Kaplan-Meier Estimates Of Overall Survival Research Articles

Efficacy of Induction Selection Chemotherapy vs Primary Surgery for Patients With Advanced Oral Cavity Carcinoma

The University of Michigan has investigated the use of induction selection (IS) with chemoradiotherapy (CRT) for patients who respond to CRT and found this approach effective in the management of advanced laryngeal cancer. The IS approach was extended to oral cavity squamous cell carcinoma (OCSCC) to help understand whether organ preservation or survival benefit resulted. To evaluate the efficacy of an IS protocol vs primary surgical extirpation and selective postoperative radiotherapy for advanced OCSCC. Retrospective matched cohort study at a tertiary care hospital. Nineteen patients with resectable stages III and IV OCSCC were enrolled into a phase 2 IS trial. Patients with a response of at least 50% underwent concurrent CRT; those with a response of less than 50% underwent surgical treatment and radiotherapy. A comparison cohort of patients treated with primary surgical extirpation during a similar time period was frequency matched for inclusion criteria and patient characteristics to those patients included from the phase 2 IS trial. No difference was noted in age, sex, pretreatment American Joint Committee on Cancer stage, T and N classifications, smoking status, alcohol consumption, or tumor subsite between the IS and surgical cohorts. Median follow-up was 9.4 years in the IS cohort and 7.1 years in the surgical cohort. Induction selection and CRT vs primary surgical extirpation with or without postoperative radiotherapy. Overall and disease-specific survival and locoregional control. The Kaplan-Meier estimate for overall survival at 5 years was 32% in the IS cohort and 65% in the surgical cohort. The Kaplan-Meier estimate for disease-specific survival at 5 years was 46% in the IS cohort and 75% in the surgical cohort. The Kaplan-Meier estimate for locoregional control at 5 years was 26% in the IS cohort and 72% in the surgical cohort. Multivariable analysis demonstrated significantly better overall and disease-specific survival and locoregional control outcomes (P = .03, P = .001, and P < .001, respectively) in the surgical cohort. Primary surgical treatment showed significantly better survival and locoregional control compared with IS in this matched patient cohort. Despite success of organ preservation IS protocols in the larynx, comparative survival analysis of an IS protocol vs primary surgical extirpation for OCSCC demonstrates significantly better outcomes in the surgical cohort. These findings support surgery as the principal treatment for OCSCC.

Overall survival is improved in mucinous adenocarcinoma of the colon

Debate persists regarding the relationship between mucin expression and outcome in colon cancer. This arises due to discrepancy in the definition of mucinous adenocarcinoma and the combination of both colon and rectal cancers in analyses. This study examines the relationship between increased mucin production and outcomes in colon cancer. Cases were classified according to the World Health Organization classification of mucinous adenocarcinoma of the colon. Accordingly, tumors were categorized as either (a) mucinous adenocarcinoma of the colon (greater than 50% of the extracellular matrix occupied by mucin) or (b) non-mucinous adenocarcinoma of the colon. Overall survival and disease-free survival were calculated. A stepwise Cox proportional hazards regression model was employed to determine the risk of death/disease recurrence. Kaplan-Meier estimates of overall survival and disease-free survival were plotted for each group and compared using a log-rank test. On univariate analysis, mucinous adenocarcinoma was associated with reduced risk of death (P = 0.01). On multivariate analysis, mucinous adenocarcinoma was also associated with reduced risk of death (hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.14-0.79, P = 0.01). Kaplan-Meier estimates confirmed improved rate of survival in the mucinous vs. non-mucinous group (P = 0.01). Mucinous adenocarcinoma did not affect disease-free survival (HR 0.75, 95% CI 0.46-1.21, P = 0.22). A comparison of Kaplan-Meier estimates for systemic recurrence demonstrated significant increases in systemic recurrence in the group with no mucin production (P = 0.04) but not for locoregional recurrence (P = 0.24). Histopathological evidence of mucinous adenocarcinoma in colon cancer is associated with improved outcomes.

Comparison Of Umbilical Cord Blood and Haploidentical Donor Grafts In Adults With High Risk Hematologic Diseases After Fludarabine Cyclophosphamide and TBI 2 Gy Based Reduced-Intensity Conditioning Regimen Stem Cell Transplantation

IntroductionHuman leukocyte antigens (HLA)-matched sibling or unrelated donor are available for around only 50-60% of patients. However, for patients without a suitably matched related donor, Alternative donors such as mismatched unrelated, cord blood and mismatched family donors could be searched. The aim of this retrospective study was to compare the results of graft source on outcome of patients after haploidentical related donor (Haplo), and the unrelated umbilical cord blood (UCB) transplantation in the setting of Non myeloabalative conditioning regimen (NMA). Patients and methodsWe retrospectively analyzed outcomes in 150 adult patients with high risk hematologic diseases who received Allo-SCT from alternative donors from two centers (Institut Paoli-Calmettes at Marseille France and Humanitas cancer center at Rozzano, Italy): These two centres have been applying common transplant approaches and procedures during the study period. 69 patients received Haplo and 81 patients received UCB. In the UCB group, the NMA regimen consisted of fludarabine (Flu), cyclophosphamide (Cy) and low dose TBI (2 Gy) combination in the two groups. The GVHD prophylaxis consisted of Cyclosporine A (CsA) and MMF in all patients in the two groups. In the Haplo group all patients received also 50 mg/kg Cy at day 3 and 4 post transplant. Of note, supportive care was the same during the whole study period. CMV infection management was also homogeneous. Patient characteristics are shown in Table 1.Table 1Patient and transplantation characteristics:Characteristic Total =150 patientsHaplo transplant (n = 69)CB transplant (n = 81)P valuePatients Age years (median) [range]44 (19-68)47 (18-66)Patients sexnsMale39 (57)46 (57)Female30 (43)35 (43)Disease typeAML3 (4)37 (46)<0.0001ALL1 (1)14 (17)<0.0001NHL24 (35)14 (17)nsHL30 (43)2 (2)<0.0001MM4 (6)2 (2)nsCLL5 (7)4 (5)nsCML01 (1)nsMDS/ MPS2 (3)7 (9)nsStatus of diseaseCR37 (54)56 (69)nsPR/SD24 (35)12 (15)0.04PD8 (11)13 (16)nsDonor typeSibiling32 (46)Parent18 (26)Child18 (26)cousin1 (2)Donor/recipient sex mis-match34 (49)56 (69)nsABO incompatibility24560.02Conditioning regimenFlu 5+Cy 1+ TBI075 (93)Flu 5+Cy 2+ TBI69 (100)6 (7)Stem cell sourcePeripheral Blood19 (28)Bone Marrow50 (72)Stem cell dose median [range] CD34+ x 106/kg3,96 (0,8-14)0,9 (0,08-1,28)GvHD prophylaxisCSA+MMF69 (100)81 (100)nsCy post transplant69 (100)0Days with ANC< 500 x 109/l20 (14-39)22 (6-67)nsDays with platelets<20 x 109/l29 (14-50)41 (18-80)ns ResultsWith a median follow-up of 59 months (8-101) and 18 months (3-51), in the UCB group versus the Haplo group, respectively. Nine patients (11%) in the UCB and 8 patients (12%) in the Haplo group had a spontaneous autologous reconstitution subsequent to primary graft failure. The median times to neutrophil and platelet recovery were 20 d (14–39) and 29 d (14–50) after Haplo and 22 d (6–67) and 41 d (18–80) after cord blood. All supportive care measures included red blood cell, and platelet transfusions were significantly increased in cord blood transplantation group. The cumulative incidence of transplant related mortality (TRM) at one year was 23% in the UCB group versus 17% in the Haplo group (P=0.39). Grade 2-4 acute graft-vs.-host disease (GVHD) and extensive chronic GVHD incidences were 52% versus 29% (P=0.05), and 12% versus 6% (P<0.0001), in the UCB group versus the Haplo group, respectively. The Kaplan-Meier estimate of overall survival at 2 years was 45% (95%CI, 34-56%) in the UCB group versus 69% (95%CI, 58-80%) in the Haplo group, (P=0.10). The estimate of progression-free survival at 2 years was 36% (95%CI, 25-47%) in the UCB group versus 65% (95% CI, 53-77%) in the Haplo group (P=0.01). Figure 1 ConclusionIn this study, relapse and PFS was lower in Haplo group than in UCB transplants. The main difference between the 2 groups was the significantly higher incidence of acute and chronic GVHD in the UCB group. Surprisingly, this did not translate into a decrease of the cumulative incidence of OS nor increase of the TRM, which may be explained by a slightly shorter follow-up in this group. Our results suggest that haploidentical transplants are a good and promising alternative option for patients with high risk hematological diseases who lack an HLA-matched donor (sibling or unrelated donor). This should be now investigated in prospective comparative studies. Disclosures:No relevant conflicts of interest to declare.

Reduced Toxicity Conditioning With Fludarabine, BCNU, Melphalan and Anti-Thymocyte Globulin Followed By Allogeneic Stem Cell Transplant For Patients With Primary and Post ET/PV Myelofibrosis: Single Center Experience At Mayo Clinic Arizona

IntroductionMyelofibrosis (MF), both primary myelofibrosis (PMF) and post essential thrombocytosis/polycythemia vera myelofibrosis (post ET/PV-MF), are chronic myeloproliferative neoplasms that are incurable with standard medical therapy. The only potential curative therapeutic modality remains allogeneic stem cell transplant (ASCT), but the optimum conditioning regimen has yet to be defined and may vary due to pre-ASCT factors such as age, donor source, and comorbidities. In the past, traditional myeloablative (MA) regimens have proven toxic. Reduced intensity conditioning (RIC) regimens have generally become the accepted standard of care for patients with PMF or Post PV/ET MF in need of ASCT, but with the potential for increase in relapse especially for high risk disease. The optimal conditioning regimen has yet to be defined. The regimen of Fludarabine, BCNU, and melphalan (FBM) is considered a reduced toxicity regimen that may afford the benefit of reduction in relapse without increase in toxicity and may “bridge the gap” between MA and RIC especially in older patients. Patients with MF have high inflammatory cytokine levels which may act as mediators of MF symptom burden and may further aggravate mediators of acute GVHD, which is one of the most frequent and severe complications of ASCT. Selection of conditioning regimen and GVHD prophylaxis are keys to MF transplant outcomes. We report here the results of 16 patients who received conditioning with FBM with rATG (FBM-A) with PMF and post PV/ET MF. MethodsWe conducted a retrospective review of all patients from October 2009 to November 2012 with PMF or post ET/PV-MF who underwent an ASCT with FBM-A. Patient demographic and transplant data were analyzed from a comprehensive database. The use of such data for reporting purpose was approved by the Mayo Clinic Arizona Institutional Review Board. Overall survival was estimated using Kaplan-Meier. ResultsThere were 16 patients analyzed who had PMF or post PV/ET MF or overlap syndromes. The median follow-up of surviving patients is 20.4 months (range 8 months – 46 months). The median age was 60 (range 47-68 yrs) with 56% of patients being ≥ 60yrs. There were 8 males and 8 females. The JAK2 V617F mutation was present in 64% of patients. 86% were high risk according to the DIPSS system with 14% being intermediate-2 risk. None of the patients underwent splenectomy prior to transplant. The median HCT-CI score was 1.5 with 6 (38%) of the patients having an HCT-CMI ≥3. Donors were related in 10 patients (8 matched, 2 mismatched at 1 antigen) and unrelated in 6 (matched, n=3, 1-antigen mismatch, n=3). GVHD prophylaxis consisted of tacrolimus, MMF, and ATG 2.5 – 5.0 mg/kg. The cumulative incidence of acute GVHD grades III-IV was 15.3% at 6 months, and the cumulative incidence of NIH-defined moderate-to-severe chronic GVHD was 25% at 2 years. No patient has relapsed, and no patient has developed graft failure. There have been 4 deaths, 3 from GVHD, and 1 from infection. Among the 3 patients who died from GVHD, all were unrelated donor transplants, and 2 were mismatched unrelated transplants.The 2-year Kaplan-Meier estimate of overall survival (OS) is 72% (95% CI, 45 – 91%). The cumulative incidence of TRM was 12.6% (95% CI 3.9%-34%) at 1 year. ConclusionThe reduced-toxicity regimen of FBM-A in PMF, Post ET/PV MF and overlap syndromes appear to provide the benefit of an ablative regimen with the tolerance of a RIC. The 2-year overall survival of 72% in our series is encouraging in an older population of predominantly high-risk patients. Treatment failure was related predominately to GVHD, which continues to be a significant obstacle to better long-term outcomes, especially in unrelated and mismatched patients. Reduced toxicity ASCT conditioning regimens in the setting of MF warrant further investigation.▪ Disclosures:Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.

Comparative multidisciplinary prediction of survival in patients with advanced cancer

The expected survival of patients with metastatic cancer can significantly impact decisions regarding treatment, care setting, and future planning. We evaluated the prognostication ability of a multidisciplinary team (MDT) experienced in providing supportive care and palliative radiotherapy. After clinical assessment of consecutive patients, survival predictions were independently made by each MDT member. Patient demographics, factors influencing predictions, and dates of death were collected. Clinical predictions of survival (CPS) were considered correct if within 30 days of actual survival (AS). Summary statistics and Kaplan-Meier estimates of overall survival were obtained. Correlations between actual and CPS were calculated using Spearman's correlation coefficient. Multivariate logistic regression analysis identified factors associated with prognostication accuracy. A total of 395 predictions (06/2010-07/2012) were made by eight disciplines. Average age was 68 years, 68.3 % of patients were male, and 48.4 % had lung cancer. Median AS was 87 days (95 % CI 66-102 days). Survival was over-estimated 72.4 % (286/395) of the time with r = 0.54 (p < 0.0001) for all predictions across all disciplines. In addition, 30.3 % (36/119) of radiation therapist (RTT) predictions were correct compared to 30.1 % (22/73) of nurses', 28.7 % (43/150) of physicians', and 15.1 % (8/53) of allied health (AH) providers. There were no differences in accuracy by discipline except for the RTT versus AH groups (p = 0.04). Factors most frequently cited as influencing correct predictions were Karnofsky performance status (KPS), extent of disease, and histology. KPS was the only significant variable on multivariate analysis (p ≤ 0.04). MDT members providing collaborative care for advanced cancer patients utilize similar factors in predicting survival with comparable accuracy.

Leucemia promielocítica aguda: Resultados del protocolo terapéutico LPA2000, Programa Nacional de Cáncer del Adulto (PANDA), Ministerio de Salud, Chile

The current recommendations for treatment of patients with newly diagnosed acute promyelocytic leukemia (APL) include all-trans-retinoic acid (ATRA) and anthracycline based chemotherapy. To evaluate the results of the Chilean protocol following the LPA99 regimen of the Spanish PETHEMA group, except for the replacement of Idarubicin by Daunorubicin. Induction consisted of Daunorubicin 45 mg/m² on days 2, 4, 6 and 8 plus ATRA 45 mg/m² daily until complete remission. Patients in complete remission (CR) received three monthly chemotherapy courses: Daunorubicin 45 mg/m²/d/4days i.v. and ATRA 45 mg/m²/d/15 days p.o. (course no. 1); Mitoxantrone 10 mg/m²/d/5 days i.v. and ATRA 45 mg/m²/d/15 days p.o. (course no. 2); Daunorubicin 60 mg/m²/d/ day 1 i.v. in the low risk group, and 1 and 2 in the intermediate-high risk groups and ATRA 45 mg/m²/d/15 days p.o. (course no. 3). Maintenance therapy consisted of mercaptopurine 90 mg/m²/d p.o., methotrexate 15 mg/m²/wk p.o. and, ATRA intermittently, 45 mg/m²/d p.o. for 15 days every three months. Between January 2000 and December 2005, 56 patients with newly diagnosed APL from 10 centers were enrolled. A total of 46 patients achieved CR (85%), 8 (15%) died of early complications, seven patients relapsed, with a 16% relapse risk at three years. The 5-year Kaplan-Meier estimates of overall survival and relapse-free survival were 64% and 84% respectively. These data indicate that this protocol has a good antileukemic effect but further reduction of early death and relapse, especially in the high risk group is needed.

An Institutional Review of Stereotactic Body Radiation Therapy for Liver Tumors

An Institutional Review of Stereotactic Body Radiation Therapy for Liver Tumors

Co-expression of receptors of the HER family correlates with clinical outcome in non-small cell lung cancer (NSCLC)

HER family receptors play a critical role in lung carcinogenesis. There is a growing body of evidence showing that cooperation between them contributes to a more aggressive tumor phenotype and impacts on their response to targeted therapy. We explored immunohistochemical co-expression of HER family receptors (HER1, HER2, HER3, HER4) and its potential role as prognostic factor in resected non-small cell lung cancer (NSCLC). Expression of HER family receptors was assessed by immunohistochemistry on 125 surgically resected NSCLC. Kaplan-Meier estimates of overall survival (OS), disease-free survival (DFS), and time to recurrence were calculated for clinical variables and HER expression, using the Cox model for multivariate analysis. HER1 and HER3 expression was detected more frequently in squamous cell carcinoma (p = 0.002 and p = <0.001, respectively). HER4 was more often expressed in patients older than 60 years (p = 0.02) and in tumors of low histological grade (p = 0.04). Cases which expressed only HER1 had a worse DFS (p = 0.01) and OS (p = 0.01) compared to cases expressing HER1 and one or more of the other family members and to cases which did not express HER1 but one of the other HERs. By multivariate analysis, stage was an independent prognostic factor for DFS and OS. Furthermore, different patterns of co-expression of HER family receptors showed a statistically significant correlation with a shorter DFS (p = 0.03) and OS (p = 0.02). Our findings suggest that expression of HER1 only is correlated with worse DFS and OS. A better understanding of the functional relationships between these receptors may lead to a useful predictive indicator of response to targeted therapy.

Effect of graft source on mismatched unrelated donor hemopoietic stem cell transplantation after reduced intensity conditioning

This retrospective report compared the results of graft source on outcome after allogeneic stem cell transplantation (allo-SCT) in patients with hematologic malignancies receiving a reduced intensity conditioning (RIC) regimen. A total of 152 patients received either a RIC allo-SCT using a 9/10 mismatched unrelated donor (MisMUD, n=42) or a double unrelated umbilical cord blood (dUCB, n=110) graft. With a median follow-up of 30.3 months, the cumulative incidence of non-relapse mortality was 26% in the dUCB group versus 24% in the MisMUD group (P=0.95). Grade 3-4 acute graft-versus-host disease (GVHD) incidence was 19.7% in the dUCB group versus 21.4% in the MisMUD group (P=0.83). The cumulative incidence of extensive chronic GVHD at 2 years was 6.4% in the dUCB group versus 21.4% in the MisMUD group (P=0.02). The Kaplan-Meier estimate of overall survival at 2 years was comparable between both groups (52.3% (95% confidence interval (CI), 42.1-61.5%) in the dUCB group versus 47.9% (95% CI, 31.6-62.4%) in the MisMUD group, P=0.55). Progression-free survival at 2 years was 43.3% (95% CI, 33.7-52.5%) in the dUCB group versus 38.3% (95% CI, 23.2-53.3%) in the MisMUD group (P=0.55). These data suggest that dUCB is a valid alternative graft source with significantly less chronic GVHD compared with MisMUD in the setting of RIC allo-SCT.

Concurrent Chemoradiation for Vaginal Cancer

BackgroundIt is not known whether the addition of chemotherapy to radiation therapy improves outcomes in primary vaginal cancer. Here, we review clinical outcomes in patients with primary vaginal cancer treated with radiation therapy (RT) or concurrent chemoradiation therapy (CRT).MethodsSeventy-one patients with primary vaginal cancer treated with definitive RT with or without concurrent chemotherapy at a single institution were identified and their records reviewed. A total of 51 patients were treated with RT alone; 20 patients were treated with CRT. Recurrences were analyzed. Overall survival (OS) and disease-free survival (DFS) rates were estimated using the Kaplan-Meier method. Cox regression analysis was performed.ResultsThe median age at diagnosis was 61 years (range, 18–92 years) and the median follow-up time among survivors was 3.0 years. Kaplan-Meier estimates for OS and DFS differed significantly between the RT and CRT groups (3-yr OS = 56% vs. 79%, log-rank p = 0.037; 3-yr DFS = 43% vs. 73%, log-rank p = 0.011). Twenty-three patients (45%) in the RT group had a relapse at any site compared to 3 (15%) in the CRT group (p = 0.027). With regard to the sites of first relapse, 10 patients (14%) had local only, 4 (6%) had local and regional, 9 (13%) had regional only, 1 (1%) had regional and distant, and 2 (3%) had distant only relapse. On univariate analysis, the use of concurrent chemotherapy, FIGO stage, tumor size, and date of diagnosis were significant predictors of DFS. On multivariate analysis, the use of concurrent chemotherapy remained a significant predictor of DFS (hazard ratio 0.31 (95% CI, 0.10–0.97; p = 0.04)).ConclusionsVaginal cancer results in poor outcomes. Adequate radiation dose is essential to ensure curative management. Concurrent chemotherapy should be considered for vaginal cancer patients.

Oncologic, Functional, and Complications Outcomes of Robot-assisted Radical Cystectomy with Totally Intracorporeal Neobladder Diversion

BackgroundRobot-assisted radical cystectomy (RARC) with totally intracorporeal neobladder diversion is a complex procedure that has been reported with good outcomes in small series. ObjectiveTo present complications and oncologic and functional outcomes of this procedure. Design, setting, and participantsBetween 2003 and 2012 in a tertiary referral center, 70 patients were operated on by two experienced robotic surgeons. Data were collected prospectively and reviewed retrospectively. InterventionRARC with totally intracorporeal modified Studer ileal neobladder formation. Outcome measurements and statistical analysisThe overall outcome of RARC with a totally intracorporeal neobladder was presented by assessing (1) surgical margins, (2) recurrence or cancer-specific death at 24 mo, (3) 30-d and 90-d complications graded according to the modified Clavien-Dindo system, (4) daytime and nighttime continence (no or one pad per day) at 6 and 12 mo, and (5) satisfactory sexual activity or potency at 6 mo and 12 mo. Survival rates were estimated by Kaplan-Meier plots. Results and limitationsMedian follow-up of the cohort was 30.3 mo (interquartile range: 12.7–35.6). We recorded negative margins in 69 of 70 patients (98.6%). Clavien 3–5 complications occurred in 22 of 70 patients (31.4%) at 30 d and 13 of 70 (18.6%) at >30 d. At 90 d, the overall complication rate was 58.5%. Clavien <3 and Clavien ≥3 complications were recorded in 15 of 70 patients (21.4%) and 26 of 70 (37.1%), respectively. Kaplan-Meier estimates for recurrence-free, cancer-specific, and overall survival at 24 mo were 80.7%, 88.9%, and 88.9%, respectively. Daytime continence and satisfactory sexual function or potency at 12 mo ranged between 70% and 90% in both men and women. Limitations of this study include its retrospective design, selection bias due to the learning curve phase, and missing data. ConclusionsIn this expert center for RARC, outcomes after RARC with totally intracorporeal neobladder diversion appear satisfactory and in line with contemporary open series.

Survival Analysis of Endometrial Cancer Patients With Positive Lymph Nodes

Patients with endometrial cancer with positive lymph nodes (International Federation of Gynecology and Obstetrics stage IIIC) have a substantially worse prognosis. This study investigates how tumor characteristics and adjuvant treatments influence overall survival (OS) in stage IIIC patients. This multi-institution, institutional review board-approved study is a retrospective review of 116 patients with surgically staged endometrial cancer with positive lymph nodes treated from 1995 to 2008. The study cohort was evaluated using Kaplan-Meier estimates of OS and proportional hazard modeling. The 5-year OS for all patients was 51%. Administration of adjuvant therapy was associated with improved OS when compared with surgery alone (P = 0.007). Five-year OS was 40% for patients treated with surgery alone (n = 26), 50% with surgery and chemotherapy (n = 8), 58% with surgery and radiotherapy (n = 43), and 54% with surgery followed by both radiotherapy and chemotherapy (n = 39). Patients who received radiotherapy (n = 82) had improved OS (57%) when compared with patients who did not (n = 34, OS = 42%; P = 0.001). Radiotherapy was associated with improved OS for patients with endometrioid histology, high-grade tumors, and positive para-aortic lymph nodes. Patients with nonendometrioid histology and low-grade tumors who received radiotherapy had a similar OS as those who did not. High-grade tumors (P < 0.001), nonendometrioid histology (P = 0.004), and more than 2 positive lymph nodes (P = 0.01) were associated with a poorer OS. After controlling for patient demographics and tumor characteristics, patients with high-grade tumors and more than 2 positive lymph nodes had a poorer OS, whereas patients who received radiotherapy had improved OS. This large institutional study of patients with lymph node-positive endometrial cancer identified prognostic factors associated with a poor OS. Radiotherapy was associated with improved survival and may be specifically indicated for patients with endometrioid histology, high-grade tumors, and positive para-aortic lymph nodes. We recommend further investigation of adjuvant therapies in randomized clinical trials.

Philadelphia-positive acute lymphoblastic leukemia in daily practice: A multicenter experience.

e18014 Background: The prognosis of Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) is generally poor. Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only accepted therapy with curative potential. Herein, we report our experience with Ph+ALL patients treated off-study. Methods: Data were collected from medical records of Ph+ALL patients diagnosed between 2005 and 2012. Survival rates were calculated using the Kaplan-Meier method and the log-rank test was used for comparison between groups. Results: This retrospective study included 41 patients (21 females and 20 males) from 7 centers in Turkey. The median age of the patients was 42 years (range, 19-70 years). Thirty (73%) patients received TKI and concurrent chemotherapy, 10 (24%) patients received chemotherapy alone and 1 (3%) patient received TKI alone. Of the patients receiving TKI, 24 (77%) received imatinib and 7 (23%) received dasatinib as induction therapy. Following induction therapy, 77% and 10% of the patients achieved complete hematologic remission and complete response with incomplete hematologic recovery, respectively. Eight (20%) patients had relapsed/resistant disease and received rescue therapy. The most common complication during therapy was febrile neutropenia (n=7, 17%). The induction mortality rate was 5% (n=2). Allo-HSCT was performed in 16 (39%) patients, 12 (75%) of whom underwent HSCT in first complete remission. Donor sources were matched siblings in 14 (88%) and unrelated donors in 2 (12%) patients. Fifteen (37%) patients died during follow-up. The Kaplan-Meier analysis revealed a median overall survival (OS) period of 12 months (range, 1-86 months) for all patients. The median OS period was 17 months (range, 5-86 months) and 2 months (range, 1-24 months) for patients who did or did not undergo HSCT, respectively (p=0.014). The Kaplan-Meier estimate of OS was 69.3% at 12 months and 49.1% at 24 months, for all patients. Conclusions: Allo-HSCT is the most important denominator of survival and the only curative therapy for Ph+ALL patients. For patients without a suitable donor or who are unable to undergo HSCT, TKI with concurrent chemotherapy is a reasonable alternative.

Reduced Toxicity Conditioning and Allogeneic Stem Cell Transplantation in Adults Using Fludarabine, Carmustine, Melphalan, and Antithymocyte Globulin: Outcomes Depend on Disease Risk Index but Not Age, Comorbidity Score, Donor Type, or Human Leukocyte Antigen Mismatch

Although reduced-intensity conditioning has become standard of care for patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation (HCT), the optimum regimen has yet to be defined, and may depend on pretransplantation patient– and/or disease-specific risk factors. We report here results in 100 adults, ages 18 to 69, with high-risk hematologic malignancy who received conditioning with fludarabine, carmustine, melphalan, and rabbit antithymocyte globulin (FBM-A). Outcomes were stratified using the disease risk index (DRI) as published by Armand et al. (Blood 2012;120:905-913). Median age was 56, and patients were ineligible for standard myeloablative conditioning because of age, organ dysfunction, or prior autologous HCT. Patients underwent transplantation for myeloid (acute myelogenous leukemia, n = 40; myelodysplastic syndrome, n = 24; myelofibrosis, n = 13; other myeloid, n = 2) or lymphoid (acute lymphoblastic leukemia, n = 8; non-Hodgkin lymphoma, n = 8; Hodgkin lymphoma, n = 4, chronic lymphocytic leukemia, n = 1) malignancy. Donors were related in 26 patients (22 matched, 4 mismatched at 1 antigen) and unrelated in 74 (mismatched at 1 or 2 HLA loci in 33); grafts were peripheral blood stem cells in 97 patients, bone marrow in 2, and double cord in 1. According to the DRI, 68 patients were classified as low (n = 1) or intermediate risk (n = 67), and 32 were classified as high (n = 28) or very high risk (n = 4). With a median follow-up of surviving patients of 18 months, the Kaplan-Meier estimate of overall survival at 2 years for patients in the low/intermediate risk group is 80%, compared with 66% in the high/very high group (P = .11). Two-year cumulative incidence of relapse and nonrelapse mortality in the low/intermediate group are 9.9% and 15%, versus 25% and 19% in the high/very high group (respective P values .07 and .81). The cumulative incidence of acute graft-versus-host (GVHD) grades III to IV at 100 days was 8.1%, and the incidence of National Institutes of Health–defined moderate to severe chronic GVHD was 22% at 2 years. No deaths were attributable to chronic GVHD. Survival was not influenced by age, hematopoietic comorbidity index score, donor type, donor gender, or presence of mismatch. We conclude that FBM-A is an effective and safe conditioning regimen for adults up to age 69 with hematologic malignancies who have low-, intermediate-, or high-risk scores according to the DRI.

Abstract LB-73: Circulating tumor cells with the invasive phenotype predict progression free survival and overall survival in preoperative patients diagnosed with advanced epithelial ovarian cancer.

Abstract Purpose: Circulating tumor cells (CTCs) might function as prognostic markers for monitoring and assessing therapy efficacy ex vivo. This study aimed to measure overall population of CTCs based on expression of epithelial lineage (Epi) markers and the subpopulation of CTCs with the invasive phenotype (iCTCs) in preoperative patients for prognosis of advanced Epithelial Ovarian Cancer (EOC). Experimental Design: CTCs and iCTCs enriched by the Cell Adhesion Matrix (CAM)-coated devices from 122 preoperative patients were identified as Epi+ nucleic acid (NA)+ hematopoietic lineage (HL)- cells and CAM uptake (CAM+) Epi+ NA+ HL- cells, respectively. CTCs and iCTCs were enumerated using multiplex flow cytometry, validated by microscopy, and correlated with overall survival (OS) and progression-free survival (PFS). Results: iCTCs were detected in 0/39 (0%) benign patients, 5/11 (45.5%) Stage I, 2/4 (50%) Stage II, 41/43 (95.3%) Stage III and 16/16 (100%) stage IV patients (P-value &amp;lt;0.001). However, healthy (n=48) and benign women had noticeable CTCs (mean=10 and 3 CTCs/1.0-mL blood, respectively), and large variation (IQR=24.5 and 30 CTCs/1.0-mL blood, respectively), although CTCs were significantly different across different stage groups. Kaplan-Meier estimates of OS at 5 years in the iCTC positive and negative groups were 15.4% (95% CI, 7.2% to 26.3%) and 94% (95% CI, 82.5% to 98%), respectively. The PFS in the iCTC positive group was also significantly lower than that in the negative group (P-value &amp;lt;0.001). In multivariable Cox models, iCTCs were independently predictive of OS (P-value &amp;lt;0.001) and provided predictive power for disease recurrence independent of diagnostic disease stages, age, debulking status and platinum sensitivity. Conclusion: CTCs show the expression of heterogeneous epithelial antigens with potential biologic relevance. Co-expression of epithelial antigens and invasiveness of iCTCs in preoperative patients provides prognosis of advanced EOC that could help tailor appropriate therapy. Citation Format: Wen-Tien Chen, Qiang Zhao, Huan Dong, Jie Yang, Qiao Zhang, Tina Fan, Marc G. Golightly, Whitney C. Dessio, Stefan Madajewicz, Melissa Henretta, Michael L. Pearl. Circulating tumor cells with the invasive phenotype predict progression free survival and overall survival in preoperative patients diagnosed with advanced epithelial ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-73. doi:10.1158/1538-7445.AM2013-LB-73

Management of cT1 micropapillary bladder cancer.

308 Background: We have previously reported that intravesical BCG is ineffective as therapy for micropapillary variant of bladder cancer. Since then, smaller reports have emerged with differing conclusions. Here we report our updated experience and expanded number of patients with micropapillary bladder cancer (MPBC), with emphasis on cT1 MPBC. Methods: An IRB approved institutional review of our bladder cancer database identified 255 patients presenting with MPBC with 72 patients staged as cT1N0M0 at the time of initial diagnosis. Statistical and descriptive analysis was performed using IBM SPSS Statistics version 20 and survival analysis was performed using the Kaplan-Meier estimator and compared using the log-rank test. Results: Of the 72 patients with cT1 MPBC, intravesical BCG was used in 38 patients (53%), while 32 (44%) proceeded directly to radical cystectomy. This included 15 (20%) who received neoadjuvant chemotherapy for lymphovascular invasion (LVI). Kaplan-Meier estimates of overall survival (OS) and disease specific survival (DSS) at 5 and 10 years were 66% and 45%, and 70% and 61%, respectively. Among those receiving BCG, 28 (74%) recurred at a median of 7 mo., and 17 (45%) progressed, including 8 (30%) who developed metastatic disease. Among the 10 post BCG patients who underwent cystectomy after progression, median DSS was 43 mo. (mean=53 mo.) and 5 year DSS was 33%, whereas among those proceeding directly to cystectomy, median DSS was not reached (mean=152 mo.) and the 5 year DSS rate was 92% (p&lt;0.001). For OS, upfront cystectomy conferred a median survival of 170 mo. versus 92 mo. for those receiving BCG as initial therapy (p=0.05). There was no association of OS with the presence of CIS, repeat transurethral resection (TUR), or history of intravesical therapy prior to the diagnosis of MPBC. Interestingly, the extent of micropapillary component in the initial TUR specimen did have prognostic value for those treated with BCG as patients with focal MPBC were 2.3 times less likely to progress (p=0.02). Conclusions: Our updated findings support the use of upfront radical cystectomy prior to progression of disease in patients with cT1 MPBC. BCG therapy should be attempted only in select patients as there is a high risk of disease progression during BCG treatment.

Validation of a novel diagnostic standard in HPV-positive oropharyngeal squamous cell carcinoma

Background:Human papillomavirus (HPV) testing in oropharyngeal squamous cell carcinoma (OPSCC) is now advocated. Demonstration of transcriptionally active high-risk HPV (HR-HPV) in fresh tumour tissue is considered to be the analytical ‘gold standard'. Clinical testing has focused on formalin-fixed paraffin-embedded (FFPE) tissue at the expense of sensitivity and specificity. Recently, a novel RNA in situ hybridisation test (RNAscope) has been developed for the detection of HR-HPV in FFPE tissue; however, validation against the ‘gold standard' has not been reported.Methods:A tissue microarray comprising FFPE cores from 79 OPSCC was tested using HR-HPV RNAscope. Analytical accuracy and prognostic capacity were established by comparison with the reference test; qRT–PCR for HR-HPV on matched fresh-frozen samples.Results:High-risk HPV RNAscope had a sensitivity and specificity of 97 and 93%, respectively, against the reference test. Kaplan–Meier estimates of disease-specific survival (DSS, P=0.001) and overall survival (OS, P<0.001) by RNAscope were similar to the reference test (DSS, P=0.003, OS, P<0.001) and at least, not inferior to p16 immunohistochemistry +/− HR-HPV DNA-based tests.Conclusion:HR-HPV RNAscope demonstrates excellent analytical and prognostic performance against the ‘gold standard'. These data suggest that the test could be developed to provide the ‘clinical standard' for assigning a diagnosis of HPV-related OPSCC.

Association of mucin production and survival in colon cancer.

512 Background: Debate persists regarding the relationship between mucin production and cancer-related outcome following curative resection for colon cancer. Lack of consensus is due to (amongst other factors) discrepancies in definition, small cohort studies and the integration of both colon and rectal cancers. This study characterizes the relationship between mucin production and cancer-related outcome in an homogenous single-institute based cohort. Methods: A database spanning demographics, clinico-pathologic characteristics and prognostic factors was generated for all patients undergoing curative-intent colonic resection in the interval 2000 to 2010. Patients were categorized simply as mucin producing (i.e. MC) or non-mucin producing adenocarcinoma (NMC). Primary outcomes included overall survival (time to death from any cause) and disease free survival (time to loco-regional and systemic recurrence). Trends were established for MC and NMC using Kaplan-Meier estimates, plotted and compared using log-rank analysis. Findings significant on univariate analysis were incorporated into multivariate analysis. Cox proportional hazards model was employed to determine the associated hazard of both death and disease recurrence in each group. Statistical analysis was performed using R version 2.15. P &lt; 0.05 was considered significant. Results: 77 mucinous carcinomas (MC) and 358 non mucinous carcinomas (NMC) were included. On univariate analysis, MC was associated with improved overall survival (OS) (P=0.007). Both N1 (HR 1.625, P=0.011) and N2 (HR 2.7, P&lt;0.001) status were associated with adverse OS. On multivariate analysis, MC approached but did not reach statistical significance for improved OS (HR 0.543, P=0.061). A comparison of Kaplan-Meier estimates for overall survival in MC and NMC groups indicated that OS was significantly improved in the MC cohort (P=0.011). There was no difference in disease free survival (P=0.224). Systemic recurrence was greater in the NMC group (P=0.042). Conclusions: Mucin production in colonic adenocarcinoma appears associated with improved overall but not disease-free survival. In addition, the absence of mucin was associated with adverse systemic but not local recurrence.

Clinical Outcomes and Dosimetric Considerations Using Stereotactic Body Radiotherapy for Abdominopelvic Tumors

To present clinical outcomes, early toxicity, and dosimetric constraints for patients undergoing stereotactic body radiation therapy (SBRT) for abdominal or pelvic tumors. From May 2008 to February 2010, 47 patients with 50 lesions in proximity to hollow viscous organs at risk, including stomach, duodenum, small bowel, and colon, underwent SBRT at Mayo Clinic. Treated sites included liver (21), lymph node (14), adrenal gland (6), intramuscular (4), pancreas (3), and spleen (2). Treatment planning was performed with full body immobilization and 4-dimensional computed tomography (CT)-based planning with daily cone-beam CT or stereoscopic kV imaging for pretreatment image guidance. SBRT was delivered in 1 to 5 consecutive daily fractions in a single week. The most commonly prescribed dose was 50 Gy in 5 fractions (median 45 Gy, range: 20 to 60 Gy). Toxicities were scored by CTCAE v.3. Local failure was defined as per the Response Evaluation Criteria in Solid Tumors. Median follow-up was 12 months (range: 2 to 28 mo). Tumor responses of the 48 target lesions evaluable by Response Evaluation Criteria in Solid Tumor were complete response in 18 lesions (36%), partial response in 12 lesions (24%), stable disease in 12 lesions (24%), and progressive disease in 6 lesions (12%). Kaplan-Meier estimates of local control, overall survival, and freedom from metastasis at 6 and 12 months were 98%, 90%, and 63%, and 87%, 62%, 37%, respectively. Treatment was well-tolerated acutely without reported grade ≥3 toxicity. Five grade 3 late toxicities were reported, and 1 patient died of complications from duodenal perforation 11 months after SBRT. No dose correlation with toxicity could be established. SBRT is a practical treatment option for patients with abdominopelvic tumors. Relapse typically occurs outside treatment fields, and most patients achieve a favorable response. The dose constraints used in this cohort of patients was associated with acceptable early treatment-related toxicity.

Donor KIR3DL1 and HLA-B Allotypes Control Leukemia Relapse After Allogeneic Hematopoietic Stem Cell Transplantation

AbstractAbstract 349Natural killer (NK) cells are vital in the control of viral infection and malignancy, in particular AML. Affinity strength between NK receptors and their HLA ligands control both NK effector function and degree of NK inhibition. Differences in binding affinity between allotypes of the NK receptor KIR3DL1 and allotypes of its ligand HLA-Bw4 depend on the expression levels of the receptor and the amino acid residue at position 80 in the ligand. Because receptor-ligand affinities are associated with differences in HIV control, we hypothesized that different affinities between donor KIR3DL1 and donor-recipient HLA-Bw4 allotypes would impact the risk for AML relapse following allogeneic hematopoietic stem cell transplantation (HCT). Methods:We evaluated 299 AML patients who underwent allogeneic HCT from an unrelated donor between 1995 and 2002. Clinical data, HLA allotyping, and donor DNA were provided by the CIBMTR. KIR3DL1 allotyping was executed using PCR- and sequence-based methods. Donors were segregated into those with high-, low- and null expressing KIR3DL1 allele groups [3DL1-H (n=130), 3DL1-L (n=69), 3DL1-N (n=82)] and HLA-B allele groups (Bw6/Bw6, Bw4-I80, Bw4-T80). 3DL1-N genotypes are predictive of poor surface expression and were analyzed separately. Patients and donors were matched at 9 or 10 HLA loci in all cases, with only 3 donor-patient pairs mismatched for HLA-Bw4 ligands. Affinity cohorts were compared using Cox regression for the time-to-event outcomes of relapse and overall mortality (OM). Kaplan-Meier estimates of overall survival and cumulative incidence estimates of relapse were obtained. Results:Recipients of 3DL1-H and 3DL1-L donors were analyzed for high and low-affinity associations with post-HCT AML relapse. Among patients with a 3DL1-H donor, those transplanted from donors with the low-affinity KIR/HLA allotype combination 3DL1-H/Bw4-T80 had lower risk of relapse when compared to those with the high-affinity 3DL1-H/Bw4-I80 combination (HR 0.22; p=.003, Table) and even moreso when compared to the extra-high affinity combinations of 3DL1-H with Bw4-I80-B*2702 or B*57 (HR 0.10; p<.001). Among patients with 3DL1-L donors, those with the low-affinity KIR-HLA combination 3DL1-L/Bw4-I80 were associated with lower relapse in patients when compared to those with the high-affinity 3DL1-L/Bw4-T80 combination (HR 0.21; P=.009). Among the combined patient groups, low-affinity combinations were strongly associated with lower relapse (HR 0.24; P<.001; FigA) and lower mortality (HR 0.62; P=.03; FigB) in patients compared to the high-affinity combinations. Lack of HLA-Bw4 ligand (HLA-Bw6/Bw6) provided intermediate protection from AML relapse compared to patients in the high-affinity group (HR 0.39; P= .002; Fig 1A). Donor 3DL1-N genotypes, predictive of poor receptor expression on the NK cell surface, were not associated with HCT outcome. Conclusions:Protection from relapse of AML after unrelated HCT is associated with the affinity between donor KIR3DL1 and HLA-Bw4, ranging from the highly protective low-affinity donor KIR3DL1/HLA-Bw4 allotype combinations to the susceptible and “super-susceptible” effects of high- and extra-high affinity KIR/HLA combinations. These data support the consideration of KIR and HLA allotype combinations in stem cell donor selection algorithms to minimize the risk of AML relapse following HCT. Because >95% of donors are positive for KIR3DL1 and 69% of patients are positive for HLA-Bw4, incorporation of KIR3DL1/HLA-Bw4 allotypes in donor selection algorithms is a highly relevant and feasible goal.KIR3DL1/HLA-Bw4 allotype combinations (proportion fail)Hazard Ratio95% CIp-valueHigh: 3DL1-H + Bw4-I80 (17/39)1——Low: 3DL1-H + Bw4-T80 (5/37)0.220.08–0.60.003No Bw4: 3DL1-H + Bw6/Bw6 (12/53)0.410.19–0.86.02Extra High: 3DL1-H + Bw4-I80; B*27, B*57 (9/15)1——High: 3DL1-H + Bw4-I80;non B*27, B*57 (8/24)0.280.11–0.75.01Low: 3DL1-H + Bw4-T80 (5/37)0.100.03–0.30<.001No Bw4: 3DL1-H + Bw6/Bw6 (12/53)0.180.07–0.45High: 3DL1-L + Bw4-T80 (8/18)1——Low: 3DL1-L + Bw4-I80 (5/22)0.210.07–0.68.009No Bw4: 3DL1-L + Bw6/Bw6 (7/28)0.310.11–0.87.03High: 3DL1-H + Bw4-I80 or 3DL1-L +Bw4-T80 (25/57)1——Low: 3DL1-H + Bw4-T80 or 3DL1-L + Bw4-I80 (10/59)0.240.12–0.51<.001No Bw4: 3DL1-H + Bw6/Bw6 or 3DL1-L +Bw6/Bw6 (19/81)0.390.21–0.71.002 [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.