Yr Disease-free Survival Research Articles

SOLE (Study of Letrozole Extension): A phase III randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph node-positive, early breast cancer (BC).

503 Background: In animal models of hormone receptor positive (HR+) breast cancer, acquired resistance to continued letrozole was shown to be reversed by estrogen-induced apoptosis. Sensitization to reintroduction of estrogen withdrawal by letrozole was hypothesized to improve treatment outcome. SOLE tested the hypothesis that 3 mos treatment-free intervals during extended adjuvant therapy will improve disease-free survival (DFS). Methods: SOLE enrolled 4884 postmenopausal women with HR+ lymph node-positive BC who had completed 4-6 yrs of adjuvant endocrine therapy (19% SERM, 43% AI, 38% both; stratification factor). Pts were randomly assigned to an additional 5 yrs continuous letrozole (2.5 mg daily; n = 2441) vs 5 yrs intermittent letrozole (taken for the first 9 mos of yrs 1-4, and 12 mos in yr 5; n = 2443). The primary endpoint was DFS (randomization until invasive local, regional, distant recurrence or contralateral BC; 2nd malignancy; death). Final analysis was at 665 DFS events, after 2 interim analyses. SOLE required 4800 pts for 80% power to detect a 20% DFS hazard reduction with 2-sided α = 0.05 using a stratified log rank test. Analysis is by intention-to-treat. Results: At 60 mos median follow-up, 5 yr DFS from randomization was 85.8% vs 87.5% for patients assigned intermittent vs continuous letrozole (HR = 1.08; 95% CI 0.93-1.26; P = 0.31). Similar outcome was observed for breast cancer-free interval (HR = 0.98; 95% CI 0.81-1.19), distant recurrence-free interval (HR = 0.88; 95% CI 0.71-1.09), and overall survival (HR = 0.85; 95% CI 0.68-1.07). AEs of grade > 3 were reported for 43.5% vs 41.6% of pts assigned intermittent vs continuous letrozole. Overall 24% pts discontinued letrozole early in both groups. Conclusions: Among postmenopausal women with HR+ BC, extended intermittent letrozole did not improve DFS vs continuous letrozole. The similar observed outcomes and incidence of AEs provides clinically relevant information on the intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks. Clinical trial information: NCT00553410.

Meta-analysis of disease free survival (DFS) as a surrogate for overall survival (OS) in localized renal cell carcinoma (RCC).

459 Background: OS is a critical endpoint for adjuvant RCC trials testing the benefit of early systemic therapy to increase cure rates, but requires long duration and significant patient resources. We explored the potential use of DFS as a surrogate for OS when assessing the efficacy of adjuvant therapy in localized RCC. Methods: We performed a systematic literature review following the PRISMA statement. Inclusion criteria required randomized controlled trials (RCT) for adjuvant systemic therapy in localized RCC, which reported on both DFS and OS. DFS was defined from randomization or nephrectomy (R/N) to the first evidence of clinical recurrence (loco-regional or distant) or death from any cause. OS was defined from R/N to death from any cause. We extracted data on hazard ratio (HR) and 5-year event free rate from Kaplan Meier estimates. We performed a meta-analysis and correlated these estimates for OS and DFS, weighted by number of DFS events. R-square >0.7 would indicate a strong correlation and potential surrogacy. Results: Of the more than 315 studies screened, 10 studies investigating various forms of cytokine and vaccine immunotherapy and angiogenesis inhibitors (e.g., sunitinib, sorafenib, thalidomide) between 1987 and 2016 were eligible for the analyses. The total enrolled patients were 5,497, with median follow-up ranging 3 to 10 years. Conclusions: Across trials of adjuvant systemic therapy for localized RCC, we observed a moderate correlation between 5 yr DFS and OS rate and between treatment effects (HRs) on these endpoints. Future meta-analyses of more mature trials in the era of modern adjuvant targeted therapy are needed to evaluate the surrogacy of intermediate endpoints. Further granularity may be achieved using individual patient data to assess different and earlier time points for surrogacy than are commonly reported. [Table: see text]

Abstract P6-09-20: Clinical utility of PgR with various cutpoints using 3 commercial assays relative to 15yr survival

Abstract Introduction: Hormone receptors ER and PgR are routinely assessed by pathologists using immunohistochemical (IHC) assays to guide treatment decisions. Patients who are hormone receptor positive are offered hormonal therapy, such as tamoxifen, which improves survival. Although both ER and PgR are evaluated, ER is primarily utilized for patient management as the clinical utility of PgR has not been clearly established according to CAP/ASCO guidelines. Notably, a meta-analysis by the Early Breast Cancer Trialists' Collaborative Group reported that PgR status was not significantly predictive of response to adjuvant tamoxifen, suggesting that PgR may not have a role in breast cancer management. More recently, the level of PgR expression has been hypothesized to be important in predicting response to endocrine therapy, where high PgR levels are more indicative of estrogen-dependent tumors, and thus more sensitive to hormonal treatment. In this study, we evaluate PgR expression using the current cut-point (Allred>2), as well as an optimized cut-point (Allred>5 to identify PgR high tumors), with regards to 15yr disease-free survival (DFS) and disease-specific overall survival (DSOS) using three commercially available ready-to-use (RTU) IHC assays from Dako, Leica and Ventana in an ER+ cohort. Methods: The Calgary tamoxifen breast cancer cohort (Calgary cohort) is a TMA series that includes 532 patients diagnosed with primary breast cancer (1985-2000) who received tamoxifen treatment regardless of hormone receptor status. All RTU assays followed vendor recommended protocols. Specific details regarding the cohort and IHC assays have been previously described (Kornaga et al. Mod Path 2016). All analyses were performed using Stata 12, and multivariate models were adjusted for age, grade, size, lymph node and HER2 status. ER status was defined by the corresponding vendor specific IHC assay. Results: Multivariate models looking at DFS are presented in Table 1. None of the assays were significant when the clinical cut-point was used; however, when the optimized cut-point was investigated, all assays found high expression of PgR was significantly associated with improved DFS. Table 2 presents the multivariate models looking at DSOS. Similarly, PgR was not found to be associated with improved DSOS using the current cut-point. When the optimized cut-point was examined, Dako and Leica assays were significantly associated with improved DSOS: The Ventana assay did not reach significance. Table 1 PgR15YR DFS CutpointHR95% CIp-valueDako>20.830.40-1.730.624Dako>50.560.35-0.910.020Leica>21.130.45-2.830.792Leica>50.520.30-0.890.017Ventana>20.730.32-1.670.460Ventana>50.570.34-0.970.037 Table 2 PgR15YR DSOS CutpointHR95% CIp-valueDako>20.740.33-1.650.464Dako>50.550.32-0.950.031Leica>20.880.35-2.220.780Leica>50.440.24-0.790.006Ventana>20.590.25-1.370.218Ventana>50.630.35-1.150.134 Conclusions: High PgR expression (Allred>5) is associated with improved 15yr DFS and DSOS in a tamoxifen-treated cohort, where PgR positivity defined using current guidelines is not associated with improved DFS or DSOS. Additionally, differences were noted between the vendor RTU assays with regards to DSOS. Citation Format: Kornaga EN, Paterson AHG, Feng X, Morris DG, Magliocco AM, Klimowicz AC. Clinical utility of PgR with various cutpoints using 3 commercial assays relative to 15yr survival [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-20.

PUB010 Intraoperative Blood Loss is an Independent Predictor of Poor Disease Free Survival for Patients Undergoing VATS Lobectomy for Lung Cancer

There are concerns regarding the independent effect of intra-operative estimated blood loss(EBL)on the oncological outcome of patients undergoing lung cancer surgery. A negative immunomodulatory effect has been hypothesized. These effects have been observed after conventional open surgery. Little is known in regards to the impact of blood loss in a VATS approach on outcome. Therefore, we sought to assess the effect of intraoperative blood loss on disease free survival for a select subset of patients undergoing VATS lobectomy for NSCLC. A prospectively collected lung cancer database was retrospectively reviewed to identify patients undergoing VATS lobectomy for NSCLC (2009-2014). Clinico-pathological characteristics and follow up data were retrieved from the database as well as the patients’ medical records. Cox regression analysis was used to identify independent predictors of disease free survival (DFS). In the study period, 551 VATS lobectomies were done (median age 72 years, 35% were males).Median Charlson comorbidity index (CCI) was 1. Median FEV1% and DLCO% were 91% and 83% respectively. The majority of patients were clinical stage 1 (459 patients, 83.3%; 3yr DFS: 85.5%). 80 % of the patients had adenocarcinoma histology, and moderately/poorly differentiated tumors represented 83%. Median OR-time and EBL were 132 minutes and 100 CC respectively. Conversion to thoracotomy was encountered in 30 patients (5.4%). 148 patients (26.9%) had post-operative complications [Clavien-Dindo (CD) >1]. Reoperation was needed in 9 patients (1.6%). 3 patients (0.5%) had 30-days postoperative mortality. Univariate predictors of poor DFS were male gender, former/current smokers, CCI>1, clinical stage III, moderate/poor differentiation, right side lobectomies and EBL ≥ 250cc.On multivariable analysis only male gender(HR: 1.79, 95%CI: 1.16-2.76), and EBL≥ 250cc (HR: 1.65, 95%CI: 1.04-2.61) independently predicted poor DFS. In patients undergoing VATS lobectomy for NSCLC, EBL was the only modifiable predictor of poor DFS. The results of this study should be cautiously interpreted and needs to be furtherly validated in larger data sets.

Non-Inferior Survival of Black Versus White Patients and Superior Outcomes for Black Females Compared to Other Race/Gender Groups Following Allogeneic Transplantation for Hematologic Malignancy: A Single Center Multivariable Analysis of 475 Allografted Patients

The effect of race on outcomes following allogeneic hematopoietic cell transplantation (allo-HCT) is unclear. Earlier studies suggested no clear difference between black and white patients for conventional allografts (Baker et al JCO 2005, 23:7032) and inferior outcomes for black patients following single unit umbilical cord blood transplants(UCBT) (Ballen et al BBMT 2012, 18:903). The advent of HLA-haploidentical donor transplantation using T-replete grafts and post-transplant cyclophosphamide (HIDT-ptCy) has improved donor availability for black patients. However, the effect of race on allograft outcomes in the era of HIDT-ptCy has not been reported. We compared outcomes by race in 475 consecutive patients (white=383, black=83, Asian =9) undergoing a first allograft for hematologic malignancy at our center between February 2005 and February 2014. Hispanic/latino was classified as an ethnicity separate from race and was not exclusive of race categories. Patients with < 8 of 8 HLA- A, B, C, DRB1 allele matched unrelated donors, and UCBT were excluded from the analysis. Supportive care algorithms and follow-up assessments were identical for all patients. Median follow-up for living patients was 45 months (range 12-120 months). Patient characteristics and outcome data were obtained from our institutional database where they had been prospectively documented. The Kaplan-Meier method was used to estimate overall survival (OS) and disease-free survival (DFS). Relapse and non-relapse mortality (NRM) were treated as competing risks. There were no significant differences in patient disease and transplant characteristics including Disease Risk Index (DRI) and HCT-CMI between the black and white patients except black patients were younger (median age 46 vs 53), more likely to receive HIDT-ptCy (61% vs. 17%) and less likely to be CMV seronegative pairs (12% vs 27%) (p<0.001 for all). Estimated outcomes at 2 yrs for black versus white patients were as follows: OS-71% vs. 62%( p=0.1, pointwise, p=0.04 Log-rank, Fig 1a); DFS 64% vs 50% (p=0.025 pointwise, p=0.06 Log-rank). Cumulative Incidences at 2 yrs were: NRM 13% vs 16%(p=0.5 pointwise, p=0.44 Gray's test) relapse 23% vs. 34% (p=0.02 pointwise, p=0.18 Gray's test). We found a strong interaction between race and gender for the outcomes assessed. Subsequent analysis were performed for four groups: Black female (BF, n=43), black male (BM, n=40), white female (WF, n=162), white male( WM, n=221). Black females had superior OS (2 yr OS 81%, 63%, 60%, 60% for BF, WF, WM, BM respectively, Log Rank p=0.02, Fig 1b) and DFS (2yr DFS 72%, 52%, 49%, 55% respectively, Log-rank p=0.04). NRM was not different between the four groups (2 yr NRM 12%, 16%, 15%, 15% respectively p=NS) but 2 yr relapse rates were significantly lower in BF (16%) than WF (32%) and WM (35%) (p=0.05 BF vs WF and p=0.01 BF vs WM). Multivariable Cox regression models were built to adjust for significant confounding variables with the race and gender combinations being the main compared group. When compared to WF as a baseline, BF had a significantly improved OS (HR 0.33, p=0.003), DFS (HR 0.49, p=0.025) and relapse rate (HR=0.45, p=0.046) but NRM was not statistically different. WM and BM were not significantly different from WF for any endpoint. These data demonstrate that in the current era when almost all black patients can find a fully matched conventional donor or a haploidentical donor, outcomes following allotransplants for hematologic malignancy for black patients are not inferior to those for white patients and may be superior for BF compared to other race/gender combinations. A lower relapse rate in BF appears to contribute to this difference. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Accelerated partial-breast irradiation (APBI) versus whole-breast irradiation (WBI) in treatment of the biological subtypes of breast cancer: An analysis of comparative effectiveness.

45 Background: To assess if partial vs whole breast irradiation (RT) in treatment of the various biological (bio-) subtypes of breast cancer would lead to differing clinical results, a match pair analysis of APBI vs WBI was undertaken. Methods: Between 3/1993 and 9/2013 all breast CA patients (pts) treated at one institute with either APBI or WBI were matched 1:1 by follow-up (FU) +/- 15 yrs, stage and bio-subtype. This yielded 772 pts of whom 640 were luminal A, 42 luminal B, 58 triple neg (TNBC), 6 HER2+, and 26 triple +. Outcomes were analyzed across the various bio-subtypes for all the pts (APBI + WBI), APBI alone and WBI alone. The endpoints assessed were local recurrence (LR), true recurrence/marginal miss (TR/MM), elsewhere failure (EF), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), and contralateral breast failure (CLBF). Results: Mean age was 66 (32-94) with a mean FU of 5.2 years (0.1-18.3). Regarding systemic therapy, 75% received endocrine Rx, while chemotherapy was documented in 21%. For all pts (APBI+WBI) there was no significant difference across the various bio-subtypes with respect to 5, 10 and 15 yr actuarial LR, TR/MM, EF, RR, DM, DFS and CLBF. Likewise, for the 386 APBI-alone treated pts, no significant difference was found between the various bio-subtypes for all the same endpoints reported. However, for the 386 WBI pts, a significant difference was seen in the 15-year actuarial LR between luminal A and TNBC (1.5% vs 7.4%, p = 0.007). Significance was also found in the 15-year actuarial DFS between luminal A/B and TNBC (98.0%, 95.2%; 86.0%, respectively, p = 0.009). Conclusions: In comparing partial to whole breast RT across the various biological subtypes of breast CA, APBI is at least as effective as WBI. However, the retrospective nature of this study along with the limited numbers of pts in the HER2+ and triple + subsets are weaknesses which are acknowledged to exist in this dataset. The addition of further pts in all the biological subtypes, particularly the HER2+ and triple + subsets, along with results from randomized trials incorporating biomarker data will be needed to substantiate these findings.

Abstract P3-09-02: Association between definitive surgery and times to administration of adjuvant chemotherapy and outcomes in early breast cancer: Analysis of adjuvant studies conducted by NCIC Clinical Trials Group (NCIC CTG)

Abstract Background: For early high risk breast cancer, adjuvant chemotherapy following definitive surgery is a current standard of care. However, the optimal time to commencement of therapy has not been well established. We evaluated the association between time to initiation of adjuvant chemotherapy after definitive surgery (sTTC) with survival. Methods: We retrospectively analyzed 4 NCIC CTG-led breast cancer adjuvant clinical trials involving women diagnosed from 1984 and 2005 with stage 1 to 3 breast cancer, who received adjuvant chemotherapy. Patient data were categorized into four time groups: &amp;lt; 4, 4-8, &amp;gt;8-12, &amp;gt;12 weeks after definitive surgery. Outcomes measured were: overall survival (OS) and disease-free survival (DFS). Results: 3837 patients were included in the final analysis. In univariate analysis, an improvement was identified for patients treated between &amp;gt;8 and 12 weeks: Number of Pts10 yr OS(%)p-value10 yr DFS(%)p-value&amp;lt;4 weeks77469.6ref60.9ref4-8 weeks226371.50.135164.70.1043&amp;gt;8-12 weeks74277.30.000272.60.0001&amp;gt;12 weeks3577.00.453173.90.2124 However, in multivariate analysis there was no significant association between any sTTC time periods and either outcome (see table below). Covariates which did show a significant association are listed in the table. OS p-valueDFS p-valueTime to Adjuvant &amp;lt;4 weeksrefref 4-8 weeks0.77620.6764 &amp;gt;8-12 weeks0.42510.1396 &amp;gt;12 weeks0.68610.9312Age&amp;lt;0.0001&amp;lt;0.0001BMI0.02380.0298Menopause Status0.01260.1226Performance Status 20.02560.1665Surgery Type&amp;lt;0.0001&amp;lt;0.0001Pathological Stage 30.00370.0229Positive Nodal Status&amp;lt;0.0001&amp;lt;0.0001ER Negative&amp;lt;0.0001&amp;lt;0.0001Chemotherapy Regimen&amp;lt;0.0001&amp;lt;0.0001 The fact that the statistical significance of sTTC in univariate analysis was lost when covariates related to DFS and OS were accounted for in a multivariate analysis suggested there might be a relationship between sTTC and the risk of adverse outcomes. A disease risk score analysis was therefore carried out, but there was no indication of an advantage to an earlier sTTC within disease risk categories. Conclusions: Within the context of chemotherapy given within 12 weeks, we were unable to demonstrate an effect on survival based on time to adjuvant chemotherapy in our multivariable analysis. Those treated later did not do significantly worse than those treated earlier. Significant covariates which effected survival were consistent with predictors of poor prognosis (younger age, poorer performance status, increased disease burden and receptor negativity). There is a potential relation of patient risk to time to treatment which requires further study. Citation Format: Ravi Ramjeesingh, Bingshu E Chen, Joseph L Pater, Liting Zhu, Margot Burnell, Vivien H Bramwell, Kathleen I Pritchard, Lois E Shepherd, Wendy R Parulekar. Association between definitive surgery and times to administration of adjuvant chemotherapy and outcomes in early breast cancer: Analysis of adjuvant studies conducted by NCIC Clinical Trials Group (NCIC CTG) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-09-02.

A Comparison of Outcomes Between Adolescents and Young Adults (AYA) and Children with Acute Promyelocytic Leukemia (APL): North American Intergroup Study CALGB 9710 (Alliance)

Purpose: Recent studies have demonstrated differential outcomes for adolescents and young adults (AYAs) vs. children treated for acute myeloid leukemia. Here we analyze outcomes by age group for APL patients treated on the North American Intergroup Study C9710.Methods: Patient characteristics and outcomes were compared between children (<15 yr, n=55) vs. AYAs (15-31 yr, n=42). To control for differences in treatment center, only young adults registered at Children’s Oncology Group (COG) treatment sites were included. Treatment included induction with daunorubicin, cytarabine and ATRA. All patients (pts) received two consolidation cycles with daunorubicin and ATRA and maintenance for one year with ATRA +/- mercaptopurine and methotrexate. Pts ≥15 yr were randomized to an additional two cycles of arsenic trioxide (ATO). Sub-group analysis was also performed to exclude pts ≥15 yr who received ATO and thus compare only patients <15 yr vs. ≥15 yr who had not received ATO.Results: Children and AYAs had similar characteristics of gender, race/ethnicity, Sanz risk grouping and M3v histology. Among all pts enrolled at COG sites on the study, complete response (CR) rates were similar (<15yr =85% vs. ≥15yr =81%, P=0.59). AYAs had improved 5 yr disease-free survival (DFS) from time of CR compared to younger pts (<15 yr =47% vs. ≥15 yr =70%, log rank P=0.05), and there was a trend toward difference in 5 yr event-free survival (EFS) (<15 yr =46% vs. ≥15 yr =63%, log rank P=0.13). Overall survival (OS) at 5 years was not significantly different (<15 yr =82% vs. ≥15 yr =75%, log rank P=0.47). Twenty-three of 42 pts ≥15 yr received ATO consolidation cycles, which may have contributed to their improved DFS and EFS. Thus, we analyzed outcomes by removing from the analysis patients ≥15 yr who received ATO consolidation cycles, and compared pts <15 yr who did not receive ATO (n=55) to pts ≥15 yr who were randomized to no ATO (n=19). CR rates were again similar (<15 yr =85% vs. ≥15 yr no ATO =84%, P=1.0). There was no significant difference in other outcomes including 5-yr DFS from time of CR (<15 yr =47% vs. ≥15 yr no ATO =63%, log rank P=0.31), 5-yr EFS (<15 yr =46% vs. ≥15 yr no ATO=53%, log rank P=0.89), or 5-yr OS (<15 yr =82% vs. ≥15 yr no ATO=79%, log rank P=0.78).Conclusions: The C9710 study demonstrated improved EFS, DFS and OS among adult patients receiving ATO consolidation compared to those who did not receive ATO (Powell et al., Blood, 2010). The current analysis of results for AYAs versus younger pediatric pts showed improved DFS among the whole AYA cohort (of which 55% received ATO consolidation) compared to pts <15 yr (of which 0% received ATO). When the analysis was restricted to AYA pts not receiving ATO, however, the results of this intergroup APL trial showed similar CR, DFS, EFS and OS for AYAs and younger pts. Thus, unlike other subtypes of AML, APL appears to have a consistent response across the pediatric and AYA age groups. The most recent COG clinical trial in APL is now evaluating whether pediatric patients can also benefit from ATO consolidation. DisclosuresOff Label Use: Daunorubicin- labeled for use in AML for adults and for pediatric ALL (not pediatric AML) Arsenic Trioxide- labeled for use in relapsed/refractory APL (not de novo APL) Mercaptopurine and Methotrexate- labeled for use in pediatric ALL (not APL).

T-Cell Depleted (TCD) Hematopoietic Stem Cell Transplantation (HCT) For Adult Patients With Acute Myelogenous Leukemia (AML) In First and Second Remission: Long-Term Disease Free Survival(DFS) With a Significantly Reduced Risk Of Graft-Versus-Host Disease(GvHD)

IntroAllogeneic-HCT is recommended for AML patients (pts) in CR2, in CR1 with poor-risk cytogenetics, and should be considered for those in CR1 with intermediate-risk. Non-relapse mortality (NRM) and GVHD remain major causes of treatment failure. Ex vivo TCD can prevent GvHD but large case series have not been published. MethodsA retrospective chart review was conducted to evaluate 178 pts with AML in CR1 and CR2 undergoing TCD-HCT between 2001 and 2011. All pts received myeloablative-conditioning. The majority received ATG for graft rejection prophylaxis. Acute (A) and chronic(c) GVHD were assessed by standard criteria. No GVHD prophylaxis was administered post-transplant. Soybean agglutination+sheepRBC rosetting (sRBCR) was used for BM TCD. CD34+ selection +/- sRBCR was used for PBSC TCD. Pt characteristics were compared using Pearson's chi-squared and Fisher's exact tests. Prognostic factors relating to overall survival (OS) and DFS, including age, gender, leukemia etiology, cytogenetic-risk group, donor-type, TCD-method, conditioning-regimen, HLA match grade, HCT-specific comorbidity index and immune reconstitution were evaluated using log-rank test statistics. Differences in cumulative incidence (CI) rates were evaluated using Gray's test. Cox proportional-hazards regression was used to further adjust for pt risk factors for OS and DFS. ResultsPt characteristics and outcomes are summarized in Tables 1 and 2. Median follow-up of survivors is 52 mo (12-134). 177 pts engrafted. One died pre-engraftment, 7 developed late graft-failure (GF), and 3 are alive after a 2nd HCT. One yr incidence of aGVHD was low (grade 2-4 13%, 3-4 3%). Only 1 pt developed cGVHD by NIH consensus criteria. Univariate association between CR status (1 vs 2), OS and DFS was not statistically significant (p=0.17 and 0.16, respectively). After adjusting for HLA status, age, sex, cytogenetic risk, and regimen, CR2 pts had an increased risk of death (HR: 1.90 (1.14-3.16), p= 0.014). In CR1 pts, cytogenetics was associated with relapse incidence (p=0.003) and was highest in patients with adverse cytogenetics (31%, 95%CI 16-48) and <10% in intermediate I-II risk pts. Overall CI relapse at 1 and 2 yrs was 13% and 16%, respectively. Causes of death were: relapse (n=29), infection (n=25), GVHD (n=7), organ toxicities (n=5), GF (n=2) and other (n=7).Female gender was significantly associated with decreased OS and DFS (p<0.002 and 0.003, respectively). Two yr estimates of OS and DFS in females vs males was 51% vs. 71% and 49% vs. 69%, respectively. These differences were due to a higher NRM in females receiving the chemotherapy based regimen (p<0.001). Gender difference was not observed in pts receiving TBI-based regimens (p=0.599). This difference persisted after adjusting for other common prognostic factors in a multivariate model. For the entire group, 2yr OS and DFS was 67% and 62%, respectively. For CR1 pts, 2 yr OS and DFS was 70% and 64%, respectively (Fig.1). ConclusionThese results support the use of TCD HCT in AML pts in CR. Durable DFS and long-term OS can be achieved with low rates of GVHD without compromising the graft-vs-leukemia effect. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Two Chemotherapy-Based Conditioning Regimens Compared To TBI-Based Conditioning Secure Consistent Engraftment Of T-Cell Depleted Allogeneic HSCT, Similarly Low Incidences Of Gvhd and Favorable Rates Of Disease-Free Survival (DFS)

To ascertain the therapeutic potential of non-TBI-based conditioning for CD34+ HPC-selected , T cell-depleted allografts, we conducted a trial comparing our standard regimen, arm (A) 1375cGy HFTBI+ thiotepa,5 mg/kg/day x 2 days + cyclophosphamide 60 mg/kg/day x 2 days vs. arm (B) Busulfex 0.8 mg/kg/6h x12 (dose adjusted) + melphalan 70 mg/kg/day x 2 + fludarabine 25 mg/m2/day x5 and arm (C) Clofarabine 20 mg/m2/day x 5 + melphalan 70 mg/m2/day x 2 + thiotepa 5 mg/kg/day x2, as preparation for T-cell depleted CD34+ PBSC transplants from GCSF-mobilized leukocytes fractionated with the CliniMACS device. Primary endpoints were engraftment, GVHD, transplant-related mortality (TRM) and 2 yr OS and DFS (Confer Table). Stratification of pts to arms A (standard), B or C was based on the patient's disease, disease stage and clinical factors such as age, prior therapy or comorbidities enhancing risks of TBI. Arm B was the non-TBI arm predominantly used for myeloid and Arm C for lymphoid malignancies. Prior to transplant, recipients of HLA-matched or non-identical transplants received rabbit thymoglobulin at 2.5 mg/kg/day x2 or 3 days respectively, to prevent graft failure. No GVHD drug prophylaxis was given post transplant. A total of 181 consecutive patients, accrued between 5/13/2010 and 6/12/2013, were analyzed (81 in arm A, 78 in arm B, 22 in arm C). These pts have been followed for a median of 12.1 months. Donors were related or unrelated and HLA-matched for 74% of the patients and 1-2 HLA allele disparate for 26%. Median age for the entire group was 50.5 years, with older pts predominating in the non-TBI groups (medians arm A ,31.9 yrs; arm B , 61.9 yrs; arm C, 44.6 yrs). The CD34+ PBSC transplants provided a mean dose of 9.7x106 CD34+ progenitors/Kg (range 1.4-89.7) and 4.5x103 CD3+ T-cells/Kg (range 0.6-25.3). All pts engrafted; but 2 pts (2.5%) in arm B experienced late graft failure, one of whom was reconstituted after a secondary graft. Overall the incidence of grade II-IV acute GVHD was 18%, and 14% for recipients of HLA-matched grafts. TRM at 1 year was 10% in Arm A, and 15% in Arms B and C. Two year OS and DFS for each arm are: arm A, 66.7% and 58.4%; arm B 62.3% and 59.5%; arm C 52% and 53%. For the 101 pts who received standard risk transplants (i.e., pts with high risk forms of AML, ALL or NHL in 1o CR, AML in 2o CR, MDS RA/RCMD, CML in 1o CP or MM in CR1, VGPR or first PR ), 2 year OS and DFS are: arm A 68% and 62%; arm B 67% and 66%; arm C 86% and 86%, with relapse rates at 2 yrs of: arm A 23%, arm B 15%, and arm C 14%. These results thus identify two non-TBI-based conditioning regimens that secure consistent engraftment of rigorously T-cell depleted allogeneic HSCT and can yield favorable long-term DFS and OS with low incidences of GVHD and relapse.Table 1Overall ResultsGraft1 YearAcute GVHD II – IV2 YearPTsENGFailureTRMALLHLA-MatchedO.S.DFSARM A8181010%23%17%66.7%58.4%ARM B7878215%12.3%13%62.3%59.5%ARM C2222015%27%20%52%53% Disclosures:No relevant conflicts of interest to declare.

1758 THE PROGNOSTIC ROLE OF PT2 STRATIFICATION IN BLADDER UROTHELIAL CARCINOMA

INTRODUCTION AND OBJECTIVES: We evaluated the prognostic role of pT2 subtaging according to 2009 TNM staging system in muscle invasive bladder cancer. METHODS: Between January 1998 and October 2010 data of radical cystectomies performed at three different institutions were collected in a prospectively-maintained database. Out of 2224 patients, we selected 368 (16.4%) patients with non metastatic pT2 urothelial carcinoma of the bladder not receiving neoadjuvant therapies. All patients underwent pelvic lymph node dissection at least up to iliac bifurcation. Univariable analysis was performed to test the effect of age, gender, pathological T (pT) and N (pN) stages, lymph-node count (LN-c), lymph-node density (LN-d) and extent of pelvic lymph node dissection (PLND) on disease-free survival (DFS) and cancer specific survival (CSS). Significant variables (log-rank p 0.05) were entered in a multivariable Cox-regression model to identify independent prognostic factors. RESULTS: Out of 368 patients, 152 were pT2a (41.3%) and 216 were pT2b (58.7%). The rate of positive nodes was 46.2%. The median number of nodes removed was 20 (IQR 12-34) and 24 (IQR range 14-41) for the pT2a and pT2b group, respectively. Significant variables at univariable analysis were age, gender, pT, pN, LN-d and extent of PLND. At log-rank test 5yr DFS and CSS of the two groups (pT2a and pT2b) were significantly different (log rank p 0.015 and 0.007 for DFS and CSS, respectively). At Cox regression analysis age, pT and LN-d were independent predictor of DFS [Age: p 0.004, HR 0.98 (95% CI: 0.96-0.99)], [pT2a vs pT2b: p 0.021, HR 1.67 (95% CI: 1.08-2.60)], [LN-d: p 0.001, HR 21.89 (95% CI: 7.17-66.83] and CSS [Age: p 0.001, HR 0.97 (95% CI: 0.95-0.98)], [pT2a vs pT2b: p 0.005, HR 2.07 (95% CI: 1.25-3.42)], [LN-d: p 0.001, HR 25.21 (95% CI: 7.18-88.54)]. CONCLUSIONS: Invasion of deep muscular layer is an independent predictor of oncologic outcome regardless of nodal status and substaging pT2 urothelial carcinomas at radical cystectomy into pT2a and pT2b has a significant prognostic role.

Positive Positron Emission Tomography (PET) Scan in Non-Hodgkin Lymphoma Pre-Transplant Had No Impact On Relapse and Survival After Allogenenic Transplantation

AbstractAbstract 1999Allogeneic donor hematopoetic stem cell transplantation (HCT) is increasingly used for patients with non-Hodgkin lymphoma (NHL). Positron emission tomography (PET) has become a standard for lymphoma evaluation and a valuable prognostic tool to risk-stratify treatment and time of the autologous HCT. Role of PET imaging in allogeneic HCT setting is controversial.We sought to investigate the value of PET status pre-transplantation and at day 100 post donor HCT as an indicator predictive of relapse and survival post allograft.Seventy-three patients (median age 50 years [range 2–69 years]) with NHL received allogeneic HCT at University of Minnesota from 2004–2010 and had PET imaging within 4 weeks pre-transplant. All PET and CT images were reviewed centrally by nuclear medicine radiologist. Follicular lymphoma (n=26) was more common than large cell, mantle cell lymphoma and others. PET scan pre-transplant was positive in 44 patients (PET+ group 57% vs PET- group 43%). Two thirds of PET+ group were in partial remission (PR), 7% CR and 16% were chemo-refractory prior to transplant compared to 25% in PR, 68% in CR and 7% refractory in PET+ cohort (p<0.01). Forty percent had PET-avid extra-nodal involvement. In both PET positive and negative groups the two thirds received reduced intensity conditioning and related donor (52% and 51%) or umbilical cord blood grafts (55% and 41%, respectively).5-years disease-free survival (DFS) and overall survival (OS) of the cohort was 51% (95%CI 35– 64%) and 60% (95%CI 44–73%). DFS and OS of PET+ group was similar to PET- group (DFS: 50% vs 52%, p=0.31; OS: 63% vs 56%, p=0.63). In univariate analysis, the lymphoma subtype, disease status at transplant, extranodal disease, elevated LDH, high B2 macroglobulin or marrow involvement at the time of transplant had no impact on survival or relapse rate.At median follow-up of 3.33 years (range 1.00–6.74) the cumulative 2 year relapse rate was 17%; similar in PET+ and PET- groups (19% [95% CI 7– 31%] vs 15% [95% CI 1– 28%]; p=0.48). Transplant mortality at 1-year was low for entire cohort (11% [95% CI 3–18%]) and particularly low in follicular lymphoma (4% [95%CI 0–10%]) compared to DL/MCL (10% [95%CI 0–21%]) and other NHL (25% [95%CI 4–46%]; p=0.51). PET status (pos vs neg) had no impact on grade III-IV acute GVHD and chronic GVHD.Fifty-four patients with available surveillance PET evaluation at day 100 post-transplant. The 1-year relapse rate and 5 yr DFS was significantly improved for those patient who were PET-negative (day 100 PET- vs PET+ group: relapse 9% vs 42%; p<0.01; DFS 57% vs 25%, p<0.01 and OS 68% vs 59%, p=0.63).In conclusion, pre-allo HCT PET scan for NHL does not predict transplant outcomes, however negative PET scan 100 days post-allo SCT is a valuable tool predictive of superior transplant DFS. Future studies evaluating role of PET in patients with specific lymphoma subsets and development of novel peri-transplant or post-transplant interventions for patients at high relapse risk are warranted. Disclosures:Off Label Use: decitabine for relapsed ALL vorinostat for relapsed ALL.

Autologous and Allogeneic Donor Transplantation for Mantle Cell Lymphoma in Rituximab Era: Impact of Pre-Transplant Burden On Survival.

AbstractAbstract 3092▪▪This icon denotes a clinically relevant abstractThe survival for patients with mantle cell lymphoma (MCL) can be prolonged by the use of rituximab-containing intensive chemotherapies and hematopoietic cell transplantation (HCT). However, the optimal application of autologous and allogeneic HCT in the rituximab era remains uncertain.We report 66 patients with MCL who underwent HCT (38 autologous and 28 allogeneic) at the University of Minnesota between 1999–2010. Eighty eight percent received a Rituximab-containing induction chemotherapy. Autologous HCT patients were older (66% were ≥60 years of age), 70% were in CR1 and all except 1 were chemosensitive. Two patients had minimal residual disease in the marrow (MRD) and two-thirds were PET negative at the time of transplant. Allogeneic HCT patients were younger (85% were <60 years old), 19% were in CR1 and 21% had chemo-resistant disease. At the time of transplant, 80% of allogeneic patients were PET positive and 18% of patients had detectable marrow MCL. Allogeneic recipients had a significantly longer time from diagnosis to transplant (allo 17.7 months vs auto 7.6 months; p≤0.01).At a median follow-up of 3.5 years (range 1.1–9.2 years), the 5-year disease free survival (DFS) and overall survival (OS) of the autologous cohort were 59% and 62%, respectively (Table). In univariate analyses for DFS, younger age, absence of splenic and extranodal disease at diagnosis and shorter time to transplant were significantly associated with better survival (age <60 vs. ≥60 yrs 92% [95 CI 57–99%] vs. 43%[95 CI 18–66%]; p=0.04; extra nodal disease positive 25% [95 CI 2–63%] vs negative 77% [95 CI 48–91%]); p=.02; diagnosis to HCT time <8 months vs. ≥8 months 79% [95 CI 51–92%] vs 32% [95 CI 7–62%]; p=0.03). Patients with residual disease pre auto HCT (PET scan + and/or MRD) had significantly worse DFS (residual disease positive: 46% (95 CI 14–73%) vs negative 68% (95 CI 33–87%); p=0.04). The type of induction chemotherapy, disease status (CR1 vs other), blastoid variant or comorbidity index did not impact DFS or OS. The cumulative incidence of relapse and treatment related mortality (TRM) are shown. Notably, none of the patients with negative pre auto- transplant PET scan and lack of MRD relapsed at 2 years (p=<.01). In multivariate analysis, residual lymphoma (by PET or MRD pos) was the single significant factor associated with 5-fold lower rate of DFS compared to no residual disease (HR: 5.26 (96% CI 1.17–23.55); p=0.03).Twenty-eight patients received allogeneic transplants (17 sibling donor, 10 umbilical cord blood, 1 unrelated donor). Half were transplanted using a reduced intensity conditioning (RIC) regimen and five patients failed a prior autograft. At a median follow-up of 6.7 years (range 1–10.3 years), the 5-year DFS and OS were 34% and 52%, respectively (Table). In univariate analysis the 5 year DFS was not significantly affected by chemosensitivity, disease status, PET positivity or MRD prior to transplant (Chemo sensitive: 41% (95 CI 20–61%) vs. resistant 17% (95 CI 1–52%) p=.38; CR1/PR1 40% (95 CI 5–75%), resistant 17% (95 CI 1–52%%), relapse 42% (95 CI 18–65) p=.66; PET pos 33% (95 CI 10–59%) vs PET neg 67% (95 CI 5–95%) p=.63). DFS following myeloablative (MA) conditioning was similar to that of RIC (43% [95 CI 16–68%] vs. 27% [95 CI 8–50%]; p=.57); MRD not shown). OS was not significantly affected by PET or marrow status prior to HCT. The cumulative incidence of 2 year relapse and 1 year TRM are shown. No relapses occurred in the MA cohort compared to a 29% relapse rate (95 CI 6–53%) after RIC HCT (p=.08). Conversely, 2 year TRM for allograft recipients was 2 times higher with MA conditioning (33% (95 CI 7–59%) compared to RIC (15% (95 CI 0–32%); p=.29).Survival of MCL patients post autologous and allogeneic HCT has improved in the last decade. Long-term disease control is observed following autologous HCT in CR1 or for relapsed MCL, particularly if a PET negative state can be attained pre-transplant. Patients with more advanced disease and higher MCL burden prior to HCT can benefit from allogeneic transplantation. Novel therapies designed to better control MCL pre-transplant and to reduce post-transplant relapse after RIC HCT may further improve survival.Transplant Type5 yr DFS (95% CI)5yr OS (95% CI)2 yr Relapse (95% CI)1 yr TRM (95% CI)Autologous59% (37-76%)62% (39-79%)14% (3-24%)5% (0-12%)Allogeneic34% (17-51%)52% (32-69%)25% (8-43%)19% (4-34%) Disclosures:No relevant conflicts of interest to declare.

Prognostic significance of high-risk human papilloma virus (HPV), p16, and p53 status in women with vulvar squamous cell carcinoma (VSCC).

5105 Background: The incidence of VSCC is increasing. Studies suggest the presence of two histologically and molecularly distinct subsets of VSCC; one contingent on and another independent of HPV infection. However, it is uncertain if HPV status has prognostic significance. HPV oncoproteins can result in degradation of the tumor suppressor p53, cell cycle deregulation and abnormal expression of cyclin dependant kinase inhibitor p16. The aim of this study was to investigate HPV infection, p16 and p53 in relation to clinical parameters in women with VSCC. Methods: Sequential cases of VSCC from patients (pts) treated at Princess Margaret Hospital (PMH) from 2000 to 2008 were reviewed. HPV infection was evaluated by Roche Linear array. A tissue microarray was constructed. p16 and p53 immunohistochemistry was performed. Clinical data was abstracted from medical records and PMH Cancer Database. Survival analysis was performed using Kaplan-Meier curves and log rank test. Results: We identified124 pts with VSCC. HPV was detected in 43/123 (35%) pts (median age 71 ± 16 yrs). HPV16 was the most common serotype (38/43; 88.4%). p16 was expressed in 30/115 (26%) pts and p53 in 59/117 (50.4%) pts. Median age of pts was not different in relation to HPV, p16 and p53 status. Expression of p16 (p&lt;0.0001) and loss of p53 (p=0.007) were associated with HPV infection. Pts with HPV positive tumors were less likely to recur (recurrence rate at 5 years (RR) 12.5% vs 50.3%, p=0.009). HPV positive VSCC were not associated with better 5 yr disease free survival (DFS), 58% vs 31%; p=0.15, or overall survival (OS), 61% vs 61% ; p=0.94. p16 positive tumors had a lower RR at 5 yrs, 23.8% vs 59%, p=0.006 and better 5yr DFS (61% vs 27% ; p=0.009) but not significant for OS (65% vs 59%; p=0.94). Among pts with HPV positive VSCC, OS and DFS were not different between p16 positive and negative VSCC. In the 46 pts treated with radiotherapy, HPV and p16 positive tumors were associated with a lower RR (p=0.004 and 0.005). p53 expression was not prognostic in any pt group. Conclusions: Women with HPV-positiveVSCC have a lower risk of disease recurrence. p16-expressing VSCC are associated with reduced disease recurrence and improved DFS.

Quantitating pathologic response to neoadjuvant chemotherapy in KRAS-mutated versus nonmutated lung cancers.

7014 Background: Trials of neoadjuvant chemotherapy in non-small cell lung cancers (NSCLC) have demonstrated that pathologic response correlates with downstaging and survival. There is controversy as to whether KRAS mutated patients (pts) have the same benefit with adjuvant chemotherapy as non-mutated pts however the impact of KRAS mutations on response to neoadjuvant therapy has not been reported. Methods: Pts with resectable stage I-III non-squamous NSCLCs were treated with 4 cycles of cisplatin, docetaxel, and bevacizumab, followed by surgical resection. Tumors were tested for KRAS mutations. Percent treatment effect (necrosis, inflammation, fibrosis) was quantified histologically. Pts were followed until disease recurrence and/or death. Binary variables were compared using the Fisher’s Exact Test. Survival was assessed by pathological response based on the literature (≥90 vs &lt;90%) using the Kaplan-Meier method, stratified by stage (IB-IIB vs. III) and by KRAS mutation. Results: We accrued 51 pts. 34/51 (67%) had clinical stage IIIA disease. 48 had molecular testing: 14/48 (29%) had KRAS mutations and 4/48 (8%) had EGFR mutations. The median follow-up was 2 years (yr) (range, 3-63 months). 41 pts had resection and analysis for pathological response. The 2 yr disease free survival (DFS) and overall survival (OS) were superior in the 11/41 (27%) with ≥90% versus those with &lt;90% treatment effect: DFS 91% vs. 56%, p=0.029 and OS 100% vs. 60%, p=0.013. These outcomes remained significant when adjusted for stage. For pts with KRAS mutations, 0 of 10 tumors analyzed had ≥90% treatment effect whereas 11 of 31 (35%) pts with wild-type KRAS had ≥90%, p=0.039. There was an inferior median OS for KRAS mutated pts (22 months) compared to pts without a known KRAS mutation, (Not Reached, p=0.03). Conclusions: Following neoadjuvant chemotherapy, pts with tumors having ≥90% necrosis had improved survival. There were no patients with KRAS mutation that achieved ≥90% treatment effect in response to cisplatin, docetaxel, and bevacizumab. Adaptive adjuvant trial strategies to improve upon outcomes of those with &lt;90% necrosis at resection and new approaches specifically targeting KRAS-mutated NSCLCs are needed.

Evaluation of relapse-free survival in T3N0 colon cancer: The role of chemotherapy—A multicentric retrospective analysis.

e14082 Background: Use of adjuvant chemotherapy (AC) in Stage II Colon Cancer (CC) is still under debate. Choice should be based on patients (pts) and disease characteristics. According to worldwide guidelines AC should be considered in high-risk (H) T3N0 pts. No data are available for better option in low-risk (L) pts. Aim of the study is to evaluate relapse-free survival (RFS) and disease-free survival (DFS) retrospectively in T3N0 CC pts related to treatment. Methods: RFS and DFS are evaluated with Kaplan Meier method. In order to find the optimal cut off for node number the receiver operating characteristics curve analysis and Maximally Selected Rank Statistics were performed. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15 respectively. Results: 1,000 pts with T3N0 CC were recruited. To date, data of 926 pts are available. Median age was 69 (29-93), M/F 513/413, Grading 1/2/3 46/668/158; 360 L (39%), 411 H (44%), 155 unknown (17%); 137 (15%) pts showed symptoms (S) at diagnosis: 51 pts had perforation (P) or bowel obstruction (BO). Median sampled lymph nodes (LN) were 15 (1-76); 383 (41%) pts were treated with AC. Median follow up (fu) was 5 years (yr) (range 3-24). Survival analysis was performed only for pts with a minimum fu of 3 yr and younger than 80 (80%). 5 yr RFS was 78% and 5 yr DFS was 76% At multivariate analysis S and AC were prognostic factors for RFS. AC is prognostic factor for all endpoints (data are shown in table). In L group 5 yr RFS was 88% in treated pts and 75% in non-treated pts (p 0.03); in H group was respectively 82% and 72% (p 0.006). Conclusions: Preliminary data confirmed the role of known prognostic factors and suggest the relevance of AC also in L stage II T3N0 CC pts. However, the highest risk in L subgroup should be identified to be submitted to AC. Data collection is ongoing, update results will be presented. [Table: see text]

Evaluation of relapse-free survival in T3N0 colon cancer: The role of chemotherapy—A multicentric retrospective analysis.

578 Background: Use of adjuvant chemotherapy (AC) in stage II colon cancer (CC) is still under debate. Choice should be based on patients (pts) and disease characteristics. According to worldwide guidelines AC should be considered in high-risk (H) T3N0 pts. No data are available for better option in low-risk (L) pts. Aim of the study is to evaluate relapse-free survival (RFS) and disease-free survival (DFS) retrospectively in T3N0 CC pts related to treatment. Methods: RFS and DFS are evaluated with Kaplan Meier method. In order to find the optimal cut off for node number the receiver operating characteristics curve analysis and maximally selected rank statistics were performed. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15 respectively. Results: 1,000 pts with T3N0 CC were recruited. To date, data of 764 pts are available. Median age was 68 (29-93), M/F 42/344, grading 1/2/3 40/561/132; 303 L (40%), 356 H (46%), 105 unknown (14%); 121 (16%) pts showed symptoms (S) at diagnosis: 43 pts had perforation (P) or bowel obstruction (BO). Median sampled lymph nodes (LN) were 15 (1-76); 339 (44%) pts were treated with AC. Median follow up (fu) was 5 years (yr) (range 3-24). Survival analysis analysis was performed only for pts with a minimum fu of 3 yr and younger than 80 (79%). 5 yr RFS was 79% and 5 yr DFS was 77%. At multivariate analysis S, LN and AC were prognostic factors for RFS. AC is prognostic factor for all endpoints (Table). In L group 5 yr RFS was 88% in treated pts and 71% in non-treated pts (p 0.004); in H group was respectively 84% and 70% (p 0.002). Conclusions: Preliminary data confirmed the role of known prognostic factors and suggest the relevance of AC also in L stage II T3N0 CC pts. However, the highest risk in L subgroup should be identified to be submitted to AC. Data collection is ongoing. [Table: see text]

A North American population-based outcome for early-stage ovarian clear cell carcinoma (OCCC).

5062 Background: OCCC is regarded as having a poor outcome and being relatively treatment resistant. Recent Japanese data instead have demonstrated high survival in early stage and radiation sensitivity. This study was carried out to reproduce/refute these findings in a North American setting. Methods: Women with OCCC who had attended one of the four British Columbia Cancer Agency (BCCA) centers have staging, pathological, treatment, and outcome data recorded in a computerized database. Irradiation (XRT) plus platin-based chemotherapy was the standard treatment. XRT usage mandated all such women provincially attending a BCCA centre. However, individual physicians within BCCA differed in their uptake of XRT. Outcomes with or without XRT could be compared. Univariate and multivariate (decision-tree analysis) analyses for disease-free survival (DFS) were performed. Results: 241 Stage I-II women attended between January 2000 and December 2008 (IA/IB n=64; Ic n=147; II n=30). 5 year and 10 year DFS for stage IA/B; IC and II were 85 and 70%; 64 and 58%; and 43 and 43% respectively. IC subsets faired differently: rupture alone (spontaneous and surgical were equivalent) - 5 yr DFS 80% versus 34% if cytologically positive and 43% with surface involvement. Decision-tree analysis identified cytologic positivity as the most important factor (recurrence 27% if negative, 72% if positive). Surface involvement then further subdivided the cytologically positive: surface involved 93% recurrence, if not involved 60%. XRT had no effect in stage IA (85% DFS at 5 yrs with or without it) but was superior to chemotherapy alone in IC (5 yr DFS 68% vs 58%, 10 yr DFS 63% vs 52%, HR 0.59). Conclusions: Stage IA OCCC has an excellent long-term outcome as does IC (rupture only). IC otherwise has a poor outcome as does stage II. XRT and chemotherapy improves outcome in stage IC versus chemotherapy alone.

Viscum album fermentatum Pini versus oral etoposide as adjuvant treatment in osteosarcoma patients after second relapse.

TPS331 Background: Patients with localized osteosarcoma can be cured in approximately 60% of cases with neoadjuvant chemotherapy, only few experimental drugs are available for relapsed and inoperable patients. We know from historical controls that after the second relapse the risk of further relapses increases. The 12-months disease-free survival (DFS) after the second relapse is about 12% in our historical controls (Fagioli F2002, Bacci G 2005). Oral etoposide is often used in clinical practice due to some evidence of effectiveness when administered iv as second-line treatment. Viscum fermented mistletoe extract (Viscum Loranthaceae) is a phytocompound popular in cancer treatment across central Europe with immunomodulatory activity. Encouraged by the preliminary findings in 4/5 osteosarcoma patients treated with Viscum: who experienced a DFS > 12 months after their second relapse, we designed a phase II study randomized, prospective study. Methods: In June 2007 after approval by ethic committee a phase II, prospective, two-arm, randomized clinical study started comparing Viscum album fermentatum Pini ( s.c., 3 times/wk) for 1 year versus etoposide (50 mg/m2 orally, day 1-21, every 28 days for 6 cycles) in patients with diagnosis of high-grade osteosarcoma free from disease after second relapse, with age > 10 yrs, ECOG performance status 0-2, no other concomitant antitumoral treatment, no other past or present malignancies, normal renal, hepatic, and bone marrow function. Principal endpoint: 1 yr DFS of 40% in one of the two arm compared to a historical group (12%). Secondary end points are quality of life according to EORTC QLQ-C30 and evaluation of immune modulation measured by Natural Killer lymphocytes T,IL2, IL12, IL15, gamma IFN, and IP10. To date we have enrolled 13 pts, 6 in the Viscum arm and 7 in the etoposide arm. Median follow-up time is 15 months (5-30) while the study is in progress. Accrual is still open to at least 20 patients. Preliminary data are reported about toxicity and DFS. No significant financial relationships to disclose.

Results of Chemotherapy Alone, with Sequential or Concurrent Addition of 52 Weeks of Trastuzumab in the NCCTG N9831 HER2-Positive Adjuvant Breast Cancer Trial.

Abstract Background: N9831 is the only randomized phase III trial comparing safety and efficacy of the addition of trastuzumab (H) to doxorubicin and cyclophosphamide then paclitaxel (Arm A: AC→T) either following (Arm B: AC→T→H) or starting concurrently with paclitaxel (Arm C: AC→T+H→H) for women with resected Stage I-III invasive HER2+ breast cancer. The 3 yr cumulative incidence of NYHA class III or IV congestive heart failure or sudden cardiac death was previously reported: 3.3% in Arm C, 2.8% in Arm B (Perez EA, et al. JCO 2008). The comparison of AC→T to AC→T+H→H was reported in a joint analysis of N9831 and NSABP B-31 in 2005 and updated in 2007, demonstrating a 52% reduction in risk of a disease event (Romond E et al., NEJM 2005; Perez EA, et al. ASCO 2007).Materials and Methods: Primary endpoint is disease-free survival (DFS). At the second planned interim analysis of Arm A vs. Arm B, the O’Brien-Fleming boundary (OFB) was crossed. NCCTG Independent Data Safety Monitoring Committee approved the release of these data as well as the data pertaining to Arm B vs. Arm C due to slow pace of events [expected 647 events in 4 yr follow-up period (f/u) vs. actual 334 events in 4.5 yr f/u]. Shortly thereafter, there were sufficient events to perform the first planned interim analysis of B vs. C. We present the results of each of these pairwise comparisons taking into account the potential for crossover to Arm C after the release of the joint analysis findings in 2005.Results: From 5/2000 to 4/2005, 2448 eligible women were enrolled for the Arm A (n=1087) vs. Arm B (n=1097) comparison. Median f/u is 5.5 yrs. with 386 events. The addition of trastuzumab sequentially to AC→T significantly improved DFS, univariately [HR(Arm B/Arm A)=0.70, 95% CI: 57-86%, logrank p=0.0005] and after adjusting for age, tumor size, number of positive nodes, and ER [PPH: HRadj=0.67 (95% CI: 0.55-0.82)]. 5 yr DFS was increased from 72% with AC→T to 80% with AC→T →H.From 5/2000 to 4/2005, 1903 eligible women were enrolled for the Arm B (n=954) vs. Arm C (n=949) comparison. Median f/u is 5.3 yrs. with 312 events. The log-rank p-value testing whether DFS differs with respect to starting time of trastuzumab was 0.019. [Not crossing pre-specified OFB for statistical significance]. After adjusting for tumor size, number of positive nodes, and ER, HRadj(Arm C/Arm B)=0.75 (95% CI: 0.60-0.94)]. 5 yr DFS was increased from 80% with AC→T →H to 84% for AC→T+H →H.Conclusions: DFS is significantly improved with the addition of 52 weeks of H (sequentially or concurrently) to AC→ T. There is a statistically significant 33% reduction in the risk of an event with the sequential addition of H following AC→T. There is a strong trend for a 25% reduction in the risk of an event with starting H concurrently with T relative to sequentially after T. Therefore, based on a positive risk/benefit ratio, we recommend that trastuzumab be incorporated in a concurrent fashion with T chemotherapy.Acknowledgements: NIH CA25224, Breast Cancer Research Foundation, Genentech. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 80. NOTE: This abstract was accepted for presentation at the Symposium after the Abstract Book went to press.