Citations

7524 Background: A multicenter study (Z4032) compared sublobar resection (SR) to sublobar resection with brachytherapy (SRB) for stage I NSCLC. Local recurrence (LR) and overall survival (OS) rates at 3-years (3-yr) were similar between arms (see abstract 113613). This analysis combines arms, and evaluates the effect of factors previously reported to impact oncological outcomes after SR. Methods: 213 patients (pts) were evaluable for analysis. LR was defined as recurrence at the staple line (local progression), same lobe away from the staple line, or within hilar nodes. Factors assessed for impact on 3-yr outcomes were: resection type (wedge/segmentectomy), margin size (<1cm /≥1cm), margin:tumor ratio (<1/ ≥1), tumor size (≤2cm/>2cm) and staple line cytology (+/-). Results: LR occurred in 27/213 (12.6%) pts and included local progression in 12/213 (5.6%). OS rate at 3-yr was 152/213 (71.4%). Trends favored the use of segmentectomy, margin:tumor ratio≥1, tumor size ≤2cm and negative staple line cytology; no factor reached statistical significance at 3-yr. The only factor significantly (p=0.02) associated with decreased 3-yr LR was margin size ≥1cm (8.3%) compared to margin<1cm (19.3%). Conclusions: SR is a good option for high-risk pts with NSCLC. The 3-yr OS rate of 71.4% and local progression rate of 5.6% are useful benchmarks to compare to other therapies. A resection margin of at least 1 cm is desirable. Clinical trial information: NCT00107172. [Table: see text]

9047 Background: Symptomatic adverse events (AE) in cancer trials are reported by clinicians using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE). To integrate the patient perspective into AE reporting, NCI contracted (HHSN261201000043C) to create a patient-reported outcomes companion tool (PRO-CTCAE). We report the validity and reliability of PRO-CTCAE’s 124 items reflecting 78 symptomatic AEs. Methods: English-speaking subjects (n=869; 44% male; median [mdn] age 59; 32% racial/ethnic minority; 34% high school or less; 17% ECOG Performance Status [PS] 2-4) receiving treatment for a range of cancers at 4 NCI-designated cancer centers and 5 sites in NCI's Community Cancer Centers Program completed a web-based survey in clinic including PRO-CTCAE and EORTC QLQ-C30. Pearson correlations were computed between PRO-CTCAE items and QLQ-C30 scales. Differences in PRO-CTCAE item scores between clinician-reported ECOG PS (0-1 vs 2-4) groups were computed. Test-retest reliability of 48 prespecified items was evaluated in a subset (n=79). Results: Correlations in the expected direction were observed for 116/124 PRO-CTCAE items with the QLQ-C30 global health scale (mdn r=-.21; range .08 to -.57). Stronger correlations were seen for PRO-CTCAE items with conceptually related QLQ-C30 domains: fatigue with physical, role and social functioning (-.54 to -.66); anxiety and depression with emotional functioning (-.54 to -.70); and concentration and memory problems with cognitive functioning (-.62 to -.72) [all p <0.001]. Fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea items strongly correlated with corresponding QLQ-C30 symptom scales (.69 to .79, all p <0.001). Scores for 98/124 PRO-CTCAE items were higher in the ECOG PS 2-4 vs 0-1 group (mdn effect size .3). Test-retest reliability was observed across all tested items (mdn intraclass correlation coeff .77; range .53 to .96). Conclusions: Results demonstrate favorable validity and reliability of PRO-CTCAE in a large, heterogeneous sample of patients undergoing cancer treatment. Further testing in multicenter treatment trials is underway.

LBA1000 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

TPS10592 Background: Angiosarcomas (ASs) are rare, aggressive, malignant endothelial cell tumors that constitute 1% to 2% of all soft tissue sarcomas with 5-year survival of 35%. Cytotoxic agents have demonstrated response rates of about 15%. Gene-array data from MSKCC has revealed up-regulation of endothelial associated genes, including active members of the angiopoietin system e.g., Tie2 and Angiopoietin 2 (Ang2). Trebananib (AMG386) is a novel agent that targets Ang1 and Ang2. We hypothesize that inhibition of angiopoietin 2 with trebananib will be an effective therapy in patients (pts) with AS. Methods: This CTEP sponsored, investigator initiated, multi-center phase II study uses trebananib, in pts with AS having metastatic/unresectable AS and conducted through the Alliance for Clinical Trials in Oncology (Alliance A091103). Pts must have adequate performance status, organ function, and measurable disease (RECIST v1.1). Patients are treated with trebananib 30mg/kg d1, 8, 15, and 22 every 28 days until either progressive disease or unacceptable toxicity. The primary endpoint is objective overall response rate (ORR) via RECIST v1.1. Secondary endpoints include the evaluation of progression-free survival (PFS) and overall survival (OS). Translational objectives include correlation of ORR, PFS and OS with i. baseline and post-treatment expression of Ang2 and Tie2 by immunohistochemistry (IHC), ii. serum levels of Ang1 and Ang2, iii. baseline and post-treatment phospho-receptor tyrosine kinase (p-RTK) status of Tie2, VEGFR-2, PI3K, MEK and MAPK, and iv. mutational status of VEGFR-2 and amplification of MYC/FLT4. A Simon Optimal two-stage phase II study design is used and one confirmed response in the first 12 pts expands enrollment to 25. Pre- and post-treatment biopsies will be performed in up to 10 pts treated at MSKCC. Enrollment began in July 2012. As of January 2013, 7 pts have been recruited. Clinicaltrials.gov#: NCT01623869. Funded by the Alliance Clinical Trials in Oncology. NIH Grant CA-25224. Clinical trial information: NCT01623869.

7502 Background: Prior studies suggest that adjuvant brachytherapy reduces local recurrence (LR) after sublobar resection (SR) for NSCLC. A multicenter randomized study was undertaken in patients (pts) with stage I NSCLC ≤3cm comparing SR to SR with brachytherapy (SRB). Methods: High-risk operable patients with NSCLC were randomized to SR or SRB. Brachytherapy involved placement of I125 seeds incorporated into Vicryl sutures or into Vicryl mesh placed over the staple line. Wedge or segmental resection was allowed. The primary endpoint was time to local recurrence (LR) defined as recurrence within the primary tumor lobe at the staple line (local progression), away from the staple line or within hilar nodes. The trial was designed to have 90% power to detect a hazard ratio (HR) of 0.315 in favor of the SRB arm using a one-sided α of 0.05 with a sample size of 100 eligible pts per arm. Follow-up CT scans were obtained serially for 36 months. Results: 224 pts were randomized; 213 (109 SR,104 SRB) were eligible. Median (range) age was 71 (49-87) yrs; 94 (44%) were male. No differences were found in baseline characteristics. Adverse events, previously reported, were not different between arms. Median (range) follow-up was 4.06 (0.04, 5.0) yrs. There was no difference between arms in time to LR (HR = 0.87; 5% CI: 0.41, 1.86, p=0.72) or to LR or death (LRD) (HR = 0.81, 95% CI: 0.50, 1.32, p=0.40). There was no difference between arms in pattern of LR (table). In subgroups of pts with potentially compromised surgical margin (margin < 1cm; margin:tumor ratio <1; positive staple line cytology) SRB did not reduce LR or LRD at 3-yrs. Overall 3-yr survival was similar for SR (71%) and SRB (72%) (p=0.81). Conclusions: LR remains a concern after sublobar resection. However, local progression at the staple line was low. This trial demonstrated that adjuvant brachytherapy does not impact oncologic outcomes. Clinical trial information: NCT00107172. [Table: see text]

1505 Background: Combined deletion of chromosomes 1p and 19q is associated with improved prognosis in pts with anaplastic oligodendroglioma. We recently discovered that the combined deletion is mediated by a chromosome 1;19 translocation: t(1;19)(q10;p10). The prognostic significance of this alteration in pts with low-grade gliomas is not known. Methods: Paraffin-embedded tumor tissue was obtained from 134 pts enrolled in two NCCTG trials for newly-diagnosed low-grade glioma: 86–72–51: a randomized phase III trial of 50.4 Gy vs 64.8 Gy radiation therapy (RT) and 93–72–02: a phase II trial of PCV for 6 cycles followed by RT. Interphase fusion of a CEP1 probe and a BAC contig probe for 19p12 was used to detect the 1;19 translocation. Analysis of 1p and 19q deletions had been previously performed by FISH. Kaplan-Meier distributions of overall survival (OS) and progression-free survival (PFS) for pts whose tumors did or did not exhibit CEP1/19p12 fusion were compared using the Wilcoxon test. Results: Of 134 pts, CEP1/19p12 fusion testing was informative for 92. CEP1/19p12 fusion prevalence was 55% among 42 oligodendrogliomas, 47% among 30 mixed oligoastrocytomas, and 5% among 20 astrocytomas. 91% of gliomas with and 11% without 1p/19q deletion had CEP1/19p12 fusion (p<0.0001, chi-square test). The frequency of the t(1;19) by tumor histology, as well as median and 5-year progression-free and overall survival are provided in the table . Conclusions: Our results strongly suggest that a t(1;19)(q10;p10) mediates the combined deletion of 1p and 19q in human gliomas. Like combined 1p and 19q deletion, the 1;19 translocation is associated with superior progression-free and overall survival in low-grade oligodendroglioma patients. FISH analysis of the t(1;19) will likely be a more sensitive and specific means to assess 1p and 19q status in patients with gliomas. (Supported in part by CA85799, CA108961 and NCCTG grants CA25224 and CA114740) [Table: see text] No significant financial relationships to disclose.

8011 Background: Maintenance therapy is generally not used in treatment of DLBCL. However, older pts are a unique group in which to study this approach, due to poorer outcome. Methods: As part of intergroup trial E4494/C9793, 415 pts >= 60 years (yr) of age with DLBCL who responded to induction therapy with CHOP or R-CHOP were randomized to MR (rituximab, 375 mg/m2 weekly {wk} X 4 every 6 months for 2 yr) starting 4 wk after the last chemotherapy (n=207) or observation (OBS, n=208) in a prospective 2 × 2 randomized trial design (J Clin Oncol 2006;24:3121). Impact of MR on failure-free survival (FFS) was the primary objective, and impact on time to failure (TTF) and overall survival (OS) were secondary objectives. All p-values are two-sided. Results: Results are presented for 352 centrally reviewed evaluable pts, with a median follow-up after maintenance randomization of 5.5 yr. All results were similar for the intent-to-treat population. Baseline characteristics and response to induction therapy are balanced among the CHOP/R-CHOP pts. At 6 yr, FFS was 46% for those pt who received MR and 36% for the OBS cohort (p=0.005, hazard rate {HR} 0.64); 6-yr OS was 62% for MR and 64% for OBS (p=0.83, HR 0.96). Outcome was also examined in the four treatment subgroups. The 6-yr FFS were: CHOP+MR 44%, CHOP+OBS 35%, R-CHOP+MR 47%, and R- CHOP+OBS 40%. No differences in 6-yr OS were observed according to maintenance randomization following CHOP (57% MR vs 55% OBS) or R-CHOP (67% MR and 72% OBS). Median TTF after maintenance randomization following CHOP+MR was 5.2 yr vs 1.6 yr for CHOP-OBS (p=0.0004), and following R-CHOP+MR was 5.6 yr vs 5.4 yr with R-CHOP-OBS (p=0.50). Proportionately more of the treatment failures occurred within 2 yr after CHOP+OBS (85%) compared to CHOP+MR (61%), p=0.01. In contrast, the proportion of failures within 2 yr was similar for R- CHOP+OBS (47%) and R-CHOP+MR (53%), p=NS. Conclusions: MR after CHOP, but not after R-CHOP, significantly prolongs TTF, but fails to prolong OS, possibly due to a delayed pattern of relapse and/or the efficacy of rituximab in the salvage setting. As 6-yr FFS declined to <50% among R-CHOP responders, with or without MR, there is a need for more effective treatment strategies in older DLBCL pts. No significant financial relationships to disclose.

5144 Background: The time course of testosterone (TST) recovery after prolonged androgen suppression (AS) is not well established. We examined TST recovery prospectively in prostate cancer (PCa) patients treated with 2 years of AS. Methods: 153 PCa men with pT3N0 or positive margins after radical prostatectomy (RP), or with PSA relapse (persistently detectable postoperative PSA [= 0.2 ng/mL], delayed detectable PSA = 6 months after surgery, or palpable/biopsy proven local recurrence after RP), were treated with radiation (RT) to the prostate bed (60 - 70 Gy in 30 - 35 fractions) plus 2 years of AS as part of a phase II study. AS consisted of nilutamide 100 mg PO tid for 4 weeks, starting within 1 week after completing RT, and busereline acetate 6.6 mg SC every 2 months for 2 years, starting within 2 weeks of nilutamide. The primary endpoint was PSA relapse-free survival. Serum TST levels were measured at baseline, every 4 months during AS, and every 6 months after completing AS. The planned sample size was 150 patients. Time to TST recovery was analyzed using the Kaplan-Meier method. Cox Proportional Hazards regression was used for a multivariate analysis of predictive factors for TST recovery. Results: 122 men completed the planned AS. Median follow up after finishing AS was 36.4 months (range 9.4 - 76.2). A castrate TST level was defined as =1.7 nmol/L (50 ng/dL), with normal levels being 10 - 40 nmol/L. All men achieved castrate TST levels on AS. Table 1 shows TST recovery at 36 months after completing AS and median times to recovery. Median recovery time to normal TST was 27 months, although 8% of men did not recover to above castrate levels by 3 years. On multivariate analysis, younger age (<60 vs. =60) predicted for a significantly shorter recovery time to normal TST (P = <0.0001), while baseline TST (<10 nmol/L vs. =10.0 nmol/L) was of borderline significance (P = 0.06). Conclusions: TST recovery after 2 years of AS is protracted. Older men have significantly longer recovery times. [Table: see text] [Table: see text]

4127 Background: The MMRpredict model, developed at the University of Edinburgh, is a web-based model developed to predict which patients diagnosed with colorectal cancer (CRC) under age 55 years have germline mutations in a DNA mismatch repair (MMR) gene [Barnetson et al., NEngJMed 2006;354:2751–63]. Stage 1 MMRpredict estimates the carrier probability for MMR mutations from clinical parameters (age of diagnosis of colorectal cancer, proximal vs distal site, family history, multiple primary CRCs). We evaluated the performance of Stage 1 of this model in a well characterized cohort of colorectal cancer patients. Methods: Cases with CRC were identified through the Minnesota Cancer Surveillance System (MCSS), a population based registry and Mayo Clinic Rochester, a clinical practice. All were consented participants in the Mayo Colon Cancer Family Registry. Of 342 cases tested for MMR mutations (MLH1, MSH2, MSH6), 45 had insufficient information on colon site and 62 were older than 55 and could not be used in the study. The remaining 235 included 110 females/125 males; 90 cases with proximal site/145 with distal site; 229/235 were self-identified as White. Results: We defined 5 probability risk groups based on output from the MMRpredict web model Stage 1: 1–10%, 11–25%, 26–50%, 51–75%, and 76–100%. In our study, the number of cases in each of these groups was 60, 45, 65, 34, and 31, respectively. The corresponding number of mutations in each group was 1 (1.7%), 4 (8.9%), 9 (13.8%), 3 (8.8%), and 11 (35.5%). Overall, 28/235 patients were found to have mutations (11.9%), compared to predicted range of 62–107 (26–45%). Conclusion: MMRpredict Stage 1 over-estimated the probability of detecting a MMR gene mutation in this study. This may reflect ascertainment issues or genetics of different populations. No significant financial relationships to disclose.

11015 Background: Immune checkpoint inhibitors have demonstrated activity in multiple tumor types but their activity in soft tissue sarcomas remains limited. In the multicenter phase II study, SARC028, the anti-PD-1 antibody, P demonstrated objective responses that were largely restricted to UPS and LPS subtypes. We now report outcomes from 2 expansion cohorts of SARC 028 in advanced UPS and LPS. Methods: To further confirm the clinical activity of P in UPS and LPS, we enrolled an additional 30 pts in each of 2 expansion cohorts for a total of 40 UPS and 40 LPS pts. Primary endpoint was investigator-assessed response by RECIST v1.1. Secondary endpoints were safety, progression-free survival (PFS), 12-week PFS rate, and overall survival (OS). An ORR of 25% was considered clinically meaningful and < 10% was considered to show lack of efficacy. P was to be considered a success if 8 or more of 40 enrolled patients had a PR or better (1-sided α = 0.042, 82% power). Pts age ≥18 with advanced, refractory UPS or LPS received 200 mg of P IV every 3 weeks until progression or unacceptable toxicity. Results: Preliminary results from the first 10 pts in each of the UPS and LPS cohorts have been reported. We now present summary data after enrolling an additional 30 pts in each cohort. The ORR in the UPS cohort was 23% (9/40), with an additional 5/30 PRs observed in the expansion cohort (total 2 CRs, 7 PRs). In the LPS cohort, the ORR was 10% (4/39 evaluable pts), with an additional 2/30 PRs observed (total 4 PRs). Median PFS for the UPS group was 3 months [95% CI: 2, 5] and 2 months [95% CI: 2, 4] for the LPS group. 12-week PFS rate was 50% in UPS [95% CI: 35, 65] and 44% in LPS [95% CI: 28, 60]. The UPS group had a median OS of 12 months [95% CI: 7, 34] and 13 months [95% CI: 8, NR] for the LPS group. P was well tolerated with no unexpected toxicities. Conclusions: The UPS cohort achieved its primary endpoint, however the activity of P in UPS deserves further evaluation in a randomized study. The activity of P was not confirmed in the LPS cohort. Ongoing biomarker analyses may direct better patient selection and guide future combination strategies. Clinical trial information: NCT02301039.