Ballman, Karla V.

7008 Background: Fluoro-deoxyglucose positron emission tomography (FDG-PET) is recommended for diagnosis and staging of known or suspected NSCLC. Meta-analyses examining the accuracy of FDG-PET to diagnose lung cancer demonstrated high sensitivity 94% and specificity 83% but were performed in select centers. The purpose of this study is to evaluate the accuracy of FDG-PET to diagnose NSCLC and examine enrolling site differences in the national prospective ACOSOG Z4031 trial. Methods: 1,074 patients with clinical stage I (cT1-2N0M0) known or suspected NSCLC were enrolled between 2004 and 2006 in the Z4031 study and underwent surgical resection. The final diagnosis was determined by pathological examination. FDG-PET results were abstracted from radiology interpretations included in the case report forms. FDG-PET avidity was categorized based on either radiologist description or reported maximum standard uptake value (SUV). The four categories were: not avid and not cancerous (SUV=0), low avidity and likely not cancerous (SUV>0 and <2.5), avid and probably cancerous (SUV>2.5 and <5) and highly avid and likely cancerous (SUV>5). Sensitivity analysis of FDG-PET diagnostic accuracy was performed for varying levels of avidity and by preoperative lesion size. Differences in accuracy by enrolling site were examined. Results: There were 51 enrolling sites in 39 cities with 969 eligible participants. Preoperative FDG-PET results were available for 682 participants. Lung cancer prevalence was 83%. FDG-PET sensitivity was 82% (95% CI: 79-85), and specificity was 31% (95% CI: 23-40). Positive and negative predictive values were 85% and 26%, respectively and accuracy improved with lesion size. There were 80 false positive scans and 69% were granulomas. False negative scans occurred in 101 patients (11were ≤10mm) with adenocarcinoma, squamous, bronchoalveolar cell and neuroendocrine tumors responsible for 64%, 12%, 10% and 8% of false negative results, respectively. Specificity did not differ between the 8 sites with >25 patients (p=0.74). Conclusions: In a national surgical population with clinical stage I NSCLC, FDG-PET to diagnose lung cancer performed poorly compared to published studies. Reasons for poor test performance should be explored.

4565 Background: The efficient delivery of adjuvant therapy after radical prostatectomy (RP) in patients with prostate cancer is limited by the lack of biomarkers, beyond clinicopathologic factors, that are able to assess the risk of clinically significant disease progression. Previously, routine FFPE patient specimens from the Mayo Clinic Radical Prostatectomy Registry with long term follow-up were selected to develop a genomic classifier (GC) to predict clinical progression. Here, we present the validation of a GC in a cohort of patients at high risk of disease progression. Methods: A case-cohort study of high-risk RP patients from the Mayo Clinic (N=219) was used to validate the genomic classifier (GC) for predicting clinical progression (defined by positive bone or CT scan post-RP). Its performance was compared to a multivariable clinical classifier (CC) and a genomic-clinical classifier (GCC) which combines GC with established clinicopathologic variables. Concordance index, Cox modeling and decision curve analysis were used to compare the different models. Results: GC and GCC were predictive of clinical progression in the high-risk cohort with c-indices of 0.79 and 0.82, respectively, compared to the clinical classifier (0.70). Multivariable survival analysis showed that the majority of prognostic information of GCC came from the GC with a minor contribution from Gleason score. Decision curve analysis showed that GCC had a higher overall net benefit compared to CC over a wide range of ‘decision-to-treat’ thresholds for the risk of progression. Conclusions: In this high-risk cohort, GC and GCC classifiers showed improved performance over CC in prediction of clinical progression. GC is an independent prognostic factor in this cohort and captures the majority of prognostic information. GC and GCC’s prognostic performance and their usefulness in guiding decision-making in the adjuvant setting after RP need further testing in studies of additional prostate cancer risk groups.

1562 Background: Prior studies have shown additive effects of CPT-11 in combination with BCNU, and radiosensitizing effects of CPT-11 in gliomas. Methods: All pts had GBM by central review prior to registration. With MTD based on a pilot study (Arm A), those not receiving anticonvulsants (non-EIAC, Arm C) received RT with concomitant CPT-11 (125 mg/M2/wk × 4, cycle 1), followed by BCNU (100 mg/M2 q 6 wk) + CPT-11 (75 mg/M2/wk × 4, q 6 wks, cycles 2–5) beginning within 4 wks of RT. Pts on EIAC (Arm B) received CPT-11 (400 mg/M2/wk × 4, cycle 1) during RT, then post-RT BCNU (100 mg/M2 q 6 wk) + CPT-11 (400 mg/M2/wk q 6 wks, cycles 2–5). Dose de-escalations (but no escalations) were allowed. Toxicity was graded by CTC v. 3.0. Primary endpoint was overall survival at 12 mo (OS12), with a interim futility analysis after 12 mos. follow up in the first 35 patients. 18 “successes” (survival > 12 mo) were required to proceed. Results: There were 56 pts treated (20 Arm A, 12 Arm B, 24 Arm C). Six pts on Arm A developed toxicity at the pilot CPT-11 cycle 2–5 dose of 125mg/M2, requiring reduction (75 mg/M2) for the remainder of Arm A and all Arm C pts. The decision rule for the first 35 patients was not met, with inclusion of the 6 Arm A pts (14 successes, 19 failures, 2 incomplete data) or without these pts ( 13 successes, 20 failures, 2 incomplete). In the 35 pts with mature data, the best confirmed response was PR in 2 (6%), REGR in 4 (11%) and stable (>4 wks, STAB) disease in 7 (20%). For the 56 pts (51 with mature data), PR, REGR and STAB were noted in 4%, 16%, and 39% respectively. Reason for end of treatment (N=56) was: completion of study treatment (13%); pt refusal (11%); adverse event (9%); progression (39%); all cause death (9%); too early (13%) or other (7%). In the 51 pts whose data is mature, progression free survival at 6 mos (PFS6) was 29.8% (95% CI: 19.1, 46.3); PFS12 was 16.5% (95% CI: 8.3, 32.9) and OS at 12 mos was 45.4% (95% CI: 32.7, 63). Overall median survival was 10.7 mos (95% CI: 7.8, 14.5). Conclusions: Although limited activity (PR+REGR+STAB) of this combination was demonstrated, the decision rule (minimum OS12 “successes”) was not reached, and tolerability of this regimen was only moderate. We consider the regimen as not superior to results obtained with other regimens in prior NCCTG studies. No significant financial relationships to disclose.

1520 Background: Multiple variables may impact endpoints utilized to assess efficacy of investigational therapies for pts with recurrent gliomas. Understanding the nature of these variables should aid interpretation of results. Methods: 583 pts were enrolled to 15 consecutive recurrent glioma clinical trials conducted between 1980 and 2004. Identical patient, tumor, treatment and time variables were identified for each trial. Central neuropathology review was completed and pts were grouped by WHO diagnoses. Pts alive and progression-free at 6 months after start of treatment were a PFS6 ‘success’. Pts whose outcome was progression at first evaluation were classified as “Immediate Progression (ImmProg)”. Response was defined as regression, partial regression, or complete regression in the absence of worsening neurologic symptoms or increased corticosteroid dose. Univariable and multivariable Classification and Regression Trees (CART) models were used to identify factors associated with OS, PFS, PFS6, ImmProg, and Response. Results: Variables associated with outcomes for each endpoint assessed by CART models are shown in Table below. Conclusions: In clinical trials of recurrent glioma, age, PS, duration of disease, primary and recurrent histologic diagnosis, and primary and recurrent extent of resection are associated with outcomes. These variables should be validated in additional datasets for potential inclusion in reports of future clinical trials. [Table: see text] No significant financial relationships to disclose.

1509 Background: Lack of MGMT methylation in GBM tumors is associated with a worse outcome with combined radiation (RT) and temozolomide (TMZ) therapy, and it is unclear whether non-methylated tumors benefit from TMZ treatment. Methods: The potential benefits of concomitant or adjuvant TMZ relative to methylation status were evaluated in 10 GBM tumors established from patient samples and maintained by serial passage in mice. For each tumor line, 32 mice with established orthotopic xenografts were randomized to A) placebo, B) TMZ PO daily × 5 (120 mg/kg or 66 mg/kg, as indicated) C) RT, 2 Gy bid × 10 fx., D) combined TMZ and RT, and mice were followed until moribund. Efficacy was evaluated by regression modeling and Kaplan-Meier statistical analyses. Results: Six lines with non-methylated MGMT (GBM10, 14, 26, 28, 36, 43) and 4 with methylated MGMT (GBM8, 12, 16, 34) were evaluated, and complete results are available in 6 lines. In all tumor lines and at both dose levels, there was a significant benefit for TMZ relative to placebo (p<0.003). Both methylated tumors (GBM8 and 12) and one non-methylated tumor (GBM14) were markedly sensitive to TMZ with greater than a 50 day extension in survival with monotherapy. Individually and in a pooled analysis, there was no evidence for a synergistic interaction between TMZ and RT in the non-methylated tumors (p=0.91 for pooled analysis). In contrast, there was a striking degree of synergy in GBM12 (p<0.001) and at least additive effects of combined treatment in GBM8 (5 of 8 mice still surviving in the RT/TMZ arm). In a pooled analysis of these 2 MGMT methylated tumors, there was a trend towards synergy (p=0.11). Conclusions: TMZ treatment did not sensitize MGMT non-methylated tumors to radiation, and with one exception, these non-methylated tumors were only modestly sensitive to TMZ alone. In contrast, treatment with TMZ appears to sensitize MGMT-methylated tumors to radiation and monotherapy is associated with marked and significant benefit. [Table: see text] No significant financial relationships to disclose.

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.

6511 Background: In March 1998, the Common Toxicity Criteria (CTC) version 2.0 introduced the collection of attribution of adverse events (AE) to study drug. Collection of attribution adds time and cost to the clinical trial process, and reporting in the literature has varied. At ASCO 2006 results were presented from NCCTG trial 97–24–51 that showed ∼ 50% of events on the placebo arm were reported as attributed to study drug and 25% of the time the same event was not consistently attributed. We sought to validate these results in a second placebo controlled trial. Methods: Patients on the placebo arm of the phase III ACOSOG trial Z9001 (imatinib mesylate vs. placebo after resection of primary gastrointestinal stromal tumors) were evaluated since the reported AEs could not be due to study drug. Attribution was collected per CTCv3.0 as not related, unlikely, possibly, probably, or definitely related, and categorized as “unrelated” (not related or unlikely) and “related” (possible, probable, or definite). Patterns were evaluated using generalized estimating equations adjusting for multiple events per patient. Results: 202 patients and 2871 AEs were included. 52% of AEs were reported as “related”. Known imatinib AEs were more likely to be reported as “related”. The reported rate of AE relatedness varied by AE type. No patterns were observed by gender, age, PS, severity or visit of AE. When the same event was reported on the same patient on multiple visits, the attribution category changed at least once 33% of the time with 19% changing from “related” to “unrelated” or vice versa. Conclusion: 52% of events on the placebo arm of Z9001 were reported as attributed to study drug and 19% of the time the same event was not consistently attributed. These data provide further evidence that attribution is difficult to determine, unreliable, and of questionable value in interpreting randomized clinical trials. No significant financial relationships to disclose. [Table: see text]

5017 Background: The majority of men with prostate cancer are diagnosed with cancers with low mortality. Such men are treated with radical prostatectomy, external beam radiotherapy, or brachytherapy and followed by serum PSA evaluations. Some men with a rising PSA therapy will have local recurrence or metastasis, but many will have no other evidence of recurrent disease other than a rising PSA. The PSA doubling time has been used to determine which of these men deserve adjuvant hormonal ablation, radiation therapy, or observation. We hypothesize that additional biomarkers will predict which men with a rising PSA post-definitive therapy would benefit from additional therapy. Methods: We designed a custom array containing 526 RNA targets whose expression has been reported to be altered in association with prostate cancer progression. We included targets from Mayo Clinic prostate cancer research. Together with a second commercial array, 530 genes implicated in prostate cancer progression and 420 other cancer-related genes were evaluated. A case-control design was used to test the association of the expression results with outcome. Cases were men post-radical prostatectomy who developed systemic progression within 5 years after PSA recurrence (N=213). Controls were matched men post-radical prostatectomy with PSA recurrence but no evidence of clinical progression within 5 years (N=213). Results: Of 426 eligible patients, paraffin blocks were available on 418 (98.1%). RNA was prepared from all 418 blocks, and both arrays were both successful on 405 (96.9%) RNAs. Upon univariate analysis, 40 genes were highly significantly over- or under-expressed in the cases versus controls (1x10-22 < p < 1x10-7). Recursive partitioning (RP) selected 4 genes (TPX2, FAM13C1, TOPO2A and TSP2) that distinguished cases from controls. Random Forest analysis selected 24 genes (including 3 of the RP 4). A multivariable ROC analysis using these 24 genes generated an AUC of 0.80 (95% CI: 0.75–0.84). Conclusions: A specific gene expression pattern was significantly associated with systemic progression after PSA recurrence. The measurement of gene expression pattern may be useful for determining which men may benefit from additional therapy after PSA recurrence. No significant financial relationships to disclose.

TPS760 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN trials. Combination immunotherapy with VEGF therapies have shown benefit in the JAVELIN 101 and KEYNOTE 426 trials over sunitinib. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter, phase 3 trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1mg/kg and NIVO 3mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, IMDC intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480mg IV every 4 weeks, pts with progression of disease (PD) switch to CABO 60mg oral daily, and pts with non-CR/non-PD are randomized to NIVO 480mg IV every 4 weeks versus NIVO 480mg IV every 4 weeks with CABO 40mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS rate will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include PFS, 12-month CR rate, ORR based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR and association of IL-6 with treatment benefit will be assessed. Other tissue-based and plasma-based biomarkers are planned. Updated enrollment will be presented. Clinical trial information: NCT03793166.

AbstractBackgroundThe optimal radiation dose for adult supratentorial low-grade glioma is unknown. The aim of this study was to provide a final update on oncologic and cognitive outcomes of high-dose versus low-dose radiation for low-grade glioma.MethodsBetween 1986 and 1994, 203 patients with supratentorial low-grade glioma were randomized (1:1) to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection.ResultsFor all patients, median overall survival (OS) was 8.4 years (95% CI: 7.2–10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3–6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve 15-year OS (22.4%) versus low-dose radiation (24.9%, log-rank P = 0.978) or 15-year PFS (high dose, 15.2% vs low dose, 9.5%; P = 0.7142). OS was significantly better for patients with preoperative tumor diameter &lt;5 cm and baseline Mini-Mental State Examination (MMSE) &gt;27 and who underwent gross total resection. PFS was improved for patients with oligodendroglioma versus astrocytoma, preoperative tumor diameter &lt;5 cm, patients who had gross total resection, and patients with baseline MMSE &gt;27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years.ConclusionsLong-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Cognitive function appeared to be stable after radiation as measured by MMSE.