Buckner, Jan C.

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.

1500 Background: Treatment of adult LGG is controversial. Favorable patients (pts) (age <40 years [yrs] who undergo gross total resection [GTR]) are typically observed. Unfavorable pts (age ≥40 who have subtotal resection [STR] or biopsy [B]) are usually given initial radiation therapy (RT), reserving chemotherapy (historically procarbazine, CCNU and vincristine [PCV]) for recurrence. In 1998, the RTOG, in conjunction with SWOG, NCCTG, and ECOG initiated prospective studies of adult LGG, the results of which are reported herein. Methods: Favorable pts were observed postoperatively in a single arm Phase II study (Arm 1). Unfavorable pts were stratified by age, histology, KPS, and presence/absence of contrast enhancement on preoperative magnetic resonance imaging and randomized to either RT alone (54Gy in 30 fractions to a local treatment field) (Arm 2) or RT followed by 6 cycles of standard dose PCV (Arm 3). Reported results include overall survival (OS) rate, median overall survival time (MOST), progression-free survival (PFS) rate, and median progression-free survival time (MPFST). Survival data are compared using Wilcoxon p-values. Results: A total of 362 eligible/analyzable pts were accrued between 1998 and 2002. Median follow-up time is 4 years. For the 111 favorable pts observed on Arm 1, OS at 2- and 5-yrs is 99% and 94%. PFS at 2- and 5-yrs is 82% and 50%. For the 251 unfavorable pts on Arms 2 (RT alone) and 3 (RT+PCV), there was no difference in OS or PFS. OS at 2- and 5-yrs was 87% and 61% with RT alone versus (vs) 86% and 70% with RT+PCV (p=0.72). MOST was not reached in RT alone pts and was 6.0 yrs in RT+PCV pts. PFS at 2- and 5-yrs was 73% and 39% with RT alone vs 72% and 61% with RT+PCV (p=0.38). MPFST was 4.0 yrs with RT alone vs 6.0 yrs with RT+PCV. Acute grade 3–4 toxicity occurred in 9% of pts who received RT alone, 67% who received RT+PCV (mostly hematologic). There were no treatment deaths on either arm. Conclusions: 5-yr PFS was poor in all three arms ranging from 39% to 61%. Only half of favorable pts were disease-free at 5 yrs. In unfavorable pts, there was no OS advantage with the addition of PCV to RT. Both PFS and MPFST were better with the addition of PCV, but not significantly. Analysis of outcome by 1p19q status is pending. No significant financial relationships to disclose.

6517 Background: In NCCTG CTs a subset of AEs are assessed at each patient (pt) evaluation based on the known safety profile of agents(s). The NCCTG routinely pre-fills the “known” AE list onto CT Case Report Forms (CRFs). Newly identified AEs may expand the AE assessment list for ongoing CTs. Our survey of NCCTG AE data (JCO 2005), demonstrated that 85% of AEs reported were pre-filled on CRFs, of which, 83% did not actually occur (Grade 0). Extending this work, we evaluated the influence of pre-filling AEs on CRFs, relative to the final AE rates reported. Methods: Our non-random sample contains 507,899 AEs collected from 1/99–6/06 on 74 NCCTG CTs, 13 of which had AEs added to the CRF pre-fill list during the CT (2,604 pts, 3 Ph I/II, 8 Ph II, 2 Ph III, 9 investigational agents). Results: An average of 2.8 AEs (range 1–6) were added to CRFs for ongoing CTs, primarily for Oxaliplatin induced AEs. 58% (21/36) of AEs added during a CT were not reported prior to the addition, 22% (8) were not reported afterwards. 5 CTs had significantly higher AE rates (p<0.01) after expanding the AE list, most notably for required blood chemistries (SGOT/alk phos/creatinine/bilirubin 14.2 vs 0.72%). Overall, the same AEs were 4-fold (range 0–25) as likely to be reported when pre-filled on the CRF. Regardless of pre-filling, only 6% of the newly required AEs were Gr 3+. Conclusions: Our data suggest a significant difference between the AE rates reported if included in the CT CRF assessment list. This may significantly influence the reported results of a CT, explaining differential AE rates reported across CTs of the same agent(s). A prospective study is planned to formally evaluate this observation. Supported by NIH Grant CA25224. No significant financial relationships to disclose.

2075 Background: Multiple variables may impact endpoints used to assess therapeutic efficacy for patients with recurrent gliomas. To identify prognostic factors for each of 3 outcome variables, a master analysis file was constructed by pooling datasets summarizing key baseline factors and outcomes obtained in 15 North Central Cancer Treatment Group (NCCTG) trials (n=583, 1980–2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n=596, 1998–2002). Methods: In addition to traditional variables (gender, age, performance score (PS), race, extent of primary resection, year of study entry, last known histology, time since initial diagnosis, baseline steroid use, prior chemotherapy (Y/N), prior nitrosoureas, baseline anticonvulsant use), we investigated prior t (TMZ), number of relapses, academic vs. community site and low grade at initial diagnosis. Outcome variables were: (1) overall survival (OS), (2) progression free survival (PFS) and (3) PFS6 = proportion of patients alive and progression-free 6 months after start of treatment. For all 3 endpoints, Classification and Regression Tree (CART) models and bootstrap samples were used to identify prognostic variables and to look for evidence of interactions among the independent variables affecting outcome. Results: For all outcomes the initial CART analysis selected last known grade (4 vs. 3) as the most important variable. Additional factors selected as predicting poor prognosis differed with grade and outcome measure and included prior TMZ, longer time since primary diagnosis, older age and poor PS. Community vs. academic was not a strong predictor in any of the models nor was low grade at initial diagnosis. Additional analyses are planned to better describe the impact of all the variables on outcome, including use of Cox models and logistic models considering all baseline variables with backwards selection. Conclusions: The results from analyses to date are consistent with current thinking that last known histology (grade) is an important factor. Time since initial diagnosis is likely a surrogate for number of relapses. More definitive conclusions await the completion of ongoing analyses. No significant financial relationships to disclose.

2004 Background: Vorinostat is a histone deacetylase inhibitor that represents a rational therapeutic target in GBM. Methods: Recurrent GBM patients (pts) having received = 1 prior chemo regimen for progressive disease were eligible. Vorinostat dose was 200 mg bid x 14 days q 3 weeks. We applied a phase II design which had 90% power to declare the regimen active if the study PFS6 rate was 25%, a 15% rate increase over PFS6 in historical controls (10%). Results: 68 patients were treated. Grade 3+ non-hematologic toxicity consisting mainly of fatigue, diarrhea and dehydration occurred in 23% of pts; Grade 3+ hematologic toxicity consisting mainly of thrombocytopenia occurred in 25% of pts. Intra-patient dose escalation to 300 mg bid resulted in higher incidence of grade 3+ thrombocytopenia (45%) and was aborted. Pts receiving enzyme-inducing anticonvulsants (EIAC) had significantly less grade 3 + non-hematologic toxicity (p=0.01) and grade 3/4 thrombocytopenia (p=0.04). Pharmacokinetic analysis showed lower vorninostat C-max and AUC (0–24h) values and higher vorinostat-glucuronide C-max and AUC (0–24h) values in EIAC pts, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy endpoint at the planned interim analysis with 5 of the first 22 patients (23%) being progression-free at 6 mo. RNA array analysis, performed in paired baseline and post-vorinostat treatment samples in a separate subgroup of 5 surgical recurrent GBM pts, who received vorinostat for 6 doses prior to surgery, showed upregulation of E-cadherin (p=0.02), thus indicating a biologic effect of the HDAC inhibitor on the glioblastoma tumors. Histone acetylation, Akt, phospho-Akt, P21Waf1/Cip1 and P27Kip1 expression analysis in all patients and correlation with outcome is ongoing. Conclusions: Vorinostat is well tolerated in recurrent GBM patients. EIAC patients have less toxicity, likely due to increased vorinostat metabolism via glucuronidation. Interim efficacy analysis is indicative of antitumor activity. Final efficacy analysis, RNA array data and correlative tissue analysis will be reported. No significant financial relationships to disclose.

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.

Abstract PURPOSE To provide a final update on oncologic and cognitive outcomes of high dose versus low dose radiation for low-grade glioma. METHODS Between 1986 and 1994, 203 patients with supratentorial low grade glioma were randomized to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Histologic subtype was oligodendroglioma (71%) or astrocytoma (29%). Primary outcome was overall survival (OS). Cognitive status was followed using Folstein Mini-Mental State Examination (MMSE). RESULTS For the entire cohort of 203 patients, median 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 OS (15-yr OS: 22.4% vs. 24.9%, log rank p=0.978) or PFS (15-yr PFS: 15.2% vs. 9.5%, p=0.7142). OS was significantly better for patients with pre-operative tumor diameter < 5 cm (15-yr OS: 39.4% vs. 15.2%, p< 0.001), baseline MMSE > 27 (15-yr OS: 27.3% vs. 9.8%, p=0.001), and for patients who underwent gross total resection (GTR) (15-yr OS: 39.3% GTR vs. 16.4% subtotal resection vs. 24.5% biopsy only, p=0.0119). PFS was improved for patients with oligodendroglioma versus astrocytoma (15-yr PFS: 13.8% vs. 8.6%, p=0.0221). PFS was also improved for patients with pre-operative tumor diameter < 5 cm, patients who had GTR, and patients with baseline MMSE > 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. CONCLUSIONS Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Minimal late decline in cognitive function after radiation was seen by MMSE. SUPPORT: U10CA180821,U10CA180882. https://acknowledgments.alliancefound.org

Abstract Background: Modern clinical practice places time restrictions on the amount of information and processing that can be done in a typical office visit. Meeting patient needs within the healthcare system is challenging, contributing to patient (pt) and clinician dissatisfaction and potential suboptimal outcomes. We developed an electronic point-of-care case management system for cancer patients. The system's goal is to obtain patient-reported quality of life (PROQOL) outcomes and provide clinicians with information regarding QOL issues to address. We tested this system in a prospective randomized study against usual care (UC). The primary objective was to determine if PROQOL system would improve mean QOL over time. Methods: Eligible pts were adults with multiple myeloma (MM) or light amyloidosis (AL), seen at Mayo Clinic. Pts were randomized 2:1 to PROQOL system or usual care. PROQOL system was offered prior to every visit. Pts select from various categories about their single biggest concern, and receive a printed list of actionable resources based on selected concern. Clinicians also receive the PROQOL results to review with pts. Providers and pts randomized to PROQOL completed a "was it worth it survey" (WIWI). An 8 item Linear Analogue Self-Assessment was used to assess QOL, the primary endpoint. Secondary endpoints included distribution of choices of most important concern and their relationship to demographic and clinical variables. The study was powered to detect a 0.5 standard deviation difference in QOL between groups. Results: There were 233 patients enrolled (171 MM, 62 AL) in this study between July 1, 2016 and April 17, 2018. Median age was 65 years (range 31-87), and 59% were male. Median time from diagnosis to study consent was 37 months (PROQOL 36.3 versus UC 39.6). Median follow up for all patients was 15 months (range: 0.7-22 months), and median follow up for PROQOL pts was 16 months and 14 months for UC pts (p=0.027). There were 25 pts that have died since enrollment and 208 alive. No statistical significant difference in QOL between PROQOL and UC (median QOL 7 vs 7, p=0.75). The most prevalent main concerns selected were Physical Health (37%) and Cancer and Diagnosis (27%), the pattern remained even when pts were given the option to pick a second major concern 26% and 20% respectively. No other concern was listed more than 8% at baseline. All category selections and percentages are shown in the Figure. The average time to complete the instrument was 6 minutes. Pts found the PROQOL system was worth their time (75%), they would choose it again (87%) and recommend it to others (82%). Eighty-two percent of clinicians did not think the PROQOL tool negatively impacted their practice and 75% believed they may see improvement in pt wellbeing. Discussion: The PROQOL system was well received by pts and clinicians but did not improve QOL relative to UC in this study. The PROQOL demonstrates that majority of patients strongly desire more information regarding ongoing therapy, clinical trials, prognosis and toxicity. Further investigation is needed to understand whether communication is limited by time or mechanism of information delivery, such as verbal or written, or whether it should be undertaken in a separate allied health care visit. Figure. Figure. Disclosures Gertz: spectrum: Consultancy, Honoraria; Abbvie: Consultancy; Research to Practice: Consultancy; annexon: Consultancy; Medscape: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Teva: Consultancy; Apellis: Consultancy; Ionis: Honoraria; celgene: Consultancy; Prothena: Honoraria. Kumar:Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Lacy:Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract Background: Severe myelosuppression (MS) and bone marrow failure (BMF) are rare but well characterized adverse effect of temozolomide (TMZ). The existing literature is limited to case reports and data reported to regulatory agencies, which usually describe very severe cases and lack long term and detailed follow-up. Methods: We identified cases of myelosuppression attributed to TMZ seen at the Mayo clinic, from 1998-2014. We also performed a literature (PubMed) search to identify published cases of TMZ induced MS and BMF. TMZ induced MS was defined as a decrease in at least 2 cell lines below normal that was clinically attributable to TMZ and persisted for > 28 days after the last TMZ dose. Severe MS was defined as bone marrow cellularity of <25% or at least 2 of: a) reticulocyte count <40,000/µL b) absolute neutrophil count (ANC)<500/ µL c) platelets <20,000/µL. Very severe MS was defined by an ANC <200/ µL. Results: A total of 15 Mayo patients and 10 published cases were identified. The baseline characteristics of patients are shown in table 1. The median interval between initiation of TMZ and diagnosis of MS was 48 days (range 26-121). The hematologic outcomes of the group are shown in table 2. Seventeen patients developed neutropenic fever, 4 had severe sepsis, and 6 experienced bleeding complications. Kaplan-Meier recovery curves for each cell line are shown in the figure. Myelosuppression was fatal in 3 cases. Most patients recovered their ANC (median-62 days, range 28-180). Persistent thrombocytopenia was seen in 19 patients, without evidence for clonal evolution or myelodysplasia. Four patients remain dependent on growth factor support (G-CSF and thrombopoietin agonists). Conclusion: MS is usually a non-fatal complication of TMZ. Most cell lines recover spontaneously and adequately with the exception of platelets, which can remain significantly suppressed for prolonged periods. Infectious complications are very common. Most patients respond to supportive care, including the use of growth factors. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

Neuroendocrine neoplasms (NENs) are malignancies with rare reports of central nervous system development. A 34-year-old woman was found to have a primary NEN of the brain, and she had recurrence with identical histology 10 years later. Extracranial NENs were excluded. She had routine surveillance for the first 5 years with MRIs and positron emission tomography/CTs after the initial presentation which was treated with radiation followed by cisplatin and etoposide. This case highlights the difference in primary NENs versus NEN metastases to the brain, and that longer periods of surveillance are likely required for primary NENs. This is important because the prognosis between primary NENs and metastatic NENs to the brain are vastly different and should not be treated as equal diseases. The patient eventually died of her recurrence secondary to complications of a ventriculoperitoneal shunt placed for treatment of hydrocephalus from the disease.