Citations

Abstract BACKGROUND: Extradural approach to the cavernous sinus, the “Dolenc” approach recognizing its developing Dr. Vinko Dolenc, is a critically important skull base approach. However, resection of the lateral wall of the cavernous sinus, most commonly for cavernous sinus meningiomas, results commonly in a defect that often cannot be reconstructed in a water-tight fashion. This may result in troublesome pseudomeningocele postoperatively. OBJECTIVE: To describe a technique designed to mitigate the development of pseudomeningocele. METHODS: We found the Dolenc approach critical for resection of cavernous lesions. However, a number of pseudomeningoceles were managed with prolonged external pressure wrapping in the early cohort. Therefore, we incorporated subgaleal to muscular sutures, which were designed to close this potential space and retrospectively analyzed our results. RESULTS: Twenty-one patients treated with a Dolenc approach and resection of the lateral wall of the cavernous sinus over a 2-year period were included. Prior to incorporation of this technique, 12 patients were treated and 3 (25%) experienced postoperative pseudomeningoceles requiring multiple clinic visits and frequent dressing. After incorporation of subgaleal retention sutures, no patient (0%) experienced this complication. CONCLUSION: Although basic, subgaleal to temporalis muscle retention sutures likely aid in eliminating this potential dead space, thereby preventing patient distress postoperatively. This technique is simple and further emphasizes the importance of dead space elimination in complex closures.

503 Background: We evaluated temporal patterns in the utilization of systemic therapy among patients undergoing cytoreductive nephrectomy (CN) for metastatic Renal Cell Carcinoma (mRCC) from a large national cancer registry and assessed patient characteristics associated with receipt of systemic treatment. Methods: We reviewed the National Cancer Database to identify patients with stage IV RCC who underwent CN between 1998-2010. Systemic therapy was defined as any treatment with immunotherapy and/or chemotherapy (including targeted agents). We evaluated the association between clinicopathologic features and receipt of systemic therapy using multivariable logistic regression with generalized estimating equations, and assessed the interaction of treatment with time, stratified as immunotherapy (1998-2004) versus targeted-therapy (2005-2010) eras. Results: Of 22,409 patients with mRCC undergoing CN, 8,830 (39%) received systemic therapy. Receipt of systemic therapy increased from 32% in 1998 to 49% in 2010 (p<0.001), largely due to increased utilization of chemotherapy (13.9% vs. 46.7%; p<0.001). Following adjustment, increasing patient age (51-60 years: OR 0.82 [CI 0.73-0.92]; 61-70 years: OR 0.67 [CI 0.59-0.76]; ≥71 years: OR 0.36 [CI 0.31-0.43]), as well as coverage with Medicaid (OR 0.61 [CI 0.5-0.74]), Medicare (OR 0.70 [CI 0.62-0.79]), or no insurance (OR 0.75 [CI 0.63-0.91]) were associated with decreased utilization of systemic therapy. Although use of systemic therapy in the elderly (≥71 years) and in patients with Medicare/Medicaid remained lower throughout the study period, each of these cohorts was significantly more likely to receive systemic treatment in the targeted versus immunotherapy era (all p values <0.05). Conclusions: Utilization of systemic therapy among patients undergoing CN has increased over time, coinciding with the introduction of targeted therapies. Nevertheless, still less than half of such patients receive systemic treatment. While the etiology for lack of treatment is likely multifactorial, the potential health policy implications of continued disparities in care warrant further investigation.

LBA9000^ Background: The humanized monoclonal IgG4 anti-PD-1 antibody MK-3475 has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated MK-3475 efficacy and safety in a pooled analysis of 411 MEL pts. Methods: A nonrandomized cohort of ipilimumab-naive (IPI-N) and IPI-treated (IPI-T) pts treated with MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W and randomized cohorts of IPI-N and IPI-T pts treated with 2 Q3W or 10 Q3W were included. Response was assessed every 12 wk by RECIST 1.1 by independent central review and by immune-related response criteria (irRC) by investigator. Results: 162 pts were treated at 2 Q3W, 192 at 10 Q3W, and 57 at 10 Q2W. 190 pts were IPI-N and 221 were IPI-T. As of the 10/18/2013 cutoff, all pts had ≥6 mo follow-up and >75% had ≥9 mo follow-up. Among the 365 pts with measurable disease at baseline, ORR by RECIST was 40% (95% CI 32%-48%) in IPI-N and 28% (95% CI 22%-35%) in IPI-T pts. Responses were durable (88% ongoing at analysis). Median PFS by RECIST was 24 wk in IPI-N and 23 wk in IPI-T pts. Median OS was not reached, with 1-y OS of 71% in all pts. Benefit was observed by both RECIST and irRC at all doses and schedules in IPI-N and IPI-T pts (Table). MK-3475 demonstrated activity in all major subgroups irrespective of ECOG PS, LDH levels, BRAFmutation, M stage, and number and type of prior therapy. Overall, 12% of pts experienced drug-related grade 3/4 AEs and 4% discontinued due to a drug-related AE. There were no drug-related deaths. Conclusions: MK-3475 showed durable responses and a manageable safety profile across dose and schedules in IPI-N and IPI-T MEL pts. The observed efficacy and safety suggest MK-3475 may be an appropriate treatment for all pts with MEL. Clinical trial information: NCT01295827. [Table: see text]

CRA9003 Background: Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation. We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel, a small molecule inhibitor of MEK1/2 (Ambrosini, CCR 2012). Methods: We conducted a 16 center randomized phase II study of hyd-sulfate sel 75 mg BID vs TMZ 150 mg/m2 daily for 5 days in 28-day cycles (or DTIC 1000 mg/m2 q21 days) for patients (pts) with metastatic UM with a Q209 Gq/11 mut who have not received prior TMZ/DTIC. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall survival (OS) and response rate (RR). Select pts underwent tumor biopsies at baseline and after 14 (+/- 3 days) of sel. Our statistical plan required ≥80 pts randomized and ≥68 events to detect a PFS hazard ratio of 0.6 (p=0.1). Randomization was stratified by mut (Gq vs G11), M stage and number of prior therapies (tx). Tumor assessment occurred every 4 weeks (wks) for 8 wks and then every 8 wks using RECIST 1.1. Pts receiving TMZ who progressed could receive sel (TMZ→sel). Results: 80 pts were randomized. Sel (n=39): median age 66 (range 32-86), 54% male, 54% G11 mut, median ECOG PS 0 (range 0-1), 97% M1c, median prior tx 0 (range 0-2). TMZ (n=41): median age 60 (range 34-81), 63% male, 58% G11 mut, median ECOG PS 0 (range 0-1), 93% M1c, median prior tx 0 (range 0-2). 11/39 (28%) pts on sel experienced grade (gr) 3 toxicity (tox) manageable with dose modification (5 CPK elevation, 3 LFT elevation, 1 rash, 1 lymphopenia, 1 edema). 1/41 (2%) pt on TMZ experienced gr 3 tox (neutropenia). No gr 4/5 tox occurred. 28 pts on sel underwent paired tumor biopsies with inhibition of pERK and cyclinD1 observed by Western blot at day 14. At interim analysis (9/25/12), 55 pts were evaluable with 45 progression events and 16 deaths. Sel (n=27): median PFS 16 wks (95% CI 8-30.9), RR 11%, median OS 11.8 months (95% CI 4.8-not reached). TMZ (n=28): median PFS 4 wks (95% CI 3.7-15), RR 0%, median OS 4.7 months (95% CI 4.3-14.3). TMZ→sel (n=25): median PFS 8.1 wks (95% CI 7-15), RR 0%. Conclusions: Sel is the first drug to ever show improved clinical activity in UM relative to TMZ. Sustained target inhibition is observed with sel. Final results will be presented. Clinical trial information: NCT01143402.

TPS505 Background: TH-302 is a hypoxia-activated, nitroimidazole-linked prodrug of bromo-isophosphoramide mustard (Br-IPM), which is released under hypoxic conditions. TH-302 is currently being studied in combination with gemcitabine (G) in a phase III trial in patients (pts) with advanced pancreatic adenocarcinoma (PDAC) (NCT01746979). Encouraging preclinical activity of TH-302 plus nab-paclitaxel (nab-P) and G provides a rationale for further study of this triplet (Sun JD et al, AACR Special Conference on Pancreatic Cancer 2014; abstract #B88). Methods: Clinical trial: NCT02047500. Open-label, phase I, dose-escalation trial of TH-302 plus nab-P and G in pts with previously untreated locally advanced or metastatic PDAC. Dose escalation: 3 + 3 design with one of 3 planned dose levels of TH-302 (170, 240 and 340 mg/m2) on days 1, 8, and 15 of a 28-day cycle, plus nab-P 100–125 mg/m2 followed by G 800–1,000 mg/m2. Expansion cohort (n≥15): TH-302 at the recommended phase II dose (RP2D) with nab-P 100–125 mg/m2 followed by G 800–1,000 mg/m2. Treatment will be continued until disease progression or intolerable toxicity. Primary objectives: To evaluate safety and tolerability, define the maximum tolerated dose and determine the RP2D of TH-302 in combination with nab-P/G. The primary endpoint is no. of pts with dose-limiting toxicities during the first 28 days. Secondary objectives: To evaluate overall safety of the triplet regimen, metabolic response rate using EORTC criteria for 18F-FDG PET, CA19–9 response rate (defined as >50% decline from baseline), and RECIST response rate of TH-302 plus nab-P/G. The pharmacokinetic (PK) profile of TH-302 and Br-IPM in the plasma of pts will also be evaluated, as will the effect of TH-302 on the PK of nab-P, and vice versa. Exploratory analyses include the association of pharmacogenomic markers, such as CYP2C9, BRCA1 and BRCA2, with PK, safety and efficacy. The association of potential hypoxia biomarkers (CA IX, GLUT1, VEGF, osteopontin) with antitumor activity will also be explored. The trial is in progress; 7 of an estimated 48 planned pts have been recruited (trial start Jan 2014, estimate end Aug 2016). Clinical trial information: NCT02047500.

708 Background: In June 2015 Cancer Care Ontario convened an expert panel to determine if there is an optimum LV dose in 5FU-LV combinations for the treatment of CRC. This request arose out of observed variation in LV dosages between some cancer centers. The research question was effect of LV dose on overall survival (OS), progression free survival (PFS), disease free survival (DFS), response rate (RR) and adverse events/toxicity, given a constant dose of 5FU. Methods: A systematic search was conducted for guidelines (GL) and comparative trials; eligibility included English language, with > 30 patients, that examined different doses of LV where dose of 5FU was not varied. Assessment of studies for inclusion was completed by 4 reviewers. Results: We identified 5 GL, 0 systematic reviews and 12 trials that defined a LV dose in combination with 5FU. None of the GL informed an optimal dose of LV. RR was assessed in 10 trials; 4 showed trends to higher RR with higher LV dose, but differences were not statistically significant (SS) between arms. PFS or DFS was reported in 6 trials and was similar between arms. Time to recurrence reported in one trial that included bevacizumab (BV) was longer in the high dose LV group that was SS. OS was addressed in 10 studies: no difference found in 7 studies; in one RCT OS was longer with the higher dose LV 55 vs. 45 months (p not reported); in one retrospective study OS was 23 vs. 20 months in favor of high dose LV (p not reported); one study of LV and BV had longer OS vs. lower dose LV at 26 vs. 21 months (SS). Toxicity: higher dose LV was associated with greater toxicity in 3 of 4 studies that reported stomatis, and increased rates of diarrhea in 9 of 11 trials. Meta-analysis was not appropriate as studies were too heterogeneous. Conclusions: There is no convincing evidence to identify an optimum dose of LV to be used in 5-FU/LV combinations. Amongst studies that did show a difference the trend was improved survival in favor of the higher dose. Similarly, differences in toxicities when identified were consistently greater with the higher dose LV. The expert panel concludes that the existing literature provides insufficient data to suggest that chemotherapy protocols should deviate from standard protocol doses.

335 Background: CCA is a hepatobiliary malignancy with poor prognosis and few treatment options following cytotoxic therapy in the first-line metastatic setting. The fibroblast growth factor receptor (FGFR) axis may promote CCA tumorigenesis. FGFR2 fusions (in up to 17% of intrahepatic CCAs) may predict FGFR inhibitor sensitivity. A prior phase 1 trial of the selective pan-FGFR inhibitor BGJ398 showed antitumor activity in a pt with CCA harboring an FGFR2 fusion. Methods: This ongoing phase 2, open-label study is evaluating oral BGJ398 125 mg once daily on a 3-week-on/1-week-off schedule (28-day cycle) in pts with advanced or metastatic CCA with FGFR2 fusions (n ≈ 40) or other FGFR genetic alterations (n ≤ 15) who progressed after cisplatin/gemcitabine or are cisplatin intolerant (NCT02150967). The primary endpoint is investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints include progression-free survival, best overall response (BOR), disease control rate (DCR), overall survival, safety, and pharmacokinetics. Results: As of 10 July 2015, 26 pts with CCA harboring FGFR2 fusions (n = 22) or other FGFR alterations (n = 4), pretreated with 1 to ≥ 4 prior regimens, were enrolled. Common adverse events (AEs; ≥ 20% of pts), were hyperphosphatemia (50%), fatigue (42%), constipation (38%), cough (23%), and nausea (23%). Grade 3/4 AEs occurring in ≥ 2 pts were hyper/hypophosphatemia, lipase increase, and hyponatremia. AEs were manageable, reversible, and rarely led to treatment discontinuation. Among 22 pts evaluable for BOR, 3 achieved partial response and 15 had stable disease, including 10 with tumor reductions (-41%, n = 1; -2% to -29%, n = 9). Overall DCR was 82%. As of the cutoff date, 18 pts remained on therapy, of which 13 were on for > 120 days. Kaplan-Meier estimated lower limit (95% CI) of median time on study was 143 days. Conclusions: BGJ398 shows impressive anti-tumor activity and a manageable safety profile in pts with advanced FGFR-altered CCA, an indication of high unmet medical need. Updated data including additional responses post data cutoff will be presented. Clinical trial information: NCT02150967.

3 Background: Previous reports suggested that AAT when combined with salvage RT following RP in patients may improve prostate cancer control outcomes. Methods: Post-RP patients with pT3pN0 or with pT2pN0 and positive margins who had or developed elevated PSA levels from 0.2 to 4.0 ng/ml were randomized on a phase III, double-blind, trial of RT + placebo (64.8 Gy in 36 fractions of 1.8 Gy) vs. RT + AAT (24 months bicalutamide, 150 mg daily) during and after RT. The primary end-point was overall survival. Trial design required 725 patients and provided 80% power to detect a reduction in death rate by at least 28.5% and a 1-sided significance level of 0.046. Results: From 3/98 to 3/03, 761 eligible patients (median age 65) were randomized to RT + AAT (384) or RT + placebo (377). 248 patients (33%) were pT2pN0 and 513 (67%) were pT3pN0. 671 (88%) had a PSA nadir after RP of < 0.5 ng/ml. 649 (85%) had an entry PSA value of <1.6, 112 patients (15%) had an entry PSA of 1.6-4. Median follow up was 12.6 years. Actuarial overall survival at 10 years was 82% for RT plus AAT and 78% for RT + placebo and a hazard ratio of 0.75 (95% CI: 0.58-0.98) with a 1-sided p value of 0.018 (2-sided p = 0.036). The 12-year incidence of PC central-reviewed deaths were 2.3% for RT + AAT and 7.5% for RT + placebo ( p< 0.001).The cumulative incidence of metastatic PC at 12 years was less in the RT + AAT arm, 14% (51 patients), vs. 23% (83 patients) in the RT + placebo arm (p < 0.001). Subgroup analyses of the relative benefits of the addition of AAT to RT are planned and will be presented. Late grade III and IV toxicity were similar in the AAT and placebo arms. The combined grade III and IV toxicities for RT + AAT and RT + placebo were: bladder 7.0% vs. 6.7%, bowel 2.7% vs. 1.6%. Gynecomastia differed significantly by treatment arm, 70% vs. 11%. Conclusions: 24 months of AAT using 150mg bicalutamide daily during and after salvage RT significantly improved long term overall survival and reduced the incidence of metastatic PC and PC death. Support: NCI grants U10CA21661, U10CA180868, U10CA180822, and U10CA37422 and AstraZeneca. Clinical trial information: NCT00002874.

LBA4 Background: WBRT significantly improves tumor control in the brain after SRS, yet the role of adjuvant WBRT remains undefined due to concerns regarding neurocognitive risks. Methods: Patients with 1-3 brain metastases, each < 3 cm by contrast MRI, were randomized to SRS alone or SRS + WBRT and underwent cognitive testing before and after treatment. The primary endpoint was cognitive progression (CP) defined as decline > 1 SD from baseline in any of the 6 cognitive tests at 3 months. Time to CP was estimated using cumulative incidence adjusting for survival as a competing risk. Results: 213 patients were enrolled with 2 ineligible and 3 cancels prior to receiving treatment. Baseline characteristics were well-balanced between study arms. The median age was 60 and lung primary the most common (68%). CP at 3 months was more frequent after WBRT + SRS vs. SRS alone (88.0% vs. 61.9% respectively, p = 0.002). There was more deterioration in the WBRT + SRS arm in immediate recall (31% vs. 8%, p = 0.007), delayed recall (51% vs. 20%, p = 0.002), and verbal fluency (19% vs. 2%, p = 0.02). Intracranial tumor control at 6 and 12 months were 66.1% and 50.5% with SRS alone vs. 88.3% and 84.9% with SRS+WBRT (p < 0.001). Median OS was 10.7 for SRS alone vs. 7.5 months for SRS+WBRT respectively (HR = 1.02, p = 0.93). Conclusions: Decline in cognitive function, specifically immediate recall, memory and verbal fluency, was more frequent with the addition of WBRT to SRS. Adjuvant WBRT did not improve OS despite better brain control. Initial treatment with SRS and close monitoring is recommended to better preserve cognitive function in patients with newly diagnosed brain metastases that are amenable to SRS. Clinical trial information: NCT00377156.

PURPOSE: Survivors of childhood and adolescent cancer are at risk for long-term effects of disease and treatment. The Childhood Cancer Survivor Study assessed overall and cause-specific mortality in a retrospective cohort of 20,227 5-year survivors. PATIENTS AND METHODS: Eligible subjects were individuals diagnosed with cancer (from 1970 to 1986) before the age of 21 who had survived 5 years from diagnosis. Underlying cause of death was obtained from death certificates and other sources and coded and categorized as recurrent disease, sequelae of cancer treatment, or non–cancer-related. Age and sex standardized mortality ratios (SMRs) were calculated using United States population mortality data. RESULTS: The cohort, including 208,947 person-years of follow-up, demonstrated a 10.8-fold excess in overall mortality (95% confidence interval, 10.3 to 11.3). Risk of death was statistically significantly higher in females (SMR = 18.2), individuals diagnosed with cancer before the age of 5 years (SMR = 14.0), and those with an initial diagnosis of leukemia (SMR = 15.5) or CNS tumor (SMR = 15.7). Recurrence of the original cancer was the leading cause of death among 5-year survivors, accounting for 67% of deaths. Statistically significant excess mortality rates were seen due to subsequent malignancies (SMR = 19.4), along with cardiac (SMR = 8.2), pulmonary (SMR = 9.2), and other causes (SMR = 3.3). Treatment-related associations were present for subsequent cancer mortality (radiation, alkylating agents, epipodophyllotoxins), cardiac mortality (chest irradiation, bleomycin), and other deaths (radiation, anthracyclines). No excess mortality was observed for external causes (SMR = 0.8). CONCLUSION: While recurrent disease remains a major contributor to late mortality in 5-year survivors of childhood cancer, significant excesses in mortality risk associated with treatment-related complications exist up to 25 years after the initial cancer diagnosis.