bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemangiogenic response after pre-operative COX2 inhibition predicts recurrence in esophageal cancer
Authors: Jin D. , Port J. L. , Lee P. , Zhang L. , Ferrara C. A. , McDonald K. A. , Meherally D. , Rafii S. , Altorki N. K.
Published: March 2020

15077

Background: Growth of esophageal cancer involves a proliferative hemangiogenic component. Biomarkers that predict this propensity in esophageal cancer and the impact of anti-angiogenic strategy on their levels as well as clinical response remain unknown. Methods: A multimodular approach was devised to assess hemangiogenic parameters in a cohort of chemotherapy naïve patients with locally advanced (T2-T3N0, T1-T3N1M0M1a) esophageal cancer pre- and 4 days post-celecoxib neoadjuvant treatment. Patients went on to receive neoadjuvant therapy with celecoxib, paclitaxel and carboplatin for 3 cycles, followed by surgical resection. This bioassay panel consists of 5 components: i) HUVEC-based angiogenic scale for functional plasma angiogenic activity, ii) flow cytometry to quantify CD133+VEGFR2+ circulating endothelial progenitors (CEPs), iii) hematopoietic colony-forming assay to quantify circulating hematopoietic progenitors (CHPs), iv) plasma SDF-1 level, and v) platelet VEGF-A level. Results: The cohort consists of 8 consecutive patients (6 men, 2 women) with median age of 58. After 18 months of followup, 6 patients remained alive and without evidence of recurrence, while 2 had tumor recurrence and metastasis. Analysis of the positive responders (pre-celecoxib baseline versus 4 days post treatment) revealed a global suppression of hemangiogenic parameters with reduction of the functional HUVEC-based angiogenic scale (mean score of 3.3 versus 1.8; p<0.05), 2.2-fold decrease in CEPs (p<0.05), and 3-fold decrease in CHPs (p<0.05). This trend also correlated with decreased plasma SDF-1 and platelet VEGF-A levels . However, in the 2 cases of tumor recurrence, the initial hemangiogenic response was blunted with no significant difference in all parameters tested during the celecoxib monotherapy period. Conclusion: Esophageal cancer development involved a hemangiogenic switch toward increased CEPs, CHPs, and functional plasma pro-angiogenic activity. COX2 inhibition with celecoxib normalized the hemangiogenic profile. Collective assessment of hemangiogenic biomarkers during neoadjuvant setting may be a promising tool in predicting clinical outcomes, recurrence, and for validating impact of anti-angiogenic therapy on esophageal cancer.

No significant financial relationships to disclose.
Neoadjuvant chemotherapy (CT) and postoperative chemoradiation (PCRT) in locally advanced, resectable, gastric cancer (LAGC). Preliminary results of a pilot study
Authors: Buonadonna A. , De Paoli A. , Sigon R. , Cannizzaro R. , Canzonieri V. , Boz G. , Innocente R. , Rossi C. , De Marchi F. , Frustaci S.
Published: March 2020

15078

Background: Curative surgery is achieved in fewer than 50% of patients (pts) in LAGC. PCRT has shown significant improvement in disease control and survival but a limited impact on metastatic disease. To improve this results, a combined modality approach, including IORT, was planned. Methods: Pts with resectable LAGC (stage T3–4 and/or N+) were eligible. EGDS, EUS, abdomen CT were used for staging. 3 cycles of ECF (Epirubicin 50mg/mq, q 3wks; Cisplatin 60mg/mq, q 3wks and 21-day c.i. 5-FU 200mg/mq/day) were planned before radical surgery. IORT (10–15 Gy) included the high risk area defined at surgery. Postop RT included gastric area, anastomosis, duodenal stump and draining lymph node stations. RT (41.4–45 Gy in 23–25 fractions) and concurrent c.i. 5-FU (200 mg/mq/day) were administered. An oral caloric intake >= 1500 Kcal was provided. Results: From June 2001 to December 2006, 22 pts (13 M and 9 F), median age 64 yrs (41–74), with uT3N1 (21pts) and uT2N1 (1pt), entered the study. Tumor location was proximal in 10, lower in 8 and middle in 4 pts, respectively. All pts underwent the planned neoadjuvant ECF with a median of 3 cycles (range 3–5). Toxicity was moderate (<= grade 3) without toxic deaths: nausea and vomiting in 3%, mucositis in 3%, hematological in 7%. Twenty/22 pts underwent surgery (in progress in 2 pts) and 15 (75%) had R0 resection. Tumor downstaging was reported in 9/20 (45%) pts (8 pT2, 1pT1). IORT with 12.5 Gy (10–15 Gy) was given to 12 pts and 12 pts had PCRT. Eight pts were excluded from PCRT for postop complications (2 pts), disease progression (3 pts) or pN3 (3 pts). All 12 pts completed RT with a median dose of 41.4 Gy (41.4–56Gy), but 3 (25%) required RT interruption and 5 pts (40%) also definitive 5-FU interruption (overall PCRT compliance of 60%). Major toxicity from PCRT consisted of G3 asthenia and anorexia, requiring parenteral nutrition. Conclusions: Neoadjuvant CT confirmed feasible in LAGC and resulted in a substantial downstaging with a favourable R0 resection rate. Combined modality approach with IORT and PCRT appears attractive, but limited compliance to PCRT was observed. A definitive evaluation and data on disease control and survival will be reported.

No significant financial relationships to disclose.
Female sex and standardized mitomycin-c dose are associated with increased risk of neutropenia after hyperthermic intraperitoneal chemotherapy
Authors: Lambert L. A. , Armstrong T. S. , Lee J. J. , Katz M. H. , Eng C. , Wolff R. A. , Ng C. S. , Smith M. L. , Gonzalez-Moreno S. , Mansfield P. F.
Published: March 2020

15091

Background: Cytoreductive sugery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are being increasingly employed in the managment of peritoneal-based malignancies. Depending on the treatment regimen, neutropenia (NP) is a common and potentially life-threatening early postoperative complication of HIPEC. However, little is known about the incidence or risk factors associated with HIPEC-induced NP. Methods: From January 1993 to October 2006, 120 CRS and HIPEC with mitomycin-c (MMC) were performed in 117 patients with appendiceal neoplasm. NP was defined as an absolute neutrophil count of < 1,000/mm3. Variables assessed as potential risk factors for HIPEC-induced NP included: age, sex, weight, BMI, BSA, splenectomy, dose of MMC (standardized for BSA and nonstandardized), percent of perfusate recovered, length of surgery, estimated blood loss, perioperative blood transfusion, and history of prior chemotherapy. Results: Total perfusate MMC doses ranged between 37.25 and 65 mg. The overall incidence of NP was 39.2%. The NP rates in female and male were 57.6% and 21.3%, respectively. Female sex, BMI, BSA, and the standardized dose of MMC were significantly associated with an increased risk of NP by univariable logistic regression. Female sex and standardized dose of MMC remained statistically significant for an increased risk of NP on multivariable logistic regression. The odds ratio (OR) of NP for females was 3.63 (95% CI: 1.54, 8.52); the OR of NP for a 1 mg/m2 increase in standardized MMC dose was 1.26 (95% CI: 1.11, 1.44). No other variables were identified as independent predictors of increased or decreased risk of NP. Compared to patients without NP, patients with NP had a higher rate of urinary tract infection (42.6% vs. 21.1%, p=0.01) and slightly higher length of stay (median: 24.0 days vs. 18.5 days, p=0.16). Conclusions: NP is a common complication after HIPEC with MMC . Female patients are at significantly increased risk for this complication. Risk of NP also increases with MMC dose standardized for BSA. With increasing interest in the use of CRS and HIPEC, understanding the risk factors for HIPEC-induced NP may facilitate reducing the morbidity associated with this procedure.

No significant financial relationships to disclose.
High complete response (CR) rate in patients (pts) with esophageal carcinoma (EC) undergoing neoadjuvant combination of docetaxel and cisplatin (DC) ± cetuximab(DCE) chemoradiation therapy—a retrospective analysis
Authors: Fillos T. J. , Hentschel P. , Watkins K. , Karpeh M. S. , Meek A. , Kim B. , Franceschi D. , Zee S. , Madajewicz S.
Published: March 2020

15093

Background: EC is a highly lethal disease with 5 year survival less than 15%. Surgery offers a chance for cure in early disease. Still, fewer than 20% of pts treated with surgery alone are alive at 5 years. Neoadjuvant chemoradiation offers the theoretical advantage of increasing R0 resections and reducing early local and distal metastases which may translate into improved survival. Several clinical trials have resulted in pathologic complete response (pCR) rates of 20–30%. Methods: Newly diagnosed pts with EC Stage 2A (T3) to 4 received weekly Docetaxel (D)25–30mg/m2 and Cisplatin (C)25–30mg/m2.for 6–8 weeks concurrently with radiation, 5040 cGy in 28 fractions. Cetuximab (E) 200mg/m2 was added after it became accepted treatment in head and neck cancers. Pts were scheduled 4 - 6 weeks later for surgery followed by the same chemotherapy for total of 16 weeks of treatment. Pts were assessed for time to progression, overall survival and toxicities. Results: Fifteen pts treated in 2005–6 underwent IRB approved evaluation; 11 male and 4 female, median age of 62(range 44–78) . Four had squamous cell (SCC) and 11 adenocarcinomas. Nine pts had Stage II, 4 pts stage III and 2 pts stage IV disease. Seven pts underwent surgery, all R0 resections. Four of them had pCR, one pPR (downstaged from T3 to T1) and two pts had stable disease. An additional 3 pts had radiological and endoscopic proven CR (medically not surgical candidates) for an objective response (CR+PR) in 8 out of 15 pts (3 SCC and 5 adenoca). Five out of 9 receiving DC had an objective response while 3 of 6 receiving DCE responded. Five pts progressed prior to surgery. Grade 3/4 neutropenia occurred in 2, nausea in 3, and 1 pt experienced Grade 3 dehydration. Four patients required dose reductions by 20%. Six patients had one cycle and 2 had 3 cycles delayed by one week each. Conclusions: Neoadjuvant chemoradiation treatment with weekly Docetaxel and Cisplatin ± Cetuximab is tolerable with high rate of CRs. There was no observed difference in response with the addition of cetuximab. A Phase III study is suggested.

No significant financial relationships to disclose.
Neoadjuvant gemcitabine/cisplatin for resectable adenocarcinoma of the pancreatic head—a prospective phase I trial
Authors: Heinrich S. , Pestalozzi B. , Schafer M. , Hany T. , Bauerfeind P. , Perren A. , Knuth A. , Clavien P.
Published: March 2020

15095

Background: Pancreatoduodenectomy (PD) alone was considered a standard treatment for cancer of the pancreatic head for a long time before the recent advent of adjuvant chemotherapy (CTX). Since adjuvant chemotherapy cannot be applied to all patients (pts), and neoadjuvant chemoradiation is toxic, we initiated a prospective phase II trial in August 2001 to test the safety and outcome of neoadjuvant CTX without radiation for resectable pancreatic cancer. Methods: Pts with cytologically confirmed resectable ductal adenocarcinoma of the pancreatic head were eligible for this phase II trial. Staging and restaging examinations included chest and abdominal CT-scan, endoscopic ultrasound with cytology, PET/CT and diagnostic laparoscopy. CTX consisted of four treatments of gemcitabine (1000mg/m2) and cisplatin (50mg/m2) every two weeks, and PD was planned at week 8. CA 19–9, prealbumin serum levels, and quality of life (QLQ- 30) were also determined before and after CTX. The primary study end-point was resectability based on re-staging examinations. Follow-up CT- scans were performed every six months. Results: Thirty-one pts entered this trial. Of these, 27 completed CTX and restaging until analysis. At restaging two pts had peritoneal metastases resulting in a resectability rate of 93% (25/27). No grade IV, and 7 transient grade III toxicities occurred in five pts. Median progression-free and overall survival after diagnosis were 9.2 months (95% CI 7.7–10.8) and 26.5 months (95% CI 15.2–37.7), respectively, for resected pts. After CTX, CA 19–9 serum levels were decreased by 48% (p=0.01). Moreover, the overall quality of life was increased by 24% (p=0.02). Prealbumin serum levels were abnormal in 40% of the pts on study entry, and normal in all but 89% after CTX (p=0.02). Conclusions: Neoadjuvant gemcitabine/cisplatin over two months is well tolerated and does not jeopardize resectability of adenocarcinoma of the pancreatic head. It offers several advantages including patient selection for surgery, improvements in the nutritional status and quality of life. A randomized trial comparing adjuvant and neoadjuvant+adjuvant treatment is being planned.

No significant financial relationships to disclose.
Population based study of islet cell carcinoma
Authors: Mares J. , Eisner M. P. , Dagohoy C. , Phan A. , Rashid A. , Evans D. B. , Yao J. C.
Published: March 2020

15103

Background: Little is known about the epidemiology and natural history of islet cell carcinoma. In this study, we examine the epidemiology, natural history, and prognostic factors impacting survival duration for islet cell carcinoma using population based registries. Methods: The Surveillance, Epidemiology, and End Results (SEER) Program database (1973 - 2003 release April 2006) was used to identify cases of islet cell carcinoma using histology codes and tumor site. Results: 1,310 (619 women and 691 men) cases were identified. Median age at diagnosis was 59 years. The annual age-adjusted incidence in the periods covered by SEER 9 (1973–1991), SEER 13 (1992–1999), and SEER 17 (2000–2003) were 0.16, 0.14, and 0.12 per 100,000 respectively. The estimated 28-year limited duration prevalence on January 1, 2003 in the United States was 2,705 cases. Insulinomas (57%), glucagonomas (53%), and VIPomas (64%) were more likely to be located in the tail of the pancreas while gastrinomas were more likely to be located in the head of the pancreas (63%). Classified by SEER stage, localized, regional, and distant stages corresponded to 14%, 23% and 54% of cases. The median survival was 38 months. By stage, median survival for patients with localized, regional, and distant disease were 124 (95% CI, 80–168) months, 70 (95% CI, 54 - 86) months, and 23 (95% CI, 20 - 26) months respectively. By multivariate Cox proportional modeling, stage (P < 0.001), primary tumor location (P = .04), and age at diagnosis (P < 0.001) were found to be significant predictors of survival. Conclusion: Islet cell carcinomas account for approximately 1.3% of cancers arising in the pancreas. Most patients have advanced disease at the time of diagnosis. Despite its reputation of being indolent, survival of patients with advanced disease remains in the range of 2 years. Development of novel therapeutic approaches is needed.

No significant financial relationships to disclose.
Correlation between the expression abnormalities of E-cadherin-β-catenin complex and lymph node metastasis (LNM) in early gastric cancer
Authors: Yoshii T. , Miyagi Y. , Nakamura Y. , Motohashi O. , Nishimura K. , Nakayama N. , Takagi S. , Kobayashi O. , Kameda Y.
Published: March 2020

15105

Background: Therapy for early gastric cancer (GC) varies according to risk of LNM. When the possibility of LNM is very remote, the primary lesion can be resected by the minimally invasive endoscopic surgery only. Therefore, useful parameters predicting LNM are needed. E-cadherin, a component of the cell-cell junctional structure, is known to correlate with GC. In vitro, previous studies elucidated that disorders of cell-cell junction increased the potential of metastasis, and that phosphorylation of β-catenin by c-erbB-2 induced loss of membranous E-cadherin and β-catenin, resulting in junctional structure disorders. Here we evaluated significance of analysis of these molecules in LNM prediction in early GC. Methods: The clinicopathological features and immunohistochemical expressions of E-cadherin, β-catenin, and c-erbB-2 in the primary lesion were studied in 28 patients (LNM +ve group: 14, LNM1 -ve group: 14) selected from 272 patients who underwent radical surgery for early GC between April 2000 to March 2004 at our hospital. All the patients consented to use of their stomach tissues for the clinical study afterwards. Statistical analysis was performed by t-test or χ2 test. Results: The clinicopathological features showed no significant differences between both groups. Loss of the membranous E-cadherin was noticed in 12 (85%) of the 14 LNM +ve patients, and in 8 (57%) of the 14 LNM -ve patients (p=0.209). This result was more remarkable in the intestinal type GC as the corresponding figures were 83% (5 of 6 ) and 16% (1 of 6) (p=0.083), respectively. Loss of the membranous β-catenin also showed a remarkable similar trend in the intestinal type GC, and the corresponding figures were 100% (6 of 6) and 50% (3 of 6) (p=0.182), respectively. Two patients showed over-expression of c-erbB2 and nuclear accumulation of β-catenin, and both had intestinal type GC with LNM. Conclusions: These results suggested that the same molecular signal pathway - as in vitro - including E-cadherin, β-catenin, and c-erbB2 induced LNM in early GC (intestinal type). We concluded that analysis of the expressions of these molecules is useful for not only LNM prediction but also determination of the therapeutic modality especially in intestinal type early GC.

No significant financial relationships to disclose.
Thiazolidinedione (TZD) exposure and risk of squamous cell carcinoma of head and neck (SCCHN)
Authors: Govindarajan R. , Siegel E. R. , Simmons D. L. , Lang N. P.
Published: March 2020

1511

Background: Peroxisome proliferator-activated receptor γ (PPARγ), a nucleic acid receptor, heterodimerizes with retinoic acid X receptor (RXR). Ligand activation of RXR leads to decreased proliferation of SCCHN cell lines. TZDs (syn: glitazones), used to treat diabetes mellitus (DM), are ligands for the RXR:PPARγ heterodimer. A retrospective study of diabetics attending the Veterans Affairs (VA) health care system was undertaken to assess the association between TZD exposure and the risk of developing SCCHN. Methods: Data were obtained from the electronic patient database VISN 16 (covering 10 VA institutions) for males aged ≥40 presenting with DM and no prior SCCHN between 10/01/96 and 12/31/03. DM and SCCHN diagnoses were identified using ICD9 codes. Subjects were followed until 12/31/05, and analyzed for SCCHN risk via Cox regression, using time-dependent covariates to model exposure to TZDs, insulin and other anti-DM agents. Results: 130,406 subjects met the study criteria. Median (quartiles) age at DM presentation was 64 (55–72).18.5% were African-American, 61.3% were Caucasian, and 20.2% were other/unknown. The table shows TZD exposure, SCCHN incidence and hazard ratios for SCCHN with exposure to TZD alone or in combination with insulin and other anti-DM agents after adjusting for age, race, BMI, and HbA1C. Conclusions: A 41%-55% reduction in the risk of SCCHN was observed in diabetic subjects treated with TZD alone, with insulin, and with other anti-DM agents. The decrease was statistically significant (P<0.05) for TZD alone and TZD with other agents, but not for TZD with insulin. These findings suggest a protective effect of TZD on the development of SCCHN. The mechanism is not clearly known but possibly mediated through RXR:PPARγ pathway.

[Table: see text]

No significant financial relationships to disclose.
Is there a role for neoadjuvant chemotherapy in the management of non-carcinoid epithelial neoplasms of the appendix?
Authors: Katz M. H. , Mansfield P. F. , Eng C. , Wolff R. A. , Diaz P. , Ng C. , Lambert L.
Published: March 2020

15115

Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS and HIPEC) are considered the standard of care for patients with pseudomyxoma peritonei (PMP) and carcinomatosis of appendiceal origin. The role of neoadjuvant chemotherapy (CTX) in the management of these patients is unknown. Methods: Retrospective analysis of all patients evaluated for the treatment of appendiceal epithelial neoplasms at a tertiary center between 1992 and August 2006. All diagnoses were confirmed pathologically and classified by a single group of pathologists. Patients with carcinoid tumors or metastases to the appendix were excluded. Tumor histology, stage, peritoneal-based disease, and the potential for complete cytoreduction dictated treatment. Results: 250 consecutive patients were evaluated, 140 of whom had low grade disease. 114 underwent CRS and HIPEC. Median follow-up was 24 mos from referral. Average time to referral was 13 mos after diagnosis (range 0–243); 85% had undergone prior surgical therapy (median 1.3 operations, range 1–4); 22% had previous CTX consisting of many different regimens. 5- and 10-year survival for patients with low grade tumors treated with CRS and HIPEC alone (n=80) were 84% and 68%, respectively. 21 patients with low grade tumors had CTX prior to CRS and HIPEC. There was no effect on overall survival (p = 0.61). 5-and 10-year survival of 39 patients with low grade histology who did not receive CRS and HIPEC was 55% and 30%, respectively (p = 0.009). 83 patients with intermediate and high-grade disease who received CTX but not CRS and HIPEC had a 5- year survival of 27%. 5-year survival for patients with intermediate or high grade disease who underwent CRS and HIPEC (n=13) was 67%. Conclusions: Patients with peritoneal-based disease from non-carcinoid epithelial neoplasms of the appendix who undergo CRS and HIPEC have a more favorable survival. Currently there is no survival advantage to the use of CTX before CRS and HIPEC for low grade appendiceal neoplasms. The role of neoadjuvant CTX and biologic agents for patients with high grade neoplasms needs to be determined. Early referral to a peritoneal malignancy center will help standardized treatment for these patients.

No significant financial relationships to disclose.
Synergistic activity of PHY906 with capecitabine in pancreatic carcinoma
Authors: Saif M. W. , Liu S. , Elfiky A. , Jiang Z. , Cheng Y.
Published: March 2020

15116

Background: Preclinical data indicates that PHY906, a traditional Chinese botanical formulation, can reduce chemo-induced gastrointestinal toxicity while simultaneously enhancing therapeutic efficacy of a broad-spectrum of common anticancer agents. Methods: Male NCR athymic nude mice were transplanted with human PANC-1 cells. To determine the best dose of combinational regimen, two dose ranges of capecitabine, 60 and 180 mg/kg bid for 14 consecutive days with two dose ranges of PHY906, 300 and 900 mg/kg bid on days 1–4 and days 8–11 were administered by gavage in the first experiment. In the second experiment, PHY906 was fixed at 500 mg/kg bid at days 1–4 and 8–11 while dose of capecitabine was increased to 360 mg/kg bid for 14 consecutive days. A dose of 180 mg/kg of capecitabine was also included for comparison with previous experiments. In the third experiment, capecitabine at 360 mg/kg was selected to evaluate effect of different doses of PHY906 ranging from 100 mg/kg to 500 mg/kg on enhancement of antitumor activity of capecitabine. PHY906 was always administered 30 minutes prior to capecitabine. Tumor size, body weight and mortality were monitored daily and mice were sacrificed when tumor size reached 10% of body weight or on Day 21. Results: PHY906 showed enhancement of antitumor activity of capecitabine when both doses of PHY906 were co-administered with both doses of capecitabine in first experiment. In second experiment, increase of capecitabine dose from 180 mg/kg to 360 mg/kg significantly increased disparity of tumor growth rates between capecitabine alone and concomitant use of both PHY906 and capecitabine. Similar results were obtained in third experiment using a dose of 360 mg/kg of capecitabine and 500 mg/kg of PHY906 (p= 0.0018) as compared with control, capecitabine or PHY906 alone. Similar observation was found in mice bearing PAN-2 murine pancreatic cancer. Conclusions: The studies demonstrate that PHY906 potentiates antitumor activity of capecitabine in human pancreatic carcinoma xenograft mouse model in all capecitabine and PHY906 dosing regimens examined. Observed effect appeared to be dependant on dosage of capecitabine. Therefore, we are employing a dose intense weekly schedule for capecitabine with PHY906 in a phase I/II study in patients with advanced pancreatic cancer.

No significant financial relationships to disclose.
Treatment of unresectable or metastatic pancreatic cancer in the VA population: Does it improve survival?
Authors: Mekan S. F. , Komrokji R. S. , Beg M. S. , Nahleh Z. A. , Safa M. M.
Published: March 2020

15121

Background: Locally advanced and metastatic pancreatic adenocarcinoma present as a treatment challenge because of poor outcomes with current treatment modalities. Therapy of unresectable or metastatic disease has not been studied in the VA population. Methods: We reviewed all cases of pancreatic cancer presenting to the system from 1995–2005. Cases were extracted from the VA Cancer Registry (VACCR). Results: There were 5522 cases identified; 5218 were adenocarcinomas. Out of these, there were 263 (5.1%) patients with unresectable locally advanced disease and 2778 (53.2%) patients with metastatic disease. Median survival for patients with unresectable disease was 5.6 months. Chemotherapy was administered to 94 patients and chemoradiation to 31 patients. No difference in survival was noted between the two groups (8.4 vs. 7.9 months, P = 0.434). In patients with metastatic disease, median survival was 2.2 months. Chemotherapy was administered to 760 (27%) patients in this group and showed improved survival as compared to patients who did not receive chemotherapy (5.3 vs. 1.5 months, p = 0.000). Conclusions: In VA patients with locally advanced unresectable disease, there is no difference in survival in patients treated with chemoradiation versus chemotherapy alone. In patients with metastatic disease, chemotherapy conferred a survival advantage.

No significant financial relationships to disclose.
Pancreatic cancer and diabetes: Is diabetes a risk factor or the outcome?
Authors: Garg P. , Gupta R.
Published: March 2020

15123

Background: Though pancreatic cancer ranks eighth among all major forms of cancer related deaths, it accounts for only 3% of all cancers worldwide. Diabetes mellitus type 2 and pancreatic cancer are known to be associated but this relationship decreases inversely with an increasing duration of diabetes. The aim of the present study is to assess whether new onset type 2 diabetes is a risk factor for pancreatic cancer or it results as an outcome of pancreatic cancer. Methods: We conducted a meta-analysis of all available studies to examine this association. Using PUBMED, EMBASE & MEDLINE we searched the literature for studies from 1980 to present. All published studies with quantitative estimates and standard errors, or confidence limits, of the association between type 2 diabetes and pancreatic cancer were included. Studies having patients with an un-defined period of diabetes or diabetes for greater than 5 years before the development of pancreatic cancer were excluded. 14 case control and 11 cohort trials with information on 5807 individuals with pancreatic cancer met the above criteria. Each study was independently reviewed by 2 reviewers. Results: The pooled odds ratio for case control studies for patients with diabetes and pancreatic cancer was 1.98 (95% CI - 1.58–2.42) while that for cohort studies was 1.88 (95% CI - 1.72–2.16). The combined odds ratio was 1.92 (95% CI - 1.62 - 2.38). However in patients who developed pancreatic cancer with in 2 years of diagnosis of diabetes the odd’s ratio was significantly higher (OR- 3.2, 95% CI - 2.24- 4.02). Conclusions: On the basis of above data pancreatic cancer is more likely to occur in new onset diabetes mellitus type 2 than the general population. However, the evidence above is insufficient to conclude that diabetes mellitus is indeed a risk factor for pancreatic cancer. Since the relative risk of developing pancreatic cancer was higher in patients with new onset type 2 diabetes in the first two years, it further supports the hypothesis that the development of diabetes may be a manifestation of early but yet undiagnosed pancreatic cancer. Large population based studies are needed to truly determine this relationship.

No significant financial relationships to disclose.
Epirubicin, cisplatin, oral UFT (ECU) combination chemotherapy in metastatic gastric carcinoma
Authors: Kaya S. , Aliustaoglu M. , Dane F. , Gumus M. , Seker M. , Ozturk A. , Salepci T. , Yaylaci M. , Mayadagli A.
Published: March 2020

15126

Background: Chemotherapy significantly improves survival in comparison to best supportive care in patients with metastatic gastric cancer. In patients for whom a three-drug-combination is considered as the treatment of choice, ECF (epirubicin, cisplatin and 5-FU as a continuous infusion) should be regarded as standard of care. Continuous 5-FU infusion may be replaced by oral fluoropyrimidines. Here, we aimed to evaluate treatment with epirubicin and cisplatin combined with oral UFT with leucovorin (ECU), replacing intravenous 5-FU infusion Methods: Fifty-three patients (17 female, 36 male) with metastatic gastric carcinoma received epirubicin, cisplatin, and oral UFT plus leucovorin in two outpatient chemotherapy clinics, in Istanbul. Epirubicin 50 mg/m2 and cisplatin 60 mg/m2 were administered on day 1; and UFT 300 mg/m2/day was administered in conjunction with oral calcium folinate at a fixed dose of either 45 or 90 mg/day in divided daily doses for 21 days continuously. The treatment was repeated every 3 weeks. The patients were evaluated radiologically for response after each three-cycle period. Age, gender, ECOG performance score (PS), primary cancer localization, and presence of primary curative surgery were analyzed for prognostic factors. Results: Median follow-up was 6 (range 1–12) months. Median age was 57 years (range 27–76). Patients received a median of three courses of treatment (range: 1–6). Over 86% of the patients had PS =1, whereas remaining 13% had PS 2. Forty-three percent of the patients were undergone curative surgery at the time of cancer diagnosis, while 57% presented as metastatic disease. The most frequent site of metastases was liver (42%). Twenty-five percent of the patients showed partial responses, while none showed a complete response. Over 28% of the patients had stable disease resulting in a tumor control rate of 53%, and 47% had progressive disease. Median TTP and OS were 6 and 8.6 months, respectively. In univariate analysis; having PS =1, and presence of primary curative surgery were independent prognostic factors (p:0.042, and p:0.019, respectively) Conclusion: ECU regimen has a significant activity in metastatic gastric cancer. It does not require an infusion pump and intravenous catheter.

No significant financial relationships to disclose.
Phase II study of irinotecan plus leucovorin and bolus 5 fluorouracil as first or second line chemotherapy in patients with advanced gastric or esophageal-gastric junction adenocarcinoma
Authors: Gerolymos M. , Koutras A. , Kontogeorgou E. , Iconomou G. , Vourli G. , Tsiata E. , Makatsoris T. , Chrysanthopoulos C. , Kalofonos H.
Published: March 2020

15128

Background: The aim of this study was to evaluate the activity and safety of 5-fluorouracil (5-FU) / leucovorin (LV) and irinotecan as first- or second-line treatment in patients with advanced gastric adenocarcinoma. Methods: Treatment consisted of irinotecan 80 mg/m2 intravenously (i.v.), followed by LV 200 mg/m2 (i.v.) and 5- FU 450 mg/m2 as an i.v. bolus. Treatment was administered weekly for 6 weeks, followed by a 2-week rest period. Results: Thirty-one patients (23 chemo-naïve, 8 chemo-exposed) were enrolled. The overall response rate was 22.6% and the disease control rate was 38.7%. Among the patients who received the regimen as first-line treatment, objective response rate was 30.4% and the disease control rate was 52.1%. However, progression of the disease was recorded in all the patients receiving the combination as second-line chemotherapy. The median time to disease progression (TTP) was 4 months and the median duration of survival was 7 months. The median TTP was 6 months for patients treated with first-line chemotherapy and 2.5 for those who received study treatment as second line. Furthermore, the median survival duration was 8 months and 6 months, respectively. The most frequent grade 4 toxicity was febrile neutropenia. Grade 3 or 4 non-hematological toxicities were rare. There were no treatment-related deaths. Conclusions: The combination of 5-FU/LV and irinotecan as first-line treatment was found to be well tolerated, with efficacy comparable to that of other regimens in advanced gastric cancer. Accordingly, this regimen can be regarded as one of first-line options, particularly in patients who can not tolerate aggressive chemotherapy.

No significant financial relationships to disclose.
Assessment of intra and interfractional organ motion during adjuvant radiochemotherapy in gastric cancer
Authors: Wysocka B. A. , Kassam Z. , Lockwood G. , Brierley J. , Dawson L. , Ringash J.
Published: March 2020

15132

Background: Adjuvant combined chemotherapy and radiotherapy (RT) in gastric cancer improves survival, however acute toxicity is substantial. Toxicity may be improved with three-dimensional (3D) RT, but organ motion must be considered in planning target volume (PTV) delineation. Methods: Participants (n=22) had baseline free breathing planning CT (CT0) with BodyFix immobilization. Abdominal CTs in free breathing (FB), inhale (I) and exhale (E) states were obtained in weeks 1, 3 and 5 of RT. Datasets were fused to CT0 in Pinnacle3 6.2 planning system using bone registration. Volumes of interest (VOIs) [right (R) and left (L) kidney, liver, stomach, pancreas, celiac axis and porta hepatis] were contoured and points of interest (POIs) were placed at each centre of mass. POIs were manually placed at the left dome of diaphragm and splenic hilum. Organ motion was determined by the difference between POI positions in cranial-caudal (CC), anterior-posterior (AP) and right-left (RL) directions. Maximal respiratory motion was determined from the difference between I and E positions. Interfractional displacement in organs relative to bones at weeks 1, 3 and 5 was determined on FB scans as compared to baseline. Results: Interfractional organ motion was maximal in CC direction with median absolute displacements (range) in mm of: splenic hilum 10 (0–52), stomach 8 (0.4–27.2), liver 7.4 (0.5–23.6), diaphragm 6 (0–28), L kidney 5.7 (0–37.3), R kidney 5.3 (0.2–35.3), pancreas 5.7 (0.3–29.1), porta hepatis 4 (0–14) and celiac axis 1.7 (0–9.1). Median interfraction displacement (range) in CC, AP and RL in mm for all organs was: 5.7 (0- 52), 2.1 (0–23.1), 2.3 (0–15.9). Positional difference between I and E state (median for all organs) was: 16 mm CC, 5.9 mm AP, and 1.7 mm RL with maximal individual breathing excursions of 59.9, 30.2 and 21.1 mm, respectively. Conclusions: Interfraction organ displacement relative to bones can be quantified and used in the safe design of 3D conformal radiotherapy. Respiratory motion can be substantial in some individuals. Accounting for organ motion in 3D RT planning is necessary and may reduce the toxicity of treatment.

No significant financial relationships to disclose.
An individual patient data meta-analysis of the immunochemotherapy using lentinan in patients with advanced gastric cancer
Authors: Oba K. , Morita S. , Matsui T. , Kobayashi M. , Kondo K. , Sakamoto J.
Published: March 2020

15136

Background: An anti-tumor effect of lentinan (LNT), a non-specific immunomodulator, via an immunological response has been reported and combination immunochemotherapy has been examined. However, the survival benefit of LNT for patients with advanced or recurrent gastric cancer (AGC) was unclear in the world. We performed an individual patient data (IPD) meta-analysis in order to evaluate the survival effect of immunochemotherapy using LNT. Methods: A computerized and a manual search procedure were performed to identify all randomized clinical trial (RCT) for chemotherapy in patients (pts) with AGC. Inclusion criteria were RCTs for AGC and to compare any chemotherapy (control group) with the same plus LNT (LNT group). The primary endpoint was overall survival, secondary endpoints includes objective tumor response and toxicity. All analyses were based on IPD. Treatment effects were displayed as hazard ratios estimated by Cox proportional hazard model. A ratio less than unity indicated benefit from LNT. Results: We analyzed IPD of 5 randomized clinical trials for AGC, which met the predetermined inclusion criteria. These 5 trials had a combined total of 650 pts (LNT: 339 pts median age=63, control: 311 pts median age=63). The number of deaths was 83.8% (286/334) in LNT group and 84.8% (262/309) in control group. The overall hazard ratio was 0.83 (95%CI, 0.70–0.98; p=0.03) with no significant heterogeneity between the treatment effects in different trials (χ2 for heterogeneity=3.69; p=0.45). Three hundred and fifty five pts were evaluable for objective tumor response and the response rate was 18.4% (21/185) in LNT group (CR, 0 pts; PR, 21 pts) and 6.3% (5/173) in control (CR, 0 pts; PR, 5 pts). There were no significant differences in the toxicity. Conclusions: This IPD meta-analysis demonstrated that LNT significantly improves both OS and tumor response in pts with AGC.

No significant financial relationships to disclose.
Prognostic relevance of the novel TNM-classification system for neuroendocrine tumors of foregut origin
Authors: Pape U. , Jann H. , Berndt U. , Wiedenmann B.
Published: March 2020

15147

Background: Until recently no TNM-classification existed for neuroendocrine tumors (NET) of the gastroenteropancreatic system. In 2006 Rindi et al. proposed a new TNM-classification system for foregut-NET of gastric, duodenal and pancreatic origin. The present study validates prognostic significance of the new TNM-classification in a cohort from a German referral center. Methods: The case files of 193 patients with histologically proven foregut NET were analyzed retrospectively. Patients were classified according to Capella (1995) and the WHO (2000) and to the new TNM-classification. Uni- and multivariate analysis was performed using log-rank and Cox regression methods. Results: Primary tumors localization was gastric (n=48), duodenal (23) and pancreatic (122); 35 patients (18%) died during the observation period. Overall 5- and 10-year survival rates (YSR) were 76% and 65% resp., while 5- and 10-YSR according to NET-related deaths (74% of all deaths, 26/35) were 83% and 74% resp.. The classifications by Capella and the WHO significantly discriminated between low and high grade malignant NET (p<0,001 and 0,002 resp.), but did not allow further prognostic differentiation. In contrast, the newly proposed TNM-classification system was able to significantly differentiate stage IV NET from all other stages (I vs. IV p=0,001; II vs. IV p=0,001; III vs. IV p=0,008) as well as stage III from stage I NET (p=0,038). Furthermore, the new classification system which includes a grading system according to the mitotic index (Ki67-index; G1 <3%, G2 3–20%, G3 >20%) was also able to significantly distinguish all three groups from each other (G1 vs. G3 p<0,001; G2 vs. G3 p<0,001). On multivariate analysis stage I and II as well as stage III-NET had a decreased hazard ratio (HR) when compared to stage IV-NET (I/II: HR 0,094, p=0,003; III: HR 0,38, p=0,096). In the same model G1 and G2-NET were associated with an decreased HR as compared to G3-NET (G1: HR 0,05, p=0,01; G2: HR 0,20, p=0,002). Conclusions: Here we demonstrate prognostic relevance of the newly proposed TNM-classification system for foregut-NET with statistical significance which therefore provides a new and powerful tool for future classification of NET.

No significant financial relationships to disclose.
A phase II study of pemetrexed in patients (pts) with advanced neuroendocrine tumors (NETs)
Authors: Bhargava P. , Earle C. C. , Zhu A. X. , Clark J. W. , Vincitore M. , Battu S. , Regan E. , Lawrence C. , Kulke M. H.
Published: March 2020

15149

Background: Traditional antifolates such as 5-florouracil have been associated with only modest activity in NETs. Pemetrexed is a multitargeted antifolate active in diseases not known to be responsive to other antifolates. We performed a prospective phase II study of pemetrexed in pts with advanced NETs to assess response, toxicity, and survival. Methods: Pts were treated with Pemetrexed administered intravenously at a dose of 500 mg/m2 every 21 days. To reduce toxicity, folic acid and vitamin B12 supplementation were mandatory. Pts were also treated with oral dexamethasone 4 mg twice daily the day prior to, day of, and day after pemetrexed administration. The study utilized a two-step design, with an initial accrual phase of 17. Pts were required to have metastatic neuroendocrine tumors (excluding small cell carcinoma), and preserved hematologic, renal, and hepatic function. Treatment with prior chemotherapy was allowed; pts receiving octreotide remained on octreotide at a stable dose level during study therapy. Results: 17 pts were enrolled with the following characteristics: M: F=4:13. median age 56 (range 38 to 72); ECOG Performance Status 0/1/2=4/12/1. Tumor types included carcinoid n=12(71%) and islet cell n=5(29%). 17 pts received treatment for a median of three, 21-day cycles; the median time on study was 10 weeks. Grade 3–4 toxicities included: fatigue n=8(47%), leukopenia n=7 (41%), neutropenia n=6 (35%), elevated alkaline phosphatase n=4 (23%), thrombocytopenia n=3 (17%), lymphopenia n=3 (17%), pneumonitis n=2 (11%), hyponatremia n=2 (11%), dyspnea n=1 (5%), hyperbilirubinemia n=1 (5%), weight loss n=1 (5%), diarrhea n=1 (5%), elevated ALT/SGPT n=1 (5%), edema n=1 (5%), weakness n=1 (5%), grade 4 proteinuria n=1 (5%). 15 pts were evaluable for response; the best treatment response was stable disease (n=9;), the remaining 6 pts experienced progressive disease as their best response to therapy. Accrual to the study was halted due to lack of observed antitumor activity. Conclusions: Pemetrexed does not have significant antitumor activity in pts with advanced NET.

No significant financial relationships to disclose.
First-line physician’s choice (PC1) or standard of care (SOC) then second-line PC2 chemotherapy (CT) in metastatic esophago-gastric adenocarcinoma (MEGA): BC Cancer Agency experience
Authors: Wilson K. S. , Barnett J. B. , Khoo K. , Kollmannsberger C. , Shah A.
Published: March 2020

15158

Background: The BCCA GI Tumor Group supports 1 CT regimen for MEGA: weekly 5FU-cisplatin [FUC] (Shah, ASCO 1992, A530) for first line SOC CT. All other regimens (PC) require “undesignated” approval for public funding. Reasons for PC requests include prior CT, results of modern CT trials, and contra-indications to FUC. Objectives: to examine response, toxicity and survival in pts. receiving either first-line PC1 CT , or SOC and second line PC2 CT. Methods: BCCA Pharmacy records (Dec. 1999 to April 2006) were searched for PC MEGA pts, charts abstracted, database constructed and KM survival analyses undertaken. Treatment responses, serious toxicities and hospitalizations were recorded. Results: Demographic summary (N = 85): 32 esophageal (10 GEJ), 53 (62%) gastric primary, 61 M, 24 F, median age 56.2 (range 28.7 - 81.8) yrs., 68 Caucasian, 15 Asian, 2 Fijian descent, 55 stage M1 at diagnosis. Prior therapy: 14 CTRT, 3 adjuvant CT, 34 radical surgery. 50 pts received PC1 of whom 25, 9 and 2 received 2nd, 3rd and 4th line CT respectively; of 35 SOC/PC2 pts, 35, 10 and 2 received 2nd, 3rd and 4th line CT for a total of 133 patient-courses of PC (including 4 repeat FUC). Docetaxel and irinotecan regimens accounted for 34% and 36%, 5% and 55%, 16% and 32% of 1st, 2nd and 3rd line PC CT regimens respectively. Partial responses were seen with SOC (11/35) and PC1 (6/50) [chi square p = 0.05]. Four responses were seen with 2nd line CT (2 SOC/PC2, and 2 PC1). Grade 3+ toxicity rates: 19/49 (39%) and 6/36 (17%) with SOC and PC1 with initial CT (p = 0.02). There were 20 hospitalizations with PC and 2 with SOC CT (p = 0.02). Median follow-up time was 8.9 months. Survival analyses are presented below. Multivariate analysis results: primary site, SOC, gender, ethnicity, prior CT, p values were 0.15, 0.23, 0.23, 0.25 and 0.25 resp. Conclusions: Benefits and risks of non-SOC chemotherapy in MEGA need careful consideration before routine adoption as primary or subsequent therapy.

[Table: see text]

No significant financial relationships to disclose.
Prognostic value of pre-operative serum MUC4 levels for predicting recurrence of pancreatic cancer
Authors: Villanueva M. H. , Stoner J. , Sasson A. , Batra S. K. , Hauke R. J.
Published: March 2020

15160

Background: The human transmembrane mucin MUC4 is aberrantly expressed in approximately 75% of pancreatic ductal adenocarcinomas, but not in normal pancreatic tissue. Preliminary data suggests serum MUC4 levels may have a diagnostic utility. Hence, we sought to determine if pre-operative MUC4 levels have a prognostic value in pancreatic adenocarcinoma. Methods: A database of MUC4 samples collected under an IRB-approved protocol was queried for subjects with pre-operative MUC4 levels. MUC4 assays were performed using RT-PCR. Descriptive statistics were used to summarize the disease and treatment characteristics of the patients. A level of 0.01 (median) was used to divide patients into high and low MUC4 groups. Kaplan-Meier method was used to summarize the time to event distributions for groups defined by MUC4 levels. Log-rank test was used to compare the time to event distributions between two groups. Results: Seventeen patients (eleven males - 65%) were identified, with a mean age of 65.8 yrs (range: 46 - 76 years) were identified. Pathologic staging was T2/T3 in 95%, 9 pts (53%) had N1 disease, while 15 patients (88%) had stage II disease. All but one received adjuvant therapy with chemotherapy (5FU ± gemcitabine) ± radiation. Patient, disease and treatment characteristics were similar in patients with low MUC4 levels (n=9) and high MUC4 levels (n=8). At a median follow-up of 1.8 years, 13 (77%) experienced disease recurrence and 14 (82%) died. There was no significant association between MUC4 levels and the risk of disease recurrence or death (p>0.9; p = 0.1, respectively). The one- year probabilities for relapse free survival (RFS) and overall (OS) were 0.9 (95% CI: 0.68 - 1.00) and 1 (95% CI: 1 - 1) for patients with low levels and 0.5 (95% CI: 0.15 to 0.85) and 0.63 (95% CI: 0.29 to 0.96) respectively, for subjects with high levels. Conclusions: Although these differences were not statistically significant, the group with high MUC4 levels appears to have higher risk features such as higher stage, regional lymph node disease and older age. Patients with high MUC4 levels had a trend towards higher risk of relapse or death.

No significant financial relationships to disclose.