Foster, Nathan R.

The purpose of the present study was to compare the impact of pulmonary function, body habitus, and stereotactic body radiation therapy (SBRT) immobilization on setup and reproducibility for upper lung tumor. From 2008 through 2011, our institution's prospective SBRT database was searched for patients with upper lung tumors. Two SBRT immobilization strategies were used: full‐length BodyFIX and thermoplastic S‐frame. At simulation, free‐breathing, four‐dimensional computed tomography was performed. For each treatment, patients were set up to isocenter with in‐room lasers and skin tattoos. Shifts from initial and subsequent couch positions with cone‐beam computed tomography (CBCT) were analyzed. Accounting for setup uncertainties, institutional tolerance of CBCT‐based shifts for treatment was 2, 2, and 4 mm in left–right, anterior–posterior, and cranial–caudal directions, respectively; shifts exceeding these limits required reimaging. Each patient's pretreatment pulmonary function test was recorded. A multistep, multivariate linear regression model was performed to elucidate intervariable dependency for three‐dimensional calculated couch shift parameters. BodyFIX was applied to 76 tumors and S‐frame to 17 tumors. Of these tumors, 41 were non–small cell lung cancer and 15 were metastatic from other sites. Lesions measured , 1.1 to 2 (50%), 2.1 to 3 (25%), and cm. Errors from first shifts of first fractions were significantly less with S‐frame than BodyFIX (). No difference in local control (LC) was found between S‐frame and BodyFIX (); two‐year LC rate was 94%. Multivariate modeling confirmed that the ratio of forced expiratory volume in the first second of expiration to forced vital capacity, body habitus, and the immobilization device significantly impacted couch shift errors. For upper lung tumors, initial setup was more consistent with S‐frame than BodyFIX, resulting in fewer CBCT scans. Patients with obese habitus and poor lung function had more SBRT setup uncertainty; however, outcome and probability for LC remained excellent.PACS number: 89.20.‐a

245 Background: Gemcitabine (GEM) monotherapy for PDA has modest activity. 17-N-Allylamino-17-demthoxygeldanamycin (Tanespimycin/17AAG), is an HSP90 inhibitor, which results in degradation of a number of client proteins such as RAF and Akt. Arlander et al (J Biol Chem. 2003 278:52572-7) have demonstrated that 17AAG targeting of HSP90 leads to Chk1 degradation. Chk1 is upregulated with GEM treatment which affects cell survival (Karnitz et al. Mol Pharmacol. 2005 68:1636-44). In vitro, the combination demonstrated in vitro synergy. Thus the potential clinical activity in pancreatic cancer of the combination was explored. Methods: A phase II multicenter prospective study was performed using GEM 750 mg/m2 d1,8 and 17AAG 154 mg/m2 d2,9 on a 21 day cycle, as defined in a previous phase I trial. Patients with stage IV PDA, with adequate liver, kidney function and counts, ECOG 0-2 and no prior therapy for metastatic disease were eligible. The primary endpoint of 60% overall survival at 6 months was considered of clinical interest. Sixty-six patients were planned for accrual, and an interim analysis was planned after 25 evaluable patients. Informed, written consent was obtained from all pts. Results: Due to lack of drug availability and failure to achieve the planned endpoint, accrual was halted at 21 pts, enrolled from 5/08 to 9/10, of which 20 were evaluable (1 cancelled prior to treatment). Median age was 61.5 yrs., 55% were male, PS 0 (50%), 1 (45%), 2 (5%); 95% were non-Hispanic white, 1 was African American. Two had received adjuvant therapy for PDA. Tolerability was moderate, with 13 pts (65%) having > grade 3 adverse event (AE), with 15% gr 4 AEs and 0% gr 5. Nausea (20%), vomiting (20%), constipation (15%), dehydration (15%), and anorexia (10%), were the most common non-heme AEs. Lymphopenia (15%), leukopenia (10%) and neutropenia (10%) were common grade 3 hematologic AEs. No complete or partial responses were seen. 40% of patients were alive at 6 months, with a median OS of 5.4 months. Conclusions: HSP 90 inhibitor 17AAG in combination with GEM does not show activity for treatment of PDA. Further trials should not be pursued with this combination. Supported by N01-CM-62205. Clinical trial information: NCT00577889.

460 Background: The immune response has emerged as a strong prognostic factor in colon cancer. Whereas CD8+ T cells mediate antitumor response, regulatory T cells expressing FoxP3+ can antagonize this effect, though prognostic data conflict. These markers have yet to be analyzed with MMR status, which is important since dMMR tumors show enhanced immune response. Methods: CD8+ and FoxP3+ density were analyzed by immunohistochemistry (IHC) in resected stage II and III colon carcinomas (N = 216) from participants in phase III adjuvant 5-fluorouracil-based trials. High vs low immune density was dichotomized at the median. MMR status, determined by IHC or analysis of microsatellite instability, was categorized as dMMR (12%) or proficient MMR (pMMR). Cox models, stratified by study, were adjusted for age, stage, grade and, where noted, MMR. Results: The association of FoxP3+ density with overall survival (OS) differed by CD8+ density (P for interaction = .040). By multivariable analysis, FoxP3+high was significantly associated with improved OS in CD8+low tumors (hazard ratio 0.43 [95% confidence interval 0.19 – 0.95]; P = .030], but not in CD8+high tumors (P = .91). Results were consistent after MMR adjustment. We then determined their prognostic impact in the larger pMMR subset (N = 119). Tumors with high FoxP3+ were associated with improved OS in cases with low, but not high, CD8+ density ( Table ). These patients (FoxP3+high, CD8+low) had similar 5-year OS rates as 107 dMMR cases from parent studies (89% vs 80%; P = .74), despite having distinct clinicopathologic features. Conclusions: The prognostic impact of FoxP3+ T cells depends on CD8+, indicating the importance of analyzing both in combination. High FoxP3+ exerts a paradoxically favorable survival impact, but only when CD8+ is low. Survival in pMMR tumors with high FoxP3+ and low CD8+ was similar to that of dMMR tumors, indicating that a favorable pMMR subset can be identified. [Table: see text]

271 Background: Epidermal growth factor inhibitors show some benefit in the treatment of advanced pancreatic cancer. A trial to evaluate the incorporation of Pmab into a conventional multimodality regimen and continuation as maintenance therapy was conducted in pts with LA disease. Methods: Pts with ECOG PS 0-1, preserved organ function and tumor encompassed within standard radiation fields were eligible. Pmab 6 mg/kg on days 1, 15, 29 and continuous infusion 5-FU 225 mg/m2/d or capecitabine 825 mg/m2 were given with RT. Pts then received weekly gemcitabine 1000 mg/m2 and Pmab on days 1, 15 for three 4-week cycles. Maintenance Pmab was then continued for additional 6 months. RT consisted of 45 Gy to the tumor and regional nodes with a 5.4 Gy boost using conformal techniques. Primary endpoint of one-year survival (OS) with secondary endpoints progression-free survival (PFS), confirmed tumor response, and adverse events (at least possibly related) are reported. Results: 51 pts (23 M: 28 F) were enrolled with a median age of 65 (range: 43-84). Twenty-two pts (43%) received at least 1 cycle of post-chemo-RT, while 29 patients only received chemo-RT. All 51 pts have ended treatment with pts going off study because of: progression (39%), adverse events (27%), refusal (25%), and other reasons (8%). Frequently occurring maximum grade 3/4 AEs across the entire treatment course (chemo-RT + post-chemo-RT chemo) are shown below. With a median follow-up of 12.3 months, survival at 12 months is 50.2% (95% CI: 37.9-66.5%), median survival 12.1 mos (95% CI: 6.8-15.9) and median PFS 7.4 mos (95% CI: 3.7-8.6). Confirmed response rate was 5.9% (1-CR, 2-PR). Conclusions: The addition of Pmab to a conventional chemo-RT regimen provides benefit in terms of median survival. This is similar to reports of other EGFR inhibitors in LA disease. Adverse events, especially during the chemo-RT portion, were considerable and affected administration of subsequent systemic maintenance therapy. [Table: see text]

419 Background: Deficient DNA mismatch repair (MMR) results in microsatellite instability (MSI) that is detected in ∼15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information. We developed a model to predict MMR deficiency using clinically available data, and thereby facilitate the selection of patient tumors for MMR testing. Methods: Data were utilized from stage II and III colon carcinoma patients (n = 2016) who participated in 5-fluorouracil-based adjuvant studies (NCCTG, FFCD, NCIC, GIVIO, NSABP) and an Italian cohort. MMR status in tumors had been determined by MSI testing or by immunohistochemistry for hMLH1 and hMSH2 proteins. Logistic regression and a recursive partitioning and amalgamation analysis was used to identify factors (histologic grade, gender, tumor site, stage, age, lymph node status, T-stage) predictive of MMR status. Results: Of the cancers, 357 (17.7%) showed deficient MMR. Tumor site was the most important predictor of MMR status followed by histologic grade, then stage (II vs. III) and then gender. Distal tumors had a low likelihood of deficient MMR (5% rate overall), whereas proximal tumors had a greater likelihood of deficient MMR (30%). For patients with proximal tumors, the addition of histologic grade and stage increased the prediction of deficient MMR (Table). Using tumor site, histologic grade, and stage, the logistic regression model showed excellent discrimination (c-statistic = 0.80). Conclusions: Routine clinicopathological data can facilitate the identification of MMR deficient cases. Tumor site and histologic grade were the strongest predictors of MMR deficiency. Within proximal, poorly differentiated tumors, stage was highly predictive. These findings suggest that our model can assist in selecting sporadic colon cancers for MMR testing for use in clinical decision-making, especially for stage II patients. [Table: see text] [Table: see text]

238 Background: Dual inhibition of the EGFR pathway using erlotinib and the monoclonal antibody panitumumab results in greater antitumor activity in preclinical pancreatic cancer models. A trial evaluating this approach was conducted. Methods: A safety analysis was initially performed with 6 patients at P 4 mg/kg every two weeks, E 100 mg daily, G 1000 mg/m2 weekly of a 28-day cycle. PGE was well tolerated with a grade 3 fatigue as only dose-limiting toxicity. Patients (pts) were then randomized to either PGE or GE alone. Eligibility included: no prior chemo, ECOG PS 0-1, bilirubin <2x UL, AST <2.5x UL. CT scans every 2 cycles. Results: 93 pts (46-GE; 47-PGE) were randomized from January to August, 2010. Median age 61 years and 65% male. ECOG PS 0 (51%) and PS 1 (49%). No significant differences in baseline characteristics observed between treatment arms. 81 pts evaluable for AEs; 37 (46%) had a maximum grade 3 (at least possibly related to treatment), and 12 (15%) maximum grade 4 or 5. Treatment arms similar with respect to the overall AEs with exception grade 1-3 acneiform rash, GE (65%) vs. PGE (85%). Commonly occurring grade 4 AEs (at least possibly related) consisted of thrombosis (3 pts) and thrombocytopenia (2 pts). Two grade 5 events occurred in PGE arm—duodenal hemorrhage (possibly related) and pancolitis with multisystem failure (unlikely). An additional PGE pt died 30 days off study (grade 5 CHF, possibly). 54 patients (67%; 31-GE, 23-PGE) ended treatment; 38 (70%) for disease progression (24-GE; 14-PGE). Other reasons for treatment discontinuation: AEs (9; 17%), pt refusal (4; 7%), death on study (2; 4%), other (1). In 81 pts with at least 1 cycle of chemotherapy, the median PFS for GE 2.0 months and 3.3 months for PGE. Accrual for the study was recently completed and overall and 6-month survival data will be presented. Conclusions: This study involved an initial run-in design to define tolerable doses of dual EGFR inhibitors, PGE, in pancreatic cancer patients. Although preliminary, the randomized phase II portion has been completed and differences between GE and PGE in terms of relevant clinical outcomes, PFS, are observed. No significant financial relationships to disclose.