bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of expression of microRNA miR-21 with prognostic characteristics in gastric cancer.
Authors: Cai Jian-Chun , Wang Lin-Pei , Tang Ya-Ling
Published: March 2020

e14629

Background: MicroRNAs may play an important role in earlt stage gastric cancer. Methods: We studied the expression of MicroRNAs in gastric cancer to understand the expression characteristics of one of the key MicroRNAs miR-21 using 65 cases of early-stage gastric cancer identified from our cancer center records between October 2007 and March 2010. First, we used an MicroRNA array (miRCURY LNA Array) that contained 1,348 known probes and compared the expression profile of these MicroRNAs in six cases of gastric cancer specimen with their surrounding normal tissues. We then studied the expression of miR-21 and correlated it with the histologic characteristics of the 65 cases by RT-PCR. Results: The expression of seven MicroRNAs (miR-374b*, miRPlus-E1212, miR-338-5p, miR-297, miR-21, miR-135b, and miR-18a) was significantly up-regulated, while nine MicroRNAs (miR-29b-2*, miR-1260, miRPlus-E1241, miR-S1-5p, miR-148a, miR-29c, miR-647, miR-196b*, ebv-miR-BART5) significantly down-regulated. Because miR-21 was highly overexpressed in gastric cancer compared to its normal surrounding tissue, we next studied if the expression of miR-21 in sixty-five cases of gastric cancer was associated with clinical and histologic characteristics of early stage gastric cancer. We found that the increased expression of miR-21 was correlated with poorly differentiated histology (high grade), T3-4 stage and nodal involvement. The average level of miR-21 expression was two to five folds higher in the cases that are poorly differentiated, T3-4 stage, or with lymph node involvement compared to the cases that were well or moderately differentiated, T1-2 stage or with negative nodal involvement. The high-grade gastric cancers were associated with the highest level of miR-21 compared to the surrounding normal tissues. These results suggest that miR-21 is a potential biological marker indicative of the aggressiveness nature of this malignancy. Conclusions: Our results demonstrate that expression of several MicroRNAs may play important roles in the development and progression of gastric cancer and the increased expression of miR-21 is associated with poor prognostic characteristics.
Neoadjuvant therapy with nanoparticle albumin-bound (nab)-paclitaxel to enhance the resectability of locally advanced pancreatic cancer (LAPC).
Authors: Cooray Prasad , Dean Andrew Peter
Published: March 2020

e14644

Background: Resection offers the only probability of cure for pancreatic adenocarcinoma but only a minority have resectable disease at diagnosis. Effective neo-adjuvant therapy for LAPC could down-size the tumor rendering it resectable. Neo-adjuvant therapy may retard cancer dissemination thought to occur early in pancreatic cancer. The aim of this study was to retrospectively evaluate if neo-adjuvant treatment with nab-paclitaxel in patients with LAPC could result in tumor down-sizing to allow resection and improve outcomes. Methods: Data was collected from the medical records of pancreatic cancer patients who presented to two clinics from 06/2009 to 12/2011 and were treated with nab-paclitaxel (n = 63). Resectability was assessed by review of imaging by the radiologist and the treating surgeon. Twenty three of 63 patients had LAPC and 40/63 had stage IV disease. Of the LAPC patients, 8/23 (35%) were classified as borderline resectable (BR) and 15/23 (65%) were classified as unresectable (UR). Patients received nab-paclitaxel (100-125 mg/m2 D1,8,15) in combination with gemcitabine or carboplatin. The BR/UR patients (n=23) received a median 5 cycles of chemotherapy. They were re-evaluated for suitability for surgical resection. Results: Following neo-adjuvant treatment, 16/23 (69%) had a radiological PR and 17/23 (74%) had a major biochemical response (defined as >70% decline in Ca19.9 level). A total of 6/23 patients (26%) were then able to undergo surgical resection, with resections planned for further 2/23 (8%) patients.Of the 6 resected patients, 4 had R0 resections and 2 had R1 resection. After a median follow up of 18 months, all 6 resected patients are alive and 4 of them remain free of cancer recurrence. The median survival for patients who remained unresectable (15/23) was 9 months. The median survival for converted patients (6/23) has not yet reached. Conclusions: These results suggest that a subgroup of patients with LAPC could be converted to a resectable stage with the use of nab-paclitaxel as neo-adjuvant therapy. Such converted patients may enjoy durable improved outcomes and this approach warrants further investigation in a phase II clinical trial.
New WHO classification for pancreatic endocrine tumors: Is time to leave the previous one?
Authors: Ricci Claudio , Campana Davide , Macchini Marina , Vecchiarelli Silvia , Taffurelli Giovanni , Sina Sokol , Santini Donatella , Di Marco Mariacristina , Tomassetti Paola , Biasco Guido , Casadei Riccardo , Minni Francesco
Published: March 2020

e14647

Background: In 2010 WHO released a new classification (NWHO) system for endocrine pancreatic tumours (NETs). The aims of this study was to compare the NWHO and previous one (OWHO) in patients affected by NETs. Methods: From January 1980 to December 2010, 89 consecutives patients underwent surgical intervention for PNETs Data regarding sex, age, presence of symptoms, hormonal status, presence of MEN1, surgical procedure, R status, TNM stage, older and new WHO classification and disease specific survival (DSS) were prospectively collected. Multivariate analysis, including OWHO and NWHO, was carried out to evaluate the independent factors related to DSS. A sensitivity analysis was performed to include patients in which NWHO was impossible to be calculated. Results: Mean age of patients was 54.7 ± 14.2 years. There were 46 (51.7%) female and 43 (48.3%) male. Symptoms were present in 68 (76.4%) patients. Fifty-two (58.4%) patients had non-functioning NETs. Left pancreatectomy was performed in 48 (53.9%) cases, atypical resection in 22 (24.7%), pancreaticoduodenectomy in 12 (13.5%), total pancreatectomy in 2 (2.2%) and palliative surgery in 5 (5.6%). R0/1 resection was carried out in 79(88.7%) cases. According TNM stage there were: I, 27 (30.3%); II 29 (32.6%); III, 22 (24.7%); IV, 11 (12.4%). According OWHO 46 (51.7%) patients had a well differentiated tumours (WDT), 32 (36%) well differentiated carcinoma (WDCa), 11(12.4%) poorly differentiated carcinoma (PDCa). The NWHO was available only in 49 (55.1 %) patients: 20 (22.5%) NET G1, 25 (28.1%) NET G2, 4 (4.5%) neuroendocrine carcinomas (NEC) G3. At multivariate analysis OWHO and R2 status were the only independent factors related to DSS (RR=6.7, p<0.001 and RR 2.0, p=0.018 respectively). OWHO stratifies DSS better than NWHO: RR 0.12 (C.I. 95% 0.01-0.99; p=0.049) and RR 0.16 (C.I 95% 0.16-0.05; p=0.002) comparing WDT vs WDCa and WDCa vs PDCa, respectively. The sensitivity analysis confirmed in two model the superiority of OWHO while in others two we did not find any difference. Conclusions: In our experience OWHO still remains the best prognostic factor to predict DSS in patients with NETs .
Single institution experience of chemoradiation with gemcitabine versus capecitabine in borderline resectable and locally advanced pancreatic cancer.
Authors: Kotowski Adam S. , Yarlagadda Naveen , Salerno May Kilian , Warren Graham Walter , Kuvshinoff Boris W. , Wilkinson Neal W. , Tan Wei , Iyer Renuka V. , Ma Wen Wee
Published: March 2020

e14659

Background: To retrospectively evaluate the outcome of borderline resectable (BR) and locally advanced unresectable (LA) pancreatic cancer patients treated with concurrent chemoradiotherapy (CRT) with gemcitabine (G) or capecitabine (C). Methods: Retrospective chart review of patients treated between August 2005 and September 2011 generated 30 BR and 40 LA pts. Cases were analyzed for patient and treatment characteristics including age, gender, weight loss, ECOG PS, albumin, stage, grade, location, pathology, laboratory values, chemotherapy (CT) regimens, radiotherapy dose and technique, and toxicity using CTCAE v.4.0. Endpoints evaluated were surgical resection rate, progression free survival (PFS), and median overall survival (mOS). Results: Patient characteristics were comparable between CRT/G and CRT/C in both BR and LA patients. Gemcitabine iv 300mg/m2 weekly or capecitabine po 825mg/m2 BID were used during CRT. Among BR patients who received CRT (n=21), 17 (56.6%) received CRT/G, 4 (13.3%) CRT/C, and others received CT alone. For BR, surgical resection was performed in 52.9% of CRT/G patients. The PFS were 17.4 months (m) and 4.8m (p=0.009), and mOS were 21.9m and 5.7m (p=0.004) for CRT/G and CRT/C respectively. For LA patients who received CRT (n=25), 18% of CRT/G underwent surgical resection and none of CRT/C did. The PFS 8.4m and 10.4m (p=0.63) and mOS were 14.9m and 11.5m (p=0.11) for CRT/G and CRT/C respectively. Comparing CRT and CT groups, mOS were not significantly different for LA patients, and longer for BR patients (14.4m vs. 5.5m) although this is likely due to confounding factors such as physician preference and patient selection. No significant differences were noted for grade 3/4 toxicities between both CRT groups. Conclusions: In this series, CRT/G in both BR and LA setting were associated with a high surgical resection rate with acceptable toxicity and potentially improved survival for patients not felt to be surgical candidates at presentation. These data warrant validation in larger prospective randomized studies.
Response evaluation using RECIST and CHOI criteria in patients with well-differentiated pancreatic neuroendocrine tumors (pNET) treated with sunitinib or everolimus.
Authors: Hentic Olivia , Dreyer Chantal , Zappa Magaly , Hammel Pascal , Mateescu Cristian , Bouattour Mohamed , Faivre Sandrine J. , Ruszniewski Philippe , Raymond Eric
Published: March 2020

e14660

Background: Despite low response rate by RECIST, sunitinib and everolimus improved the progression-free survival of patients (pts) with well-differentiated pNET in two large phase III controlled trials. RECIST being a poor surrogate endpoint for PFS, this study aimed evaluating the value of CHOI criteria in PNET pts. Methods: Data for this analysis were collected from pts with well-differentiated PNET treated consecutively with sunitinib or everolimus in our center between 10-2006 and 11-2010. All pts had tumor progression within 12 months (m) prior to treatment. Pts were considered evaluable if CT-scans were performed within 6 weeks prior treatment and <3 months following treatment initiation. A radiologist blinded for clinical data evaluated responses according to RECIST and CHOI criteria. Best responses were correlated with Kaplan Meier estimates of time-to-progression (TTP) and overall survival (OS). Results: A total of 25 pts were treated with either sunitinib or everolimus. Among them, three pts were evaluated using MRI and thus were not evaluable in this study. Twelve pts received sunitinib and ten pts were treated with everolimus (Male/female: 8/14, median age: 57, range 38-76). All pts had tumor progression within 12 m prior to sunitinib or everolimus. Pts were either treated in 1st line (n=6), 2nd line (n=9), 3rd line (n=7) or 4th line (n=1) after cytotoxic chemotherapy. At the first CT-scan evaluation, 2 pts presented a partial response (PR), 18 pts had a stable disease (SD), and 2 pts had a progressive disease (PD) by RECIST. Using CHOI criteria, 11 PR, 8 SD, and 3 PD were observed. Nine of 18 pts (50%) with SD according to RECIST were reallocated to the responders (PR) using CHOI criteria. Median TTP and OS for all pts were 14.0 m and 35.8 m, respectively. According to RECIST, TTP was higher in pts with PR+SD compared to PD (14.2m vs 3.3m, p<0.0001). According to CHOI criteria, TTP was 26.1m in pts with PR, 8.7m in pts with SD, and 3.5m in pts with PD (p=0.038). Conclusions: Response byCHOI criteria is a prognostic factor for TTP and may identify among SD pts by RECIST those benefiting the most of targeted therapy.
Survival outcome of small bowel adenocarcinoma (SBA) in the last 12 years: Meta-analysis.
Authors: Armaghany Tannaz , Shi Runhua , Shows Joseph Ryan , Mills Glenn Morris
Published: March 2020

e14667

Background: Due to rarity, management of SBA is currently controversial. Despite results from several single institutional studies showing no survival benefit with adjuvant chemotherapy, data extrapolated from established colorectal cancer studies are commonly used to manage this cancer. Here we report results of a meta-analysis on data from 14 retrospective studies published in English between years 2000 and 2011. Methods: PubMed database was searched using relevant keywords. Patients with SBA were included. Studies involving ampulary, periampulary and ileocecal valve tumors were excluded. The combined location and stage distribution were adjusted by sample size of each study. Primary outcome for the magnitude of benefit analysis were OS. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted. A random-effect model according to the method of DerSimonian and Laird was used; a heterogeneity test was used. The effect of adjuvant chemotherapy and/or radiation treatment after curative surgery was evaluated. Effect of stage, grade, and positive lymph node ratio was also evaluated. Results: With available information within 14 studies, mean age of patients was 59.3(95% CI: 56.4 and 62.1). Duodenum was the most common site of primary tumor followed by the jejunum, ileum and not specified sites (59.27%, 23.49%, 11.42%, and 3.03%), respectively. Overall median survival was 17.2 months (95% CI: 13.9 and 20.5). Adjuvant treatment vs. non adjuvant treatment showed a HR of 1.17 (95% CI: 0.71-1.93) that was not statistically significant. HR for low grade vs. high grade tumors was 3.90 (95% CI: 2.15- 7.06). HR for stage was 3.09 (95% CI: 0.89-10.67, p=0.07) comparing high stage with low stage which suggested a marginally statistically significant effect. HR for positive lymph node ratio (LNR) was 4.63 (95% CI: 2.67-8.03). Conclusions: Our meta-analysis suggests adjuvant treatment after cancer directed curative intent surgery does not improve overall survival compared to observation in SBA. Grade of tumor and positive LNR are significant predicators of overall survival whereas stage has marginally significant effect on survival. Future trials investigating new or innovative adjuvant therapy in SBA are needed.
The relationship between HER-2 and TOPO-2A gene expression and clinicopathologic results in gastric cancer.
Authors: Ozkan Metin , Turak Esra Ermis , Karaca Halit , Inanc Mevlude , Berk Veli , Deniz Kemal , Eroglu Celalettin
Published: March 2020

e14670

Background: HER-2 and Topo-2A genes are settled on a chromosome 17 and their co-amplification rates are high. In this study, early gastric cancer patients who received adjuvant chemo-radiotherapy and chemotherapy were evaluated with HER-2 and Topo-2A expression in association with clinical and histopathologic findings. Methods: A total of 103 gastric cancer patients were included the study. The HER-2 and Topo-2A levels were measured by immunohistochemistry in postoperative tumor materials. A standard evaluation method was admitted for HER-2 positivity, while Topo-2A nuclear staining 3+ and 4+ were considered as overexpression. Those with level 2+ or 3+ of HER-2, the FISH test were attempted. Results: The median follow-up was 19 months (ranges 2–70 months). Forty-six patients (44%) relapsed during follow-up whereas 60 patients (58%) had died. The median overall survival (mOS) was 23 months. Histopathologies of HER-2 positive patients were intestinal type in 7 (87.5%) and diffuse type in one (12.5%) patient. In the follow-up period 4 patients (50%) were died (mOS was 17 months in this group). Median overall survival was 23 months in HER-2 negative group (p=0.6). Histopathologies of Topo-2A positive patients were intestinal type in 9 (64.2%) and diffuse type in 5 (35.8%) patient. In the follow-up period 8 patients (57%) were died (mOS was 22 months in this group). Median overall survival was 23 months in Topo-2A negative group (p=0.8). Three patients (37.5%) who had HER-2 positive histopathologies also had Topo-2A positivity. Conclusions: Overexpression rates of HER-2 in gastric cancer were reported 6.8-34%. Racial differences and different scoring techniques thought to be impact the results. Co-amplification rate of HER-2 and Topo-2A was reported 34% in gastric cancer. In our study HER-2 and Topo-2A overexpression rates were 7.7% and 13.6% respectively and co-amplification of HER-2 with Topo-2A rate was 37.5% is also similar to the other studies. Stages of patients with HER-2 and Topo-2A overexpression were similar to the distribution of the overall patients. While intestinal subtypes showed a higher rate of HER-2 overexpression, the median survival times tend to be shorter in HER-2 positive patients.
Sorafenib (SFB) treated elderly patients (E) with hepatocellular carcinoma (HCC): Chromogranine A (CGA) plus vascular endothelial growth factor (VEGF) as predicting factors (PF) of treatment outcome.
Authors: Carreca Ignazio Ugo , Piazza Dario , Castagneto Bruno , Condemi Giovanni , Cova Dario , Gambardella Antonio , Foa Paolo ,   on behalf of A.I.R.O.N.A. Italian Association of Oncogeriatry Research
Published: March 2020

e14676

Background: HCC accounts for approximately 90% of all primary liver cancers, and is the fifth most common cancer in the world and prognosis is so far very poor,particularly in E patients.Between all tentative of treatment till know SFB seems to be the most promising drug in patients with advanced or metastatic HCC.Aim of the study is to investigate if SFB is efficient and safe also in E HCC patients despite the comorbidities and other problems. Objectives: To investigate if CgA and VEGF work as predicting factors of Sorafenib treatment outcomes. Methods: 51 patients, mean age 68,9 (65-85) with HCC were enrolled . Serum CgA, VEGF and αFP were evaluated at baseline and after end of treatment (SFB 400mg p.o. bid), until disease progression. Clinical response (RECIST), Comprehensive Geriatric Assessment and PFS were considered as well. Results: CgA mean value (baseline: 77.9 – after treatment: 26.25 UI/L) and VEGF levels (baseline: 67.3 – after treatment 47.2 pg/ml) seems to have a predictive role in clinical benefit. A correlation between lower values of CgA and VEGF was noted in pts with longer PFS. Furthermore 3-4 toxicity was not observed in these pts. OS median was 11 months. Conclusions: The most relevant data in this study refer to the role of serum CgA and VEGF levels, for prediction of tumor response. If these findings were confirmed in future largest studies, it could be sufficient to measure these markers levels for identification of those HCC patients who have more probability of obtaining clinical benefit from a sorafenib treatment.
High C-reactive protein (CRP) level and leukocytosis as a prognostic factor for metastatic pancreatic cancer (MPC) patients with good performance status.
Authors: Ozaka Masato , Ishii Hiroshi , Yukisawa Seigo
Published: March 2020

e14677

Background: Prognostic factor for metastatic pancreatic cancer patients (pts) with good performance status has not been fully evaluated. The objective is to investigate the prognostic factor for metastatic pancreatic cancer patients with good performance status. Methods: Data was collected from the medical records of patients at our hospital. The selection criteria were as follows: 1) histologically proven MPC, 2) ECOG performance status 0 or 1, 3) inoperable or recurrent metastatic disease treated with systemic chemotherapy between Sep. 2007 and June 2011. Results: There were 123 pts who met selection criteria in this study. The median age was 65 years (range, 41-86); male/female, 70/53 pts; the metastatic site was liver/peritoneum/lung/lymph nodes/others in 75/31/15/10/ pts. Median overall survival was 9.5 months, respectively. Of the 123, 11 pts showed leukocytosis (WBC>10000) and 19 pts showed High CRP level (CRP>2.0). Pts with leukocytosis and high CRP level showed significantly poor overall survival (4.44 and 4.44 months). A multivariate analysis demonstrated that a leukocytosis and high CRP level were independent unfavorable prognostic factors. Conclusions: High CRP level and leukocytosis may be a poor prognostic factor for MPC patients with good performance status.
Greater than 3-year follow-up of concomitant gemcitabine, capecitabine, and radiation therapy in locally advanced or incompletely resected pancreatic cancer.
Authors: Sherman William H. , Chu Kyung , Allendorf John , Chabot John A , Schrope Beth , Fine Robert
Published: March 2020

e14708

Background: When either gemcitabine (G) or capecitabine (X) are combined with RT, the median survival is less than 12 months. Approximately 30% of patients progress during the 9 week period of treatment and re-assessment. The benefit of RT in the post-op setting has been questioned. Co-administration of G and X is synergistic against pancreatic cancer cells and both are radiation sensitizers. They were combined with RT. Methods: A retrospective analysis was done on 48 patients treated with GTX (G, docetaxel (T) and X) followed by radiation therapy with concomitant G and X. RT was delivered by conformal fields or IMRT in 180 cGy fractions to 5040 cGy. X, 1,000 mg/m2 was given days 1 to 10 and days 16 to 25 of RT and G, 750 mg/m2 over 90 minutes, was given on days 5, 10, 20 and 25 of RT. The end-points were toxicity and local disease control. Results: 14 patients with positive margin of resection were treated adjuvantly and 34 patients with arterial involvement were treated neo-adjuvantly. No patient developed evidence of metastasis within the 9 weeks after starting RT. There were no bowel perforations, pancreatitis or delayed strictures. The therapy was well tolerated. Grade 3/4 toxicities were: thrombocytopenia 29%, leucopenia 38%, anemia 43%, enteritis 10% and infection 8%. 2 patients had GI bleeding from telangectasias more than 6 months after completing RT. The group of 14 treated adjuvantly had survival of 100% at 1 year, 86% at 2 years. 7 (57%) are beyond 3 years and have not relapsed. 34 patients treated neo-adjuvantly had one year survival of 85%. Of the 34 patients, 16 (47%) are alive with a median survival of 24 months (95% CI 20.7, 31.7.) 22 had resections with a median OS of 25.7 M (range 8.8 to 74.8 M.) 13 have not relapsed (13.6 to 74.8 M.) On pathology, there were 3 CR’s (14%,) 6 (27%) with scattered microscopic disease and 13 (59%) with macroscopic residual disease. Conclusions: G and X can be combined safely with radiation therapy to achieve local control of pancreatic cancer. Our results suggest that the aforementioned therapy, when combined with surgery, increases the long-term disease-free survival over results reported in the literature.
Adjuvant chemoradiotherapy in patients (pts) with resectable gastric (GC) or gastroesophageal junction cancer (GEJC): A monoinstitutional experience.
Authors: Soini Barbara , Pani Giuseppe , Caffo Orazio , Frisinghelli Michela , Veccia Antonello , Brugnara Sonia , Caldara Alessia , DiPasquale MariaChiara , Ferro Antonella , Mussari Salvatore , Murgia Viviana , Russo Lucianna , Valduga Francesco , Tumulo Salvatore , Galligioni Enzo
Published: March 2020

e14711

Background: Several studies have investigated the role of adjuvant chemotherapy ± radiotherapy showing conflicting results. In this retrospective study we report our monoinstitutional experience in pts with resectable GC or GEJC, treated with adjuvant chemoradiotherapy. Methods: Between January 2004 and August 2010 a consecutive series of 48 pts (34 male and 14 female) with a median age of 61 years (range 45-76) underwent a curative resection for GC or GEJC. All pts were treated with adjuvant chemoradiotherapy according to Mc Donald protocol (NEJM 2001;345:725-30). Thirty-three tumors (69%) were localized at the antrum or corpus level and 9 (19%) at the cardias. Thirty-one patients (64 %) had a T3-T4 tumor and 46 (95%) had nodal metastases.Treatment consisted of fluorouracil (5FU) 425 mg/m2 per day plus leucovorin (L) 20 mg/m2 per day, for 5 days, followed by radiotherapy 4500 cGy at 180 cGy per day, given 5 days per week for 5 weeks, with 5FU (400 mg/m2 per day) and L (20 mg/m2 per day) during the first four and the last three days of radiotherapy. One month after the completion of RT, two five-day cycles of 5FU (425 mg/m2 per day) plus L (20 mg/m2 per day) were given one month apart. Results: The treatment was completed in all but 4 pts: 2 pts stopped treatment due to chemotherapy side effects, 1 pt died due to intestinal perforation, and 1 pt declined radiotherapy. Major toxicities consisted of: grade 3/4 neutropenia in 6 pts (12%) and grade 3/4 gastrointestinal toxicity in 8 pts (16 %). At a median follow-up of 25.5 months (range 7 - 68), the median disease free-survival (DFS) was 41 months (2-y DFS 59%, 3-y DFS 53%) and the median overall survival (OS) was 57 months (2-y OS 77%, 3-y OS 68%). Conclusions: Concomitant chemo-radiotherapy appears in our experience a feasible adjuvant regimen in curatively resected node positive gastric cancer. Despite the short follow-up, local control and survival rates seem promising and comparable to those reported in the literature.
Neoadjuvant carboplatin/paclitaxel with concurrent radiotherapy followed by surgery for esophageal/gastroesophageal junction adenocarcinoma: A single-institution experience.
Authors: Platz Timothy Alan , Nurkin Steven J. , Fong Mei Ka , Malhotra Usha , Yendamuri Saikrishna S. , Nava Hector R. , Warren Graham Walter , Salerno May Kilian
Published: March 2020

e14712

Background: Esophageal and gastroesophageal junction (GEJ) adenocarcinoma is increasingly treated with trimodality therapy. We present our experience using carboplatin/paclitaxel and radiotherapy followed by surgery. Methods: Consecutive patients with distal esophageal/GEJ adenocarcinoma (≥T2 or N+) treated from July 2010 to October 2011 were identified. All patients received neoadjuvant carboplatin/paclitaxel with concurrent radiotherapy (CRT) to 50.4 Gy using an IMRT technique and then Ivor Lewis esophagogastrectomy. PET/CT was performed prior to and after CRT. Patient/treatment characteristics and tumor response were analyzed. Results: Over this timeframe,17 patients completed trimodality therapy using this regimen. All were male with a median age of 59 years (45-72). All tumors were grade 2-3 adenocarcinoma with mean tumor length of 4.4 cm (1-9). A median of 6 cycles (5-9) neoadjuvant carboplatin/paclitaxel were administered, 3 patients received additional adjuvant therapy. Average time from diagnosis to CRT completion was 78 days (44-141) and from CRT end to surgery was 62 days (35-92). Neoadjuvant CRT was well tolerated with mean weight loss of 3.5 kg. All pts had R0 resections. No anastomotic leaks or perioperative mortality occurred. Mean hospital stay was 13.6 days (8-28). Pathologic complete response (pCR) was seen in 41% of patients, microscopic residual disease (isolated tumor cells or <2mm) in 29%, and macroscopic residual disease remained in 29%. Mean SUV reduction was 41% (0-100). Of 12 patients with ≥35% SUV decrease, 50% had pCR and 25% had microscopic residual disease. Three patients had signet ring features; of these 2 had no SUV reduction and all had gross residual disease, including the only patient with pN disease. Conclusions: Trimodality therapyutilizing carboplatin/paclitaxel and CRT to 50.4 Gy IMRT followed by Ivor Lewis esophagogastrectomy was well tolerated and resulted in significant pathologic complete response or minimal residual disease. Further investigation of predictive factors for response is needed to best tailor therapy in the management of esophageal/GEJ adenocarcinoma.
Cumulative impact of algorithm-integrated multidisciplinary treatments for cholangiocarcinoma.
Authors: Hirschfeld Azriel , Bruckner Howard , Stega Jeanetta , Schwartz Myron E.
Published: March 2020

e14732

Background: Pancreatic Ca (PC) treatments (rxs) are often applied to patients (pts) with cholangioC (CC). Analyses support parallel "testing" of neoadjuvant (NeoA) and adjuvant (A) rx for CC pts. The rxs below “doubled” phase II objective response (OR) and survival (OS) vs PC. Methods: With pre-registration and IRB consent over ten years: GFLIP>GFLIO >GFLIO docetaxel (D) -/+mitomycin -C (MM-C) (Bruckner ASCO 01, 05, 08, 11) were applied to pts with PC and CC; stage adjusted, “possible best" choices for PC rxs were applied as NeoA and A rxs for high risk CC pts. Risk was defined by: margin, +; size, large; location, surgical difficulty, central; LNs, involved (or suspect), number of sites (and distance); pathology, atypical, high virulence and relapse (second surgery). These are the worst half of resected pts. Pts with unresectable (U) and metastatic (IV) CC were eligible with or without prior failure of some of the rx drugs. Targeted rx (TT) was briefly added, bevacizumab (B) 5mg/kg or cetuximab (C), as needed, to convert stable disease (SD) to NeoA eligible OR. Gallbladder Ca (GBC) pts were also treated. The algorithm's goal was to both optimize surgery for tumor reduction to improve rx and to select “timely” drug partners to reduce tumor size and allow further surgery. Results: No fatal AEs; Of 16 high risk, Adjuvant, resected pts, at 18 mos, 14 are alive, 10/11at 2 yrs, 6/7 (86%) at 3 yrs, 1 lost contact CC U/ IV, N=28, 4 lost contact 16/19 (84%) alive at 18 mos; 12/16 alive at 2yrs; 8/12 alive at 3 yrs. This vs. 50% (18mo) MST (ASCO 11). Of 7 NeoA, 4/4 were alive at 3 yrs, 3 others alive < 3 yrs. (3 had best R with TT). *RR GFLIO ~ 60% add DMM-C ~ 60% € ~84% add TT ~20% €~ 87%. Conclusions: Rxs are safe, economical and well tolerated. € RR and OS adding (FI, D, D-MMC and selectively TT) are testworthy. Both 12 mos OS and NeoA/A are testworthy for GBC pts. B and C are individually active, safe and cost effective in brief NeoA usage applications. Low dose multi drug rxs are ideal safe platforms for TT. High serial € RR encourage 1° and 2° attempts at both debulking - strategic palliative and definitive surgery, ideally in trials to optimize (pt conditioning, eligibility) and compare NeoA vs A rxs.
The preclinical activity of lenalidomide in urothelial carcinoma (UC).
Authors: Levitt Jonathan M. , Chan Keith S. , Jian Weiguo , Lerner Seth P. , Sonpavde Guru
Published: March 2020

e15002

Background: Lenalidomide is approved for multiple myeloma and deletion 5q myelodysplastic syndromes (MDS) and demonstrates immune modulation, anti-angiogenic activity and direct anti-tumor cytotoxicity. A rationale can be made to evaluate the preclinical activity of lenalidomide in urothelial carcinoma (UC) based on the importance of these pathways. Methods: The in vitro anti-tumor activity of lenalidomide was evaluated in 4 human (5637, TCC-SUP, RT4, RT112) and 1 murine (MB49) cell line. Anti-proliferative activity activity (MTT assay), apoptosis (Annexin-FITC immunohistochemistry [IHC], flow cytometry) and cell viability by colony forming assay were measured. In vivo examination of activity of daily oral lenalidomide 10 mg/kg orally once daily or placebo for 4 weeks is examined in a syngeneic immunocompetent mouse model employing MB49-Luc25 cells injected subcutaneously in C57BL/6 mice. Murine tumors will be studied for anti-tumor activity. Results: In vitro activity of lenalidomide was detected at low ~1 µM concentrations (attainable in human subjects) against a non-invasive human UC cell line (RT4). Long-term cultures of RT4 cells for 10 days with daily repletion of lenalidomide reduced cell viability and colony forming ability to 75.6% of controls. Induction of apoptosis in RT4 was demonstrated by Annexin-FITC IHC and flow cytometry compared to control (30.11 vs. 14.74%). Invasive human UC cells and murine MB49 cells did not demonstrate apoptosis with lenalidomide exposure in vitro. Futher, lenalidomide did not inhibit overall tumor growth in the syngeneic immunocompetent murine model; immune activity and stem cell directed activity will be presented. Conclusions: Lenalidomide demonstrated preclinical anti-tumor activity against non-invasive human UC cells. Given its favorable toxicity profile compared to cytotoxic chemotherapy, clinical evaluation in patients with non-muscle-invasive bladder cancer and recurrence after BCG therapy may be warranted.
Evaluation of ERCC1 and RRM1 as prognostic biomarkers in urothelial cancer (UC) treated with adjuvant platinum and gemcitabine chemotherapy.
Authors: Harshman Lauren Christine , Bepler Gerold , Quinn David I. , McKenney Jesse , Hawes Debra , Simon Noah , Srinivas Sandy , Dorff Tanya B.
Published: March 2020

e15005

Background: Adjuvant (adj) treatment of UC generally entails platinum (plat)- and gemcitabine (gem)-based chemotherapy (chemo). Two candidate prognostic and predictive biomarkers are the excision repair cross-complementation group 1 gene (E1) and the regulatory subunit of ribonucleotide reductase (R1). Studies in advanced UC patients (pts) suggest that high E1 and R1 expression confers chemoresistance to cisplatin (cis) and gem respectively. We identified UC pts treated with adj chemo to assess for differences in time to recurrence (TTR) and overall survival (OS) based on tumoral E1/R1 expression and chemotherapy regimen. Methods: 184 pts, who received adj plat or gem for T2-4NxM0 UC from 1984-2009, were identified. Tissue microarrays were created from their primary bladder tumor and involved nodal tissue. E1 and R1 protein expression was assessed using AQUA (HistoRx). The median (med) values were established a priori as the cutoff for high and low expression. Medical records were retrospectively reviewed for pathology, treatment, and outcomes data. Results: 154 pts who had both clinical and gene expression data were eligible for analysis. Pts received cis (134), carboplatin (carbo, 20) and gem (62) based regimens. Med age was 65 yrs. The majority were male (79%) and had pT3 (48.7%) or nodal disease (53.2%). At med followup of 3.9 yrs, 53.4% have recurred. Med TTR and OS were 1.2 and 2.1 yrs. Primary tumor E1/R1 Spearman correlation was moderate at 0.49 but less between primary and nodal disease (E1 0.34, R1 0.23). Irrespective of chemo, E1 and R1 expression were not prognostic for TTR (E1 p=0.8, R1 p=0.3) or OS (E1 p=0.25, R1 p=0.83). Degree of E1 expression did not impact TTR or OS in plat-treated pts nor did R1 expression in gem-treated pts. Stage predicted increased TTR and OS (<0.00001). Cis-treated pts had significantly longer TTR (p=0.02) than carbo-treated pts. Conclusions: Tumoral E1 and R1 expression were not prognostic biomarkers for UC pts treated with adj plat and gem chemotherapy in our cohort. Our data was limited by missing tissue in 22% of planned pts. Reproducibility by a second laboratory and heterogeneity analysis between primary and nodal tissue will be presented.
The natural history, treatment pattern, and survival of the patients with micropapillary bladder.
Authors: Wang Jue
Published: March 2020

e15015

Background: Micropapillary bladder carcinoma (MPBC) is a rare variant of urothelial carcinoma. The objective of this study was to examine the epidemiology, natural history, and prognostic factors of MPBC using population-based registry. Methods: The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify cases of MPBC by tumor site and histology codes. The clinical, demographic characteristics, treatment and survival of MPBC were examined. Results: A total of 98 cases of histology confirmed MPBC were identified between 2001 and 2007, this accounted for approximately 0.01% of all primary bladder tumors during the study period. Median age of the patients was 72 years (range 26-95). Of all the patients with MPBC, 56.1% had muscle invasive disease; 75.5% of patients had poorly or undifferentiated histology. A total of 30.6% of all patients (2.3% superficial disease; 52.7% of muscle-invasive MPBC) had radical or partial cystectomy. By logistic regression analysis, nonmuscle-invasive MPBC (OR 62.5, 95% CI 7.2-542.3) was associated with lower rate of utilization of cystectomy. The 1-, 3- and 5-year overall survival rate of MPBC were 84.5%, 57.3% and 42.3%. In multivariate analysis, tumor stage (HR 4.7, 95% CI 1.0-21.8) was found to be the only significant predictor for cancer-specific survival. Conclusions: The optimal therapy for MPBC remains undermined. Emphasis on early detection is needed to improve the outcome for patients with this malignancy.
Extensive lymph node dissection in the era of increasing perioperative chemotherapy for muscle-invasive urothelial carcinoma of the bladder.
Authors: Holder Dara Denise , Lin James , Whalen Micheal , McKiernan James M. , DeCastro Guarionex
Published: March 2020

e15018

Background: The efficacy of perioperative chemotherapy (CHT) in the management of muscle invasive urothelial carcinoma of the bladder (UCB) has been attributed to its ability to eliminate occult disease, which when coupled with a cystectomy can reduce recurrence. The therapeutic role of lymphadenctomy (LND), with an appropriate template and nodal yield, during radical cystectomy (RC) is well established. To date, there have been no studies examining the integrative effect of an extended LND and the use of perioperative CHT for patients with muscle-invasive UCB. As such we examined the interaction between survival and extent of LND based on whether patients received perioperative CHT or RC only. Methods: Review of our urologic oncology database yielded 314 patients with cT2-4N0M0 UCB who underwent RC with and without perioperative CHT between 1990- 2011. Extended lymph node dissection was defined as the removal of ≥11 nodes. Clinical and pathological variables were analyzed using Cox Hazard and Kaplan Meier models. The primary endpoints examined were overall (OS) and disease-specific (DSS) survival. Results: Two hundred and four (65%) patients were identified who underwent RC only, while 110 (35%) patients received perioperative CHT and RC. There was no significant difference between the 2 groups in common demographic and pathologic variables. Fifty-one percent of patients who underwent CHT and RC and 42% who underwent a RC only had an extensive LND (p=0.16), with a mean nodal yield of 9. Extended LND was associated with a non-significant decreased risk of death in the RC-only group (HR=0.54, CI: 0.23-1.20, p=0.14), and a non-significant increase in patients who underwent perioperative CHT (HR=1.25, CI: 0.71-2.81, p=0.56). Kaplan Meier analysis showed an increase in the probability of DSS at 2 years in the RC-only group who underwent an extended LND vs. a standard LND (0.96 vs. 0.84, p= 0.12) while no such trend was observed in the perioperative CHT patients (0.75 vs. 0.75, p=0.35). Conclusions: Surgical management of occult micrometastatic disease through extended LND improves survival in patients undergoing RC only, but offers no additional benefit over perioperative CHT.
Addition of darbepoetin alfa to sequential high-dose VIP chemotherapy for patients with advanced metastatic germ cell cancer.
Authors: Hartmann Joerg Thomas , Metzner Bernd , Binder Claudia , Mergenthaler Hans-Guenther , Rick Oliver , Sayer Herbert G , Mayer Frank , Beyer Joerg , Lorch Anja , Berdel Wolfgang E. , Frickhofen Norbert , Bokemeyer Carsten , Schleicher Jan , Gauler Thomas C. ,   German Testicular Cancer Study Group (GTCSG)
Published: March 2020

e15026

Background: High-dose VIP chemotherapy plus ABSCT given as first line treatment might be a strategy in patient with advanced germ cell tumors (GCT) with poor prognosis. The objective of the trial was to investigate the addition of darbepoetin alfa to HD-VIP in order to reduce anemia/red blood cell (RBC) transfusions. Methods: This was a randomized, open-label multicenter phase 2 study conducted in 20 hospitals. Darbepoetin 2.25 mcg/kg weekly or 500 mcg Q3W s.c., started with high dose VIP (dose level 6) was applied in arm B (arm A: HD-VIP alone). The primary objective was freedom from blood transfusions (FFT). Secondary objectives included objective remission rate (ORR) after chemotherapy, 24 mos PFS and OS, median course of hemoglobin (Hb) levels during 3 HD-VIP cycles as well as drug safety. Results: Between 7/2003 and 11/2008 108 pts were allocated to the study, and 106 were included in the intention-to-treat (ITT) analysis. By March 2011 the median follow-up time after randomization was 20 mos. Localisation of primary was gonadal in 66%, retroperitoneal in 19% and mediastinal in 14%s. A favourable treatment outcome (CR/NED/PR m-) in conjunction with secondary surgery (n = 76 pts) was achieved in 58% of pts with no difference between arms A and B. Overall FFT occurred in 2 pts (4.2%) in arm A and 3 pts (5.6%) in arm B, and in 23%/15%/15% and 15%/17%/19% of pts during cycles 1-3, respectively. No differences in baseline Hb, severity of anemia, no of RBC transfusions and area under the curve of Hb levels during HD-VIP was observed. Pts assigned to darbepoetin had similar treatment toxicity compared to those assigned to HD-VIP alone. 24-mos OS in arm A was 86.3% compared to 67.8% (p=.064) in Arm B. 2-year RFS was 66.8% in arm A vs 55.5% in Arm B (p=0.45). Darbopoetin was generally well tolerated with 2 pts discontinuing treatment due to thrombosis. Since compliance to study protocol was generally poor (6 out of 55 pts never received study drug during HD-VIP) a per-protocol analysis is in preparation. Conclusions: Based on ITT analysis, the addition of darbepoetin alfa to the high dose regimen compared to HD-VIP alone does not appear to impact on FFT, ORR, and 2-year survival rate in poor prognosis GCT pts (NCT00204633).
Comparison of standard versus high dose of paclitaxel with ifosfamide and cisplatin (TIP) in salvage therapy of germ cell tumors (GCTs).
Authors: Mardiak Jozef , Mego Michal , Miskovska Viera , Sycova-Mila Zuzana , Obertova Jana , Palacka Patrik , Usakova Vanda , Rajec Jan , Liskova Stefania , Vertakova-Krakovska Bibiana , Chovanec Michal , Salek Tomas , Reckova Maria
Published: March 2020

e15028

Background: Currently, TIP with higher dose of paclitaxel (250mg/m2) is considered standard salvage chemotherapy in GCTs with good prognostic features. However, until 2007, we utilized regimen with standard dose of paclitaxel (175mg/m2). The aim of this study was to compare the efficacy of TIP with the standard versus higher dose of paclitaxel as first salvage therapy for patients with relapsed GCTs. Methods: This retrospective study included 64 patients with relapsed GCTs treated with TIP as first salvage therapy between 1998 and 2010 in two major cancer centers in Slovakia. Forty five patients (70%) patients had favorable prognostic features for response (testis primary tumor site and prior complete response to induction chemotherapy regimen). Four cycles of standard dose (175mg/m2, 37 patients) or higher dose (250 mg/m2, 27 patients) of paclitaxel (day 1) with ifosfamide 1.2 g/m2 (day 1-5) and cisplatin 20 mg/m2 (day 1-5) were given 21 days apart with G-CSF support, followed by resection of resectable radiographic residua. Results: Nineteen of 37 (51%) patients treated with standard dose of paclitaxel achieved favourable response (complete remission or partial remission with negative serum tumor markers) compared to 20 of 27 (74%) patients treated with higher dose of paclitaxel (p = 0.07). In median follow-up of 23.9 months 37 patients (58%) experienced disease relapse and 33 (52%) patients died. Patients treated with higher dose of paclitaxel had better progression-free survival (median: not reached vs. 7 months, HR = 0.54, 0.28 - 1.04; p = 0.06) and overall survival (median: not reached vs. 33 months, HR = 0.69, 0.34-1.39; p = 0.31) compared to patients treated with standard dose of paclitaxel. Conclusions: Our data support the hypothesis that higher dose of paclitaxel with ifosfamide and cisplatin is associated with better outcome compared to standard dose of paclitaxel in patients with relapsed GCTs treated in first relapse.
Updated results of a prospective noninterventional study of everolimus after use of 1 VEGFR-TKI.
Authors: Bergmann Lothar , Goebell Peter J. , Kube Ulrich , Kindler Manfred , Herrmann Edwin , Janssen Jan , Schmitz Joerg , Weikert Steffen , Kloss Susanne , Steiner Gabriel , Jakob Andreas , Staehler Michael D. , Steiner Thomas , Overkamp Friedrich , Guderian Gernot , Doehn Christian
Published: March 2020

e15044

Background: Everolimus (EVE, Afinitor) is approved for the treatment of metastatic renal cell cancer (mRCC) after failure of VEGF-targeted therapy. The option to treat mRCC with six approved targeted agents has sparked debate on proper sequencing of these agents. However, data beyond clinical trials is limited. Here, we report prospective non-interventional data on EVE in routine use after failure of the 1st VEGFR-TKI. Methods: A prospective, single arm non-interventional study for patients with mRCC enrolled 383 patients in Germany between 08/2009 and 01/2012 to determine effectiveness defined as time between first EVE intake until disease progression due to any cause (TTP) and treatment duration. A first interim analysis was previously conducted and presented (Bergmann et al., J Clin Oncol 29: 2011 [suppl; abstr 4552]). Here we present a second interim analysis which was carried out 10 months after the first to corroborate the previous results. Results: 196 pts were included at 79 sites between 08/2009 and 07/2011 and had been followed for a median of 4.5 months at the time of analysis. The safety population (pts with information on EVE treatment) and efficacy population (pts who fulfilled all criteria per observational plan) consisted of 195 pts and 165 pts, respectively. At the cut-off date for the interim analysis, 136 pts (69%) had discontinued the study. Median treatment duration was 7.3 months (95% CI: 4.7 mo; 10.9 mo) and median time to progression (TTP) was 7.0 months (95% CI: 5.1 mo; 9.0 mo) for the efficacy population. A total of 600 AEs were reported in 70% of pts of the safety population including 148 SAEs in 67 pts (34%). Subgroup analysis according to duration of prior VEGF-targeted treatment <6 months and ≥6 months revealed median TTPs of 6.8 months (95% CI: 4.4 mo; 13.4 mo) and 7.4 months (95% CI: 4.6 mo; 10.1 mo), respectively. Conclusions: This 2nd interim analysis of a non-interventional study on EVE in treatment of mRCC after prior failure of the 1st VEGFR-TKI confirms the longer TTP reported in the 1st interim analysis compared to the pivotal trial. The results also provide evidence that TTP under EVE does not necessarily correlate with time on prior treatment.