Median Survival Follow-up Time Research Articles

Frailty, periinterventional complications and outcome in patients undergoing percutaneous mitral and tricuspid valve repair.

Frailty is common in elderly and multimorbid patients and associated with increased vulnerability to stressors. In a single centre study frailty according to Fried criteria was assessed in consecutive patients before transcatheter mitral and tricuspid valve repair. Postprocedural infections, blood transfusion and bleeding and renal failure were retrospectively assessed from records. Median follow-up time for survival was 560 days (IQR: 363 to 730 days). 90% of 626 patients underwent mitral valve repair, 5% tricuspid valve repair, and 5% simultaneous mitral and tricuspid valve repair. 47% were classified as frail. Frailty was associated with a significantly increased frequency of bleeding (16 vs 10%; p = 0.016), blood transfusions (9 vs 3%; p = < 0.001) and infections (18 vs 10%; p = 0.006), but not with acute kidney injury (20 vs 20%; p = 1.00). Bleeding and infections were associated with longer hospital stays, with a more pronounced effect in frail patients (interaction test p < 0.05, additional 3.2 and 4.1 days in frail patients, respectively). Adjustment for the occurrence of complications did not attenuate the increased risk of mortality associated with frailty (HR 2.24 [95% CI 1.62-3.10]; p < 0.001). Bleeding complications and infections were more frequent in frail patients undergoing transcatheter mitral and tricuspid valve repair and partly explained the longer hospital stay. Albeit some of the complications were associated with higher long-term mortality, this did not explain the strong association between frailty and mortality. Further research is warranted to explore interventions targeting periprocedural complications to improve outcomes in this vulnerable population.

The Role of High-Dose Regimens Followed By Autologous Stem Cell Transplantation for Salvage Chemotherapy-Sensitive DLBCL Patients

CONCLUSION INTRODUCTION： It has been reported that lisocabtagene maraleucel improved event-free survival and complete response rate compared with standard care as second -line therapy for early relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) patients(pts). However, CAR T-cell therapy could not be available for some candidates with rrDLBCL due to socioeconomical issues and manufacturing limitations. High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is a conventional curative treatment for salvage chemotherapy-sensitive DLBCL. We have devised AECC regimen (Usui, Clin Lymph; 2005, and Yano, Clin Lymph and Myeloma; 2007) for auto-SCT. Further, we have also used ranimustine (MCNU) based MEAM regimen due to not availability for carmustine in Japan. In this retrospective study, we compared the efficacy and safety of AECC with MEAM. METHODS： We retrospectively analyzed 68 pts with DLBCL who received AECC or MEAM followed by auto-SCT from January 2006 to December 2021 at the Jikei University Hospital and the Jikei University Kashiwa Hospital. AECC regimen consists of nimustine 200mg/m 2 on day -7 to day -6, etoposide (ETP) 30mg/kg on day -5 to day -4, cyclophosphamide 60mg/kg on day -3 to day -2, carboplatin 700mg/m 2 on day -3 to day -2. MEAM regimen consists of MCNU 300 mg/m 2 on day -7, ETP 200 mg/m 2 on day -6 to day -3, cytarabine 200 mg/m 2 q12 hrs on day -6 to day -3, and melphalan 140 mg/m 2 on day -2. In this study, early relapsed DLBCL (erDLBCL) was defined as DLBCL pts relapsed within 2 years from diagnosis. We retrospectively analyzed overall survival (OS), progression-free survival (PFS) and adverse events (AE). Thirty-five pts received AECC and 33 pts MEAM in DLBCL, respectively. AECC was mainly used from 2006 to 2013, and MEAM was used from 2014 to 2021. The patient characteristics between AECC and MEAM were as bellows; the median follow-up time for survival was 109 (0-193) vs 35(1-83) months ( P &amp;lt;0.01), the median age at auto-SCT was 54(25-65) vs 58 (40-68) years ( P = 0.01), 66% vs 61% were male ( P = 0.80), the median years from diagnosis to auto-SCT was 1.43(0.39-12.79) vs 1.67(0.39-22.40) years ( P = 0.41), the number of pts who receive 2 lines of therapy before auto-SCT were 18 vs 23 ( P = 0.144). Disease status at auto-SCT in the AECC and MEAM groups were 16 vs 12 pts in complete response (CR), 15 vs 21 pts in partial response (PR), and 4 vs 0 pts in stable disease or progressive disease (SD/PD) ( P = 0.06). The 2-year OS and PFS rates in the AECC and MEAM groups were 76.9% vs 68.3% ( P =0.323), and 68.2% vs 59.4% ( P =0.137), respectively. In addition, we focused er DLBCL pts whose disease status at auto-SCT was CR or PR, named as “chemotherapy-sensitive er DLBCL”. Twenty-one pts were treated with AECC and 19 pts were received MEAM. The patient characteristics between AECC and MEAM were as bellows; the median age at auto-SCT in the AECC group was younger than those in the MEAM group (53(25-65) vs 60 (47-68) years, P = 0.01), the number of pts with CR in the AECC group was higher than those in the MEAM group. (10 vs 3, P = 0.046). The OS and PFS in the AECC group were significantly higher than those in the MEAM group (2-year OS 85.4% vs 48.5% ( P = 0.019), and 2-year PFS 75.6% vs 39.0% ( P &amp;lt;0.01), respectively). Additionally, AECC achieved long-term survival with 8-year OS and PFS of 80.4% and 75.6% in the chemotherapy-sensitive er DLBCL, respectively. At the time of data analysis, deaths had been reported in 12 of 35 pts in the AECC and 12 of 33 in the MEAM. The most common cause of death was disease progression (10 pts in the AECC and 8 in the MEAM). Non-relapse mortality (NRM) was observed in 2 pts of the AECC (drug-induced cardiomyopathy (n = 2)), and 4 of the MEAM (liver failure (n = 2), pneumonia (n = 1), and suicide (n = 1)). It should be mentioned that grade 3 or higher heart failure was observed in the AECC group (n = 8) compared to in the MEAM group (n = 0). Treatment related mortality (TRM) within 100 days was 2 pts in the AECC group due to cardiomyopathy and 0 in the MEAM group. AECC followed by auto-SCT achieved both long-term OS and PFS compared to MEAM in chemotherapy-sensitive er DLBCL pts. Further validation for efficacy is needed due to the differences in patient's background and follow-up period in the study. However, AECC was associated with a higher incidence of cardiac toxicity and TRM within 100 days. It was suggested that auto-SCT with AECC may be a treatment option when CAR T-cell therapy was not available.

Local control of bone metastasis treated with palliative radiotherapy in patients with lung cancer: An observational retrospective cohort study.

Bone metastasis is common in advanced lung cancer, with the incidence reported to be 30%, and radiotherapy (RT) is used for pain relief from bone metastasis. The present study aimed to identify factors affecting local control (LC) of bone metastasis from lung cancer and to assess the significance of moderate RT dose escalation. This was a retrospective cohort study, where LC of bone metastasis from lung cancer that had received palliative RT was reviewed. LC at RT sites was evaluated with follow-up computed tomography (CT). The influence of treatment-, cancer- and patient-related risk factors for LC was assessed. A total of 317 metastatic lesions in 210 patients with lung cancer were evaluated. The median RT dose (biologically effective dose calculated using an α/β of 10 Gy; BED10) was 39.0 Gy (range, 14.4-50.7 Gy). The median follow-up time for survival and median radiographic follow-up time were 8 (range, 1-127) and 4 (range, 1-124) months, respectively. The 0.5-year overall survival and LC rates were 58.9 and 87.7%, respectively. The local recurrence rate in RT sites was 11.0%, and bone metastatic progression, except in RT sites, was observed in 46.1% at the time of local recurrence or the last follow-up CT of the RT sites. According to multivariate analysis, RT sites, pre-RT neutrophil to lymphocyte ratio (NLR), post-RT non-administration of molecular-targeting agents (MTs), and non-administration of bone modifying agents (BMAs) were significant unfavorable factors for LC of bone metastasis. Moderate RT dose escalation (BED10 >39 Gy) tended to improve the LC of RT sites. In cases without MTs, moderate dose escalation of RT dose improved the LC of RT sites. In conclusion, treatment (post-RT MTs and BMAs), cancer (RT sites) and patient (pre-RT NLR)-related risk factors had a large impact on improving the LC of RT sites. Moderate RT dose escalation seemed to have a small impact on improving the LC of RT sites.

An easy tool to predict survival in patients with bone metastatic lung cancer treated with palliative radiotherapy.

This study aimed to devise a simple assessment system for bone metastases (BMs) from lung cancer (LC). A total of 368 LC patients with BMs who underwent radiotherapy (RT) were retrospectively reviewed. Prognostic factors were evaluated using multivariate analysis, and a scoring system based on regression coefficients was devised. The median follow-up time for survival was 4.3 months, and the 0.5-year overall survival (OS) rate was 44.7%. In the multivariate analysis, the significant prognostic factors were performance status (PS), metastases to internal organs, and post-RT molecular-targeting therapies (MTs) (tyrosine kinase inhibitors, and/or immune checkpoint inhibitors). A scoring system aggregating points assigned to each risk factor was created (2 points; non-administration of post-RT MTs, 1 point; PS ≥3 and metastases to internal organs). The median OSs were 25.0 months, 12.8 months, and 2.5 months in patients with a total score of 0 (n = 22), 1-2 (n = 124), and 3-4 (n = 221), respectively (p < 0.01). This easy-to-use scoring system is useful for selecting patients who received comparatively high-dose fractionated RT for BMs from LC. Updates are required to follow the progress of systemic therapy.

Presenting limb severity is associated with long-term outcomes after infrainguinal revascularization for chronic limb-threatening ischemia

ObjectiveThe SVS Wound, Ischemia, foot Infection (WIfI) limb staging system was established to estimate risk of major amputation in chronic limb-threatening ischemia (CLTI) and better stratify outcomes comparisons. There is little data on treatment outcomes beyond 1 year based on presenting WIfI stage. MethodsThis is a single-institution retrospective study of 413 patients who underwent infrainguinal revascularization for CLTI (2011-2021) with data available for WIfI staging. Patient characteristics and outcomes were gathered from the electronic medical record. Data were analyzed based on presenting WIfI stage and initial treatment received at our center. ResultsPresenting WIfI stages were 1 to 2 (23%), 3 (27%), and 4 (50%). Index revascularization approach was endoluminal (59%), autogenous vein bypass (29%), or non-autogenous bypass (13%). Operative mortality within 30 days was 2.9% and was not associated with WIfI stage or revascularization approach. Median limb follow-up time was 502 days (interquartile range [IQR], 112-1256 days), and median survival follow-up time was 932 days (IQR, 343-1770 days). Major amputation or death occurred in 19% and 46% of patients at median times of 119 days (IQR, 28-314 days) and 739 days (IQR, 204-1475 days), respectively. WIfI stage was independently associated with major amputation (P = .001), as was initial revascularization approach (P = .01). In a Cox proportional hazards model, factors independently associated with major amputation were male sex (hazard ratio [HR], 1.4; 95% confidence interval [CI], 1.04-2.0; P = .03), diabetes (HR, 1.8; 95% CI, 1.3-2.5; P = .001), WIfI stage 4 (HR, 2.3; 95% CI, 1.5-3.5; P < .001), and non-autogenous bypass (HR, 2.9; 95% CI, 2.1-4.2; P < .001). In a Cox proportional hazards model for mortality, independently associated factors were age (HR, 1.04; 95% CI, 1.02-1.05; P < .001), end-stage renal disease (HR, 2.8; 95% CI, 1.9-4.0; P < .001), congestive heart failure (HR, 1.9; 95% CI, 1.4-2.5; P < .001), chronic obstructive pulmonary disease (HR, 1.5; 95% CI, 1.1-2.1; P = .02), and WIfI stage 4 (HR, 1.6; 95% CI, 1.04-2.2; P = .03). Among those presenting with WIfI stage 4 limbs, Kaplan-Meier estimated rates of freedom from major amputation or death at 2 years were 71% ± 3.7% and 68% ± 3.5%, respectively. In an inverse propensity weighted Cox proportional hazards model, non-white race (HR, 1.5; 95% CI, 1.01-2.2; P = .047), diabetes (HR, 2.0; 95% CI, 1.2-3.3; P = .008), Global Anatomic Staging System infrapopliteal grade (HR, 1.2; 95% CI, 1.05-1.3; P = .005), non-autogenous bypass (HR, 3.2; 95% CI, 1.9-5.3; P < .001), and endoluminal revascularization (HR, 2.6; 95% CI, 1.6-4.3; P < .001) were independently associated with major amputation in the WIfI stage 4 subgroup. ConclusionsPresenting WIfI stage is strongly associated with long-term risks of major amputation and death following infrainguinal revascularization for CLTI and should be used to stratify outcomes comparisons. Effective revascularization is critical in WIfI stage 4 disease, and autogenous vein bypass provides durable long-term limb preservation.

336. IMPACT OF TIME TO SURGERY AFTER CHEMORADIOTHERAPY ON TUMOR REGRESSION AND SURVIVAL IN THE MULTICENTER RANDOMIZED CONTROLLED NEORES II TRIAL

Abstract Time to surgery after termination of neoadjuvant chemoradiotherapy for esophageal cancer has traditionally been 4–6 weeks. Observational studies have suggested that delay of surgery for up to three months may lead to improved tumor regression and better outcomes. NeoRes II is the first randomized trial to address this in esophageal cancer. No difference in surgical morbidity or mortality between early and delayed surgery was reported in a previous publication from the trial. A multicenter clinical trial with randomized 1:1 allocation of standard time to surgery of 4–6 weeks, or delay of surgery to 10–12 weeks, after termination of chemoradiotherapy. The primary endpoint was complete histological tumor regression in patients with adenocarcinoma. Secondary endpoints included tumor regression grade, tumor free resection margins and overall survival in all patients, and stratified by histological subtype. In total 249 patients were randomized, 204 with adenocarcinoma and 45 with squamous cell carcinoma. There was no significant difference in histological complete response between adenocarcinoma patients allocated to standard time to surgery (20.6%) compared to delayed (25.6%) surgery (P = 0.18). Tumor free resection margin was achieved in 97.4% after standard time to surgery and 97.1% after delayed surgery (P = 1.0). The median follow-up time for survival was 51 months. Delayed time to surgery was associated with a 35% higher overall mortality, hazard ratio 1.35 (95% CI:0.94–1.95), (P = 0.11). No significant difference in complete histological tumor regression or tumor free resection margins comparing standard and delayed time to surgery after chemoradiotherapy was observed. There was a non-significant trend towards inferior overall survival after delayed surgery, suggesting caution in delaying surgery for more than 6 weeks after neoadjuvant chemoradiotherapy.

Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning regimen for blastic plasmacytoid dendritic cell neoplasm patients in complete remission: a single center study

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic malignancy characterized by poor prognosis even following an allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed 15 patients diagnosed with BPDCN who underwent an allo-HSCT with myeloablative conditioning (MAC) at our center. The male to female ratio was 11:4. The median age of 36 (range: 6–70) years, all patients initially presented with extramedullary lesions (13 with cutaneous lesions, 1 in the breast and 1 in the lymph nodes) and involved the bone marrow, two cases were diagnosed as central nervous system leukemia (CNSL). Nine patients were in CR1 and six patients were in CR2 status prior to HSCT. All patients received the MAC regimen and an unmanipulated graft. All patients successfully engraftment and achieved full donor chimerism. One patient developed poor graft function, three patients developed aGVHD (Grade I, II, and IV), and seven patients developed cGVHD (mild in 6; moderate in 1). The median follow-up time for survival was 34 (range: 6–64) months. The primary endpoint, overall leukemia-free survival (LFS) rate and overall survival rate was 73.3 ± 10.5%. Allo-HSCT with MAC is a valid option for BPDCN patients in complete remission.

Augmenting Real-World Data Through Modeling Key Clinical Trial Eligibility Criteria: An Example of Patients With Non-small-Cell Lung Cancer Treated With Pembrolizumab.

To compare and characterize baseline characteristics and overall survival (OS) differences by key oncology eligibility criteria for real-world patients from the Flatiron Health database with advanced non-small-cell lung cancer (NSCLC) who received pembrolizumab monotherapy. Real world data (RWD) were from the Flatiron Health advanced NSCLC database and include patients who initiated pembrolizumab monotherapy (first, second, or third line of therapy) by November 30, 2019. At the data cutoff (May 31, 2020), the median survival follow-up time was 8.4 months. Eligible patients satisfy the criteria of Eastern Cooperative Oncology Group performance status of 0/1 and laboratory values indicative of adequate organ function. RWD were analyzed for all patients and patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. Patients were divided into three categories: ineligible, eligible, and unknown (who satisfy all observed criteria, with at least one missing). An augmented population was also formed, which combines the latter two groups through a propensity-based adjustment. At the data cutoff, N = 3,877 patients with NSCLC received pembrolizumab monotherapy (1L = 2,682, 2L = 946, and 3L = 249). OS was consistently lower for the ineligible with similar survival for the eligible and augmented. Among all patients, the median OS in months (95% CI) was 8.2 (7.5 to 9.6), 16.3 (14.5 to 18.4), 16.4 (15.1 to 19.3), and 16.8 (15.6 to 18.5) for the ineligible (47%, n = 1,827), unknown (27%, n = 1,045), eligible (26%, n = 1,005), and augmented, respectively. The results were similar for patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. Real-world patients who received pembrolizumab monotherapy and meet key clinical eligibility criteria exhibited similar baseline characteristics and OS profiles as the unknown and augmented patient groups. Population augmentation is a feasible approach for improving the power of RWD analysis.

Overall Survival With Second-Line Pembrolizumab in Patients With Non–Small-Cell Lung Cancer: Randomized Phase III Clinical Trial Versus Propensity-Adjusted Real-World Data

To compare and characterize overall survival (OS) differences between clinical trial data from the KEYNOTE-010 trial and real-world data (RWD) from the Flatiron Health database in patients with programmed death ligand 1 (PD-L1)-expressing advanced non-small-cell lung cancer (NSCLC) who received second-line pembrolizumab monotherapy. Clinical trial data were from the randomized phase II/III KEYNOTE-010 trial that enrolled patients from August 28, 2013, to February 27, 2015. At data cutoff for KEYNOTE-010, the median survival follow-up time for pembrolizumab patients was 11.2 months. RWD were from Flatiron Health advanced NSCLC database and included patients who initiated second-line pembrolizumab from January 26, 2015, to February 28, 2019. At data cutoff for Flatiron, the median survival follow-up time for pembrolizumab-treated patients was 6.1 months. Clinical trial data from KEYNOTE-010 and RWD from Flatiron were analyzed without adjustment, with propensity adjustment, and filtered per the main KEYNOTE-010 eligibility criteria (EC) of histologically/cytologically confirmed PD-L1-positive NSCLC, Eastern Cooperative Oncology Group performance status of 0/1, no prior therapy with docetaxel for NSCLC, and laboratory values indicative of adequate organ function in addition to prior line of therapy requirements. Among 243 patients from KEYNOTE-010 and 782 from Flatiron, median age was 63 v 68 years, and 64% v 54% were male, respectively. OS data from KEYNOTE-010 and Flatiron were similar without any adjustment (n = 782; hazard ratio [HR], 0.96; 95% CI, 0.80 to 1.15) and after both filtering and propensity adjustment (n = 221; HR, 0.99; 95% CI, 0.73 to 1.34). Without any adjustment, as well as after applying similar EC and appropriate statistical methods, RWD demonstrated similar effectiveness for pembrolizumab in second-line NSCLC as observed in randomized clinical trials.

Characteristics and prognosis of primary treatment-naïve oral cavity squamous cell carcinoma in Norway, a descriptive retrospective study.

ObjectivesIncidence of oral cavity squamous cell carcinomas is rising worldwide, and population characterization is important to follow for future trends. The aim of this retrospective study was to present a large cohort of primary oral cavity squamous cell carcinoma from all four health regions of Norway, with descriptive clinicopathological characteristics and five-year survival outcomes.Materials and methodsPatients diagnosed with primary treatment-naïve oral cavity squamous cell carcinomas at all four university hospitals in Norway between 2005–2009 were retrospectively included in this study. Clinicopathological data from the electronic health records were compared to survival data.ResultsA total of 535 patients with primary treatment-naïve oral cavity squamous cell carcinomas were identified. The median survival follow-up time was 48 months (range 0–125 months) after treatment. The median five-year overall survival was found to be 47%. Median five-year disease-specific survival was 52%, ranging from 80% for stage I to 33% for stage IV patients. For patients given treatment with curative intent, the overall survival was found to be 56% and disease-specific survival 62%. Median age at diagnosis was 67 years (range 24–101 years), 64 years for men and 72 years for women. The male: female ratio was 1.2. No gender difference was found in neither tumor status (p = 0.180) nor node status (p = 0.266), but both factors influenced significantly on survival (p<0.001 for both).ConclusionsWe present a large cohort of primary treatment-naïve oral cavity squamous cell carcinomas in Norway. Five-year disease-specific survival was 52%, and patients eligible for curative treatment had a five-year disease-specific survival up to 62%.

Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC).

688 Background: BRAFV600E mutation occurs in 10%-–15% of patients (pts) with mCRC and confers a poor prognosis. After first-line therapy, standard second-line therapies provide limited benefit, with objective response rates (ORRs) &lt; 10%, and overall survival (OS) of 4–6 months (mo). BEACON CRC (NCT02928224) is a 3-arm phase 3 trial of triplet therapy with the BRAF inhibitor ENCO + MEK inhibitor BINI + anti–EGFR antibody CETUX vs ENCO + CETUX vs a control arm (irinotecan/FOLFIRI + CETUX) in pts with BRAFV600E mCRC in the second or third-line setting. A safety lead-in (SLI) of the triplet therapy was conducted in 30 pts prior to initiation of the randomized part of the trial. Previously reported confirmed ORR in 29 pts with BRAFV600E mCRC was 48% and median progression-free survival (PFS) was 8.0 mo (Van Cutsem E, et al. Ann Oncol. 2018;29:O-027). Here we present updated safety and efficacy results including mature OS. Methods: All pts in the SLI received ENCO 300 mg once daily + BINI 45 mg twice daily + CETUX standard weekly dose. Assessments included efficacy (ORR, duration of response, time to response, PFS, and OS), safety, and tolerability. Results: Among 30 pts treated, 1 had a BRAF non-V600E mutation and is not included in the efficacy analyses. At data cutoff, the median follow-up time for survival was 18.2 mo and median exposure was 7.8 mo (range 0.5–21.4 mo). The confirmed ORR and median PFS remain unchanged from the previous report (ORR, 48% [95%CI, 29.4–67.5]; PFS, 8.0 mo [95% CI, 5.6–9.3 mo]). Mature median OS is 15.3 mo (95% CI, 9.6 mo–not reached). The triplet continues to be well-tolerated with no unexpected toxicities. The most common grade 3/4 toxicities were fatigue (13%), anemia, increases in creatine phosphokinase and/or aspartate aminotransferase, and urinary tract infections (each 10%). The rate of grade 3/4 skin toxicities continues to be lower than generally observed with CETUX in mCRC. Conclusions: With longer follow-up, triplet therapy with ENCO + BINI + CETUX continues to be well tolerated. Median PFS and now mature median OS are substantially improved over historical data for current standard-of-care options. Clinical trial information: NCT02928224.

Primary breast lymphoma: A single center study.

The aim of the present study was to summarize the clinical characteristics of primary breast lymphoma (PBL) and evaluate its management approaches. A total of 29 patients newly diagnosed with PBL, and treated between April 2006 and May 2013, were analyzed retrospectively. The median survival follow-up time for all patients was 66.8 (range, 25.4-110.0) months. The results of the follow-up revealed 22 living lymphoma-free patients and 7 patients who had succumbed to PBL. Of the 7 deceased patients, 6 had succumbed to lymphoma and 1 to chemotherapy-associated hepatic failure. In total, 1 patient who presented with bilateral breast lymphoma developed left breast relapse following lumpectomy and chemotherapy, 2 patients developed a bone marrow relapse, 1 patient developed lung and mediastinal lymph node relapses, and 1 patient developed a skin relapse. The Kaplan-Meier estimator predicted 5-year overall survival and progression-free survival rates for all patients of 74.4 and 74.6%, respectively. PBL appears to be a rare disease with a good overall prognosis and low incidence of local relapse, following chemotherapy alone or in combination with other treatments. Further studies investigating the development of effective agents for use in treatment-resistant patients are required.

Early Relapse of Follicular Lymphoma after Rituximab-Based Biologic Doublet Upfront Therapy Is Associated with Increased Risk of Death: A Combined Analysis from CALGB Studies 50402, 50701 and 50803 (Alliance)

Background:In follicular lymphoma (FL) patients treated with first-line R-CHOP, early progression of disease (POD) within 2 years after diagnosis is associated with high risk for death (hazard ratio 6.4) and a 50% 5-year overall survival (Casulo et al. JCO 2015). Whether these observations hold for patients treated without chemotherapy is unknown. The Alliance for Clinical Trials in Oncology conducted three frontline rituximab-based non-chemotherapy-containing biologic immunotherapy doublet clinical trials: R-Galiximab (Anti-CD80, CALGB 50402), R-Epratuzumab (Anti-CD22, CALGB 50701) and R-Lenalidomide (CALGB 50803). We performed a retrospective analysis of 174 patients to determine outcomes of early progressors after initial biologic, non-cytotoxic treatment and risk factors for early POD.Methods:CALGB 50402 (n=60), CALGB 50701 (n=57), and CALGB 50803 (n=57) had similar eligibility criteria: previously untreated follicular lymphoma, grade 1, 2 or 3a with stage III, IV or bulky (single mass >7 cm) stage II disease, and ECOG PS 0 to 2. Early POD was defined as progression within 24 months from study entry. Univariate and multivariate logistic regression modeling using forward selection was performed to identify predictors of early POD. Kaplan-Meier (KM) method was used to estimate 2-year and 5-year overall survival probability. Hazard ratios (HR) and 95% CI were calculated using a univariate and multivariate Cox regression model adjusting for FLIPI.Results:Twenty-seven percent (48/174) of patients had early POD. Median survival follow-up time from study entry was 5.5 years (2.1 to 10.1 years) and median time from diagnosis to enrollment was 2 months (0.2 to 115 months). Median age was 54 (range: 22-90), 49% were male and 24% had low-, 52% intermediate- and 24% high-risk FLIPI (Table 1). Early POD from study entry conferred a worse OS [HR=4.86 (95% CI 1.90-12.4), p < 0.001]. After adjusting for FLIPI, patients with early POD from study entry had a worse OS compared with patients who did not progress within 2 years [HR=4.77 (95% CI 1.70-13.4), p=0.003]. For early POD, the 2-year survival probability was 89% (76-95%) vs. 100% for non-early POD, and the 5-year survival was 76% (60-86%) vs. 99% (95-99%), respectively (Figure 1). When the 2-year early POD interval was taken from time of diagnosis, similar findings were noted (n=171, HR for OS 5.27 (95% CI 1.98-14.0), p 0.0009) [Table 2].Univariate analysis revealed age >60 (p=0.019), male sex (p=0.002), higher FLIPI (p<0.001), hemoglobin <10 (p=0.021), number of nodal sites >4 (p=0.010), elevated LDH (p=0.004), nodal size >7 cm (p=0.002), albumin <3.5 (p=0.030) and CD10 positivity (p=0.015) were associated with early POD, while grade and bone marrow involvement were not. Histologic biomarkers PD1 and Ki67 were not associated with early POD in this analysis. A multivariate logistic regression model showed that male sex, albumin <3.5, low absolute monocyte count, interfollicular CD10 expression and high-risk FLIPI were predictors of early POD.Conclusions:Early relapse within 2 years after diagnosis in patients receiving front-line rituximab-based biologic non-cytotoxic therapy is associated with an increased risk of death. These data are similar to previous findings in patients treated with R-CHOP from the National LymphoCare study, suggesting that the adverse survival of patients with early POD may be independent of systemic treatment modality. Novel clinicopathological approaches are needed at diagnosis to identify patients who are likely to have unfavorable outcomes, and for whom biologic doublets are efficacious.Support: U10CA180821, U10CA180882.ClinicalTrials.gov Identifier: NCT00117975 (CALGB 50402), NCT00553501 (CALGB 50701), and NCT01145495 (CALGB 50803) [Display omitted] [Display omitted] DisclosuresLansigan:Pharmacyclics: Consultancy; Teva: Research Funding; Celgene: Consultancy; Spectrum: Consultancy, Research Funding. Cheson:Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Czuczman:Celgene: Employment. Martin:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Teva: Research Funding; Acerta: Consultancy; Novartis: Consultancy; Gilead: Consultancy, Other: travel, accommodations, expenses. Hsi:Eli Lilly: Consultancy; Abbvie: Consultancy; Cellerant Therapeutics: Consultancy; Seattle Genetics: Honoraria; HTG molecular diagnostics: Honoraria. Bartlett:Gilead: Consultancy.

Single Center Results following Proton Beam Therapy in Children with Atypical Teratoid Rhabdoid Tumors of the Central Nervous System

Abstract Purpose: Atypical teratoid rhabdoid tumor is a rare, embryonal, central nervous system tumor seen predominantly in infancy and childhood. Outcomes are generally dismal, with median survival estimated at 6 months to a year. The purpose of this study was to evaluate proton beam therapy (PBT) outcomes in this population. Materials and Methods: Sixteen patients with a diagnosis of atypical teratoid rhabdoid tumor were treated from November 2007 to January 2013 at the Indiana University Health Proton Therapy Center. All patients were treated with PBT. Fraction sizes of 1.8 Gy/fraction were used to deliver 28 to 33 fractions. Seven patients received craniospinal PBT. There were 12 male and 4 female patients. The median age at diagnosis was 18.5 months (range, 5 months to 39 years). Eight had metastatic disease at diagnosis. Fourteen patients underwent surgery. Fifteen patients received chemotherapy. Results: Median survival follow-up time was 3.18 years (or 38.2 months). The mean overall survival was e...

Low albumin-to-globulin ratio associated with cancer incidence and mortality in generally healthy adults

Chronic inflammation is known to be one of the main steps in carcinogenesis. Identification of those with chronic inflammation may help identify subjects at risk of cancer. Previous studies have reported low albumin-to-globulin ratio (AGR) to be associated with increased cancer mortality in cancer patients, but there has been no study based on healthy populations. Our retrospective cohort study involved 26 974 generally healthy adults aged 30 or older who visited Seoul National University Hospital Health Promotion Center for self-referred health checkup. National medical service claims data were used to determine cancer incidence, and Korean death registry data was used to determine mortality. Median follow-up time for survival was 5.9 years (interquartile range 4.1 years). Compared with subjects with AGR ≥ 1.5, subjects with 1.1 > AGR ≥ 1.0 and 1.0 > AGR showed adjusted hazard ratio (aHR) 2.69 (95% confidence interval, CI, 1.54-4.72) and aHR 6.71 (95% CI 3.56-12.66) for all-cause mortality, aHR 2.95 (95% CI 1.42-6.11) and aHR 4.38 (95% CI 1.57-12.25) for cancer mortality, and aHR 2.07 (95% CI 1.28-3.36) and aHR 3.99 (95% CI 2.10-7.58) for cancer incidence, respectively. When cancer incidence events after 2 years from baseline were separately analyzed, subjects with 1.1 > AGR ≥ 1.0 and 1.0 > AGR were associated with aHR 1.88 (95% CI 1.01-3.48) and aHR 2.55 (95% CI 1.03-7.11) for cancer incidence, respectively. Cancer events were increased in all types of cancer, but especially in liver and hematologic malignancies. Low AGR is a risk factor for cancer incidence and mortality, both short- and long terms, in a generally healthy screened population. The results of this study need to be replicated in larger studies, along with the determination of the sensitivity and other diagnostic values of low AGR.

Phase II trial of combination therapy using S-1, cisplatin, and radiation for distant metastatic esophageal cancer (stage IVb).

e14596 Background: S-1 is an orally active fluoropyrimidine that enhances the efficacy of radiotherapy (RT) and has low gastrointestinal toxicity. Our previous phase II study demonstrated that definitive chemoradiotherapy (CRT) with S-1 and cisplatin was well-tolerated and had favorable activity for locally advanced esophageal cancer (Iwase H et al, Proc. ASCO 2011, Abst 4034). The present study was a phase II trial of combination therapy using S-1, cisplatin, and RT for distant metastatic esophageal cancer (DMEC). Methods: S-1 (80 mg/m2/day) was given orally for 14 consecutive days from Day 1 and cisplatin (70 mg/m2) was administered on Day 14, both with 3 weeks of RT (2.0 Gy per traction) 5 times per week for the primary lesion and metastases in the neck, which initiated on Day 1. One Cycle equals 5 weeks, 2 weeks of chemotherapy concurrent with 3 weeks of RT followed by 2 weeks of complete rest. After 2 cycles, only chemotherapy with S-1 and cisplatin were administered. Results: Forty-one patients with DMEC (Stage IVb) were enrolled between March 2002 and February 2011. 37/male7/female, median age 67.5 years (48-82). The median survival follow-up time was 16.6 months and 37 patients (90.2%) completed the combination treatment. The most common adverse event was neutropenia. Grades 3 and 4 neutropenia were observed in 29.2% and 12.2%, respectively. In general, non-hematological adverse events were mild and the most common were Grade 2 nausea (34.1%), esophageal pain and oral mucositis (17.1% each), and renal dysfunction (9.8%). The overall response rate was 65.9% comprising 93.2% in the primary lesion, 60% in the liver metastasis, 64.3.% in the lung, 54.5% in the distant lymph node, 83.3% in the regional lymph node metastasis, and 50% in the other distant metastases. Thirty-nine patients (88.6%) showed improvement in their dysphagia score. The median progression-free and overall survival durations were 5.3 [95% confidence interval (CI), 4.1 to 6.0] and 13.1 months (95% CI, 9.8 to 15.6), respectively. Conclusions: Combination therapy using S-1, cisplatin, and RT has a promising safety and efficacy profile. Potentially, this regimen could become the baseline treatment for patients with DMEC.

Phase I trial of dose escalation with growth factor support in patients with previously untreated diffuse aggressive lymphomas: determination of the maximum-tolerated dose of ProMACE-CytaBOM.

The aim of this study was to determine the maximum-tolerated dose (MTD) of cyclophosphamide, doxorubicin, etoposide, prednisone, bleomycin, cytarabine, methotrexate, and leucovorin (ProMACE-CytaBOM) when the myelotoxic drugs cyclophosphamide, doxorubicin, etoposide, and cytarabine are escalated. Thirty-eight eligible patients with diffuse aggressive non-Hodgkin's lymphoma were treated on a phase I trial of dose escalation using the ProMACE-CytaBOM regimen and granulocyte-macrophage colony-stimulating factor (GM-CSF; Schering, Kenilworth, NJ). Patients were treated with recombinant (r)GM-CSF 10 microg/kg/d subcutaneously from day 9 to 19. Twenty-seven patients had stage IV disease, four had stage III, and seven had bulky stage II. Half of the patients had bone marrow involvement. The median age was 45 years. We found that the MTD was 200% for the escalated drugs in this regimen (although we never escalated above the MTD or defined by dose-limiting toxicity) and that the normalized dose-intensity (NDI; defined as the ratio of the received dose-intensity to the 100% dose-intensity of ProcMACE-CytaBOM) decreased with each cycle and was lower for the day-8 drug (cytarabine) than for the day-1 drugs. The complete response (CR) rate was 66%, and 92% of patients who achieved CR are alive without disease with a median follow-up time for survival of 3.6 years. The MTD of cyclophosphamide, doxorubicin, etoposide, and cytarabine in the ProMACE-CytaBOM regimen given with growth factor support is 200%, and this dose should be tested in larger phase II trials.