bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between plasma BRCA1 mRNA expression and sensitivity to docetaxel and cisplatin in gastric cancer.
Authors: Shen Jie , Wei Jia , Guan Wen xian , Wang Hao , Ding Yi tao , Qian Xiaoping , Yu Lixia , Zou Zhengyun , Xie Li , Taron Miquel , Rosell Rafael , Liu Baorui
Published: March 2020

e14509

Background: Tumor-derived RNA species successfully detected in plasma may have potential for use in disease and treatment assessment. Although BRCA1 mRNA expression levels in tumor are associated with cisplatin sensitivity but docetaxel resistance, the role of plasma BRCA1 mRNA as a predictive biomarker remains to be known. The aim of this study was to investigate the association between plasma BRCA1 mRNA expression and in vitro chemosensitivity to docetaxel and cisplatin in gastric cancer. Methods: 150 freshly-removed gastric tumor specimens and corresponding blood samples before surgery were collected. Docetaxel and cisplatin sensitivity was determined by histoculture drug response assay (HDRA) procedures. Plasma and tumor BRCA1 mRNA expression levels were determined by quantitative RT-PCR. Results: A significant correlation was observed between plasma and tumor BRCA1 mRNA expression levels (rho=0.558, P<0.001). Plasma BRCA1 mRNA expression level was positively correlated with in vitro sensitivity to docetaxel (docetaxel-sensitive sub-group: 1.25, 95% CI: 1.04-1.47; docetaxel-resistant sub-group: 0.50, 95% CI: 0.23-0.78; p<0.001) but negatively correlated with sensitivity to cisplatin in gastric cancer (cisplatin-sensitive sub-group: 0.84, 95% CI: 0.61-1.08; cisplatin-resistant sub-group:1.20, 95% CI: 0.84-1.56; p=0.083). There was no significant association between clinical characteristics and plasma BRCA1 mRNA levels or in vitro chemosensitivity. Conclusions: It was demonstrated for the first time that plasma BRCA1 mRNA expression was associated with in vitro chemosensitivity to docetaxel and cisplatin, which provided preliminary evidence for using plasma mRNA expression as an approach to predict response to docetaxel or cisplatin based chemotherapy in the clinic.
Multi-institutional experience using 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in patients with pancreatic cancer (PCA).
Authors: Goncalves Priscila Hermont , Ruch Joshua Michael , Byer Jennifer , Shields Anthony Frank , Choi Minsig , Kim Richard D. , Zalupski Mark M. , Philip Philip Agop
Published: March 2020

e14519

Background: FOLFIRINOX resulted in significant improvement in survival in a recent phase III trial. However, the toxicity associated with its use may be significant. Theobjectives of this study were to determine the tolerability and outcome in patients with advanced PCA treated with FOLFIRINOX in 3 cancer centers in the USA. Methods: This was a retrospective analysis in pts with PCA treated with FOLFIRINOX at Karmanos Cancer Center (Detroit, MI), University of Michigan (Ann Arbor, MI) and Moffitt Cancer Center (Tampa, FL) from 2010 to 2012. Results: 54 patients with advanced PCA (61%males, median age 57.5 years [range 34-73], 72 % Caucasians) were evaluable. 67% of the primary tumors were in the head of the pancreas and 48% of patients had biliary stents prior to treatment. ECOG performance status (PS) was 0-1 in 91%. 91% of the patients had stage IV disease mostly with liver metastases. The median number of cycles received per patient was 5 (1-24). At the outset of treatment, bolus 5FU was omitted in 15% of pts and granulocyte growth factor was given in 89% of the cases. 80% of patients experienced at least one grade 1 or 2 toxicity (fatigue in 44%). Grade 3 toxicities occurred in 26 (48%) pts (fatigue [9]; neutropenia [7]; vomiting [7]; diarrhea [5]; neuropathy [4]; anemia [4]; thrombocytopenia [2] and infection [2]). 13% of patients (7) experienced grade 4 toxicities (vomiting [3]; febrile neutropenia [2] and neutropenia [2]). There was no grade 5 toxicity. Dose reduction was necessary in 87% of pts. 17% of pts required hospitalization during treatment. Partial responses were documented in 39% and stable disease in 29%. Side effects were the reason for treatment discontinuation in 35% of this population. Median PFS and OS were 3.8 (0.9 – 13.6) and 7.2 (0.5 – 17.8) months, respectively. Conclusions: In this multi-institutional experience in pts with PCA, significant grade 3 and 4 toxicities were associated with the FOLFIRINOX regimen leading to treatment discontinuation in a third of the population. PFS and OS represented a modest improvement over what would be expected from using single agent gemcitabine despite the relatively high objective response rate.
A multicenter analysis of prognostic factors in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib.
Authors: Smith Alan D. , Chan Kelvin K. , Lim Howard John , Cheung Winson Y.
Published: March 2020

e14532

Background: Established clinical prognostic systems for advanced HCC were previously developed in the era of conventional chemotherapy. In 2008, the molecularly targeted agent sorafenib became the new standard of care. It is unclear if these existing models provide useful prognostic information for patients receiving sorafenib. Our aims were to: 1) evaluate the current utility of 4 known prognostic systems, including the Okuda, CLIP, BCLC, and French classification systems; and 2) identify new prognostic factors for patients treated with sorafenib. Methods: All patients diagnosed with advanced HCC from 2008 to 2010 and treated with sorafenib at any 1 of 6 regional cancer cancers in either British Columbia or Ontario, Canada were reviewed. Patients were risk-stratified using each of the 4 established prognostic systems to determine if these correlated with overall survival (OS). Cox proportional hazards models were also constructed to examine for associations between other clinical factors and OS. Results: Of 205 patients identified, 193 were evaluable: median age was 66 years, 79% were men, and 49% / 19 % / 16% had hepatitis B, C, and alcohol-related liver disease, respectively. The mean number of sorafenib cycles was 5.5 and median OS was 7.1 months. Of the 4 known prognostics models, only the French system proved useful where the high, intermediate, and low risk groups demonstrated a median OS of 2.4, 7.0, and 16.8 months, respectively (p<0.0001). Among other clinical factors, univariate analyses showed that poor performance status, presence of ascites, and large tumor size >5cm were associated with worse OS as were an elevated serum AFP, AST, GGT, or ALP level and a low albumin or hemoglobin level (all p<0.05). In multivariate analyses, none of these clinical factors continued to be independently predictive of outcome (all p>0.05). Conclusions: Except for the French classification system, clinical prognostic factors that were identified in the era of conventional chemotherapy were not useful in this Western cohort of advanced HCC patients treated with sorafenib. There is a need for molecular biomarkers that may provide better prognostic information.
Survival trends of patients with metastatic pancreatic cancer: A Surveillance Epidemiology and End Results registry trend analysis from 1988 to 2008.
Authors: Worni Mathias , Guller Ulrich , White Rebekah Ruth , Pietrobon Ricardo , Cerny Thomas , Gloor Beat , Koeberle Dieter
Published: March 2020

e14544

Background: Pancreatic adenocarcinoma (PAC) is a disease with dismal prognosis. Only a minority of patients with PAC presents with a resectable tumor and can potentially be cured. Therapeutic options for non-resectable, metastatic tumors are limited and chemotherapy with or without radiation is purely palliative. The aim of the present study was twofold: first, to evaluate predictors of overall survival (OS), and second, to assess trends in OS and in the use of palliative radiotherapy among patients with metastatic PAC. Methods: Patients with metastatic PAC were extracted from the SEER cancer registry from 1988 to 2008. While SEER does contain information regarding radiotherapy and surgery, data on chemotherapy cannot be ascertained. Predictors and trends of OS were assessed using univariate and multivariable Cox proportional hazard models. The trend in use of radiotherapy was analyzed using univariate and multivariable logistic regression models. Results: Overall, 23,387 patients were included (mean age: 68.0±11.8 years); 47.0% of patients were female, tumor location was in the pancreatic head in 57.7% of all patients. Median OS was 3 months. In risk-adjusted analyses, tumor location in the pancreatic body/tail was associated with worse overall survival compared to tumors of the pancreatic head (HR: 1.10, CI: 1.07-1.13, p<0.001). Increasing age, African-American ethnicity, male gender, and non-married civil status were associated with significantly worse OS. From 1988 to 2008, OS increased from a median survival of 2 (95% CI: 2-2) to 3 months (CI: 3-4) months (HR per year: 0.978, CI: 0.976-0.981, p<0.001). From 1988 to 2008, radiotherapy use decreased from 13.2% to 5.8% (adj. OR per year: 0.95, CI: 0.93-0.96, p<0.001). Conclusions: Metastatic PAC remains a disease with poor prognosis with only minimal improvement in OS over a 20-year time-period. The use of palliative radiotherapy has decreased. Tumor location in the body/tail of the pancreas, increasing age, African-American ethnicity, male gender, and non-married civil status were associated with worse OS. Future research is needed to improve OS of metastatic PAC on a population-based level.
A nomogram associated with high probability of malignant nodes in the surgical specimen after trimodality therapy of patients with esophageal cancer (EC).
Authors: Blum Mariela A. , Hayashi Yuki , Xiao Lianchun , Suzuki Akihiro , Sabloff Bradley , Maru Dipen M , Taketa Takashi , Welsh James , Lin Steven H , Lee Jeffrey H , Bhutani Manoop S. , Weston Brian , Hofstetter Wayne Lewis , Swisher Stephen , Ajani Jaffer A.
Published: March 2020

e14547

Background: The presence of malignant lymph nodes (+ypNodes) in the surgical specimen after preoperative chemoradiation (trimodality therapy) in patients with EC portends a poor prognosis for overall survival (OS) and disease-free survival (DFS). Currently, none of the clinical variables highly correlates with +ypNodes. We hypothesized that a combination of clinical variables could generate a model that associates with high likelihood of +ypNodes after trimodality therapy in EC patients. Methods: We report on 293 consecutive EC patients who received trimodality therapy. A multivariate logistic regression analysis that included pretreatment and post-chemoradiation variables identified independent variables that were used to construct a nomogram for +ypNodes after trimodality in EC patients. Results: Of 293 patients, 91 (31.1%) had +ypNodes. OS (p=0.0002) and DFS (p<0.0001) were shorter in patients with +ypNodes compared to those with –ypNodes. In multivariable analysis, the significant variables for +ypNodes were: baseline T-stage (odds ratio [OR], 7.145; 95% confidence interval [CI], 1.381-36.969; p=0.019), baseline N-stage (OR, 2.246; 95% CI, 1.024-4.926; p=0.044), tumor length (OR, 1.178; 95% CI, 1.024-1.357; p=0.022), induction chemotherapy (OR, 0.471; 95% CI, 0.242-0.915; p=0.026), nodal uptake on post-chemoradiation positron emission tomography (OR, 2.923; 95% CI, 1.007-8.485; p=0.049), and enlarged node(s) on post-chemoradiation computerized tomography (OR, 3.465; 95% CI, 1.549-7.753; p=0.002). The normogram after internal validation using the bootstrap method (200 runs) yielded a high concordance index of 0.756. Conclusions: Our nomogram highly correlates with the presence of +ypNodes after chemoradiation and upon validation; it could prove useful in individualizing therapy for EC patients. Supported by UTMDACC and generous donors.
Inverse-probability weighted and propensity score-based analysis of long-term clinical outcomes comparing 3D conformal radiotherapy (3DCRT) with intensity-modulated radiation therapy (IMRT) in the treatment of esophageal cancer.
Authors: Lin Steven H. , Wang Lu , Myles Bevan H , Thall Peter F. , Hofstetter Wayne Lewis , Swisher Stephen , Lee Jeffrey Edwin , Bhutani Manoop S. , Maru Dipen M , Ajani Jaffer A. , Ho Linus , Cox James D. , Komaki Ritsuko , Liao Zhongxing X.
Published: March 2020

e14548

Background: IMRT has clear dosimetric advantages in the sparing of normal tissues when compared to the more conventional 3DCRT technique for the treatment of esophageal cancer, but there is currently no clinical outcomes evidence to support the use of IMRT. We hypothesized that the theoretical advantages of IMRT should translate to clinical outcomes benefits compared to 3DCRT. Methods: We analyzed a cohort of 676 patients (3DCRT=413, IMRT=263) treated with chemoradiation with or without surgery between 1998-2008. To correct for potential bias inherent in observational studies, we employed inverse probability of treatment weighted (IPW) methods based on propensity scores. Treatment probabilities (propensity scores) were estimated using logistic regression. Results: IMRT patients were less likely to receive induction chemotherapy and had poorer performance status. A fitted multivariate IPW-adjusted Cox model showed that overall survival was significantly associated with age, KPS, having surgery, tumor location, stage, having PET for staging, and radiation modality. Compared to IMRT, 3DCRT patients had a significantly greater risk of dying (72.6% vs 52.9%, IPW log rank test: p<0.0001) and for local-regional recurrence (LRR) (p=0.0038). The improvement in LRR was only apparent in the non-surgically treated patients due to better tumor control in the primary site, but not in the recurrence in regional nodal sites. There was no difference in cancer-specific mortality, distant metastasis, or postoperative deaths between the two groups. An increased cumulative incidence of cardiac deaths was seen in the 3DCRT group (p=0.049), but the cause of most deaths were unknown (5 year estimate: 11.7% in 3DCRT vs 5.4% in IMRT, Gray’s test, p=0.0029). Analyses using propensity score as a covariate gave very similar results. Conclusions: Our results indicate IMRT improves treatment outcomes in the management of esophageal cancer when compared to 3DCRT. These results, while retrospective, support the use of IMRT for the treatment of esophageal cancer.
Baseline demographics of neuroendocrine tumor patients presenting to seven National Comprehensive Cancer Network (NCCN) institutions: Development of a multi-institutional outcomes database.
Authors: Zornosa Carrie C. , Choti Michael A. , Bobiak Sarah , Kulke Matthew , Yao James C. , Bergsland Emily K. , Nakakura Eric K. , Bloomston Mark , Benson Al B. , Shah Manisha H. , Strosberg Jonathan R.
Published: March 2020

e14551

Background: Diagnostic strategies, management paradigms, and clinical outcomes of patients with neuroendocrine tumors (NETs) are diverse and poorly characterized. The National Comprehensive Cancer Network (NCCN) created a comprehensive database to characterize patients treated for NETs at seven participating institutions. Preliminary results from the database are reported. Methods: Member IRB approval was obtained to identify patients at least 18 years of age presenting to each of seven NCCN institutions between 2004 and 2007 with pathologically confirmed newly or previously diagnosed NETs via hospital medical records. Eligible patients included those with carcinoid (any site); goblet cell or adenocarcinoid; composite carcinoid; poorly differentiated gastrointestinal small cell tumor; pancreatic NET; NET of unknown primary site; pheochromocytoma; and paraganglioma. Baseline demographic characteristics were summarized for this analysis. Results: Among the 2,798 patients identified with a NET diagnosis, patients most frequently presented with carcinoid tumor (53%), pancreatic NET (26%) and NET of unknown primary site (8%). Median age at diagnosis was 56 (SD=14). Fifty-three percent of patients were female. Most (86%) were Caucasian and 8% were African American. Thirty percent of patients were diagnosed with NET before presenting to the NCCN. Among these, the median time between initial NET diagnosis and presentation to the NCCN was 2 years (SD=6). Significant differences in provider specialty referral patterns were observed between institutions. The institutional point of entry for the majority of patients was medical oncology (institutional range: 17-93%) or surgery (institutional range: 3-62%). Conclusions: The baseline demographic characteristics of NET patients in this new database are consistent with those previously reported in population-based registries. The database will provide a valuable resource for further exploration of patterns of diagnosis, treatment, and consistency with established guidelines, as well as clinical outcomes in patients with this condition.
A phase II study of the histone deacetylase inhibitor panobinostat (LBH589) in low-grade neuroendocrine tumors.
Authors: Rajguru Saurabh , Lubner Sam Joseph , Mulkerin Daniel , Schelman William R. , Winterle Natalie , Holen Kyle D. , Leverson Glen , Chen Herbert , LoConte Noelle K.
Published: March 2020

e14554

Background: Neuroendocrine tumors (NETs) are a diverse and rare group of neoplasms arising from the neuroendocrine system. The most common subtypes are pancreatic islet cell tumors and carcinoid tumors. Although they represent only 2% of all gastrointestinal malignancies, given their overall favorable prognosis, the prevalence is much higher. Histone deacetylase (HDAC) inhibitors have already been shown to suppress tumor growth and induce apoptosis in a variety of solid tumors in preclinical data. We have previously shown that in NET cells, HDAC inhibitors have resulted in increased Notch1 expression and subsequent inhibition of growth. Methods: A single arm phase II study was performed. Adult patients with histologically confirmed, metastatic, low-grade NETs and an ECOG performance status of ≤ 2 were treated with the oral HDAC inhibitor panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. Results: 15 patients were accrued and 13 were evaluable for response (66.7% male, age range 40-80 years old (mean 59.4 years old), 66.7% carcinoid, 33.3% pancreatic NET). The median number of prior therapies was 1 (range 0-2) and no patient had previously received everolimus. The response rate was 0%. The stable disease rate was 92.3% as defined by stability seen on the first CT scan. Median progression-free survival was 11.8 months. The 1 year PFS was 42%. Thrombocytopenia and fatigue were the most common treatment-related grade 3 toxicities. There was one grade 4 toxicity of thrombocytopenia. The study was stopped early at the planned interim analysis based on lack of meaningful clinical efficacy outlined in the Simon two-stage design. Conclusions: The HDAC inhibitor panobinostat had infrequent grade 3 and 4 events in this patient population and resulted in a large percentage of subjects with disease control. The disease control rate, however, needs to be considered in the context of the typical slow growth rate of NETs. These data alone do not support continued evaluation of HDAC inhibitors in low-grade NETs. This study was supported by Novartis.
Complete clinical (CC) responders to definite chemoradiation or radiation therapy (CRT/RT) for esophageal cancer (EC): A survival analysis.
Authors: Mirabel Xavier , Tresch Emmanuelle , Romano Olivier , Dewas Sylvain , Amela Eric , Fournier Charles , Clisant Stephanie , Mariette Christophe , Adenis Antoine
Published: March 2020

e14560

Background: For pts with EC being treated with definite CRT/RT, predictors of outcome are baseline nutritional status and CC response to CRT. As data concerning predictors of outcome for CC responders are lacking, we tried to identify them. Methods: Among 402 consecutive pts with EC who underwent definite CRT/RT in our institution from 1/1998 to 12/2003, 110 were found CC responders, and were retrospectively reviewed. Baseline staging included endoscopy with biopsies, and CT-scan and/or EUS. CC responders were defined as pts without evidence of tumor on morphological examination with biopsies, 4 to 6 weeks after treatment. Univariate and multivariate analyses were performed using log-rank and Cox proportional hazards models, and survival curves were estimated using the Kaplan-Meier method. Results: Pts were staged according to EUS-AJCC staging (stage I-II=39, stage III-IVa=37, ukn=34) and/or CT staging (stage I-II=54, stage III-IVa=32, ukn=24). Baseline pt and tumor characteristics were as follows: M/F = 98/12, median age = 60, ADK/SCC = 7/103, tumor site (upper/middle/lower third) = 41/50/19, weight loss none/<10%/≥10% = 36/45/29, dysphagia gr.0/1/≥2 = 30/14/65. Pts received a median dose of RT of 50.4Gy (30-65), and concomitant chemotherapy in 95/110 cases. Post treatment nutritional characteristics were : weight loss during treatment none/<10%≥10% = 35/38/37, remaining dysphagia gr.0/1/≥2 = 54/24/32. During follow up (median: 6 [0.4-9.8] years), 16 pts got esophagectomy (recurrence: 3, some reasons: 13). Median survival was 2.5 years, and 3- and 5-year survival rates were 46.9%, and 33.5%, respectively. Neither TNM classification nor stage grouping, histological type, gender, or treatment types were found to have any influence on outcome. Predictors of improved OS were: absence of weight loss during treatment, and absence of dysphagia with normal oral intakes after treatment. Conclusions: One EC pt out of 3 with CC response after definite CRT/RT is still alive at 5 years. The absence of weight loss during treatment, and of remaining dysphagia after treatment are significant predictors of better survival in pts found CC responders to definite CRT/RT for EC.
The effect of telotristat etiprate on clinical and biochemical responses in patients with symptomatic carcinoid syndrome: Preliminary results of an ongoing phase II, multicenter, open-label, serial-ascending dose study.
Authors: Wiedenmann Bertram , Pavel Marianne E. , Seufferlein Thomas , Freiman Joel , Law Linda , Banks Phillip Lee , Frazier Kenneth , Jackson Jessica , Zambrowicz Brian
Published: March 2020

e14564

Background: Excess serotonin (5-HT) may contribute to gastrointestinal (GI) symptoms such as diarrhea in carcinoid syndrome (CS) patients. Telotristat etiprate, an oral serotonin synthesis inhibitor (SSI), is designed to reduce peripheral 5-HT levels and alleviate GI distress. Methods: This study evaluates the safety and tolerability of ascending doses (150 mg, 250 mg, 350 mg, and 500 mg tid) of telotristat etiprate in symptomatic CS patients, averaging ≥4 bowel movements (BMs)/day, either therapy-naïve or receiving somatostatin analogs. Secondary objectives include symptomatic response (change in: number of BMs/day, stool form/consistency, sensation of urgency to defecate, sensation/severity of nausea, global assessment of symptoms, assessment of abdominal pain/discomfort, reduction of cutaneous flushing episodes), and assessment of plasma drug concentrations, pharmacokinetics, and pharmacodynamics (urinary 5-hydroxyindolacetic acid [u5-HIAA] and blood 5-HT). All patients began dosing at 150 mg. Dose will be increased following 2 weeks of therapy with no dose-limiting toxicity. If dose-limiting toxicities occur, the dose will be reduced to prior level. Treatment will continue at the individual maximum-tolerated dose for 4 weeks; patients may elect to continue in an extension phase. Results: As of 1/2012, 13 patients, refractory to octreotide LAR have enrolled and been treated with telotristat etiprate. Eight (8) of 9 patients have completed the 12-week ascending dose study and 6 of 6 eligible patients have enrolled into the long-term extension, up to 72 weeks; 4 more patients are eligible for the long-term extension. Mean age: 63 years (range 51-81), mean BMs at baseline: 6.0 (range 4.7-8.5) for the 9 patients. Upon completion of 12 weeks of dosing, 7 of 9 patients (78%) had sustained reductions of ≥30% in BMs/day. All 7 of these patients had multiple assessments indicating ≥50% BM reductions) during the 6 weeks while on their highest dose. No major safety issues were detected. Conclusions: Telotristat etiprate produced biochemical and clinical responses/benefit in CS.
The impact of HER2 positivity on survival in metastatic gastric and GEJ cancer in the province of British Columbia: An updated analysis.
Authors: Lim Howard John , Kumar Aalok , Zhou Chen , Huntsman David , Kollmannsberger Christian K. , Gill Sharlene
Published: March 2020

e14568

Background: HER2 positive gastric (GC) and GEJ adenocarcinoma has been associated with a worse survival outcome. This study examines the survival rate of patients with metastatic HER2 positive GC and GEJ adenocarcinomas in the province of BC. Methods: Formalin fixed embedded tissue from patients (pts) with resected gastric or GEJ adenocarcinoma from 2004-2011 were identified retrospectively through the BC Cancer Agency registry and prospectively for pts with a new diagnosis of advanced disease. Biopsies and resection samples were analyzed via previously validated methods. IHC scores of 3 were considered positive (+), 2 were equivocal and 0 or 1 were negative (-). A 10% cut-off was used to determine positive samples. Equivocal staining was considered positive via FISH or SISH with a ratio of > 2.2 considered amplified. Patient characteristics were abstracted to an anonymized database. Kaplan-Meier curves were calculated to evaluate overall survival from time of diagnosis or relapse to death for pts with HER2 + or - disease. Results: 179 of 304 pts were identified with metastatic or relapsed gastric or GEJ adenocarcinoma without Traztumumab treatment. 21 (12%) pts were HER2 + either by IHC, FISH or SISH. Refer to the table for characteristics of both groups. Median survival was not significantly different among HER2 + and - pts (4.0 mo vs. 7.3 mo, p=0.089). Conclusions: The rate of HER2 positivity is similar to that seen in trial data. HER2 positivity trends to a worse prognosis but was not significant in this study. [Table: see text]
A phase II study of lapatinib and capecitabine in second-line treatment of metastatic pancreatic cancer.
Authors: Wu Zheng , Marshall John , Hwang Jimmy J. , Pishvaian Michael J. , Wellstein Anton , Weiner Louis M. , He Aiwu Ruth
Published: March 2020

e14569

Background: The anti-EGFR therapy erlotinib was FDA approved for the treatment of patients with advanced pancreas cancer. Human epidermal growth factor receptor 2 (HER-2), a member of the ErbB family of growth factor receptor tyrosine kinases to which EGFR belongs, is found overexpressed in 20% of pancreatic cancers . Targeting EGFR and HER-2 with separate specific monoclonal antibodies showed synergistic inhibition of pancreatic cancer tumor progression in mice bearing xenograft of human pancreatic cancer cell lines. We performed an open-label single arm phase II study to evaluate the combination of lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2, and capecitabine in the second-line treatment of metastatic pancreatic cancer. Methods: Patients with metastatic, unresectable, gemcitabine-refractory pancreatic cancer with adequate performance status (ECOG 0-2) and normal hepatic and renal function were eligible. Patients received lapatinib 1,250 mg PO daily, and capecitabine 1,000 mg/m2 PO twice daily on days 1-14 of each 21-day cycle. Restaging studies were performed every 2 cycles. The primary endpoint was median overall survival (OS). Secondary endpoints included response rate (RR) and progression free survival (PFS). Results: Between 9-2009 and 8-2011, 17 patients received treatment. Six of 17 patients (24%) had disease progression after 2 cycles, 2 of 17 patients (12%) progressed after 4 cycles and 4 of 17 patients (24%) had stable disease and received more than 6 cycles. The median number of treatment cycles was 3 (range 1-22 cycles). The median PFS was 9 weeks (95% CI 7.1-18.9). Median OS was 25 weeks (95% CI 11 -34). Grade 3 nausea, vomiting in 3 patients (17%), grade 3 diarrhea in 2 patients (12%), grade 3 limb edema in 1 patient (6%), and grade 3 fatigue in 1 patient (6%). Serum was collected at baseline, three weeks and time of disease progression for microRNA analysis to identify biomarkers correlated with clinical outcome. Conclusions: The combination of lapatinib and capecitabine is a tolerated regimen for patients with gemcitabine-refractory metastatic pancreatic cancer. Some patients were able to receive 6 or more cycles of therapy. Molecular analysis of patients’ biosamples is ongoing.
A phase I/II study of oral paclitaxel in patients (pts) with advanced gastric cancer.
Authors: Lee Kyung Hee , Park Young-Iee , Zang Dae Young , Lee Keun-Wook , Shin Dongbok , Park Kyung-Mi , Son Jeewoong , Bang Yung-Jue
Published: March 2020

e14572

Background: Paclitaxel is not absorbed from GI tract because of the over- expression of P-glycoprotein by intestinal cells. In previous study, Oraxol, which composed of paclitaxel solution and HM30181A tablet, a novel P-glycoprotein inhibitor, had been administered to 25 pts with advanced solid cancer. Thereafter, the formulation of Oraxol was changed from paclitaxel slolution to paclitaxel capsule. Methods: Primary objective for Phase I study was to determine the maximum tolerable dose (MTD) or recommended dose (RD) of Oraxol using standard 3+3 dose escalation design at three pre-specified doses (180, 240, 300 mg/m2/week of paclitaxel capsule, fixed dose of 15 mg/day HM30181AK tablet). Oraxol was administrated twice a week, total 6 times per cycle (day 1, 2, 8, 9, 15 and 16), every 4 weeks.Eligible ptswere ≥ 19 years with advanced malignancies refractory to standard therapies in Phase I portion. Primary objective for phase II study was to evaluate the clinical response of pts with advanced or metastatic/recurrent gastric cancer after failure of 1 previous chemotherapy. In the phase II study, patients were enrolled in 2 stages Results: In pase I study, 10 pts were enrolled and 4 had treatment-related AEs. One pt had treatment-related grade 3 anemia, 2 pts had treatment-related grade 2 AEs: neutropenia, thrombocytopenia and asthenia. No DLT was observed in the dose range of this study and the RD for phase II was defined at 300 mg/m2/week (150 mg/m2 x 2) based on the safety profiles and plasma concentration profiles. The phase II study is ongoing. Thirty patients have been enrolled to date. Of 25 pts evaluable for efficacy, 1 had complete response (not confirmed) after 8 weeks of therapy, 3 subjects had partial response (duration of treatment: 8.83 mo+, 3.07 mo+, 3.03 mo+), and 10 had stable disease (SD) as best response. Conclusions: Oraxol has been well tolerated and has shown promising efficacy in gastric cancer patients. Updated results will be presented at the meeting.
Above-label doses of octreotide-LAR in patients with metastatic small-intestinal carcinoid tumors.
Authors: Weber Jill M. , Feldman Max , Kvols Larry , Strosberg Jonathan R.
Published: March 2020

e14579

Background: Octreotide LAR is indicated for treatment of the malignant carcinoid syndrome, and has been studied at doses of 10-30mg intramuscularly every 4 weeks. It has also been proven to delay time to progression of metastatic midgut carcinoid tumors at a dose of 30mg every 4 weeks. In clinical practice, higher doses are often prescribed for patients who experience refractory carcinoid syndrome (flushing and/or diarrhea) or tumor growth while on the maximal labeled dose. We performed a retrospective, longitudinal review of octreotide LAR administration at a tertiary institution to determine the frequency of ‘above-label’ dosing and outcomes. Methods: A retrospective chart-review was performed using a database of patients with metastatic small-bowel carcinoid tumors treated at the Moffitt Cancer Center between the years 2000 and 2010. Data included the maximal dose of octreotide LAR administered, reasons for change in dose or frequency (above the labeled dose of 30mg every 4 weeks), and clinical responses to dose change. Results: 337 patients were considered evaluable, among whom 99 patients (27%) underwent at least one increase in dose or frequency of octreotide-LAR above the standard labeled dose. The most common maximal doses were 40mg every 4 weeks (37 patients), 60mg every 4 weeks (34 patients), and 30mg every 3 weeks (17 patients). The indications for dose increase were worsening carcinoid syndrome (60 patients), radiographic progression (33 patients) and rising urine 5-HIAA (6 patients). Among patients whose doses were increased for refractory carcinoid syndrome, 62% experienced improvement in diarrhea and 56% experienced improvement in flushing. Conclusions: In clinical practice, octreotide LAR is commonly prescribed in doses or schedules above the labled dose and frequency. Patients with refractory carcinoid syndrome appear to experience a clinical benefit from the change. Prospective data is needed to evaluate this strategy.
Risk factors for sporadic pancreatic neuroendocrine tumors (PNETs): Updated results from a single-center case control study.
Authors: Halfdanarson Thorvardur Ragnar , Bamlet William R , McWilliams Robert R. , Hobday Timothy J. , Burch Patrick A. , Petersen Gloria M.
Published: March 2020

e14594

Background: PNETs are uncommon malignancies and little is known about risk their factors and association with other cancers. Our aim was to evaluate smoking, alcohol use, personal history of diabetes and a family history of PNET and other cancers as potential risk factors. Methods: PNET cases seen at Mayo Clinic Rochester from 2000 to 2011 were evaluated. Insulinoma and high-grade PNETs were excluded. Primary care patients served as controls and were matched (2:1 ratio) to cases on age, sex and region of residence. Cases and controls completed questionnaires at the time of evaluation. Categorical variables were compared with the chi-square test; continuous variables were compared using a two-sample t test. Results: 355 cases were evaluated, mean age was 56.6 years, 52% were males and 96% were White. Personal smoking history was not associated with PNETs (cases 51%, controls 47%, p=0.24). Ever-alcohol use was less common among cases (54% vs. 67%, p=0.001). 19% of cases reported a history of diabetes compared with 11% of controls (p<0.001). Cases were more likely than controls to report a family member with sarcoma (p=0.02), PNET (p=0.024), gall bladder cancer (p=0.024), ovarian cancer (p=0.04) and stomach cancer (p=0.01). Conclusions: Cases with PNETs were more likely than controls to report a history of diabetes and less likely to report alcohol use. There was no association with smoking. Several types of cancer were more commonly reported in family members of cases than controls.
Serum levels of macrophage inhibitory cytokine-1 (MIC1) and matrix metallopeptidase-7 (MMP7) as diagnostic and prognostic markers in gastric cancer (GC) patients (pts).
Authors: Valladares-Ayerbes Manuel , Tarrío Nuria , Blanco-Calvo Moisés , Haz-Conde Mar , Santamarina Cainzos Isabel , Medina Villaamil Vanessa , Rodríguez-Rigueiro Teresa , Figueroa Angelica , Reboredo Margarita , Antón-Aparicio Luis
Published: March 2020

e14595

Background: MIC1 and MMP7 are secreted cytokines involved respectively in the modulation of immunological processes and in extracellular matrix remodeling. Their expression were found deregulated in different tumors, including GC. However, few data are available about their serum levels, their diagnostic potential, and their prognostic significance in GC pts. Here, we analyze the diagnostic performance of these markers and we present data linking them with short survival in GC pts. Methods: Serum samples were assayed in duplicate for MIC1 and MMP7 levels by ELISA. The diagnostic performance of markers was assessed by ROC curve analysis and the cut-offs were set using the Youden index approach. The cut-offs for prognostic purposes were determined using X-tile software. Differences in progression free (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and logrank test. Cox regression was used to determine the prognostic independence of biomarkers. Results: From November 2006 to July 2010, 52 GC pts and 28 healthy donors were consecutively recruited. The follow-up of pts was performed until their death or the end of study (September 2011). The AUCs for MIC1 and MMP7 were respectively 0.897 and 0.865 (p < 0.001). Using the optimal cut-off to diagnose GC pts, we obtained a 73.08% of sensitivity (Ss) and a 92.86% of specificity (Sp) for MIC1, and a 78.85% of Ss and an 85.71% of Sp for MMP7. In the survival analysis, high serum levels of MIC1 and MMP7 were significantly associated with shorter PFS (p < 0.001) and OS (p < 0.001 and p = 0.003, respectively). In univariate analysis, pts with high serum levels of MIC1 and MMP7 had an increased risk of progression (HR = 3.608, p<0.001 for MIC1; HR = 4.172, p<0.001 for MMP7) and death (HR = 3.843, p=0.001 for MIC1; HR = 2.602, p=0.006 for MMP7). However, MIC1 and MMP7 failed to reach prognostic independence in multivariate analysis. Conclusions: We obtained cut-off values of MIC1 and MMP7 in serum for diagnostic purposes in GC. In addition, we established a correlation between increased levels of MIC1 and MMP7 in serum and shorter PFS and OS in GC. These findings justify studies with a larger number of pts.
Evaluation of transcatheter arterial chemoembolization (TACE) plus sorafenib in Chinese patients with unresectable hepatocellular carcinoma: A subgroup analysis of START trial.
Authors: Han Guohong , Yang Jijin , Shao Guoliang , Teng Gaojun , Wang Maoqiang , Yang Jianyong , Liu Zhaoyu , Feng Gansheng , Yang Renjie , Lu Ligong , Chao Yee , Wang Jianhua
Published: March 2020

e14605

Background: The therapeutic effect of TACE plus Sorafenib (Sor) for unresectable hepatocellular carcinoma (uHCC) was evaluated in the START (Study in Asia of the Combination of TACE with Sor in Patients with Hepatocellular Carcinoma) trial. The preliminary results presented at ILCA 2011 showed encouraging safety and efficacy profiles of TACE plus Sor in HCC, with a median time to progression (TTP) of 9.3 months and median overall survival (OS) not reached. Here we present results of a subgroup analysis of Chinese patients with more updated data. Methods: Patients with uHCC and candidates for TACE were enrolled. TACE with lipiodol and doxorubicin (30-60 mg) was performed every 6 to 8 weeks. Sor (400mg bid) was administrated 4 days after first TACE, and then continuously with interruption 3 days before and after the TACE procedure. Tumors were assessed 4 weeks after every TACE, and every 3 months thereafter if no TACE was indicated. Patients who do not require TACE due to complete response or intolerability continued to receive Sor until disease progression (PD) or unacceptable toxicity. This analysis was conducted to evaluate the efficacy of TACE plus Sor on TTP based on modified RECIST criteria, OS and response rate (RR) in Chinese patients with uHCC. Cut-off date for the efficacy analysis is Sep 30th, 2011. Because no new or unexpected side effects were noted during this study period, safety data were not collected in this subgroup analysis. Results: A total of 64 patients enrolled from Sep. 2009 to Apr. 2010, were evaluated. The median age was 62 yr (range, 31-75) and all patients were ECOG Performance Status 0-1. The main etiology for HCC was hepatitis B in 94.9% of patients. The mean dose of Sor in this group of patients is 787.63mg.The median treatment duration was 6.4 months. The median TTP was 10.6 months, and the median OS was 16.5 months. The objective RR was 44.3%, and 11.5% of patients had PD. Conclusions: This subgroup analysis suggests that Chinese patients with uHCC may benefit from TACE and Sor combination therapy, with better improvement of TTP, compared to the interim analysis results of the overall population from the START trial.
Correlation between toxicity and outcome after multimodality therapy of locoregionally advanced (LRA) adenocarcinoma (ACA) of the esophagus (E) and gastroesophageal junction (GEJ).
Authors: Osei-Boateng Kwabena , Rybicki Lisa A. , Rice Thomas W. , Rodriguez Cristina P. , Videtic Gregory M.M. , Saxton Jerrold P. , McNamara Michael J. , Ives Denise I. , Bodmann Joanna , Adelstein David J.
Published: March 2020

e14611

Background: Multiagent concurrent chemoradiation (CRT) and surgery is a standard curative-intent approach for patients (pts) with LRA ACA of the E/GEJ. This single institution retrospective analysis examined whether toxicities occurring during induction chemoradiation (ICRT) were independently prognostic for outcome. Methods: Between 11/99 and 7/06, 152 pts with T3, N1 or M1a ACA of the E/GEJ were entered onto one of two Cleveland Clinic trials. ICRT with 96 hour infusions of cisplatin (20mg/m2/d) and fluorouracil (1000mg/m2/d) beginning on day 1 of radiation (30Gy@1.5Gy bid), was followed by surgery and identical post-operative CRT. 75 pts also received 2 years of oral gefitinib. Multivariable Cox analysis was used to identify prognostic factors for overall survival (OS), freedom from recurrence (FFR), locoregional (LRC) and distant metastatic control (DMC). Both clinical features (including demographics, tumor characteristics, symptomatic and pathologic response), and ICRT- related toxicities (including nausea/vomiting, mucositis/dysphagia, neutropenia, thrombocytopenia, neutropenic fever and any unplanned hospitalization) were analyzed. Results: Of the 152 pts enrolled, resection proved possible in 138 (91%). With a median follow-up of 90 (range 57-126) months, the 5-year Kaplan-Meier projected OS is 22%, FFR 24%, DMC 27% and LRC 69%. As expected, in multivariable analysis, earlier clinical stage disease and a pathologic and symptomatic response to ICRT all proved favorable for treatment outcomes. In addition, the development of grade 3-4 (vs. grade 0-2) mucositis and/or dysphagia during ICRT was a significant risk factor for distant recurrence [HR 2.62 (1.34-5.12), p=0.005]; any recurrence [HR 2.08 (1.08-4.00), p=0.027] and death [HR 2.00 (1.07-3.74), p=0.031]. Neutropenic fever was also correlated with distant recurrence [HR 1.82 (1.03-3.22, p=0.039] and any recurrence [HR 2.19 (1.23-3.90) p=0.007]. Conclusions: Neutropenic fever and the development of grade 3-4 mucositis and/or dysphagia during ICRT are independently associated with worse outcomes after multimodality therapy for E/GEJ ACA.
Retrospective evaluation of resected ampulla of vater adenocarcinoma (AOVA): Clinicopathologic variables and long-term outcomes—REAL study.
Authors: Desai Neelam Vijay , Zuluaga Toro Tania , Duckworth Lizette Vila , Sommerfeld Alex , Alkhasawneh Ahmad , Hou Wei , Ivey Alison , George Thomas J.
Published: March 2020

e14612

Background: AOVA accounts for about 1% of GI cancers. 30% of patients receive curative intent resection with 5-year survival between 20-50%. Limited data are available concerning the value of adjuvant therapy. AOVA may be intestinal or biliary based on histology with each associated with a different natural history and prognosis. This study aims to characterize clinicopathologic features of this disease and associate these with outcomes. Methods: An IRB-approved retrospective review of all patients at the University of Florida between 2000-2011 was undertaken to identify patients with resected AOVA. Periampullary tumors were excluded. Independent histologic review to define intestinal versus biliary subtype and molecular phenotype (including CK 7, 19, 20, SMAD4, CDX2 and MUC1) was undertaken. Chi-square test was used to determine significance between variables. Results: 68 total patients were identified and analyzed. Clinical variables, relapse and survival data are presented (Table). For patients <70 years old, median OS was 69 months vs 13 months for patients >70 years (P=0.0115). Histologic and molecular subgroup analysis is ongoing. Conclusions: AOVA long-term outcomes are consistent with previous publications with 5-year survival of 32%. Age and stage appear to have a substantial impact on survival. Histologic and molecular analysis may further define patient subsets and will be reported. [Table: see text]
Use of inflammation-based prognostic score to predict survival in patients with advanced gastric cancer receiving biweekly docetaxel and S-1 combination chemotherapy.
Authors: Kunisaki Chikara , Takahashi Masazumi , Ono Hidetaka , Oshima Takashi , Fujii Shoichi , Kosaka Takashi , Makino Hirochika , Akiyama Hirotoshi , Endo Itaru
Published: March 2020

e14624

Background: The Glasgow Prognostic Score (GPS), an inflammation-based prognostic score composed of C-reactive protein (CRP) and albumin measurements, has been reported to be a prognostic factor in patients with various cancers. This study was conducted to determine the prognostic value of GPS for patients with advanced cancer. Methods: The GPS was classified according to a previous study. A total of 83 advanced gastric cancer patients receiving bi-weekly docetaxel/S1 treatment (DS) were included. Correlation of clinicopathological factors and the GPS was assessed. To identify the impact of GPS as prognostic factors for disease-specific survival (DSS) and progression-free survival (PFS), univariate and multivariate analyses were performed. Results: Of these 83 patients, unresectable tumors were observed in 78 patients and recurrent tumors were detected in 5 patients. Of these, 13 patients underwent surgery and 12 patients underwent gastrectomy. There were significant correlations between the GPS and the neutrophil to lymphocyte ratio (NLR). Univariate analysis revealed that the GPS, ECOG-PS and gastrectomy after DS treatment significantly affected prognosis. The Cox proportional regression hazard model showed that the GPS, age and gastrectomy independently influenced DSS, and that the GPS and gastrectomy also influenced PFS. The Cox proportional regression hazard model restricted patients without gastrectomy showed that the GPS and age independently influenced DSS, and that the GPS influenced PFS. Conclusions: The GPS may be an useful prognostic factor for advanced gastric cancer patients receiving uniform first-line treatment (DS). The impact of the GPS should be confirmed in a well-designed prospective trial in many patients.