Prospective Study of Interim 18FDG-PET Response Assessment in Esophageal Cancer Patients Treated With Neoadjuvant Chemoradiation and Esophagectomy.

E180

International Journal of Radiation Oncology  Biology  Physics

2456

we sought to identify immune-related biomarkers as a part of this study that correlated with treatment response and/or toxicity. Materials/Methods: Blood samples were collected from 11 patients enrolled on the trial before the initiation of treatment, every week during radiation and then at 1, 3 and 6 months following radiation. The serum from each time point was then analyzed using MesoScale V-Plex electrochemiluminescent array to determine the level of 40 different analytes from four categories: angiogenesis, cytokines, vascular injury and chemokines. Differences between baseline levels and subsequent time points were analyzed using two-way ANOVA. Results: All 11 patients studied received the entire course of veliparib, gemcitabine and radiation (RT). We found that during RT that levels of inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA), interleukin (IL)-6 increase significantly by 4 weeks of treatment. This rise in inflammatory markers is also accompanied by increases in cytokines including IL-5 and IL-15 which affect the polarization and homeostasis of immune cells, particularly T cells. We also find that markers of angiogenesis Phosphatidylinositol-glycan biosynthesis class F protein (PIGF) and vascular endothelial growth factor (VEGF)-D are also elevated in the serum in a parallel pattern to the inflammatory markers and cytokines. All patients demonstrated a similar cytokine pattern suggesting a common pathway of inflammation in response to combined therapy. Conclusion: The results from this study indicate that there is a common and stereotyped inflammatory response to chemoradiation. From this we hypothesize, that chemoradiation induces an inflammatory program that results in a pro-angiogenic through PIGF and VEGF and pro-tumor via IL5 tumor microenvironment. This data further suggests that there may be inflammation-related biomarkers of response to therapy and identifies potential targets for immunomodulating agents. Author Disclosure: S.L. Shiao: Employee; Cedars-Sinai Medical Center. Research Grant; ASTRO. P. Noe: None. Y. Kubota: None. W. Yang: Research Grant; NIH. N.N. Nissen: None. A.E. Hendifar: None. R. Tuli: Research Grant; Merck.

Outcomes After Neoadjuvant or Definitive Chemoradiation Therapy for Esophageal/Gastroesophageal Junction Carcinoma L. Zamdborg,1 K.C. Lee,1 A. Harris,2 F. Doo,2 D.B. Gersten,1 I.S. Grills,1 and J. Robertson1; 1Beaumont Health System, Royal Oak, MI, 2Oakland University William Beaumont School of Medicine, Rochester, MI Purpose/Objective(s): To evaluate outcomes after neoadjuvant chemoradiation therapy followed by surgery (NCRT) or definitive chemotherapy (DCRT) for esophageal carcinoma. Materials/Methods: From 2006 to 2015, 123 patients underwent CRT at a single institution. Sixty-five percent (80) underwent DCRT, while 35% (43) underwent NCRT followed by surgery. The median age was 68 years (range, 27-92) but differed from DCRT & NCRT (73 vs 61, pZ1.15E-05), indicating that younger patients were more likely to have surgery. Eighty percent were male, Twenty percent were female. Eighty percent were white, 5% AA, and 15% other. Disease grade (1/2/3 was 4%/25%/50%, not reported for 21%. Sixty-nine percent had adenocarcinoma histology, 24% squamous, 7% other. A total of 81.3% of tumors were located in the distal esophagus/GEJ. Clinical stage (AJCC 6) I/IIA/IIB/III/IVA (celiac nodal)/ TxN0M0 was 5%/21%/11%/39%/15%/9%. Sixty-nine percent underwent baseline EUS staging, 82% PET staging. Median weight loss prior to RT was 15 lbs (range, 0-100). Thirty-five percent (15) of NCRT patients had transhiatal esophagectomies, 44% (19) Ivor-Lewis, and 7% (3) McKeown. Twenty-one percent (9) were minimally-invasive. The median RT dose was 50.4 Gy (range, 14.4-66.6) in 28 (7-37) fractions. Eighty percent of DCRT patients received at least 50.4 Gy. Sixty-one percent of NCRT patients were treated daily to at least 50.4 Gy, while 30% had 45 Gy in 1.5 Gy BID fractions. Seventy-two percent of RT was delivered with 3DCRT, and 27% with IMRT. Multiple patient, treatment, and tumor characteristics had descriptive statistics calculated, compared between NCRT and DCRT with two-sample proportion, Student’s t, and Mann-Whitney U tests. Effects on overall survival (OS), and freedom from local (FLR), locoregional (FLRR), and distant failure (FDM) were estimated with univariate Cox regression. Survival was compared between groups with log-rank tests. Results: Median follow-up for survivors was 67 mos (range, 7-387). Median OS for all patients was 2.2 y (0.2-12.7). In the DCRT group, median OS was 1.5 y (0.2-12.7), while it was 3.0 y for NCRT (0.3-11.9, pZ0.057). 3-year OS, FLR, FLRR, FDM were 48%, 73%, 62%, and 70%, respectively. 3-year OS was 59% for NCRT, and 41% for DCRT. FLR, FLRR, and FDM rates were 71%, 58%, 69% for DCRT and 75%, 68%, and 59% for NCRT, respectively. Differences in recurrence-free rates were not statistically significant. The number of lymph nodes dissected was predictive for OS (pZ0.037), but not the number positive for tumor (pZ0.39). Conclusion: In this series, NCRT was associated with longer median and OS and improved FLRR when compared to DCRT for esophageal cancer. Age, however, was a prominent factor for determining surgical candidacy. Extent of nodal dissection correlated with improved OS. Author Disclosure: L. Zamdborg: None. K.C. Lee: None. A. Harris: None. F. Doo: None. D.B. Gersten: None. I.S. Grills: None. J. Robertson: None.

2457 Chemoradiation Induces a Proangiogenic and Protumor Circulating Cytokine Profile S.L. Shiao, P. Noe, Y. Kubota, W. Yang, N.N. Nissen, A.E. Hendifar, and R. Tuli; Cedars-Sinai Medical Center, Los Angeles, CA Purpose/Objective(s): Locally advanced pancreatic cancer has a dismal prognosis with current treatment modalities. Given this poor outcome, we initiated a Phase I trial of concurrent veliparib, gemcitabine and fractionated radiation therapy for patients with locally advanced pancreatic disease. With the recent recognition of the important role played by the immune system in the response to radiation and other cytotoxic therapy,

2458 Prospective Study of Interim 18FDG-PET Response Assessment in Esophageal Cancer Patients Treated With Neoadjuvant Chemoradiation and Esophagectomy. M. Palta,1 K. Higgins,2 Q.R.J. Wu,1 B. Czito,1 C.G. Willett,1 and S.K. Das3; 1Duke University Medical Center, Durham, NC, 2Duke University, Durham, NC, 3University of North Carolina, Chapel Hill, NC Purpose/Objective(s): Randomized data suggests that surgery after neoadjuvant chemoradiation improves local control, but does not impact survival. Strategies to identify treatment responders from non-responders under active treatment could potentially alter patient management with treatment intensification or alteration in non-responders and treatment deescalation or omission of surgical resection in responding patients. This work investigates the utility of an 18FDG-PET scan acquired during the course of chemoradiation therapy as a predictor of pathological response. Materials/Methods: Patients planned for neoadjuvant chemoradiation underwent 18FDG-PET/CT simulation scanning prior to radiation therapy (RT) and again during RT (after delivery of w32 Gy). The physiciancontoured GTV on the planning CT scan was used to automatically segment a PET-based GTV on the pre-RT PET (GTV-pre-PET) as the volume with >40% of the maximum GTV PET SUV value. The pre- and interim-RT CTs were deformably registered to each other to transfer the GTV-pre-PET to the interim-RT PET (GTV-interim-PET). The fractional decrease in the mean SUV, maximum SUV, and the SUV to the highest intensity 10% - 90% volumes from GTV-pre-PET to GTV-interim-PET were compared to pathological response assessed at the time of surgery. Results: Twenty patients (3 squamous cell, 17 adenocarcinoma) underwent pre-RT PET, intra-RT PET and subsequent surgical resection. The majority (19/20) had tumor located in the lower esophagus/gastroesophageal junction. Based on post-treatment pathology of the 20 patients, 9 were classified as having favorable response (treatment effect grade  1) and 11 as

Volume 93  Number 3S  Supplement 2015 having unfavorable response (treatment effect grade > 1). Neither the mean SUV nor maximum SUV were significant between the favorable and unfavorable response groups. However, the fractional decrease in SUV10% (SUV to the highest 10% volume), SUV20%, and SUV30% were significant (p Z0.04 for all) with an area under the Receiver Operating Characteristics (ROC) curve of 0.78 for all. Conclusion: The fractional decrease in SUV to the volume with highest 10%, 20% and 30% intensity from pre- to interim-RT 18FDG-PET imaging may be used to distinguish responders from non-responders with high sensitivity and specificity. The ability to distinguish esophageal cancer patients treated with neoadjuvant chemoradiation as responders versus non-responders may further advances toward individualized patient care. Author Disclosure: M. Palta: Honoraria; Oakstone, Med-IQ. K. Higgins: None. Q. Wu: None. B. Czito: None. C.G. Willett: None. S.K. Das: None.

2459 Interim Analysis of a Phase I Study of Veliparib With Gemcitabine and IMRT in Patients With Borderline and Locally Advanced Unresectable Pancreatic Cancer R. Tuli,1 N.N. Nissen,1 S. Lo,2 M. Tighiouart,1 A. Rogatko,3 A. Osipov,1 M. Bryant,3 H.M. Sandler,1 and A.E. Hendifar1; 1Cedars-Sinai Medical Center, Los Angeles, CA, 2Cedars-Sinai Medical Center, Los Angeles, CA, 3 Cedars-Sinai Medical Center, Los Angeles, CA Purpose/Objective(s): Targeted inhibition of PARP1/2 may further exploit the well-known synergy between gemcitabine (G) and radiation therapy (RT) in pancreatic cancer (PC). This synergy may be further exploited by targeting tumors with pre-existing defects in double-strand DNA repair. Our laboratory findings have shown enhanced control of pancreatic tumors with the PARP1/2 inhibitor, veliparib (V), in combination with RT. We report interim results of a phase 1 study (NCT01908478) evaluating the optimal dose of V with G and RT in PC. Materials/Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of V with 40% probability of a dose limiting toxicity (DLT). Secondary objectives are to: 1) measure clinical activity using RECIST 1.1, PFS and OS; 2) evaluate pre-treatment tumor biopsies and longitudinal blood samples for predictors of response or resistance to therapy. Inclusion criteria: borderline or locally advanced PC, age > 18 years, KPS  70%, life expectancy > 6 months, normal organ and marrow function. The treatment cycle is 3 weeks followed by evaluation for adverse events. G (1000 mg/m2) is administered on days 1, 8, 15. RT (36 Gy) is given in 15 fractions (2.4 Gy/day). V is administered BID in 20 mg increments beginning at a dose of 20 mg BID for 21 days. Patients are evaluated for an additional 6 weeks for DLT prior to initiating standard of care. Dose escalation follows an extension of the Bayesian escalation with overdose control (EWOC) design where the time to DLT is modeled. Results: Since October 2013, 18 patients have consented with 14 enrolled. Four have borderline and 10 have locally advanced PC. Median age is 71 (range 32-82). Median follow up is 8 months. V has been escalated to 60 mg BID. The following DLTs have occurred: G4 neutropenia (nZ1), G4 lymphopenia (nZ4), G3 febrile neutropenia (nZ1), G3 abdominal infection (nZ1), and G3 abdominal pain (nZ1). Other non-DLT G3 GI toxicities included: diarrhea (nZ1), hyperbilirubinemia (nZ1), AST elevation (nZ1) and ALT elevation (nZ1). Conclusion: This phase I trial represents the first combination of PARP inhibition along with chemo-radiation therapy for PC. The tolerated dose of V in combination with G and RT based on current accrual is 60 mg BID. Dose escalation using the EWOC design continues. Most toxicities are hematologic. GI toxicities have been acceptable. Clinical and correlative results will be reported. Author Disclosure: R. Tuli: None. N.N. Nissen: None. S. Lo: None. M. Tighiouart: None. A. Rogatko: None. A. Osipov: None. M. Bryant: None. H.M. Sandler: Consultant; Medivation, Bayer, Janssen, Astra Zeneca, Blue Earth Diagnostics. Advisory Board; Eviti. A.E. Hendifar: None.

Poster Viewing Session E181

2460 Posttreatment PET-CT is Predictive of Local Control After Liver Stereotactic Body Radiation Therapy E.C. White,1 J. Shaffer,1,2 K.A. Kumar,3 M.S. Binkley,4 A.C. Koong,1,2 and D.T. Chang1,2; 1Stanford University, Stanford, CA, 2Stanford Cancer Institute, Stanford, CA, 3Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA, 4Stanford University School of Medicine, Stanford, CA Purpose/Objective(s): To determine if post-treatment PET-CT response after stereotactic body radiation therapy (SBRT) for liver lesions is predictive of local control. Materials/Methods: Consecutive patients at a single institution who were treated with SBRT for liver tumors between 2005 and 2014 and had a posttreatment PET-CT were retrospectively reviewed. A total of 52 patients were treated to 71 lesions. Doses were converted to the biologically effective dose (BED) using the standard linear quadratic model with a/b of 10. The maximum SUV (SUVmax) at the treated site from the posttreatment PET-CT was determined. Local control was assessed with serial imaging. Kaplan Meier survival analysis and multivariate Cox proportional hazard modeling was performed. Results: The median follow-up was 19 months (range 3-80). The median age was 68 (range 39-88) and 50% were male. Fifteen lesions were primary tumors and 56 were metastases. Metastatic histologies includes colorectal carcinoma (nZ23), melanoma (nZ7), gastric (nZ5), lung (nZ5), pancreatic (nZ4), breast (nZ4), renal cell carcinoma (nZ3), and others (nZ5). Primary histologies included cholangiocarcinoma (nZ13) and hepatocellular carcinoma (nZ2). The median GTV size was 22.2 cc (range 0.33-147.1 cc).The median BED10 was 100 Gy (range 48-151.2 Gy). The post-treatment PET-CT was obtained at a median of 3 months post-treatment (range 1-13 months). Overall, the median post-treatment SUVmax was 3.8 (meanZ4.5, range 2-13.7). For the entire cohort, the local control rate at 1 and 2 years was 74% and 67%, respectively. The overall survival at 1 and 2 years was 83% and 58%, with a median overall survival of 40 months. Using a threshold post-treatment SUVmax of <4.0 vs. 4.0, the 1 and 2 year local control rate was 89% vs. 50% and 78% vs. 42%, respectively (HRZ0.20, 95% CI 0.08-0.39, p<0.0001). In a multivariate model including post-treatment SUVmax, primary vs. metastatic lesion, GTV size, and BED10, SUVmax was found to be highly significant for local failure (HR 1.48, 95% CI 1.24-1.76, p<0.0001). Conclusion: Post-treatment PET-CT after liver SBRT is highly predictive of local tumor control. Author Disclosure: E.C. White: None. J. Shaffer: None. K.A. Kumar: None. M.S. Binkley: None. A.C. Koong: None. D.T. Chang: None.

2461 The Potential Role for 18F-FDG PET/CT Scan as an Imaging Biomarker in Unresectable Hepatocellular Carcinoma Y.A. Abuodeh, A.O. Naghavi, P.S. Venkat, S.E. Hoffe, K. Latifi, K.A. Ahmed, J.A. Oliver, G.G. Zhang, E.G. Moros, T.J. Dilling, J.M. Frakes, R. Shridhar, J. Montilla-Soler, B. Biebel, J. Choi, B. Kis, J. Sweeney, and G. El-Haddad; Lee Moffitt Cancer Center and Research Institute, Tampa, FL Purpose/Objective(s): 18F-FDG PET/CT scans are not incorporated in the initial work up of hepatocellular carcinoma (HCC) due to low sensitivity. The aim of this study is to evaluate the value of 18F-FDG PET/ CT scan as an imaging biomarker in patients with unresectable HCC treated with radioembolization. Materials/Methods: After obtaining IRB approval, we identified 34 patients with HCC who received targeted liver therapy with Y-90 glass microspheres (Therasphere) between 2009 and 2013 at our institution. A pretreatment 18F-FDG PET/CT scan was obtained in the initial workup for liver masses of unknown etiology. Visceral arteriography and lung shunt studies were done prior to each procedure and radiation dose calculations were done based on volume of liver to be treated. The patients were followed after treatment with imaging and Alpha-fetoprotein (AFP) levels at