressed in 15%–45% of gastric cancers, making them potential targets. Patients and methodsThe primary objective of this study was to assess response rate. Secondary objectives included overall survival (OS), toxicity, and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome. Lapatinib was administered to chemonaive metastatic gastric cancer patients at a dose of 1500 mg orally daily for 28 days. ResultsThe study enrolled 47 patients from February 2005 until May 2006. Four patients (9%) had a confirmed partial response (PR), 1 (2%) had an unconfirmed PR, and 10 (23%) had stable disease. Median (95% confidence interval) time to treatment failure was 1.9 (1.6–3.1) months and OS was 4.8 (3.2–7.4) months. Significant adverse events: one grade 4 cardiac ischemia/infarction, one grade 4 fatigue, and one grade 4 emesis. One treatment-related death was due to central nervous system ischemia. An exploratory analysis of markers revealed gene expression of HER2, interleukin (IL)-8 and genomic polymorphisms IL-8, and vascular endothelial growth factor correlated with OS. ConclusionsLapatinib is well tolerated, with modest single-agent activity in advanced/metastatic gastric cancer patients. Potential molecular correlatives were identified which warrant further validation.

Survival Disparities Between African-American and Caucasian Patients Treated with Autologous Stem Cell Transplantation for Multiple Myeloma Are Eliminated in the Era of Novel Therapeutics

Abstract 2017 Background:Multiple myeloma (MM) remains an incurable disease and is the most common hematologic malignancy among African-Americans. In the United States, MM and its precursor monoclonal gammopathy of undetermined significance (MGUS) are twice as common in African Americans (Hari et al 2010). Analysis of the Surveillance Epidemiology and End Results (SEER) database from 1969 to 2003 demonstrated African-Americans have twice the mortality from MM compared to Caucasians. However this may be a function of the considerable difference in incidence of MM between Caucasian and African-American populations. Retrospective data from Southwest Oncology Group showed comparable outcomes between groups before the advent of autologous stem cell transplantation (auto-HCT). Recently Hari et al. determined that African-American and Caucasians have similar outcomes after auto-HCT for MM. In the age of novel therapy, Waxman et al addressed racial disparity in population based query of SEER and found disease specific survival was greater for African-Americans than Caucasians; and over time, survival improvement was much less pronounced among African-Americans than Caucasians. Nevertheless transplant specific data is sparse in the contemporary era with novel treatment options. Methods:We performed a retrospective review of 196 African-American multiple myeloma patients (pts) and 806 Caucasian patients initially seen at the M.D. Anderson Cancer Center from 1/1/2002 to 12/31/2010 who underwent autologous transplantation after high dose chemotherapy. The year 2002 was used to incorporate patients who had been exposed to novel agents. Results:A total of 1002 patients were analyzed, 196 African American and 806 Caucasian pts with multiple myeloma who underwent an autologous transplant. Median age at diagnosis was 59 years for both cohorts. Initial response prior to transplant was fairly evenly matched between groups (TABLE 1) as well as final response after transplant. 25% of Caucasian pts and 21% of African-American pts achieved a very good partial response (VGPR) while 28% of Caucasian and 21% of African-American pts achieved a complete response (CR). For evaluable patients, the International Staging System (ISS) at diagnosis was determined. The percentage of stage I, II and III patients in the African-American group was 27%, 20% and 17% respectively. The percentage of stage I, II and III patients in the Caucasian group was 26%, 19% and 17% respectively. Importantly 133/806 of Caucasians and 33/196 of African Americans were diagnosed at ISS stage III (p value=0.91). There was no measurable difference in progression free survival (figure 1) or overall survival (figure 1figure 2) with a maximum follow-up of >100 months.Table 1Caucasian (n = 806)African-American (n = 196)Median age at auto-HCT59 (31–80)59 (34–78)Age over 65 at auto-HCT178/806 (22%)26/196 (13%)Response prior to transplantPD = 46 (6%)PD = 13 (6%)SD = 68 (8%)SD = 12 (6%)MR = 29 (3. 5%)MR = 11 (6%)PR = 437 (54%)PR = 102 (52%)VGPR = 179 (23%)VGPR = 38 (19%)CR = 35 (4%)CR = 13 (7%)Untreated = 2 (0. 2%)Unknown = 7 (4%)Unknown = 10 (1. 3%)Median time from diagnosis to transplant237 days (51– 7985)238 days (83 – 6495)Final ResponsePD = 24 (3%)PD = 9 (5%)< PR = 90 (11%)< PR = 32 (16%)PR = 260 (32%)PR = 69 (35%)VGPR = 198 (25%)VGPR = 42 (21%)CR = 227 (28%)CR = 41 (21%)Unknown = 7 (1%)Unknown = 3 (2%)ISS scoreI = 210 (26%)I = 52 (27%)II = 157 (19%)II = 39 (20%)III = 133 (17%)III = 33 (17%)Unknown = 306 (38%)Unknown = 72 (36%)Median PFS36 months34 monthsMedian OS46 months48 monthsPD: progressive disease SD: stable disease MR: minimal response PR: partial responseVGPR: very good partial response CR: complete response [Display omitted] [Display omitted] Conclusion:In this retrospective single-center study we demonstrated no difference in progression free survival or overall survival between African-American and Caucasian patients with MM treated in the era of novel agents and autologous stem cell transplantation. These findings concur with previous studies showing no difference in response to treatment between racial groups. In light of older SEER data this may be an effect of novel agents, improved access of care for African Americans or a combination of both. Disclosures:No relevant conflicts of interest to declare.

Targeted Therapy in Lung Cancer; Lessons Learned from Past Experiences

Targeted Therapy in Lung Cancer; Lessons Learned from Past Experiences

S0356: A Phase II Clinical and Prospective Molecular Trial With Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy Before Surgery for Patients With Esophageal Adenocarcinoma

Pathologic complete response (pCR) after neoadjuvant therapy for locally advanced esophageal adenocarcinoma is associated with improved survival. The Southwest Oncology Group designed a trimodality, phase II, single-arm trial with objectives of achieving a pCR rate of 40% with prospective exploratory analyses of intratumoral molecular markers postulated to affect response and survival. Patients with clinically staged II or III esophageal adenocarcinoma received oxaliplatin 85 mg/m(2) on days 1, 15, and 29; protracted-infusion fluorouracil (PI-FU) 180 mg/m(2)/d on days 8 through 43; and external-beam radiation therapy (EBRT) 5 days a week at 1.8 Gy/d for 25 fractions; surgery was performed 28 to 42 days after neoadjuvant therapy. Chemotherapy was planned after surgery. Tumors were analyzed for mRNA expression and polymorphisms in genes involved in drug metabolism and DNA repair. Ninety-three patients were evaluable. Two deaths (2.2%) were attributable to preoperative therapy, and two deaths (2.2%) were attributable to surgery. Grade 3 and 4 toxicities were recorded for 47.3% and 19.4% of patients, respectively. Seventy-nine patients (84.9%) underwent surgery; 67.7% of patients had R0 resections. Twenty-six patients (28.0%) had confirmed pCR (95% CI, 19.1% to 38.2%). At a median follow-up of 39.2 months, estimates of median and 3-year overall survival (OS) were 28.3 months and 45.1%, respectively. Intratumoral ERCC-1 gene expression was inversely related to progression-free survival and OS. Neoadjuvant oxaliplatin, PI-FU, and EBRT for esophageal adenocarcinoma is active and tolerable. Because the regimen failed to meet the primary end point, it does not define a new standard. However, future trials can be built on this platform to validate the role of ERCC-1 in determining the best systemic regimen for individual patients.

Commentary on adjuvant chemotherapy for the older woman with early stage breast cancer

The number of older women diagnosed with early stage breast cancer has increased in recent years, due to improved general health and an average life expectancy of around 80 years in many countries. In the US, the average age at diagnosis of breast cancer is 63 years and in most instances is early stage disease. Many of these women are fit with no or minimal co-morbid illnesses and have a predicted longevity of many years into the future. Thus, decisionmaking regarding adjuvant chemotherapy options is an increasingly common clinical challenge. What age defines an “older woman with breast cancer” in and of itself is controversial, but for the purpose of this commentary will generally refer to 65 years of age and older. The extent of clinical trial-based evidence on the benefit of adjuvant chemotherapy in older women is limited, resulting in a lack of statistical power to address the benefits and risks of these treatments in age subgroups over 65, especially 70+ or 75+ years. Meta-analyses help in this regard, but outcomes are still unstable in the 70+ age group due to relatively small subsets. This leads to uncertainty in degree of benefit to adjuvant chemotherapy in older women. While large cancer clinical trials cooperative groups generally accrue women and African Americans at rates commensurate with their frequency in the general population, this is not the case for older persons with cancer. For example, in the Southwest Oncology Group (SWOG) experience, marked underaccrual of patients over age 65 occurred, even after mandates to Medicare to cover the costs of clinical trials. Across 12 common cancer types for the years 1993–1996, 1997–2000 and 2000–2003, respectively, only 25%, 31% and 38% were over age 65, versus 61% in the general population. The reason for this under-accrual of older patients (and resulting limited data on chemotherapy efficacy) is multi-factorial, but more recent analyses suggest that stringent trial eligibility criteria and

Liver, Gastrointestinal, and Cardiac Toxicity in Intermediate Hepatocellular Carcinoma Treated With PRECISION TACE With Drug-Eluting Beads: Results From the PRECISION V Randomized Trial

The purpose of our study was to evaluate hepatic, gastrointestinal, and cardiac toxicity after PRECISION transarterial chemoembolization (TACE) with drug-eluting beads (DEB) versus conventional TACE with doxorubicin in the treatment of intermediate-stage hepatocellular carcinoma (HCC). Two hundred twelve patients (185 men and 27 women; mean age, 67 years) were randomized to TACE with DEB or conventional TACE. The majority of patients (67% in both groups) presented in a more advanced stage. Safety was measured by rate of adverse events (Southwest Oncology Group criteria) and changes in laboratory parameters. Cardiotoxicity was assessed with left ventricular ejection fraction (LVEF) mainly on MRI or echocardiography. The mean maximum postchemoembolization alanine transaminase increase in the DEB group was 50% less than in the conventional TACE group (p < 0.001) and 41% less in respect to aspartate transaminase (p < 0.001). End-of-study values returned to approximately baseline levels but with greater variability in conventional TACE patients. Treatment-emergent adverse events in the hepatobiliary system organ class occurred in 16.1% of DEB group patients compared with 25% of conventional TACE patients. There were fewer liver toxicity events in the DEB group. There was a small but statistically significant difference in mean change from baseline in LVEF between the two groups of 4 percentage points for the conventional TACE group (95% CI, 0.71-7.3; p = 0.018). PRECISION TACE with DEB loaded with doxorubicin offers a safe therapy option for intermediate-stage HCC, even in patients with more advanced liver disease.

Impact of residual normal metaphases in core binding factor acute myeloid leukemia

Karyotype allows for stratification of outcomes in acute myeloid leukemia (AML) patients. Previous data suggested that the presence of residual normal cells improved the prognosis in patients with monosomy 7. The Southwest Oncology Group (SWOG) reported the impact of residual normal metaphases in AML patients with monosomal karyotype (MK) and found a similar relationship. We determined the influence of residual normal metaphases in patients with core binding factor (CBF) AML. The presence and total number of normal and abnormal metaphases were tallied for patients with CBF AML treated in 10 consecutive SWOG trials and used as a variable to determine the effect on complete remission, refractory disease, and overall survival (OS) rates. Among 113 CBF AML patients, median age of diagnosis was 45 years (range, 18-77 years), and median OS was 4 years (CI-2 years-not reached). Patients with inv(16) and no normal metaphases had improved OS compared with those with 1+ normal metaphases (P = .00005), whereas no difference was noted for patients with t(8;21). Multivariate analysis demonstrated that having cells with a normal karyotype had a negative impact on survival (HR, 2.11; 95% CI, 1.09-4.08; P = .026). This shorter survival was a consequence of a higher rate of refractory disease in older patients (OR, 1.03; 95% CI, 0.9998-1.06; P = .05) and in those with normal metaphases (HR, 1.26 95% CI, 1.04-1.51; P = .02). In patients with CBF AML, the presence of cells with normal metaphases and increasing age negatively affect the prognosis, especially in patients with inv(16).

Abstract PL03-03: High-risk/triple-negative breast cancer and African ancestry

Abstract Variation in breast cancer incidence and outcome is well-documented between geographically separated populations on a worldwide basis. Several factors contribute to these trends and observations, including lifestyle, diet, environment, culture, and genetics. The United States is characterized by a richly-diverse population with regard to ethnic/racial background as well as all of the other factors listed that account for differences in cancer burden. Disparities in breast cancer burden between ethnic/racially-delineated subsets of the American population are well-documented by the Surveillance, Epidemiology, and End Results (SEER) Program, the Centers for Disease Control (CDC) and the North American Association of Central Cancer Registries (NAACCR)(1–3). Ward et al (1) demonstrated the expected adverse effects of poverty on cancer survival for men and women of all ethnic backgrounds, and prevalence of socioeconomic disadvantages is higher for ethnic minorities such as African Americans and Hispanic/Latino Americans. Even within discrete strata of socioeconomic status however, disparities in cancer survival are seen between communities defined by ethnic background. However as shown by Newman et al (4), breast cancer survival studies that account for socioeconomic status reveal a persistent nearly-30% higher mortality hazard for African American compared to White American patients. Disentangling the effects of race/ethnicity, culture, and socioeconomic resources on cancer risk is further confounded by the fact that we rely on self-reporting of patient race/ethnic background when in fact an individual's lineage may have included contributions from several different ancestral populations. The ethnic/racial composition of the U.S. is shifting in favor of increased diversity. An improved understanding of the multi-factorial etiology of healthcare disparities is therefore critical for improved cancer control among contemporary as well as future generations of our diverse patient population. Clinical trials and the study of breast cancer subtypes are shedding more light on breast cancer risk as it correlates with ethnic/racial background. Among the 156,570 prospectively-followed postmenopausal participants of the Women's Health Initiative protocols followed for a median of 6.3 years, risk of being diagnosed with estrogen receptor-negative, high-grade breast cancer was nearly five time higher for African American compared to White American women (adjusted OR = 4.70, 95% CI = 3.12 to 7.09), and mortality was higher for the African American breast cancer patients as well (HR = 1.79, 95% CI = 1.05 to 3.05). Carey et al (5) analyzed immunohistochemical surrogate markers for basal breast cancer subtypes among the Carolina Breast Cancer Study dataset, and reported an increased prevalence of these more aggressive tumors among premenopausal African American women (39%) compared with postmenopausal African American women (14%) and non-African American women (16%) of any age (P&amp;lt;.001). Albain et al (6) reviewed the collective, organ-specific protocols of the Southwest Oncology Group (SWOG) and found that equal treatments within the context of the standardized clinical trials mechanism, except for the hormonally-driven cancers such as breast and prostate. For these cancer sites, significantly worse outcomes were observed for the African American clinical trial participants. The triple-negative molecular marker status has become a common clinical surrogate to identify the basal breast cancer subtype, and several population-based as well as single institution studies have now documented an approximately two-fold higher risk of triple-negative breast cancer among African American compared to White American women. Furthermore, an expanding database of international breast cancer studies are now revealing even higher risk of triple-negative breast cancers among western sub-Saharan African women. It is possible that use of genotyping technology will refine studies of cancer risk related to ancestral heritage. Use of Ancestry Informative Markers (AIMs), also called Ethnic Difference Markers, may provide a more objective strategy for defining and quantifying racial/ethnic background. These AIMs can estimate the extent of an individual's West African, European, Native American, East Asian, and South Asian ancestry (7–17). Ongoing studies seek to evaluate the optimal genetic patterns and markers for these types of association studies. This presentation will include preliminary findings from an ongoing international collaboration between the University of Michigan and the Komfo Anoyke Teaching Hospital in Kumasi, Ghana. This research partnership involves the study of breast disease patterns and molecular markers in western, sub-Saharan Africans compared with those of African Americans and White Americans. This collaborative effort has demonstrated a correlation between frequency of high-risk/triple-negative breast cancer and presumed extent of African ancestry (18), and it has also served as a model for establishing other international oncology research programs. (19, 20)

8546 POSTER A Phase II Study of Docetaxel, Cisplatin, and Oral S-1 Induction Chemotherapy Followed by Chemoradiotherapy in Advanced Squamous Cell Cancer of the Head and Neck – Preliminary Results: a Trial of the Korean South West Oncology Group

8546 POSTER A Phase II Study of Docetaxel, Cisplatin, and Oral S-1 Induction Chemotherapy Followed by Chemoradiotherapy in Advanced Squamous Cell Cancer of the Head and Neck – Preliminary Results: a Trial of the Korean South West Oncology Group

Chemotherapy-Based Treatment for Castration-Resistant Prostate Cancer

Most men with metastatic prostate cancer respond to various types of androgen ablation but progress to castration-resistant disease. The TAX 327 and Southwest Oncology Group (SWOG) 99-16 clinical trials established docetaxel-based chemotherapy as preferred first-line treatment for most men with symptomatic metastatic castration-resistant prostate cancer (mCRPC). However, only about half receive benefit from docetaxel, and those who respond initially progress and eventually die of (or with) mCRPC. Both cellular mechanisms and the tumor microenvironment are implicated in the development of resistance to docetaxel. New agents are being evaluated for men with mCRPC, either as first-line treatment in combination with docetaxel, or in men progressing during or after treatment with docetaxel. Thus far, agents evaluated in phase III trials in combination with docetaxel have not improved outcome, including the vaccine GVAX, high-dose vitamin D (DN-101), and the antiangiogenic agent bevacizumab. In contrast, cabazitaxel, a taxane that is not cross-resistant to docetaxel, substantially improved the outcome of men progressing during or after treatment with docetaxel-based chemotherapy when compared with mitoxantrone and prednisone. However, translation of benefit of cabazitaxel demonstrated in the TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer) trial into general oncologic practice will be challenging because this agent may cause serious toxicity. With the approval of less toxic hormonal agents (eg, abiraterone acetate) in the setting of docetaxel-resistant mCRPC, clinicians will have an opportunity to balance benefits and harms of new agents in an individual patient and may be able to use different agents in sequence.