bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular detection of occult nodal metastases in esophageal adenocarcinoma
Authors: Altomare I. , Pennathur A. , Xi L. , Gooding W. E. , Litle V. R. , Luketich J. D. , Godfrey T. E.
Published: March 2020

4540

Introduction: Esophageal adenocarcinoma (EAC) is an aggressive malignancy whose incidence is on the rise. Approximately 40% of patients with N0 disease will recur after theoretically curative surgery, suggesting that in early stage disease, metastatic spread is often undetected by routine pathology. Molecular techniques may more accurately detect micrometastatic spread of EAC, but the correlation between molecular analysis of nodes and prognosis is unknown. Our lab has previously identified and validated 4 markers whose gene expression levels are able to distinguish benign nodes from nodes with metastatic EAC: CK19, CK20, CEA and TACSTD1. We used quantitative real-time RT-PCR to evaluate the expression of these 4 markers in lymph nodes from 68 N0 and 62 N1 EAC patients to see if molecular staging is predictive of a worse clinical outcome. Methods: RNA was isolated from 1456 lymph nodes obtained from 130 patients who underwent resection of EAC. QRT-PCR was used to analyze gene expression for each of the 4 markers. Relative expression of each marker was compared with expression in 53 benign esophageal lymph nodes previously analyzed. Results: Analysis of 778 lymph nodes from 68 pN0 patients identified 71 nodes (9%) from 30 patients (44%) which showed positive expression of at least one marker, indicating occult metastases (and molecular upstaging). Analysis of 678 lymph nodes from 62 pN1 patients revealed 141 nodes (21%) from 40 patients (65%) which had positive expression of at least one marker in nodes that were pathologically negative. In the pathologically positive nodes from N1 patients, there was an encouraging 88% concordance between pathological and molecular analysis. After a median follow-up of 2 years, 13 N0 patients had recurrence of their cancer. Gene expression levels of 3 of the 4 markers (CK20, CEA and TACSTD1) correlated with significantly worse disease-free and overall survival among these N0 patients, with p values <0.05. Conclusion: We have shown that QRT-PCR of 3 independent genetic markers is predictive of significantly worse disease-free and overall survival among node-negative EAC patients by identifying lymph nodes with occult metastatic disease. Further analysis will reveal if the N1 patients with molecularly positive lymph nodes had significantly worse outcomes as well.

No significant financial relationships to disclose.
The impact of cetuximab on the gemcitabine/cisplatin combination in first-line treatment of EGFR-positive advanced pancreatic cancer (APC): A randomized phase II trial of GISCAD
Authors: Cascinu S. , Berardi R. , Siena S. , Labianca R. , Falcone A. , Aitini E. , Barni S. , Di Costanzo F. , Frontini L. , Tonini G. , Zaniboni A.
Published: March 2020

4544

Background: Cetuximab, an EGFR antibody inhibitor, has been shown to increase the activity of gemcitabine (GEM) in APC. Based on data from randomised trials and meta-analyses suggesting that the combination of a GEM with a platinum analog significantly improves survival as compared to GEM alone, we assessed the activity and feasibility of a combination of GEM/cisplatin (CDDP) plus cetuximab. Methods: Multicenter, randomised two-arm phase II trial: GEM 1,000 mg/m2 day 1,8 and CDDP 35 mg/m2 day 1,8 every 21 days alone or in combination with cetuximab 250 mg/m2 weekly after a loading dose of 400 mg/m2. Treatment was limited to a maximum of 9 cycles. With 37 patients in each arm the power was 90% to select the truly better arm if the true between arm difference in response rate (RECIST) is at least 15%. The study was open for accrual until June 2005. Results: We present here the results of 74 patients including in the study. In all the patients, the first response rate are available (investigators’ assessment after 3 cycles) as well as toxicity data. Conclusions: Cetuximab does not seem to positively interact with GEM/CDDP combination in terms of activity especially concerning time to progression. Although toxicity was not increased by cetuximab, this combination should not be assessed in a phase III trial.The trial was supported in part by by Merck KGaA.

[Table: see text]

No significant financial relationships to disclose.
Sentinel node mapping for esophageal cancer
Authors: Takeuchi H. , Kitagawa Y. , Saikawa Y. , Suto A. , Mukai M. , Nakahara T. , Kubo A. , Kitajima M.
Published: March 2020

4552

Background: Extended radical esophagectomy with three-field lymph node dissection has been recognized as a standard procedure for esophageal cancer in Japan, even for clinically node negative cases. However, a significant increase of morbidity and mortality after the invasive procedure was reported in randomized trials. To eliminate the uniform application of highly invasive surgery, we hypothesized that sentinel node (SN) mapping plays a key role to obtain individual information and allows modification of the surgical procedure for early esophageal cancer. Methods: We have established radio-guided method to detect SNs in patient with early esophageal cancer using endoscopic injection of technetium-99m tin colloid. Preoperative lymphoscintigraphy and intra-operative use of hand held gamma probe were reliable to locate the radioactive SNs. Intra-operative gamma probing was also feasible in thoracoscopic or laparoscopic surgery using a special gamma detector which is introducible from trocar ports. Results: SN mapping has been performed for 105 patients with clinically N0 early esophageal cancer in our institute since 1999. Detection rate of hot node using our procedure was 93% (98/105). The mean number of sentinel nodes per case was 5.1. Thirty-three of 37 cases with lymph node metastasis showed positive sentinel nodes. The sensitivity to detect metastasis based on SN status was therefore 89% in our experience. Accuracy of metastatic status based on SN was 96% (94/98). SNs widely spread from cervical to abdominal areas. In more than 80% of the cases, at least one SN was located in the 2nd or 3rd compartment of regional lymph nodes. Conclusions: Our results suggest that SN concept for clinically N0 early esophageal cancer could be validated, and individualized selective and modified lymphadenectomy targeted on sentinel node basins for clinically N0 early esophageal cancer should become feasible and clinically useful as less invasive surgical procedures.

No significant financial relationships to disclose.
Polymorphisms of the serotonin transporter and Monoamine Oxidase A gene in patients with metastatic midgut carcinoid tumors
Authors: van der Horst-Schrivers A. , de Vries E. , Willemse P. , Kema I. , Links T. , Boezen H. , Wymenga A.
Published: March 2020

4557

Background: In patients with metastatic midgut carcinoid tumors increased serotonin secretion is related to the carcinoid syndrome and mortality. Free serotonin is taken up via the serotonin transporter (5-HTT) in the liver and the lung and metabolized to 5- hydroxyindolacetic acid (5-HIAA) by Monoamine Oxidase A (MAO-A). The 5-HTT gene has a functional polymorphism in the promoter region (5-HTTPLR), with a short (S, less active) and long (L) allele and a polymorphic region in the second intron with variable number tandem repeats (VNTR-2). The MAO-A gene contains a length polymorphism in its promoter region (MAOA-LPR). To determine the clinical effects of the serotonin metabolizing capacity of individual patients, the association between different genotypes and symptoms (flushes and diarrhea) and survival was studied. Methods: 107 patients with metastatic midgut carcinoid tumors were genotyped for 5-HTTPLR, VNTR-2 and MAO-A-LPR. Differences were tested using Chi-square test and survival according to genotypes was analyzed using Kaplan Meier survival curves and tested with a log rank test. The independent effect of genotypes on survival was studied with multivariate Cox regression analysis with adjustments for the urinary 5-HIAA level, age at presentation and the presence of liver metastases. Results: The various genotypic variants were not related to flushes or diarrhea. Patients with the SS variant of 5-HTTLPR had a shorter median survival (45 months, 95% Confidence Interval (CI) 0.50–90) compared to patients with the LS (113 months, 95% CI 53–172) and the LL variant (90 months, 95% CI 64–115) (P=0.02). After adjustment, survival in patients with the SS variant remained worse with an odds ratio of 0.43 (95% CI 0.23–0.83; P=0.009) and 0.63 (95% CI 0.33–1.11; P=0.1) compared to patients with the LS and the LL variant respectively. Survival was not influenced by the VNTR-2 or MAOA-LPR. Conclusions: The SS genotype of the 5-HTTLPR is independently associated with a worse survival in patients with metastatic midgut carcinoid tumors.

No significant financial relationships to disclose.
Biweekly oxaliplatin with gemcitabine and capecitabine in advanced gastrointestinal malignancies: A phase I study
Authors: Tan B. R. , Brenner W. S. , Picus J. , Suresh R. , Sorcher S. , James J. S. , Fournier C. , Mcleod H. L.
Published: March 2020

4560

Background: Oxaliplatin (OX), gemcitabine (GEM) and capecitabine (CAP) are all active agents against various gastrointestinal and other malignancies and have different mechanisms of action and toxicity profiles. This Phase I study aims to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) associated with this triplet regimen. Methods: The modified Fibonacchi 3/cohort dose escalation schema was used to determine the MTD and DLT of OX, GEM and CAP. Oxalipaltin [85–100 mg/m2] IV over 2 hours and gemcitabine [800–1,000 mg/m2] were given at a constant rate infusion of 10 mg/m2/min on days 1 & 15, while CAP [600–800 mg/m2] was given PO BID on days 1–7 and 15–21. 1 cycle = 28 days. Pharmacogenomic correlates including ERCC2, GSTP1, TYMS, TS del and TSER G>C were also obtained. A structured neurological toxicity assessment and questionnaire was also performed. Once MTD was established, additional patients were treated at the MTD and pharmacokinetic studies were performed on these additional patients. Results: 30 patients (M:F 2:1; 23% non-caucasian) with median age of 62 (range: 38–78) and PS of 0–1 were enrolled from 3/05 to 8/06. All patients had advanced GI malignancies (19 pancreatic, 6 biliary, 2 duodenal, 1 gastric, 1 esophageal, 1 GI unknown primary). Dose levels, # patients, DLT and best responses are tabulated below. Conclusions: The MTD of this triplet regimen is OX at 100 mg/m2, GEM at 800 mg/m2 days 1 & 15 with CAP at 800 mg/m2 PO BID days 1–7, 15–21. DLTs for this regimen include grade 3 fatigue and dyspnea as well as Grade 4 thrombocytopenia. CR is achieved in 2 patients (cholangiocarcinoma and pancreatic), while a patient with a GI unknown primary achieved PR. Several patients with pancreatic cancer achieved prolonged SD. An exploration of any association of toxicities and response with pharmacogenomic correlates is ongoing. A Phase II study in patients with pancreaticobiliary cancers is planned. This study is supported by Sanofi-Aventis Pharmaceuticals.

[Table: see text]

[Table: see text]
Preoperative induction chemotherapy with docetaxel-cisplatin followed by concurrent docetaxel-cisplatin and radiation therapy in patients with locally advanced esophageal cancer: A prospective, multicenter phase ll trial of the Swiss Group for Clinical Cancer Research
Authors: Ruhstaller T. , Widmer L. , Balmer Majno S. , Mingrone W. , Hess V. , von Moos R. , Borner M. , Schnider A. , Koeberle D. , Popescu R.
Published: March 2020

4562

Background: The role of preoperative therapy in patients (pts) with locally advanced esophageal cancer remains unclear. Non-randomized and randomized studies were often performed in single and highly specialized centers. The purpose of this study was to investigate 1) the efficacy and toxicity of preoperative docetaxel-cisplatin together with radiation therapy (RT) 2) the feasibility of a complex preoperative strategy in a community-based multicenter setting. Methods: Eligibility criteria: resectable, locally advanced (uT3 or uN1, T4 if deemed resectable) squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus or gastroesophageal junction (Siewert type l); staged by EUS, CT and PET scan; age 18–70y; PS <2; normal organ functions. Treatment: 2 cycles of docetaxel 75mg/m2 and cisplatin 75mg/m2 q3w, followed by weekly x5 docetaxel 20mg/m2 and cisplatin 25mg/m2 with concomitant 45 Gy RT in 25 fractions; surgery 3- 8 weeks after RT. A two stage-design was used with two primary endpoints: 1) efficacy (TRG : tumor regression grade ); 2) feasibility (successful completion of entire therapy and being alive 30 days after surgery). Results: 66 pts, 56 males, were included from 11 institutions; median age 61y (35–70y); AC 53%; SCC 46%; 53 pts (80%) completed the preoperative therapy, underwent resection and were alive 30 days after surgery; 10 pts (15%) had no resection (4 progressive disease, 4 medical reasons, 2 patient’s refusal). Of 56 (85%) pts who had surgery, 51 pts had RO-resection (91%), 5 pts (9%) died due to complications after surgery (3 after > 30 days). Conclusion: Our trimodality treatment shows encouraging antineoplastic activity with 57% histopathological responders (TRG1 and 2) and acceptable feasibility in a community-based multicenter setting.

[Table: see text]

No significant financial relationships to disclose.
Molecular signature of esophageal adenocarcinoma derived from microarray analysis of paraffin-embedded specimens predicts systemic recurrence following resection
Authors: Oh D. S. , Cooc J. , DeMeester S. R. , Mori R. , Kuramochi H. , Rizzetto C. , Danenberg K. , Danenberg P. , Hagen J. A. , Harpole D. H. , DeMeester T. R.
Published: March 2020

4563

Introduction: Surveillance endoscopy in patients with Barrett’s esophagus has resulted in the diagnosis of an increasing number of early-stage adenocarcinomas. Surgical resection alone is curative in the majority of these patients, yet some will succumb to systemic disease. We hypothesize that among patients with early esophageal adenocarcinoma, there are distinct molecular signatures of tumors that are associated with systemic recurrence and those that are cured with resection alone. Methods: From a total of 36 patients with early-stage adenocarcinoma (T1–3, less than or equal to 4 involved nodes), 20 who were alive and without recurrence at a median follow-up of 61 months after resection alone were compared by microarray analysis with similar stage tumors from 16 patients that developed systemic disease and died at a median of 13 months after esophagectomy. Following microdissection of paraffin-embedded specimens, RNA was isolated, amplified, labeled, and hybridized to Affymetrix U133 Plus 2.0 GeneChips. Results: A T-test with unequal variance assumption identified 328 differentially expressed probe sets (false discovery rate <0.05; p67 mos. vs. 13 mos., respectively; p<0.001). Significant canonical pathway deregulation between long and short survivors included GABA receptor, PDGF, PPAR, IL-6 signaling, oxidative phosphorylation and the pentose phosphate pathway. Conclusion: The molecular signature of early-stage esophageal adenocarcinomas may be able to distinguish patients at increased risk for the development of systemic disease and thereby guide use of adjuvant therapy and the intensity of follow-up. Confirmation of these findings in additional patients should prompt a prospective clinical trial.

[Table: see text]
Chemoimmunotherapy with 5-fluouracil, leucovorin and interferon alpha-2b as adjuvant therapy after surgery in Gastric Carcinoma patients
Authors: Gonzalez H. A. , Londoño H. , Quiroz J. , Parra A. , Ramirez A. , González M. , Rodríguez A. , Varón C. , Romero N.
Published: March 2020

4581

Background: The main treatment of Gastric Carcinoma(GC) is Surgery, but 5 years recurrence risk is 70% and mortality 50%. So that, effective adyuvant therapy, like chemotherapy, is needed to impact on survival ; results, however have been inconsistent at best. Inmunotherapy with interferon alpha, in gastric carcinoma, has only been employed in metastatic disease. The objective of this study was evaluate chemoimmmunotherapy role of interferon alpha - 2b,5-FU and LCV as adjuvant therapy in GC Methods: This is a randomized prospective study. Beginning 2/Oct /97 and finalizing 31/march/2005. Patiens with gastric adenocarcinoma, clinical stages II, III and non metastatic IV, after gastrectomy, without cancer antecedent were included. Treatment groups were assigned at random: Group A: 5-FU: 400 mg/m2, days (1–3), leucovorin: 50 mg. days (1–3), interferon alpha - 2b: 5x10^6 units sq, every other day, days (1–15). Group B: 5-FU, LCV without interferon alpha, at the same doses. Nine (9) monthly cycles were aplied. Clinical and paraclinical follow up was made appropriately. Statistic analysis was performed by Kaplan Meier method. Results: 52 patients were studied, 25 in group A and 27 in group B. Both of them had similar characteristics in median age, sex, histology, differentiation grade, gastric location, clinical stage: A: II: 28%, III: 72% (IIIB: 56%). B: II: 29,6%, III: 70% (IIIB: 55%).General survival (SG) analysis: Mean SG (%): A: 64%. B: 18,5%. Mean SG (months): A: 68,5 m. (CI 95%: 59–78,15). B: 27,98 ( CI 95%: 18,92–37,04). Survival curves comparison, minimum until 5 years: Log Rank, Breslow, Tarone Ware: P<0,00001, all of them in favor to group A. Mortality: Total:31/52: 59,6%. A: 36%. B: 81,48% (P<0,05). Disease free survival (DFS) analysis: Mean DFS (%): A: 52%. B: 18, 52%. Mean DFS(months): A: 58,85m (CI 95%: 47,4–70.3). B: 24,98m (CI 95 %: 15,3–34.6). DFS curves comparison: Log Rank: 0,0008. Breslow: 0,0003. Tarone Ware: 0,0004. All of them in favor to group A. Recurrence (%): Total: 34/52:65%. A: 48%. B: 81,48% ( P <0,05). Conclusions: This is the first study of adjuvant chemoimmunotherapy (CI) that includes interferon alpha - 2b in GC. This study shows CI with 5-FU, LCV and interferon alpha -2b is effective as adjuvant treatment in GC.

No significant financial relationships to disclose.
Phase I study of stereotactic radiotherapy for unresectable hepatobiliary cancer and liver metastases
Authors: Dawson L. A. , Tse R. , Kim J. , Dinniwell R. , Lockwood G. , Sherman M. , Knox J. J. , Gallinger S.
Published: March 2020

4590

Background: Safety of stereotactic radiotherapy (SRT) for unresectable hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CC) and liver metastases (LM) has not been well established. Results from a phase I study of 6 fraction SRT are reported. Methods: Eligible patients had unresectable or medically inoperable HCC, CC or LM, liver enzymes < 6 fold higher than normal, platelets > 80,000 bil/L, Child score A, > 800 cc uninvolved liver, KPS = 60 and unsuitability for standard therapies. Patients were treated with breath hold and image guided 6 fraction SRT. Dose was individualized to maintain the same risk of liver toxicity at three risk levels (I-5%, II-10%, III-20%). Escalation to level II and III occurred once at least 3 patients had been followed for >3 months without dose limiting toxicity (grade 4/5 < 1 month or grade 4/5 liver < 3 months) for each stratum. Stratification was based on diagnosis and liver volume irradiated (low <20%, mid 20–50%, high 50–80%). Results: From Aug. 2003 to Dec. 2006, 82 patients initiated SRT. Two patients discontinued SRT after 1 fraction for progressive disease (LM) and a variceal bleed (HCC). 80 patients completed SRT (38 LM, 32 HCC, 10 CC). Median age was 64 years (38–92 years). Median tumor volume was 293 cc (3–3088 cc). 24 patients (30%) had extra-hepatic disease. 17 HCC patients had portal vein thrombosis (53%), 14 HBV, 12 HCV and 4 alcoholic cirrhosis. The median prescribed dose was 40 Gy (24 Gy - 60 Gy) in 6 fractions. Within 3 months post SRT, no dose-limiting grade 4/5 toxicity or classic radiation liver toxicity was observed. Grade 3 liver enzymes (2 new, 9 pre-existing), thrombocytopenia (3), nausea (3) and fatigue (1) was observed. Child score declined in 8 patients (5 HCC, 2 CC, 1 LM), 6 with progressive disease. Late toxicity included 1 tumor-duodenal fistula, 1 bowel obstruction and 2 GI bleeds. The in-field response rate was 60% (LM 57%, CC 50%, HCC 67%): CR 14%, PR 46%, SD 23%, PD 17%. Actuarial 12 month local control was 78% (95% CI: 58- 90%). The median survival for LM, CC and HCC was 16.6 months (7.9–25.6), 13.1 months (6.0–28.4) and 11.0 months (8.6–20.8) respectively. Conclusions: Individualized SRT is a safe, promising treatment for unresectable liver cancer.

No significant financial relationships to disclose.
Phase I/II trial of preoperative oxaliplatin, docetaxel, capecitabine, and radiation for localized esophageal cancer
Authors: Meluch A. A. , Spigel D. R. , Greco F. A. , Yardley D. A. , Burris H. A. , Farley C. , Peyton J. D. , Shipley D. L. , Steis R. G. , Hainsworth J. D.
Published: March 2020

4595

Background: Preoperative chemoradiotherapy is a primary treatment option for patients (pts) with resectable esophageal cancer. Combination regimens using newer agents may improve pt outcomes. This multicenter community-based trial examined a modern triplet regimen comprised of oxaliplatin (O), docetaxel (D), and capecitabine (C) combined with radiation (RT). Methods: The primary endpoints were objective response rate (ORR) and safety. Eligibility criteria: pts with resectable stage I-III cancer of the mid-/distal-esophagus or gastroesophageal junction, measurable disease, ECOG PS 0–1, and informed consent. Treatment: O 40 mg/m2 IV and D 20 mg/m2 IV weekly x 5; C 1,000 mg/m2 PO twice daily D1–7, 15–21, 29–35; and concurrent RT to 45 Gy. Pts were resected 4–8 weeks later. O/D/RT safety was determined in a phase I portion (n=10) before adding C in a phase II portion. Results: 43 pts were enrolled from 9/04 to 12/06 (trial ongoing, n=60 planned). Data on 38 pts are available for analysis. Baseline characteristics: median age 61 years; male/female, 76%/24%; ECOG PS 0/1, 32%/68%; adenocarcinoma/squamous, 74%/26%; and stage I, II, III, 8%/45%/47%. The ORR was 58% (95% CI 42%-72%), with 4 complete and 18 partial responses. 37% had stable disease, and 1 pt had progressive disease (PD). 26 pts (68%) were resected. Unresected pts: awaiting surgery, 3 pts; poor PS, 4 pts; PD, 1 pt; pt choice, 1 pt; death, 3 pts. Pathologic complete responses were seen in 17 pts (65%). With a median follow-up of 16 months, 1-year progression-free survival (PFS) and overall survival (OS) are 58% and 64%, respectively. Median PFS and OS have not been reached. Grade (G) 3/4 non-hematologic toxicity: anorexia (21%), dehydration, esophagitis (16% each), nausea (13%), and dysphagia, fatigue, vomiting, and pain (11% each). Other G3/4 non- hematologic toxicities were = 5%. No G3/4 hematologic toxicities or treatment-related deaths occurred. Conclusions: O/D/C/RT appears safe and active as a preoperative regimen for resectable esophageal cancer - with a G3/4 esophagitis rate that compares favorably with historical combination regimens. Additional accrual and follow-up are needed to determine if these benefits are sustained.

No significant financial relationships to disclose.
Detection and significance of circulating tumor cells (CTC) in patients with metastatic pancreatic cancer (PC) receiving systemic therapy
Authors: Ko A. H. , Scott J. , Tempero M. A. , Park J. W.
Published: March 2020

4596

Background: Detection of CTC in the peripheral circulation of pts with solid tumors may provide useful prognostic and predictive information. In a previously reported pilot study, we detected CTC in approx 2/3rds of pts with all stages of PC using a flow cytometric-based approach. This study examines the significance of CTC using two separate methods in pts with metastatic PC undergoing systemic rx. Methods: Blood was obtained at baseline and after 2 months of rx from pts with metastatic PC participating in a phase II trial of gemcitabine, cisplatin, and bevacizumab. Two methods for measuring CTC were tested: immunomagnetic capture/flow cytometry (IC/FC) using anti-EpCAM Abs, and the Veridex CellSearch system. Wilcoxon Rank tests were used to test the association of CTC concentration at each time point, and change in concentration over time, with overall survival, time to tumor progression, and CA19–9 response. Results: CTC were measured in 48 indiv pts at baseline (31 using IC/FC, 23 using CellSearch, 6 using both methods) and in 39 indiv pts after 2 months of rx (20 IC/FC, 23 CellSearch, 4 both methods). No correlation was found between CTC concentration at either baseline or at 2 mos and any clinical endpoints (see table ). This was true for both IC/FC and CellSearch methods. 25 pts had serial CTC measurements using consistent methods at both time points (17 IC/FC, 12 CellSearch, 4 both methods). CTC concentration decreased in 9 of 17 pts (52.9%) tested by IC/FC and in 5 of 12 pts (41.7%) tested by CellSearch; however, change in CTC concentration over time was not associated with clinical outcomes. Too few pts have been tested by both methods at a given time point to establish a significant correlation betw the two methods. Conclusions: CTC can be detected in pts with metastatic PC using both methods tested in this study, albeit at low concentrations. The small sample size to date precludes our ability to determine the prognostic and predictive significance of these cells in this disease setting.

[Table: see text]

No significant financial relationships to disclose.
Curcumin and pancreatic cancer: Phase II clinical trial experience
Authors: Dhillon N. , Aggarwal B. B. , Newman R. A. , Wolff R. A. , Kunnumakkara A. B. , Abbruzzese J. L. , Hong D. S. , Camacho L. H. , Ng C. , Kurzrock R.
Published: March 2020

4599

Background: Pancreatic cancer is virtually always lethal, and the only FDA-approved therapies–gemcitabine and erlotinib–produce objective responses in less than 10% of patients. Curcumin (diferuloyl methane) is a plant-derived dietary ingredient that suppresses NF-κB and numerous other pathways relevant to pancreatic cancer and has potent preclinical anti-tumor activity. Herein, we evaluated the safety and potential antitumor activity of curcumin against advanced pancreatic cancer, and its impact on biologic correlates. Methods: Patients received 8 grams of curcumin by mouth daily for two months and were then restaged. Maintenance therapy was continued at the same dose and schedule until disease progression. Results: Twenty-five patients were enrolled as of the date of analysis, with 21 evaluable for response. Circulating curcumin was detectable, albeit at low steady-state levels (about 31 ng/ml), suggesting poor oral bioavailability. To date, two patients have had prolonged stable disease (8 and 12+ months). Interestingly, one patient had a brief, but marked tumor regression (73%) (accompanied by significant increases (4–35-fold) in serum cytokine (interleukin-6 (IL-6), IL-8, IL-10, and IL-1 receptor antagonist (IL-1RA) levels). No toxicities have been observed. Curcumin down-regulated expression of NF-κB, COX-2 and phosphorylated STAT3 in peripheral blood mononuclear cells (PBMC) from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers)although the decrease did not reach statistical significance for p65. Curcumin was determined in patient plasma samples after enzymatic digestion with glucuronidase enzyme. While there was considerable variation in plasma curcumin levels from patient to patient, drug levels peaked at 22–41 ng/ml and remained relatively constant over the entire 4 week experimental period. Conclusions: We conclude that oral curcumin is well tolerated and, despite its limited absorption, has biologic activity in patients with pancreatic cancer.

[Table: see text]

No significant financial relationships to disclose.
Sunitinib as second-line treatment for advanced gastric cancer: preliminary results from a phase II study
Authors: Bang Y. , Kang Y. , Kang W. , Boku N. , Chung H. , Lanzalone S. , Lechuga M. J. , Sherman L. , Chao R. , Sobrero A.
Published: March 2020

4603

Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. We investigated the safety and activity of SU monotherapy in pts with previously-treated gastric cancer. Preliminary results from this open-label, multicenter, phase II study are reported. Methods: Eligibility criteria included measurable stage IV disease; 1 prior chemotherapy regimen; and ECOG PS =1. Pts took SU 50 mg/day for 4 wks followed by 2 wks off treatment in 6-wk cycles. A Simon 2-stage design was used with a target accrual of 38 pts in the first stage, expanding to 63 pts if =2 partial responses (PRs) were observed. The primary endpoint was RECIST-defined objective response rate. Secondary endpoints included duration of response and safety. Pharmacokinetic (PK) Ctrough parameters were also monitored. Results: As of Sept 15 2006, 38 evaluable pts (median age 56 years [range 29–78]; 2–3 metastatic sites [63%]; prior treatment with 5-FU ± platinum [P] [24%], capecitabine ± P [13%], TS-1 ± P [26%], other [37%]) have received a median of 2 SU cycles (range 1–3). Of 21 pts evaluable for efficacy, 1 PR has been confirmed and 8 pts had stable disease (SD), 4 with SD for =2 cycles. The most commonly reported AEs were typically grade 1/2 in severity and included stomatitis, skin discoloration, fatigue, anorexia, diarrhea, hand-foot syndrome (HFS), nausea and vomiting. Grade 3/4 toxicities included HFS (10.5%), fatigue (7.9%), anorexia (7.9%) and mucosal inflammation (5.3%). Grade 3/4 hematologic toxicities included neutropenia (29%), thrombocytopenia (29%) and anemia (11%). 7 pts experienced serious SU- related AEs requiring dose modifications in 3 pts and treatment discontinuation in 1 pt. Preliminary PK investigations indicate that concentrations seen in gastric pts are similar to those seen in other pts treated with SU. Conclusions: These initial findings show that SU is generally well tolerated and may have single-agent antitumor activity in pre-treated gastric cancer pts. Further trials with SU in combination with standard chemotherapy regimens are planned.

No significant financial relationships to disclose.
Combination of gefitinib, cisplatin and 5-FU chemotherapy, and radiation therapy (RT) in newly-diagnosed patients with esophageal carcinoma
Authors: Sunpaweravong P. , Sunpaweravong S. , Sangthawan D. , Puttawibul P. , Mitarnun W.
Published: March 2020

4605

Background: Efficacy of chemotherapy and RT in patients with esophageal carcinoma has been established in addition to surgical treatment. EGFR protein expression is prevalent in esophageal carcinoma; adding gefitinib to chemoradiotherapy may improve treatment outcome in this less favorable cancer. Methods: In this phase II study, untreated ECOG PS 0–2 patients with stage 2–4 esophageal carcinoma were recruited. Stage 2–4a patients were given gefitinib in combination with concurrent chemoradiation whereas stage 4b patients received only gefitinib and chemotherapy. Gefitinib 250 mg was taken daily in combination with cisplatin 80 mg/m2 D1 and 5-FU 1,000 mg/m2, 24 hour CI, D1–5 every 3 weeks to the maximum of 6 cycles. Concurrently with chemotherapy, stage 2–4a patients received RT, 2 Gy single daily dose to the total of 60 Gy. After a cohort of 10 patients, initial daily chemotherapy dose was reduced to cisplatin 65 mg/m2 and 5- FU 800 mg/m2 in pts who received concurrent RT due to gr 3–4 neutropenia and mucositis. Results: Thirty-seven patients, 33 esophageal squamous cell carcinoma (ESCC) and 4 adenocarcinoma (EAC) were accrued between August 2005 and November 2006. Twenty- seven patients were stage 2–4a and 10 patients were stage 4b. Twenty-five (93%) stage 2–4a patients completed chemoradiation. In stage 2–4a patients, 4 (15%) CR, 17 (63%) PR, 3 (11%) SD, and 3 (11%) PD were achieved. Four (15%) stage 2–4a patients thereafter underwent esophagectomy and 1 (25%) achieved pathological complete response. In stage 4b patients, 5 (50%) PR, 3 (30%) SD, and 2 (20%) PD were observed. Twenty-three (62%) ESCC responded whereas 3 (75%) EAC did. Major grade 3–4 toxicities included neutropenia (19%), leukopenia (19%), and anemia (16%). Diarrhea occurred in 70%, dry skin in 30%, mucositis/esophagitis in 27%, and rash in 14% of patients, mostly grade 1- 2. One patient had a chemotherapy-related death due to neutropenic septicemia. Conclusions: This combined EGFR inhibitor and chemoradiation regimen was feasible and efficacious in patients with newly-diagnosed esophageal carcinoma. Further investigation in Phase III trial is encouraged to better assess the benefit of this approach in comparison to conventional treatment.

No significant financial relationships to disclose.
Neoadjuvant chemotherapy for resectable adenocarcinoma of the panctreatic head - a prospective phase II trial
Authors: Pestalozzi B. C. , Heinrich S. , Schäfer M. , Pierre-Alain C.
Published: March 2020

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Background: Pancreatoduodenectomy alone was considered the standard treatment for resectable adenocarcinoma of the pancreatic head in Europe. Recently adjuvant chemotherapy without radiation has become a new standard worldwide. Neoadjuvant chemotherapy has advantages over adjuvant chemotherapy. Methods: Patients (pts) with histologically or cytologically confirmed ductal adenocarcinoma of the pancreatic head judged to be resectable were entered into this single center prospective phase II trial. After written informed consent staging with thoracic/abdominal CT-scans, endoscopic ultrasound, PET-CT and diagnostic laparoscopy were performed. Preoperative chemotherapy consisted of 4 treatments with gemcitabine (1,000mg/m2) and cisplatin (50mg/m2) every 2 weeks. Re-staging was followed by (classic or pylorus-sparing) pancreatoduodenectomy about 8 weeks after the start of chemotherapy. CA 19- 9, prealbumin serum levels, and quality of life (QLQ-30) were also assessed before and after chemotherapy. The primary study end-point was the resectability rate. Results: Twenty-eight pts entered this trial between June 2002 and January 2007, 27 have completed chemotherapy. The resectability rate after chemotherapy was 93% (25/27). Neoadjuvant chemotherapy was well tolerated, although 7 episodes of transient Grade III/IV toxicities occurred in 5 pts. While median recurrence-free survival from diagnosis was 9.2 months (95% CI 7.7–10.8), median overall survival was an excellent 26.5 months (12.2–40.8). CA 19–9 serum levels decreased by 48% (p=0.01) after neoadjuvant chemotherapy, while overall quality of life increased by 24% (p=0.02). Nutritinoal status also improved: Prealbumin levels were normal in 89% after chemotherapy compared to 60% before (p=0.02). Conclusions: Neoadjuvant gemcitabine/cisplatin for two months is well tolerated and does not jeopardize surgical resectability in adenocarcinoma of the pancreatic head. Furthermore, it offers several advantages over primary surgery including patient selection, improvements in nutritional status and quality of life. We are currently planning a randomized study comparing the combination of neoadjuvant and adjuvant chemotherapy versus adjuvant treatment alone.

No significant financial relationships to disclose.
A phase I study of erlotinib, bevacizumab and gemcitabine in patients with advanced pancreatic cancer
Authors: Gomez-Martin C. , Camara J. C. , Cortes H. , Jara C. , Gravalos C. , Rubio B. , Amador M. L. , Hidalgo M.
Published: March 2020

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Background: Erlotinib is an EGFR TKI active in combination with gemcitabine in p with advanced pancreatic cancer (PC). The combination of gemcitabine and bevacizumab is also active in PC. A phase I of gemcitabine, bevacizumab and erlotinib in p with unresectable locally advanced or metastatic PC is being conducted. Methods: Two cohorts of 6 patients with advanced PC have been treated either with erlotinib (150 mg/day po), bevacizumab (5 mg/Kg iv, days 1 and 15, every 28 days), and either 10 mg/m2/min infusion of gemcitabine 850 mg/m2 or 1,000 mg/m2 days 1 and 15 every 28 days. P received a maximum of 6 cycles of 28 days. Cohort 1: Daily erlotinib 150 mg po + bevacizumab 5 mg/kg iv days 1 and 15 + gemcitabine 850 mg/m2 over 10 mg/m2/min infusion days 1 and 15. Cohort 2: daily erlotinib 150 mg po + bevacizumab 5 mg/kg iv days 1 and 15 + gemcitabine 100 mg/m2 over 10 mg/m2/min infusion days 1 and 15. Results: 12 p have been included in this study (6 cohort 1 and 6 cohort 2), being evaluable for toxicity. 11 p have concluded the study and 7 have received complete treatment as per protocol. Median age 62.6 yrs (range 38–71); male/female: 5/7 (42%/58%); stage III/IV: 3/9 (25%/75%); Karnofsky index 100%/80%: 2/10. 3 of 6 p in cohort 1 developed gr. 3 asthenia (50%), 2 p gr. 3 neutropenia (33.3%), whereas 1 p had grade 3 leucopenia and gr. 3 skin rash. In cohort 2, most severe adverse events were: 1 case of grade 4 GGT elevation, 1 p gr. 3 skin rash and 1 p. experienced asthenia gr. 3. No severe hematological toxicity in cohort 2 was reported. One p of each cohort required dose reduction of erlotinib, both due to skin rash. Mild diarrhea was reported in 11 of 12 p evaluated. No dose limiting toxicities has been reported. All p were available for response: 2 p reached partial response (both included in cohort 1) and 7 showed stabilization (3 and 4 in cohorts 1 and 2, respectively). No complete responses were observed. Overall disease control index was 75%. Conclusions: The combination of gemcitabine, erlotinib and bevacizumab is well tolerated. MTD has not been reached. Encouraging clinical activity in advanced pancreatic cancer has been observed. Phase I is still ongoing. Toxicity data for all the p will be presented.

No significant financial relationships to disclose.
Phase II of trastuzumab and cisplatin in patients (pts) with advanced gastric cancer (AGC) with HER2/neu overexpression/amplification
Authors: Cortés-Funes H. , Rivera F. , Alés I. , Márquez A. , Velasco A. , Colomer R. , García-Carbonero R. , Sastre J. , Guerra J. , Grávalos C.
Published: March 2020

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Background: Trastuzumab(T) exhibits activity in human gastric cancer cells that overexpress HER2/neu. We previously reported a 13.5% HER2/neu overexpression/amplification in AGC or gastroesofageal junction (GEJ) cancers (Grávalos C, et al. J Clin Oncol 24, 18S, 200s, abstr # 4089). We designed a phase II trial to determine the efficacy and tolerability of T and cisplatin(C) in pts with ACG with HER2/neu overexpression/amplification. Exploratory objectives include analysis of c-erbB-2 extracellular domain and correlation of the results with histological erB-2/neu overexpression and with clinical response Methods: Chemo-naïve pts with adenocarcinoma histopatologically confirmed, HER2/neu overexpression/amplification, measurable, no operable, locally advanced or metastatic AGC, age ≥ 18, ECOG ≤ 2, FEVI ≥ 50% and adequate organ function were eligible. Prior adjuvant radiotherapy or/and chemotherapy were allowed. Immunohistochemistry (IHC) was performed using herceptest. A fluorescence in situ hybridization (FISH) assay was done when IHQ was = 2. HER2/neu expression was considered negative if IHC= 0, 1 or IHC=2 and FISH -; and positive if IHC=2 and FISH + or IHC=3. T 8 mg/kg d1 (loading dose in first cycle) and 6 mg/kg (maintenance doses) and C 75 mg/m2 d1 were administered every 21 days until progression, unacceptable toxicity or withdrawal inform consent Results: 21 pts has been included. 17 are evaluable. 16 were men. Median age 66 (50–78). ECOG 0/1: 5/12. Histological subtypes were: 50% intestinal, 25% diffuse and 25% unknown. 56% had gastric localization and 44% GEJ. 16 pts had metastases (59% liver, 47% lymph nodes, 23% peritoneum, 17% lung, and 24% others). Prior treatment: 5 pts underwent surgery and 2 had adjuvant chemotherapy. Median cycles 2 (1–14). Efficacy: 6 (35%) pts achieved response (1/5 CR/PR), 3 (17%) stabilization (52% control disease = RC + PR+SD), 4 pts with progression disease, 4 pts too early Tolerance: There was no grade 4 toxicity. Main grade 3 adverse events included: asthenia (3 pts), nauseas/vomiting (3), diarrhea (2), hiporexia (2) and neutropenia (1) Conclusions: Trastuzumab and cisplatin is a well tolerated regimen with a promising activity. The study is ongoing and an update will be presented at the meeting.

No significant financial relationships to disclose.
A 10-year retrospective analysis of risk factors, patterns of cancer recurrence, and survival after liver transplant for cirrhosis and hepatocellular carcinoma
Authors: Kaseb A. O. , Bansal M. , Wollner I. , Shah V. , Moonka D. , Divine G. , Abouljoud M.
Published: March 2020

4617

Introduction: Determining eligible patients who are likely to have better outcomes following orthotopic liver transplant (OLT) for cirrhosis and hepatocellular carcinoma (HCC) is an ongoing challenge. In addition, tumor recurrence represents a major limitation of long-term survival in this setting. Patients and Methods: The study analyzed 72 OLT recipients for cirrhosis and HCC, between 1996–2006. The endpoints were frequency, patterns, localization, and risk factors of recurrence. Survival from time of OLT to recurrence was compared with primary tumor and patient characteristics, and type of treatment received pre- and post-OLT using univariate and multivariate analyses. Survival was estimated using Kaplan-Meier plots. Results: 13 recurrences (18%) occurred after a median of 33.4 months follow up (6–123 months). 11/13 (84.6%) were distant metastases. Using cox regression analysis and log-rank p-value; bilobar involvement, a tumor number of =3, tumor grade 2 or 3, size >3 cm, vascular invasion, and elevated AFP at diagnosis were all positively associated with recurrence (either distant or any). Tumors that met Milan criteria were associated with a lower likelihood of recurrence. In addition, Pre and post-OLT treatments were not found to be associated with significantly improved disease-free survival. Conclusions: Our analyses confirmed that advanced pathologic features are independently associated with significantly shorter disease-free survival. Pre- and post-OLT treatment modalities were not observed to improve disease-free survival for patients with bad prognostic indicators. However, this is limited due to our small sample size and our univariate anaylsis. We conclude that careful patient selection based on prognostic indicators would maximize benefit from use of this expensive and limited resource.

[Table: see text]

No significant financial relationships to disclose.
A randomized phase II trial of PEXG (cisplatin, epirubicin, capecitabine, gemcitabine) or PDXG (docetaxel) regimen in advanced pancreatic adenocarcinoma
Authors: Reni M. , Cereda S. , Passoni P. , Rognone A. , Mazza E. , Nicoletti R. , Arcidiacono P. G. , Zerbi A. , Balzano G. , Di Carlo V.
Published: March 2020

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Background: Four-drug regimen significantly improved the outcome of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine in a phase III trial (Reni Lancet Oncol 2005). The current study was an attempt to further improve progression-free survival (PFS) by replacing epirubicin with docetaxel. Methods: Patients with stage III or metastatic PA, age 18–75y, Karnofsky performance status (PS) >50 were randomized to receive either D (arm A: 25 mg/m2 day 1 and 14) or E (arm B: 30 mg/m2 day 1 and 14) while P (30 mg/m2 day 1 and 14), G (800 mg/m2 day 1 and 14) and X (1250 mg/m2/day days 1 to 28) remained unmodified in the two arms. Cycles were repeated every 28 days. The primary endpoint of the study was PFS. The sample size was calculated on the probability of being PF at 6 months (PFS6) from treatment start. Assuming P0=25% and P1=45%, with a .05 and b.20, the study was to enroll 32 patients per arm. Results: Between July 2005 and January 2007, 64 patients were enrolled at a single institution, stratified by stage and randomized (32 per arm). Main patient characteristics were balanced (A/B): median age 61/58, PS > 70 93/84%, metastatic disease 69/69%. Treatment is ongoing in 6/7 patients; 16/15 patients concluded at least 6 cycles of chemotherapy while 9/10 interrupted treatment due to progressive disease (PD) and 1/0 due to consent withdrawal. To date, 51 patients are assessable for response and PFS6: 16 of 26 (62%) arm A patients and 12 of 25 (48%) arm B achieved a partial response. PFS6 was 54%/44%. Final results of toxicity, activity, PFS6 and survival will be available at time of meeting. Conclusion: PEXG regimen yielded similar results when compared to historical series treated by PEFG regimen, suggesting that the use of capecitabine instead of 5- fluorouracil did not compromise the outcome. The inclusion of D instead of E seems to be promising. The present trial further confirms the relevant impact on outcome of advanced PA of four-drug regimens.

No significant financial relationships to disclose.
Normal esophageal mucosae adjacent to esophageal adenocarcinomas in both Japanese and U.S. patients have a field defect of methylation changes
Authors: Nasu M. , Orita H. , Gibson M. , Brock M. , Herman J. , Gabrielson E. , Tsurumaru M. , Forastiere A.
Published: March 2020

4636

Background: Esophageal mucosae that reside next to gross cancer are often without histological premalignant changes. We hypothesized that DNA hypermethylation could be detected in “normal” tissues adjacent to esophageal adenocarcinomas (EAC). Methods: A cohort of patients from Japan (J, n=14) and the United States (US, n=41) with locally advanced EAC were evaluated for methylation status. Esophagectomy specimens provided a source of paired normal and tumor tissues. After DNA extraction, methylation specific PCR was used to evaluate the promoters of APC, p16 and MGMT in all samples. Methylation frequency was calculated for each patient and expressed as a percentage of total. Results: Age, gender, pathologic stage and epigenetic analyses of primary tumors were similar in each cohort. Methylation frequency of tumors was: APC (66% US; 70% J). p16 (39% US; 20% J). MGMT (63% US; 75% J). In adjacent histologically “normal” esophageal mucosae, the percentage of patients with methylation at 0, 1, 2 or 3 genes was 79%, 14%, 0%, 7% for the J group and 56%, 44%, 10% and 2% for the U.S. group. In both cohorts, the majority of the normal samples had no methylation changes. In over half of the total cohort, however, there was at least one gene in the adjacent histologically “normal” tissue positive for DNA hypermethylation. Very few samples in either group, however, had more than one gene methylated in histologically “normal” esophageal mucosae. In general, the same methylation pattern present in the “normal” tissue persisted in the primary malignancy. Conclusions: Histologically negative esophageal mucosae adjacent to cancer frequently show at least one hypermethylated gene in a multiple gene panel. These data suggest that for patients with EAC, regardless of nationality, there is a field defect of promoter hypermethylation changes in adjacent esophageal mucosae. These events reflect those of the primary malignancy, and are probably early and cumulative during carcinogenesis.

No significant financial relationships to disclose.