Goshen Center for Cancer Care

Goshen, United States

Goshen Center for Cancer Care

Goshen, United States
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Hassan M.S.,Indiana University | Hassan M.S.,Harper Cancer Research Institute | Awasthi N.,Indiana University | Awasthi N.,Harper Cancer Research Institute | And 10 more authors.
PLoS ONE | Year: 2017

Esophageal adenocarcinoma (EAC) has become the dominant type of esophageal cancer in United States. The 5-year survival rate of EAC is below 20% and most patients present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Improvement of EAC patient outcome requires well-characterized animal models in which to evaluate novel therapeutics. In this study we aimed to establish a peritoneal dissemination xenograft mouse model of EAC that would support survival outcome analyses. To find the best candidate cell line from 7 human EAC cell lines of different origin named ESO26, OE33, ESO51, SK-GT-2, OE19, OACM5.1C and Flo-1 were injected intraperitoneally/subcutaneously into SCID mice. The peritoneal/xenograft tumor formation and mouse survival were compared among different groups. All cell lines injected subcutaneously formed tumors within 3 months at variable rates. All cell lines except OACM5.1C formed intraperitoneal tumors within 3 months at variable rates. Median animal survival with peritoneal dissemination was 108 days for ESO26 cells (5×106), 65 days for OE33 cells (5×106), 88 days for ESO51 cells (5×106), 76 days for SK-GT-2 cells (5×106), 55 days for OE19 cells (5×106), 45 days for OE19 cells (10×106) and 82 days for Flo-1 cells (5×106). Interestingly, only in the OE19 model all mice (7/7 for 5×106 and 5/5 for 10×106) developed bloody ascites with liver metastasis after intraperitoneal injection. The median survival time of these animals was the shortest (45 days for 10×106 cells). In addition, median survival was significantly increased after paclitaxel treatment compared with the control group (57 days versus 45 days, p = 0.0034) along with a significant decrease of the relative subcutaneous tumor volume (p = 0.00011). Thus peritoneal dissemination mouse xenograft model for survival outcome assessment after intraperitoneal injection of OE19 cells will be very useful for the evaluation of cancer therapeutics. © 2017 Hassan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Background: Concurrent chemoradiation with etoposide and cisplatin (EP/XRT) is standard treatment for inoperable stage III locally advanced non-small-cell lung cancer (LA-NSCLC). Consolidation docetaxel (D; Taxotere) after EP/XRT resulted in increased toxicity but no improvement in survival compared with observation (O). We report updated survival for the entire study population and include an analysis of efficacy and tolerability of EP/XRT with or without D in patients aged ≥ 70 years. Patients and methods: Hoosier Oncology Group LUN 01-24 enrolled 243 patients with LA-NSCLC and randomized 166 after EP/XRT to three cycles of D versus O. the trial was terminated after an analysis of the first 203 patients demonstrated futility of D. Results: Median survival time (MST) for the overall study population was 21.5 months, and 3-, 4-, and 5-year survival rates were 30.7%, 18.0%, and 13.9%, respectively. No differences in MST or 3-year survival were noted between D and O arms. Older patients had similar MST (17.1 versus 22.8 months for younger patients, P = 0.15) but higher rates of grade 3/4 toxicity and hospitalization during induction. Conclusions: Consolidation docetaxel after EP/XRT does not improve survival in LA-NSCLC. Fit older adults with LA-NSCLC benefit from concurrent chemoradiation similarly as younger patients but experience higher rates of hospitalization and toxicity. © the Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Weixler B.,University of Basel | Warschkow R.,Kantonsspital St. Gallen | Warschkow R.,University of Heidelberg | Ramser M.,University of Basel | And 5 more authors.
BMC Cancer | Year: 2016

Background: It remains a matter of debate whether colorectal cancer resection in an emergency setting negatively impacts on survival. Our objective was therefore to assess the impact of urgent versus elective operation on overall and disease-free survival in patients undergoing resection for colorectal cancer by using propensity score adjusted analysis. Methods: In a single-center study patients operated for colorectal cancer between 1989 and 2013 were identified from a prospectively maintained database. Median follow-up was 44months. Patients with neoadjuvant treatment were excluded. The impact of urgent operation on overall and disease-free survival was assessed using both Cox regression and propensity score analyses. Results: Of 747 patients with colorectal cancer, 84 (11%) had urgent and 663 elective cancer resection. The propensity score revealed strongly biased patient characteristics (0.22 ± 0.16 vs. 0.10 ± 0.09; P < 0.001). In unadjusted analysis urgent operation was associated with a 35% increased risk of overall mortality (hazard ratio(HR) of death = 1.35, 95% confidence interval(CI):1.02-1.78, P = 0.045). In risk-adjusted Cox regression analysis urgent operation was not associated with poor overall (HR = 1.08, 95%CI:0.79-1.48; P = 0.629) or disease-free survival (HR = 1.02, 95%CI:0.76-1.38; P = 0.877). Similarly in propensity score analysis urgent operation did not influence overall (HR = 0.98, 95% CI:0.74-1.29), P = 0.872) and disease-free survival (HR = 0.89, 95%CI:0.68 to 1.16, P = 0.387). Conclusions: This study provides evidence that worse oncologic outcomes after urgent operation for colorectal cancer are caused by clinical circumstances and not due to the urgent operation itself. Urgent operation is not a risk factor for colorectal cancer resection. © 2016 Weixler et al.

Rangwala F.,Duke University | Bendell J.C.,Sarah Cannon Research Institute | Kozloff M.F.,Ingalls Memorial Hospital | Arrowood C.C.,Duke University | And 23 more authors.
Investigational New Drugs | Year: 2014

Purpose: To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. Design: This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. Results: Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. Conclusions: Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m2 BID days 1-14; oxaliplatin 100 mg/m2 and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC. © 2014 Springer Science+Business Media.

Vlahovic G.,Duke University | Meadows K.L.,Duke University | Uronis H.E.,Duke University | Morse M.A.,Duke University | And 12 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2012

Purpose: Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination. Methods: Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Results: Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5 mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5 mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91 %), mucositis/stomatitis (75 %), hypomagnesemia (72 %), hypocalcemia (56 %) and hypokalemia (50 %). There were 3 partial responses; an additional 10 subjects had stable disease ≥6 months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40 months. Conclusions: The recommended phase II dose is everolimus at 5 mg three times weekly plus panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors. © 2012 Springer-Verlag.

Strickler J.H.,Duke University | Starodub A.N.,Duke University | Starodub A.N.,Goshen Center for Cancer Care | Jia J.,Duke University | And 9 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2012

Purpose To define the maximum tolerated dose, clinical toxicities, and pharmacodynamics of bevacizumab, everolimus, and panobinostat (LBH-589) when administered in combination to patients with advanced solid tumor malignancies. Experiment design Subjects received 10 mg of panobinostat three times weekly, 5 or 10 mg everolimus daily, and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Protein acetylation was assessed in peripheral blood mononuclear cells (PBMC) both at baseline and on treatment. Results Twelve subjects were evaluable for toxicity and nine subjects for response. DLTs in cohort 1 included grade 2 esophagitis and grade 3 oral mucositis; DLTs in cohort -1 were grade 2 ventricular arrhythmia and grade 2 intolerable skin rash. Common adverse events were diarrhea (50 %), headache (33 %), mucositis/stomatitis (25 %), hyperlipidemia (25 %), and thrombocytopenia (25 %). There was 1 partial response; an additional 2 subjects had stable disease as best response. No consistent changes in protein acetylation in PBMC were observed in samples available from eight patients on treatment compared with baseline. Conclusions Bevacizumab, everolimus, and panobinostat in combination at the lowest proposed doses did not have an acceptable safety and tolerability profile and did not consistently inhibit HDAC activity; therefore, we do not recommend further evaluation. © Springer-Verlag 2012.

Gulec S.A.,Goshen Center for Cancer Care | Gulec S.A.,Florida International University | Cohen S.J.,Fox Chase Cancer Center | Pennington K.L.,Goshen Center for Cancer Care | And 9 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Humanized antibody hPAM4 specifically binds a mucin glycoprotein expressed in pancreatic adenocarcinomas. This phase I study evaluated a single dose of 90Y-clivatuzumab tetraxetan (90Y-labeled hPAM4) in patients with advanced pancreatic cancer. Experimental Design: Twenty-one patients (4 stage III; 17 stage IV) received 111In-hPAM4 for imaging and serum sampling before 90Y-hPAM4. Study procedures evaluated adverse events, safety laboratories, computed tomography (CT) scans, biomarkers, pharmacokinetics, radiation dosimetry, and immunogenicity (HAHA). Results: 111In-hPAM4 showed normal biodistribution with radiation dose estimates to red marrow and solid organs acceptable for radioimmunotherapy and with tumor targeting in 12 patients. One patient withdrew before 90Y-hPAM4; otherwise, 20 patients received 90Y doses of 15 (n = 7), 20 (n = 9), and 25 mCi/m2 (n = 4). Treatment was well tolerated; the only significant drug-related toxicities were (NCI CTC v.3) grade 3 to 4 neutropenia and thrombocytopenia increasing with 90Y dose. There were no bleeding events or serious infections, and most cytopenias recovered to grade 1 within 12 weeks. Three patients at 25 mCi/m2 encountered dose-limiting toxicity with grade 4 cytopenias more than 7 days, establishing 20 mCi/m2 as the maximal tolerated 90Y dose. Two patients developed HAHA of uncertain clinical significance. Most patients progressed rapidly and with CA19-9 levels increasing within 1 month of therapy, but 7 remained progression-free by CT for 1.5 to 5.6 months, including 3 achieving transient partial responses (32%-52% tumor diameter shrinkage). Conclusion: 90Y-Clivatuzumab tetraxetan was well tolerated with manageable hematologic toxicity at the maximal tolerated 90Y dose, and is a potential new therapeutic for advanced pancreatic cancer. ©2011 AACR.

Ocean A.J.,Cornell University | Pennington K.L.,Goshen Center for Cancer Care | Guarino M.J.,Helen aham Cancer Center | Sheikh A.,University of North Carolina at Chapel Hill | And 16 more authors.
Cancer | Year: 2012

Background: It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. Methods: Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m2 weekly for 4 weeks with 90Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2-4). In the first part of the study, 19 patients received escalating weekly 90Y doses of 6.5 mCi/m 2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m 2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2. Results: Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute's Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses. Conclusions: Fractionated radioimmunotherapy with 90Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma. © 2012 American Cancer Society.

The impact of immediate breast reconstruction on the time to first adjuvant therapy is controversial.Retrospective study design comparing time to first treatment in women undergoing mastectomy with and without immediate reconstruction in a community cancer center.Seventy-six cases fit inclusion criteria of which 44 (58%) underwent mastectomy with immediate reconstruction. Women undergoing immediate reconstruction were younger, had more bilateral mastectomies and had fewer prior breast procedures. The median time to first adjuvant therapy was longer in the immediate reconstruction group [80.5days (36-343) versus 53.5 days (18-96), p=0.003]. Fifteen of 44 patients had the start of adjuvant treatment over 90 days after resection, 14 of whom (93%) had immediate reconstruction versus 1 (7%) who did not (p=0.01).In this study immediate breast reconstruction was associated with a longer time to first adjuvant treatment, with adjuvant therapies being more likely delayed over 90 days.The impact of immediate reconstruction on the time to adjuvant therapy is controversial. Most data originate from tertiary referral centers whose data may not necessarily apply to the community setting. We studied the impact of immediate reconstruction on the time to first adjuvant treatment in a community cancer center setting.

PubMed | Goshen Center for Cancer Care
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

15011 Background: Concurrent chemotherapy and radiation in colorectal cancer(CRC) can improve outcome of local or regional disease. This study is an attempt to derive a similar benefit using chemotherapy and a novel method of radiation therapy for patients with CRC metastatic to liver. Yttrium-90 (Y-90) microsphere selective internal radiation treament (SIRT) has proven to be a safe and effective mode of radiation delivery technique in patients (pts) with CRCLM as a single modality and with 5-FU and FUDR. This is a phase II trial of Y-90 microspheres and concurrent multiagent chemotherapy for management of CRCLM. This study is designed to measure response using updated methods of measurements based on pet scan and computer modeling as well as common criteria. Assessment of toxicity, especially hepatotoxicity and myelotoxicity, is the second major objective.20 patients with disease limited predominantly to the liver were recruited for the study. Pre-treatment studies included a liver-protocol PET-CT, angiogram and 99mTc-MAAA (macroaggregaated albumin) imaging. Chemotherapy (Fol-Fox or Fol-Firi) was planned every 2 weeks for 8 cycles. SIRT with Y-90 resin microspheres (Sirtex Medical, Wilmington, MA) was administered on day 2 of the first chemotherapy course either lobar or whole-liver fashion. Administered activity of Y-90 microspheres ranged from 0.2 to 3.8 GBq (mean 1.8 GBq). CEA levels, tumor anatomic volume (V20 patients have been treated and 19 are evaluable. 13 patients were chemo-naive, 7 had prior chemo. 3 received whole liver, 16 received lobar, one segmental SIRT. 16/19 patients had a VChemo-SIRT with modern chemotherapy results in a high objective response rate with acceptable toxicity and deserves further study. [Table: see text].

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