bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and a prospective evaluation of the of the association between tumor hENT1 expression and clinical outcome with gemcitabine treatment.
Authors: Poplin Elizabeth , Wasan Harpreet , Rolfe Lindsey , Raponi Mitch , Ikdahl Tone , Bondarenko Ihor , Davidenko Irina , Bondar Volodymyr , Garin August , Boeck Stefan Hubert , Heinemann Volker , Bassi Claudio , Evans T. R. Jeffry , Voong Cynthia , Kaur Paramjit , Isaacson Jeffrey D. , Allen Andrew R.
Published: March 2020

4007

Background: Gemcitabine requires membrane transporter proteins to cross the cell membrane. Low expression of the human equilibrative nucleoside transporter-1 (hENT1) may play a role in gemcitabine resistance in PDAC. CO-101 (also known as CP-4126), a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1 and to circumvent transporter-mediated resistance. We conducted a randomized, controlled trial (LEAP) in patients with mPDAC to determine whether CO-101 improved survival vs gemcitabine in patients with low hENT1 tumors. The study also prospectively tested the hypothesis that gemcitabine is more active in patients with hENT1 high than hENT1 low tumors in metastatic disease. Methods: Patients were randomized to CO-101 or gemcitabine. An immunohistochemistry test measuring tumor hENT1 expression was developed in parallel with the recruitment phase of LEAP. To dichotomize the population, a hENT1 cut-off was defined using primary PDAC tumor samples from an adjuvant trial. LEAP participants provided a metastasis sample during screening for blinded hENT1 assessment, and the cut-off was applied to these samples. The primary endpoint of the study was overall survival in the low hENT1 subgroup. Results: 367 patients were enrolled, with metastasis hENT1 status available for 358/367 (97.5%). 232/357 (65%) were hENT1 low. There was no difference in overall survival between CO-101 and gemcitabine in the hENT1 low subgroup, or overall, with hazard ratios of 0.994 [95% CI 0.746, 1.326] and 1.072 [95% CI 0.856, 1.344] respectively. Within the gemcitabine arm, there was no difference in survival between the hENT1 high and low subgroups (HR 1.147 95% CI 0.809, 1.626). The observed side effect profile was typical of gemcitabine and was similar in both treatment arms, in the hENT1 low subgroups and overall. Conclusions: CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1 expression. Metastasis hENT1 expression did not predict gemcitabine treatment outcome in patients with mPDAC. Clinical trial information: NCT01124786.
A Bayesian network meta-analysis of systemic regimens for advanced pancreatic cancer.
Authors: Chan Kelvin K. , Coyle Doug , Cameron Chris , Lien Kelly , Ko Yoo-Joung
Published: March 2020

4015

Background: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) in randomized control trials (RCTs). Few have been compared with each other directly in RCTs and the relative efficacy and safety among them are unclear. Methods: A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Contorlled Trials and ASCO meeting abstracts up to Jan 2013 to identify RCTs that included metastatic pancreatic cancer comparing the following regimens: G, G+5-flourouracil (GF), G+capecitabine (GCap), G+S1 (GS), G+cisplatin (GCis), G+oxaliplatin (GOx), G+erlotinib (GE), G+Abraxane (GA) and FOLFIRINOX. Studies were reviewed by two authors and discrepancies were resolved by consensus or by a third author. Data including overall survival (OS), progression-free survival (PFS), response rate (RR), and side-effects were extracted. A Bayesian network meta-analysis with random effects was performed using WinBUGS to compare all regimens simultaneously. Results: Twenty-two studies involving 6,252 patients were identified, with 21 RCTs involving G, 4 with GF, 3 with GCap, 2 with GS, 6 with GCis, 3 with GOx, 1 with GE, 1 with GA and 1 with FOLFIRINOX. Median OS, PFS and RR for G arms from all trials were similar, suggesting the absence of significant clinical heterogeneity among RCTs. For OS, the results of the Bayesian network meta-analysis found that the probability that FOLFIRINOX was the best regimen was 71%, while it was 19% for GS, 7% for GA and 2% for GE respectively. The OS hazard ratio (HR) for FOLFIRINOX vs. GS was 0.82 (95% credible region (CR): 0.53-1.35), the OS HR for FOLFIRINOX vs. GA was 0.77 (95% CR: 0.51-1.23), and the OS HR for FOLFIRINOX vs. GE was 0.67 (95% CR: 0.45-1.08). Similar ranking and probabilities were observed for the best regimen for PFS. Conclusions: FOLFIRINOX appeared to be the best regimen for advanced pancreatic cancer probabilistically, with a trend towards improvement in OS and PFS when compared with GS, GA, or GE by indirect comparisons. In the absence of direct pairwise comparisons of these regimens from RCTs, network meta-analysis helps synthesize evidence and inform decision making.
25-hydroxyvitamin D levels and survival in patients with advanced pancreatic cancer (APC): Findings from CALGB 80303.
Authors: Van Loon Katherine , Owzar Kouros , Jiang Chen , Kindler Hedy Lee , Mulcahy Mary Frances , Niedzwiecki Donna , O'Reilly Eileen Mary , Fuchs Charles S. , Innocenti Federico , Venook Alan Paul
Published: March 2020

4022

Background: Data from animal and cell line models suggest that vitamin D metabolism is important in pancreatic tumor maintenance and may contribute to this tumor’s chemoresistance. While vitamin D has been implicated in a variety of cancers, the prevalence of vitamin D deficiency among patients with advanced pancreatic cancer (APC) and the effect of baseline vitamin D levels on survival outcomes are unknown. Methods: CALGB 80303 was a randomized controlled trial of patients with APC which demonstrated no difference in OS among patients treated with gemcitabine (GEM) vs. GEM + bevacizumab. We retrospectively measured baseline serum 25(OH)D levels and examined associations between baseline 25(OH)D levels and selected patient characteristics. Using the Cox rank score test, we examined the association between 25(OH)D level and PFS and OS. The differences in the levels among racial populations were tested using the Kruskal-Wallis test. Results: Of 256 patients with available serum, the median 25(OH)D level was 21.7 (range 4–77). 44.5% of patients were vitamin D deficient (25(OH)D <20), 32.4% were insufficient (25(OH)D ≥20 and <30), and 23% were sufficient (25(OH)D≥30). Serum 25(OH)D levels were lower in patients self-reported as black compared to white patients and patients of other/undisclosed race (median 10.7 [4.0–36.3] vs. 22.4 [4.0–77.0] vs. 20.9 [12.6 – 31.8], respectively; p<0.00001). Adjusting for race, baseline 25(OH)D levels were not associated with PFS (HR 1.00, 95% CI 0.98–1.01) or OS (HR 1.00, 95% CI 0.99-1.01). Conclusions: Vitamin D deficiency was highly prevalent among patients with a new diagnosis of APC. Black patients had significantly lower 25(OH)D levels than white patients. In this cohort of patients with APC receiving GEM-based chemotherapy, baseline 25(OH)D levels were not associated with PFS or OS.
A phase III study of S-1 plus cisplatin versus fluorouracil plus cisplatin in patients with advanced gastric or gastroesophageal junction adenocarcinoma.
Authors: Xu Rui-hua , Sun Guo-ping , Lu Hui-shan , Yun Peng Liu , Xu Jian-ming , Zhong Mei-zuo , Zhang He-long , Yu Shi-ying , Li Wei , Hu Xiao-hua , Wang Jie Jun , Cheng Ying , Zhou Jun-tian , Guo Zeng-qing , Guan Zhongzhen
Published: March 2020

4025

Background: A combination of S-1 and cisplatin (DDP) has been shown to be effective and safe for the first-line treatment of advanced gastric cancer in Japan. This is the first randomized phase III trial to compare S-1 plus DDP with 5-fluorouracil (5-Fu) plus DDP in Asia. Methods: This is an open-label, multicenter, phase 3, randomized controlled study. Patients with gastric or gastro-oesophageal junction adenocarcinoma were eligible for inclusion. Patients were randomly assigned in a 1:1 ratio to receive S-1 plus DDP (experiment group) or 5-Fu plus DDP (control group) for 6 cycles. In the experiment group, the dose of S-1 was 80 mg/m2/day, po, twice daily on day 1-21 and DDP was 20mg/m2 iv on day 1-4, repeat every 5 weeks. In the control group, 5-Fu was given as 0.8g/m2/d CI 120h ,and the dose of DDP was the same with the experiment group, while repeat every 4 weeks. Allocation was by block randomization stratified by Eastern Cooperative Oncology Group performance status, sites of metastasis and prior gastrectomy. The primary endpoint was time to progression (TTP). Secondary end points included time to failure (TTF), overall survival (OS), and quality of life. Results: Totally 255 patients were enrolled into the study, of whom 236 were included in the analysis (n=120; n=116). Median TTP was 5.51 months (95% CI 4.59-6.26) in those assigned to experiment group compared with 4.62 months (95% CI 4.00-6.33) in the control group (hazard ratio [HR] 1.03; 95%CI 0.76-1.39, p=0.86). In the experiment and control groups, response rates were 22.5% vs 21.5%; P=0.86. Median OS was 10.00 months (95% CI 8.59-14.52) in the experiment group compared with 10.46 months (8.92-13.84) in the control group (HR 1.05; 95%CI 0.71-1.54, p=0.82). The most common adverse events in both groups were anemia (S-1 plus cisplatin, 80.17% vs 5-Fu plus cisplatin, 71.19%), leukopenia (71.90% vs 62.71%), neutropenia (68.60% vs 55.93%), nausea (50.41% vs 60.17%), thrombocytopenia (44.63% vs 26.27%), vomiting (42.98% vs 42.37%) and anorexia (38.02% vs 41.53%). Conclusions: S-1 plus DDP is an effective and tolerable option for patients with advanced gastric or gastro-oesophageal junction adenocarcinoma. Clinical trial information: NCT01198392.
Sorafenib (S) alone versus S combined with gemcitabine and oxaliplatin (GEMOX) in first-line treatment of advanced hepatocellular carcinoma (HCC): Final analysis of the randomized phase II GONEXT trial (UNICANCER/FFCD PRODIGE 10 trial).
Authors: Assenat Eric , Boige Valerie , Thézenas Simon , Pageaux Georges-Philippe , Peron Jean-Marie , Becouarn Yves , Dahan Laetitia , Merle Philippe , Blanc Jean-Frédéric , Bouche Olivier , Ramdani Mohamed , Mazard Thibault , Bleuse Jean-Pierre , Ychou Marc
Published: March 2020

4028

Background: HCC is a vascular tumor with poor prognosis. Although S has been shown to improve survival, its ability to induce tumor shrinkage is very low. Given the activity of Gemcitabine and Oxaliplatin (GEMOX) in HCC, a phase II trial combining S with GEMOX was undertaken to define efficacy and safety profile. Methods: Patients with inoperable advanced and/or metastatic HCC (BCLCC B or C), with or without prior palliative chemoembolization, Child pugh score A, WHO performance status (PS) 0-1, were eligible for this two-stage, randomized phase II trial. Patients received S (400 mg BID) alone (arm A) or in combination with GEMOX every 2 weeks (gem. 1000 mg/m² [10 mg/m²/min] on D1; oxaliplatin, 100 mg/m² on D2) (arm B). Randomization was stratified according to CLIP score (0-1 vs. 2-3) and center. Primary endpoint was crude 4-mo Progression-Free Survival (PFS) rate (H0, < 50%; H1, ≥ 70%; α = 10%; 1- β= 90%). Results: From Dec 2008 to Oct. 2011, 94 pts were enrolled: median age, 64 yrs; male, 88%; PS 0 (69%) 1(31%), CLIP 0-1 (48%) 2-3 (52%), cirrhosis (63%), portal vein thrombosis (29%), extra liver metastasis (69%). These characteristics were well balanced in both arms. Median duration and dose intensity of S were 4 mo (1-27) and 81% in both arms, respectively. Median number of GEMOX cycles was 7 (1-12) in arm B. Main severe (grade 3-4) toxicity (arm A/B) consisted of neutropenia (grade 3-4: 0%/7%), fatigue (18%/24%), thrombocytopenia (0%/9%), diarrhea (grade 2-4: 10%/21%), peripheral neuropathy (grade 2-3: 0%/10%), and hand foot syndrome (grade 2-3: 13%/7%). For evaluable pts (n = 83), ORR was 9% / 16% and DCR was 70%/77% in arms A/B, respectively. For all pts (median follow-up, 17.6 mo), 4-mo PFS rate was 54%/61%, median PFS was 4.6 (3.9-6.2)/6.2 (3.8-6.8) mo, and median OS was 13.0 (10.4-22.2) /13.5 (7.5-19.1) mo in arms A/B, respectively. Conclusions: S plus GEMOX was feasible in HCC. This trial met its primary endpoint (4-mo PFS ≥ 50%) and ORR, median PFS and OS were encouraging data. Exploratory analyses are underway to identify subgroups of patients likely to derive most benefit from this combination. Clinical trial information: NCT00941967.
Prospective randomized phase II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: A study of the CESAR Central European Society for Anticancer Drug Research-EWIV.
Authors: Richly Heike , Maute Luise , Heil Gerhard , Rüssel Jörn , Jäger Elke , Koeberle Dieter , Fuxius Stefan , Weigang-Koehler Karin , Aulitzky Walter , Woehrmann Bernhard , Hartung Gernot Georg , Moritz Berta , Burkholder Iris , Scheulen Max E. , Bergmann Lothar
Published: March 2020

4035

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours, but PDAC is still associated with a poor prognosis in advanced disease with an overall 5-year survival of only about 15%. Therefore there is a need for new treatment strategies. To improve the standard therapy with gemcitabine we initiated a prospective randomized phase-II trial with gemcitabine (GEM) vs. gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. Methods: Patients (N=113) with locally advanced or metastatic PDAC were prospectively randomized to receive gemcitabine alone (GEM) at a dosage of 1000 mg/m² day 1, 8, 15 q28 or to a combination of gemcitabine and sunitinib (SUNGEM) at a dosage of GEM 1000 mg/m² d1+8 and sunitinib 50mg p.o. d1-14, qd21 (based on a phase-I trial). The primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), time to progression (TTP), overall response rate (ORR) and toxicity. Results: The confirmatory analysis of PFS was based on the ITT population (N=106). The median PFS was 13.3 weeks (95 %-Cl: 10.4-18.1 weeks) in the GEM group and 11.6 weeks in the SUNGEM arm (95 %-Cl: 7.0-18.0 weeks) (one-sided logrank: p=0.74). The 6-month PFS rate was 26.8 % (95 %-Cl: 15.4-39.5 %) in GEM arm and 25.0 % in SUNGEM arm (95 %-Cl: 14.0-37.8 %). The overall response rate was 6.1 % (95 %-Cl: 0.7-20.2 %) in the GEM arm and was a slightly but not significantly higher for the SUNGEM arm with 7.1% (95%-Cl: 0.9 – 23.5%).The median time to progression (TTP) was 14.0 weeks (95 %-Cl: 12.4-22.3 weeks) for the GEM arm and 18.0 weeks (95 %-Cl: 11.3-19.3 weeks) for the SUNGEM arm (two-sided logrank: p=0.60). The median OS was 30.4 weeks (95 %-Cl: 18.1-37.6 weeks) for the SUNGEM and 36.7 weeks (95 %-Cl: 20.6-49.0 weeks) for the GEM arm (two-sided logrank: p=0.44). With regard to toxicities, at least one AE of grade 3 or 4 was reported in 78.8% in the SUNGEM arm and 72.2% in the GEM arm. Conclusions: The combination of gemcitabine plus sunitinib (SUNGEM) did not improve the PFS in locally advanced or metastatic PDAC compared to gemcitabine alone. Clinical trial information: NCT00673504.
A phase I trial of a local delivery of siRNA against k-ras in combination with chemotherapy for locally advanced pancreatic adenocarcinoma.
Authors: Golan Talia , Hubert Ayala , Shemi Amotz , Segal Amiel , Dancour Alan , Khvalevsky Elina Zorde , Ben-David Eliel , Raskin Stephen , Goldes Yuri , Inbar Yael , Lahav Maor , Domb Avi , Galun Eithan
Published: March 2020

4037

Background:K-Ras mutation G12D is most prevalent in pancreatic adenocarcinoma (PDAC). siRNA against the K-RasG12D(siG12D) mutant had showed significant preclinical anti-tumor effects. siG12D LODER - miniature biodegradable polymeric matrix that encompasses anti-K-RasG12D siRNA drug, is placed with Endoscopic US biopsy and designed to continuously release the drug regionally over a period of 4 months. Methods: Open label phase I study of patients with locally advanced non-operable PDAC in the first-line setting. Patients were assigned to receive siG12D LODERs in dose escalation cohorts: 0.025mg, 0.75mg and 3.0mg. Gemcitabine 1000 mg/m2IV was given weekly, following siG12D LODER insertion. The RP2D (recommended phase II dose) was further examined in 3.0 mg dose cohort in combination with modified Folfirinox (Oxaliplatin 85mg/m2, Irinotecan 150mg/m2, Fluorouracil infusion 2,400mg/m2 46 hours, every 2 weeks). Follow up period was 8 weeks and survival follow up until death. Primary study objectives were to determine the dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). Results:15 patients have been enrolled. 2 patients were omitted from study due to metastatic disease detected on day 1 post siG12D LODER implant imaging . Median age = 70 (range 52-85); male:female 8:7. Among 13 treated patients, the most frequent adverse events observed in the study were typically grade 1- 2 in severity; 4 patients experienced serious adverse events (SAE), one procedure related. No DLTs were observed. MTD was not reached. CT performed 8-10 weeks following the procedure showed stable disease in all patients. Reduction in tumor marker CA 19-9 was observed in 64% (7/11) of patients. The median survival of 13 patients was 16 months ( 8/13 patients still alive at analysis). Conclusions: The combination of siG12D LODER and chemotherapy is well tolerated. The combination has demonstrated promising efficacy in locally advanced PDAC with durable responses. Phamocodynamic endpoints are currently being examined in an expansion cohort in operable patients. A phase II randomized trial is planned in order to investigate efficacy of siG12D LODER in locally advanced non-operable PDAC. Clinical trial information: NCT01188785.
Extended neoadjuvant chemotherapy (CT) in borderline resectable pancreas cancer (BRPC).
Authors: Rose J Bart , Rocha Flavio G. , Lin Bruce S. , Alseidi Adnan , Biehl Thomas A. , Moonka Ravi , Ryan John A. , Traverso L. William , Helton Scott , Picozzi Vincent J.
Published: March 2020

4043

Background: The optimal surgical (S) approach to BRPC is unknown. We evaluated an approach to BPRC using extended course chemotherapy (CT) without routine neoadjuvant chemoradiation (CRT). Clinical outcomes were evaluated on an "intent to treat" basis. Methods: Patients (pts) were identified from a prospectively-maintained database started in 2008. Pts required 1) Dx BRPC with non-tail primary per radiographic staging using AHPBA/NCCN guidelines 2) No prior therapy (Rx) 3) Negative staging/exploratory laparoscopy prior to S 4) All cancer Rx at VMMC prior to S. Pts received gemcitabine/docetaxel (G/D) as initial CT. Pts with systemic progression/comorbid complication prior to 24 wks were not offered local Rx; pts with localized cancer at 24 wks judged likely to achieve R0 resection were offered S; all other pts were offered fluoropyrimidine-based CRT. Results: Of 76 identified pts (median age 66), 12 (16%) are on initial CT and not fully evaluable. G/D as sole CT achieved 24 wk disease control in 46/64 (72%) pts and >50% decline in baseline CA 19.9 in 39/55 pts (71%). 53/64 fully evaluable pts (83%) completed 24 wks CT, 11/64 pts (17%) did not (4 systemic progression, 3 Rx- related, 4 intercurrent illness). 50/53 pts attempted local Rx (40 S, 10 CRT, 2 unfit, 1 refused). 30/40 pts (75%) had successful S (all R0), 10/40 pts (25%) had inoperable disease (4 local-subsequently received CRT, 6 systemic). 23/30 pts (77%) have received some form Rx post R0 resection. With median f/o of 20 mo, 23/44 (52%), 17/30 (57%), and 6/14 (43%) receiving any local Rx, S, and CRT-only remain progression free. 13/30 S pts recurred, 3 local (10%) and 10 systemic (33%). 1-yr, 2-yr, 3-yr, and median overall survivals (OS) for fully evaluable pts respectively are 82%, 50%, 36%, and 27 mo. Median OS for pts receiving CT-only (20 pts), CT+CRT (14 pts), and R0 pts are 12 mo, 17 mo, and >20 mo, respectively. 25/30 R0 pts remain alive (range 6-54 mo). Conclusions: 1) Extended neoadjuvant CT without routine neoadjuvant CRT is a feasible approach to BRPC. 2) G/D has significant activity in BRPC. 3) Pretreatment surgical staging combined with the above Rx yields a high probability of R0 resection. 4) OS for both resected and non-resected pt was superior to usual literature comparators.
Development and validation of a predictive model to assess an individual's risk of pancreatic cancer.
Authors: Nam Byung-Ho , Yu Ami , Woo Sang Myung , Yang Hye-Ryung , Joo Jungnam , Lee Woo Jin , Park Sang Jae
Published: March 2020

4045

Background: Due to the very low survival of pancreatic cancer (PC), early detection is a critical strategy to improve the outcome of PC.Screening individuals with genetic syndromes associated with a high incidence of PC or families predisposed to PC is increasing. However, those populations account for only 10% of all PC cases. A different approach for developing an effective surveillance tool is needed to identify high-risk individuals without hereditary risks. The goal of this study was to develop and validate risk prediction models for filtering purposes as part of the sporadic PC surveillance activities. Methods: Based on an eight-year follow-up of a cohort study involving 1,289,933 men and 557,701 women in Korea who had biennial examinations in 1996-1997, gender-specific risk prediction models were developed using the Cox proportional hazards model. The models were validated using independent data of 500,046 men and 627,629 women who had biennial examinations in 1998-1999. The models’ performance was evaluated with respect to their discrimination and calibration abilities based on the C-statistic and the Hosmer-Lemeshow (H-L) type χ2-statistic. Results: Age, height, BMI, fasting glucose, urine glucose, smoking, and age at smoking initiation were included in the model for men. In the model for women, height, BMI, fasting glucose, urine glucose, smoking, and drinking habits were included. Smoking was the most significant risk factor for developing pancreatic cancer in both men and women. Model validation showed excellent model performance with C-statistics (95% confidence interval) of 0.813 (0.800−0.826) and 0.804 (0.788−0.820) for men and women, respectively. The H-L type χ2-statistics (P-values) were 7.478 (0.587) and 10.297 (0.327) for men and women, respectively. Five different risk groups could be identified with hazard ratios (HR) greater than 20 in the highest risk group compared to the lowest risk group in both the men and women. Conclusions: Gender-specific individualized risk prediction models for PC were developed and validated with a high level of performance. These models can be used to identify high-risk individuals who may benefit from increased surveillance of PC.
Circulating tumor cells in locally advanced pancreatic adenocarcinoma: The ancillary study Circe 07 of the LAP 07 trial.
Authors: Huguet Florence , Bidard Francois-Clement , Louvet Christophe , Mineur Laurent , Bouche Olivier , Chibaudel Benoist , Artru Pascal , Desseigne Francoise , Bachet Jean Baptiste , Gasmi Mohamed , Nguyen Suzanne , Wander Lionel , Mathiot Claire , Pierga Jean-Yves , Hammel Pascal ,   GERCOR
Published: March 2020

4046

Background: Pancreatic carcinoma is one of the leading causes of cancer-related mortality. At time of diagnosis, 30% of patients present with a locally advanced unresectable but non metastatic carcinoma (LAPC). Theoretically, patients with micrometastatic dissemination at diagnosis should benefit from systemic treatments, whereas radiation therapy should be favored in the others. Based on the hypothesis that circulating tumor cells (CTC) count is a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients. Methods: LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of gemcitabine-based chemotherapy whether to administrate a chemoradiotherapy could increase overall survival versus continuation of chemotherapy alone. A subgroup of patients included in LAP 07 trial were prospectively screened for CTC before the start of the chemotherapy and after two months of treatment, using the CellSearch technique. Clinico-pathological characteristics and survival of patients were obtained prospectively and were correlated with CTC detection. Results: Seventy-nine patients were included in this ancillary study. One or more CTC/7.5ml were detected in 5% of patients before treatment and in 9% of patients after two months of chemotherapy (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (p=0.04), and with shorter overall survival in multivariable analysis (RR=2.5, p=0.01), together with anemia (p=0.005). Conclusions: The evaluation of micrometastatic disease using CTC detection appears as a promising tool which could help to personalize treatment modalities in LAPC patients. Clinical trial information: NCT00634725.
Is successful resection following neoadjuvant radiation therapy for borderline resectable pancreatic cancer dependent on improved tumor-vessel relationships?
Authors: Dholakia Avani Satish , Hacker-Prietz Amy , Wild Aaron Tyler , Raman Siva P. , Wood Laura D. , Laheru Daniel A. , Zheng Lei , De Jesus-Acosta Ana , Huang Peng , Le Dung T. , Schulick Richard D. , Edil Barish H. , Ellsworth Susannah G. , Pawlik Timothy M. , Iacobuzio-Donahue Christine A , Hruban Ralph H. , Cameron John L. , Fishman Elliot K. , Wolfgang Christopher Lee , Herman Joseph M.
Published: March 2020

4057

Background: Margin-negative (R0) surgical resection is the only potentially curative therapy for pancreatic cancer. For patients deemed borderline resectable (BL), neoadjuvant chemoradiotherapy (NRT) increases the likelihood of subsequent R0 resection and improves overall survival. Prognostic factors for achieving resection following NRT have yet to be clearly identified. Methods: Fifty consecutive patients with BL-PDAC evaluated by a multidisciplinary tumor board who received NRT from 2007-2012 were retrospectively identified. Computed tomography (CT) scans pre- and post-radiation and surgical specimens were centrally reviewed. Results: 29 patients underwent resection following NCRT, while 21 remained unresectable. Between the two groups, age, gender, mean RT dose, and proportion of pancreatic head tumors were not significantly different. Smaller tumor volume and lack of the following factors was associated with selection for resection: superior mesenteric/portal vein encasement (p=0.01), superior mesenteric artery involvement (p=0.02), ascites (p=0.01), and questionable/overt metastases (p=0.01). Notably, celiac artery involvement/encasement, common hepatic artery encasement, and percentage change in tumor volume were not significant predictors of resection (all p>>0.05). Interestingly, tumor volume and degree of individual vessel involvement did not significantly change from scans before and after NCRT (all p>>0.05). Median OS was 22.9 vs.13.0 months in resected and unresected patients, respectively (p<0.001). Of resected patients, 93% had negative margins, 28% had positive nodes, 27% demonstrated <10% viable tumor, and 12% had pathologic complete response at surgery. Dpc4 expression was retained in 68% of specimens with viable tumor. Conclusions: Although the apparent radiographic extent of vascular involvement does not change significantly after NRT, subsequent R0 resection rates are high, nodal involvement is low, and outcomes are similar to resected patients who receive adjuvant therapy. Resection attempts should not be deferred solely based on lack of improvement in tumor-vessel interactions.
Customizing surveillance of patients with esophageal or esophagogastric junction adenocarcinoma (E-EGA) after trimodality therapy (TMT).
Authors: Taketa Takashi , Correa Arlene M. , Sudo Kazuki , Blum Mariela A. , Wadhwa Roopma , Skinner Heath D. , Komaki Ritsuko , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Liao Zhongxing X. , Rice David C. , Swisher Stephen , Hofstetter Wayne Lewis , Ajani Jaffer A.
Published: March 2020

4085

Background: Follow-up strategy for E-EGA patients after TMT has varied and is debated often due to the lack of evidence. It is an expensive endeavor and the literature provides little guidance. Methods: Between 2000 and 2010, we identified 518 E-EGA patients who had TMT. We reviewed the timing/pattern of recurrence after TMT and grouped them as local-regional (LR) or metastatic (M). Results: The median follow-up time from date of surgery was 29.3 months (range, 0.8 to 149.2 months). 215 (41.5%) had a relapse (M=188 [87.5%] and LR=27 [12.5%]). Among LRs, regional node only in 16 (7.4%) and intra-luminal only occurred in 11 (5.1%). The frequency of relapses was highly associated with the surgical stage (p<0.001). >90% of all relapses occurred within 29.2 months of surgery. In addition, almost all intra-luminal only relapses occurred within 24 months (see Table). Conclusions: Our data suggest that it may be possible to customize surveillance of patients after TMT based on the surgical stage. Additionally, intra-luminal only relapse are rare and are unlikely after 24 months. Our data can contribute to the development of an evidence-based surveillance strategy. [Table: see text]
A phase II trial of induction epirubicin, oxaliplatin, and flourouracil, surgery and post-operative concurrent cisplatin and fluorouracil chemoradiotherapy (CRT) in patients (pts) with loco-regionally advanced (LRA) adenocarcinoma (ACA) of the esophagus (E) and gastroesophageal junction (GEJ).
Authors: McNamara Michael J. , Rice Thomas W. , Rybicki Lisa A. , Rodriguez Cristina P. , Videtic Gregory M. M. , Saxton Jerrold P. , Stephans Kevin L. , Greskovich John , Sohal Davendra , Mason David P. , Murthy Sudish C. , Ives Denise I. , Bodmann Joanna , Adelstein David J.
Published: March 2020

4087

Background: In pts with LRA ACA of the E/GEJ, CRT and surgery results in excellent locoregional control. Distant failure remains common, however, suggesting potential benefit from additional chemotherapy. This single arm phase II study investigated the addition of induction chemotherapy to surgery and post-operative CRT. Methods: Pts with an ultrasound-based clinical stage of T3, N1 or M1a (AJCC 6th) ACA of the E/GEJ were eligible. Induction chemotherapy with epirubicin 50mg/m2 d1, oxaliplatin 130mg/m2 d1, and flourouracil 200mg/m2/day continuous infusion for 3 weeks, was given every 21 days for 3 courses and was followed by surgical resection. Adjuvant CRT consisted of 50-55Gy at 1.8-2.0 Gy/d and 2 courses of cisplatin (20mg/m2/d) and flourouracil (1000mg/m2/d) given as 96 hour infusions during weeks 1 and 4 of radiotherapy. Results: Between 2/08 and 1/12, 60 evaluable pts enrolled; 95% male, 97% white and 78% with GEJ tumors. Resection was accomplished in 54 pts (90%) and adjuvant CRT in 48 (80%). Toxicity included 1 death during induction (2%), and 2 post-operative deaths (4%). Unplanned hospitalization was required in 18% of pts during induction and 19% during adjuvant CRT. Induction chemotherapy produced a symptomatic response in 79% of pts, a clinical (ultrasound) response in 48% and a pathologic response in 41% (5% complete). With a median follow-up of 31 months, the Kaplan-Meier 3-year projected locoregional control (LRC) is 84%, distant metastatic control (DMC) 44%, relapse-free survival (RFS) 39%, and overall survival (OS) 42%. Symptomatic response to induction and the percentage of remaining viable tumor at surgery proved the strongest predictors of DMC, RFS, and OS. Conclusions: Induction chemotherapy, surgery and adjuvant CRT is feasible and produces outcomes similar to other multimodality treatment schedules in LRA E/GEJ ACA. Despite excellent LRC, projected DMC and OS remain poor. A symptomatic response to induction and less residual viable tumor at surgery are associated with improved outcomes. Clinical trial information: NCT00601705.
PI3K pathway as a major determinant of resistance to HER2-targeted therapy in advanced gastric cancer.
Authors: Kim Hyo Song , Zhang Xianglan , Park Kyu Hyun , Park Ji Soo , Kim Ki Hyang , Chung Hyun Cheol , Rha Sun Young
Published: March 2020

4089

Background: Despite the improvement of survival with trastuzumab treatment, it is still unclear why majority of patients are initially nonresponsive or eventually become resistant to HER2-based therapy. To evaluate resistant mechanism and stimulate the development of rational drug, we investigated the role of phosphoinisitide 3-kinase (PI3K) pathway activation. Methods: With tumor tissues from HER2-overexpressing advanced gastric cancer, PIK3CA mutation status (by pyrosequencing of exon 9 and 20) and phosphatase and tensin homolog (PTEN) expression levels (using immunohistochemical analysis) were evaluated for the therapeutic response to HER2-based therapy. Results: Forty nine patients received trastuzuamb (n=39) or lapatinib (n=10) in combination with chemotherapy regimen. The age at diagnosis was 61 years and all the cases were HER2 positive and/or amplified. PTEN-loss was found in 67% (n=33) and all the patients showed PIK3CA wild-type tumors. Twenty nine patients (59%) responded to HER2-based therapy (complete and partial response), without significant difference between PTEN-loss and normal tumors (61% vs 62%). Among the patients with responsive disease, time to best response was not different but duration of response was shorter for the PTEN deficient patients (155 vs 244 days, P=0.016). In addition, PTEN-deficient patients have significantly shorter progression-free survival (median 160 vs 286 days, P=0.018), which implying the functional role of PTEN for the acquired resistance to HER2-based therapy. Conclusions: This data suggests PTEN as an important predictor for the early progression and acquired resistance to HER2-based therapy. Activated PI3K pathway may provide a biomarker to identify patients who may need additional or alternative therapies.
Surgery-induced peritoneal metastasis and its intraoperative treatment.
Authors: Murata Satoshi , Takebayashi Katsushi , Kojima Masatsugu , Yamamoto Hiroshi , Yamaguchi Tsuyoshi , Naitoh Hiroyuki , Ishida Mitsuaki , Mekata Eiji , Shimizu Tomoharu , Shiomi Hisanori , Sonoda Hiromichi , Naka Shigeyuki , Mori Tsuyoshi , Akabori Hiroya , Murakami Koichiro , Ueki Tomoyuki , Mizuno Aya , Abe Hajime , Okabe Hidetoshi , Tani Tohru
Published: March 2020

4092

Background: A large number of advanced gastric cancer patients undergoing curative gastrectomy with D2 lymph node dissection (D2 gastrectomy) show peritoneal metastasis. The source of these metastatic cells and their treatment remain unclear. We examined the mechanism of surgery-induced peritoneal metastasis and determined the appropriate intraoperative treatment. Methods: (1) Curative gastrectomy was performed for 102 gastric cancer patients. Peritoneal lavage fluid was collected before and after gastrectomy. Cytology, RT-PCR, and cell culture were used to determine the presence of cancer cells. Proliferative potential of tumor cells was evaluated using Ki-67 staining. Tumorigenic capacity was assessed by cell injection into the peritoneal cavity of NOD/ShiJic-scid mice. (2) Fifty clinical T3(SE) or T4(SI) advanced gastric cancer patients undergoing curative D2 gastrectomy prospectively received intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) in a phase II trial. HIPEC comprised 50 mg CDDP, 10 mg MMC, and 1000 mg 5-FU in 5 L saline maintained at 42–43C° for 30 min. Results: (1) Of 102 peritoneal lavage fluid samples obtained before gastrectomy, 57 from both early and advanced cancer patients did not contain CEA or CK20 mRNA amplification products or cancer cells. Of these 57 samples, CEA or CK20 mRNA was detected in 35 and viable cancer cells were identified in 24 after gastrectomy. Viable cancer cells in all 24 cases showed Ki-67 positivity, indicating proliferative activity. Cultured viable cancer cells developed into peritoneal tumor nodules after spill over into the peritoneal cavity in NOD/ShiJic-scid mice. (2) Fifty patients were eligible for the phase II clinical trial. The overall 5-year survival rate for all patients was 92.4%. This rate in patients with pT2(ss) (n = 12), pT3(se) (n = 35), and pT4(si) (n = 3) disease was 90.0%, 92.3%, and 100%, respectively. Only 2 patients (4%) showed peritoneal relapse. Conclusions: Viable tumorigenic cancer cells spilled over the peritoneal cavity during curative gastrectomy. Intraoperative HIPEC following curative D2 gastrectomy effectively prevented peritoneal metastasis, thereby potentially improving the prognosis of patients with advanced gastric cancer.
Multicenter, phase II study of trastuzumab and paclitaxel to treat HER2-positive, metastatic gastric cancer patients naive to trastuzumab (JFMC45-1102).
Authors: Iwasa Satoru , Nishikawa Kazuhiro , Miki Akira , Noshiro Hirokazu , Tsuburaya Akira , Nishida Yasunori , Miwa Hiroto , Masuishi Toshiki , Yoshida Kazuhiro , Kodera Yasuhiro , Boku Narikazu , Yamada Yasuhide , Morita Satoshi , Sakamoto Junichi , Saji Shigetoyo , Kitagawa Yuko
Published: March 2020

4096

Background: The ToGA study indicated that first-line treatment using trastuzumab (T-mab) combined with capecitabine and cisplatin conferred a survival (OS) benefit to patients with HER2-positive metastatic gastric cancer (mGC). However, no reports have described the efficacy and safety of second-line treatment of HER2-positive mGC patients with T-mab who were naïve to the drug. Methods: JFMC45-1102 was a multicenter, Phase II study. Patients positive for HER2 (IHC3+ or IHC2+/FISH+) with gastric adenocarcinoma confirmed histologically; older than ≥ 20 y; who received one or more prior chemotherapies but no prior therapy with T-mab; and normal left ventricular ejection fraction (LVEF ≥ 50%) were eligible. Patients received paclitaxel (80 mg/m2on days 1, 8, and, 15 q4w) plus T-mab (8 mg/kg initial dose, followed by 6 mg/kg q3w). Treatment continued until their disease progressed; there was unacceptable toxicity or patient’s refused further treatment. The primary endpoint was overall response rate (ORR) evaluated according to RECIST ver. 1.0. Threshold and expected ORR were estimated at 15% and 30%, and secondary endpoints included progression free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. Results: Fourty-six patients were enrolled between September 2011 and March 2012. Patients characteristics were: gender (M/F) 37/9; median age 69; ECOG PS0/1/2, 35/10/1; unresectable/recurrence 25/21; number of prior treatments (1/2), 41/5. The ORR was 37.2% (95% CI: 23.0-53.3%). The median PFS and TTF were 5.2 months (95% CI 3.9-6.6) and 5.2 months (95% CI 3.9-6.6), respectively. The protocol was discontinued for 27 patients (87.1%) for disease progression, and one patient each (3.2%) for severe adverse events, physician’s recommendation, patient refusal, and treatment related death. Conclusions: Combination chemotherapy of paclitaxel plus T-mab showed promising activity and was tolerated well by patients naïve to T-mab who were positive for HER2 and treated previously for mGC. Clinical trial information: UMIN000006223.
Nimotuzumab plus paclitaxel and cisplatin as first-line treatment for esophageal squamous cell cancer: A single center prospective clinical trial.
Authors: Zhang Xiaodong , Lu Ming , Wang Xicheng , Li Jie , Li Yan , Li Jian , Zhang Xiaotian , Gao Jing , Zhou Jun , Lu Zhihao , Gong Jifang , Jia Jun , Cui Yan , Yu Jing , Shen Lin
Published: March 2020

4097

Background: The aim of this present phase II study is to explore the safety and efficacy of paclitaxel (T), cisplatin (C), and nimotuzumab (N), a humanized anti-EGFR monoclonal antibody combination (TCN) as first-line treatment in advanced esophageal squamous cell cancer (ESCC). Methods: Patients with histologically confirmed advanced ESCC, measureable tumor, and no prior chemotherapy and radiotherapy except adjuvant treatment were enrolled. Patients were given cisplatin 60mg/m2, paclitaxel 175mg/m2per 21 days for at least 2 cycles. The nimotuzumab was given 200mg weekly. Radiotherapy was admitted for patients with unresectable local advanced disease after 4 cycle of TCN treatment. The primary endpoints were safety and objective response rate (ORR). The secondary endpoints were progression-free survival (PFS) and over-all survival (OS). The expression of EGFR and ERCC1 were also analyzed by histoimmunochemical staining. Results: Between Mar. 2011 and Dec. 2012, 55 patients with advanced ESCC were enrolled and 53 (96.4%) were eligible for evaluation. The ORR was 54.7% (29/53) and the DCR was 94.3% (50/53). The expression of EGFR and ERCC1 were detected in 46 and 31 patients respectively. The ORR had no relation to both the expression of EGFR (55.3% vs 62.5%, p=0.71) and ERCC1 (41.7% vs 58.3%, p=0.47). As a median follow-up of 15months, the median PFS was 10.5 months (95% CI 8.7 to 12.3 months).The TCN combination treatment was well tolerated and the most common adverse events were alopecia (86.8%), leukopenia (84.9%), anorexia (84.9%), vomiting (73.6%), fatigue (73.6%), pain (66.0%), and anaemia (39.6%). And 18 (34%) patients had Grade 3 to 4 leukopenia. The median OS have not yet been reached. Conclusions: In this study, the ORR, DCR and PFS are superior to previous published studies. The addition of anti-EGFR treatment of nimotuzumab to standard chemotherapy was well tolerated with no serious AEs. But the expression of EGFR by IHC could not predict the outcome of nimotuzumab treatment. A phase III study of TCN followed by radiotherapy in unresectable local advanced ESCC had been designed to explore the survival benefits. Clinical trial information: NCT01336049.
Preoperative chemotherapy plus bevacizumab with early salvage therapy based on FDG-PET response in locally advanced gastroesophageal junction and gastric adenocarcinoma.
Authors: Ku Geoffrey Yuyat , Kelsen David Paul , Strong Vivian E. , Schöder Heiko , Janjigian Yelena Yuriy , Shah Manish A. , Coit Daniel G. , Brennan Murray F. , Capanu Marinela , Ilson David H.
Published: March 2020

4101

Background: Response on FDG-PET scan during preoperative chemotherapy has prognostic significance. We performed a phase II trial to examine the effectiveness of FDG-PET directed early switching to salvage chemotherapy measured by 2-year disease free survival (DFS). Methods: Pts with PET avid, endoscopic ultrasound and laparoscopically staged T3 or N+ resectable gastric or GEJ adenocarcinoma received induction epirubicin 50mg/m2, cisplatin 60mg/m2 Day 1, capecitabine 625mg/m2 BID Days 1-21 (ECX) and bevacizumab 15mg/kg Day 1. PET scan was repeated at Week 3. PET responders (≥35% decline in SUV) continued with ECX for 2 more cycles. PET non-responders were switched to 2 cycles of salvage therapy: docetaxel 30mg/m2 and irinotecan 50mg/m2Days 1 and 8 q21 days and bevacizumab 15mg/kg Day 1. All pts went to surgery 4 weeks after Cycle 3. Results: Twenty of planned 60 pts were enrolled before the study closed for poor accrual. Eleven (55%) had a PET response after induction. Ten of 11 underwent R0 resection: 1/10 path complete response, 3/10 path partial response. Nine PET non-responders were switched to the salvage regimen. Seven of 9 non-responders had R0 resection, none achieved a pathological response. The median DFS for PET responders was 27.8 mos (95% CI 10.3-27.8) and DFS in salvage group has not been reached. There was no significant difference in DFS between the two groups (p= 0.4). Follow up for overall survival is ongoing. Conclusions: Response on PET scan during induction chemotherapy can identify early treatment failures. The results for therapy cross-over indicate a potentially improved DFS with salvage chemotherapy. Results from this trial are hypothesis generating and merit evaluation in a larger clinical trial. Updated survival data will be presented. Clinical trial information: NCT00737438.
Early results of a randomized phase II, compass trial to compare regimen and duration of neoadjuvant chemotherapy for gastric cancer.
Authors: Yoshikawa Takaki , Tanabe Kazuaki , Nishikawa Kazuhiro , Ito Yuichi , Matsui Takanori , Kimura Yutaka , Morita Satoshi , Miyashita Yumi , Tsuburaya Akira , Sakamoto Junichi
Published: March 2020

4102

Background: Prognosis for stage III gastric cancer was not satisfactory even by D2 gastrectomy and adjuvant chemotherapy. Neoadjuvant chemotherapy is another promising approach. This study investigated the outcomes of two and four courses of neoadjuvant S-1/cisplatin (SC) and paclitaxel/cisplatin (PC) using a two-by-two factorial design for locally advanced gastric cancer. Methods: Patients with stage II schirrhous/junctional tumors, stage III, or resectable stage IV, received S-1 (80 mg/m2 for 21 days with 1 week rest)/cisplatin (60 mg/m2 at day 8) or paclitaxel/cisplatin (80 mg/m2 and 25 mg/m2, respectively, on days 1, 8, and 15 with 1 week rest). The primary endpoint was 3-year OS. Key secondary endpoints included pathological/clinical response, R0 resection, and adverse events. Sample size was set at 60 to 80 to achieve 10% improvement of 3-year OS by four courses or by PC with approximately 80% probability of the correct selection. Results: Between Oct 2009 and July 2011, 83 patients were assigned to arm A (2 courses of SC, n=21), arm B (4 courses of SC, n=20), arm C (2 courses of PC, n=21), and arm D (4 courses of PC, n=21). Clinical response (arm A/B/C/D) was 29%/40%/33%/24%. R0 resection (arm A/B/C/D) was 76%/75%/57%/76%. Pathological response (arm A/B/C/D), defined as tumor regression more than two third in the primary tumor, was 43%/40%/29%/38%. Pathological complete response (arm A/B/C/D) was 0%/10%/0%/10%. Major grade 3/4 toxicities (arm A/B/C/D) were anemia (14%/15%/0%/28.6%), neutropenia (10%/15%/14%/33%), nausea (0%/10%/5%/5%), and appetite loss (5%/10%/0%/5%). Pathological complete response by per-protocol analysis (arm B/D) was 17% and 12%. Treatment discontinuation (number of patients, arm A/B/C/D) was disease progression (1/3/0/1), toxicities (1/4/0/3), and others (0/1/0/0). No surgical mortality was observed. Grade 3 morbidity classified by Clavien-Dindo was leakage in 5% (arm A), pancreatic fistula in 5% (arm C), and postoperative hemorrhage in 5% (arm B). Conclusions: Pathological complete response could be induced by four courses of neoadjuvant chemotherapy without a marked increase of toxicities, regardless of a SC or PC regimen. Clinical trial information: UMIN000002595.