bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of patients who most benefit from hepatic arterial infusion (HAI) combined or not with systemic chemotherapy for the treatment of unresectable colorectal liver metastases
Authors: Pilati P. , Mocellin S. , Lise M. , Nitti D.
Published: March 2020

14565

Background: Although locoregional treatments such as hepatic arterial infusion (HAI) claim the advantage of delivering higher doses of anticancer agents directly into the affected organ, there is substantial lack of evidence for benefit in terms of overall survival (OS). To test the hypothesis that systemic chemotherapy affects OS of patients with unresectable colorectal liver metastases treated with HAI. Furthermore, we investigated patient- and tumor-related predictive factors that might identify patients who most benefit from HAI regimen. Methods: In this retrospective study, 153 consecutive patients treated at our institution were considered. In group-A (n=72), patients were treated with HAI alone (floxuridine (FUDR) 0.2 mg/Kg + leucovorin (LV) 4 mg/m2 + desamethasone 20 mg 14 days/month) between 1994 and 1999. In group-B (n=81), patients were treated with the same HAI regimen combined with systemic chemotherapy (5-fluorouracil (5FU) 450 mg/m2 + LV 20 mg/m2) between 1999 and 2003. Results: No difference in OS was observed between group-A and group-B (median OS: 18.0 and 19.1 months, respectively). Considering all patients (group A + group B), low tumor load was associated with a better tumor response rate, but none of the traditional clinico-pathological prognostic factors correlated with OS. Median OS was better in patients with less than 50% of liver parenchyma involvement (21.3 vs 13.2 months; P<0.0001) as well as in responders (complete or partial response) versus non-responders (24.4 vs 13.4 months; P<0.0001). The combination of low tumor load with good tumor response to HAI was the only variable retained at multivariate analysis, and identified a subgroup of patients with a very favorable clinical outcome (median survival: 34.2 months; hazard ratio: 0.347, CI: 0.249–0.564, P< 0.0001). Conclusions: Combination with 5FU+LV systemic chemotherapy did not lead to an OS benefit over FUDR-based HAI alone. The identification of tumor response predictors is urgently needed, as it would lead to the tailored treatment of patients with low load but unresectable metastatic liver disease who most benefit from HAI therapy.

No significant financial relationships to disclose.
Topoisomerase I expression in locally advanced rectal cancer as predictive marker for response to preoperative chemoradiation
Authors: Horisberger K. E. , Hofheinz R. D. , Muessle B. , Findeisen P. , Hochhaus A. , Post S. , Willeke F.
Published: March 2020

14566

Background: In locally advanced rectal cancer combined modality treatment has become the standard therapeutical intervention. Preoperative downstaging is known as a predictor concerning lower local recurrence rate and probably better overall-survival. However, efficacy of neoadjuvant chemoradiation is compromised in some patients by so far unknown factors. The aim of the present study was to investigate topoisomerase I expression as a potential parameter for predicting response to irinotecan-based chemoradiation. Methods: 15 patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited to receive weekly neoadjuvant irinotecan (1 hour before radiation) and capecitabine as well as cetuximab with a concurrent RT dose of 50.4 Gy (45+5.4 Gy). Surgery was scheduled 4–6 weeks after the completion of chemoradiation. Samples of normal and tumor tissues of all patients were collected before neoadjuvant treatment. Initially, RNA-oligonucleotid-array of three patients (one good responder and two non-responders) was accomplished to show qualitatively different gene expression. To quantify the differences, real-time PCR of topoisomerase I was performed. Results: The differences of gene expression in the RNA-oligonucletoidarray were correlated to the clinical response to neoadjuvant chemoradiation as topoisomerase I showed a significant higher expression in the tumor tissue of the good responder before treatment (p<0.0001). PCR-analysis showed a relatively higher median expression of topoisomerase I in normal tissue (1.7 vs. 0.9; p=0.85) and in tumor tissue (1.5 vs. 1.3; p=0.36) of the subsequent good responding patients (n=10). Conclusion: Patients respond differentially to chemoradiation in terms of clinical response and gene expression shifts. The oligonucleotidarray results leads us to assume that response may be predictable. The preliminary results of PCR demonstrate that TopoI expression describes a valuable parameter for prediction of efficiency of irinotecan in advanced rectal cancer. The small number of patients may have caused the missing of the statistical significance. We are intending an extension of the PCR analysis to more powerful series based on the achievements of the current investigation results.

No significant financial relationships to disclose.
Cetuximab plus bevacizumab in patients (pts) with metastatic colorectal cancer (mCRC) who have failed on irinotecan, oxaliplatin and fluoropyrimidines-based chemotherapy
Authors: Souglakos J. , Kalbakis K. , Vamvakas N. , Kalykaki A. , Kotsakis A. , Agelaki S. , Karampeazis A. , Gioulbasanis J. , Georgoulias V.
Published: March 2020

14576

Background: Bevacizumab (AVASTIN®) and Cetuximab (ERBITUX®) are IgG1 monoclonal antibodies targeting the Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR), respectively. Both are active in mCRC pts as first and/or second line treatment. Preclinical data suggest potentially synergistic effect for the combination of the two antibodies. This phase II trial evaluates the safety and efficacy of cetuximab combined with Bevacizumab in the treatment of mCRC pts who have failed on Irinotecan, Oxaliplatin and Fluoropyrimidines-based chemotherapy. Methods: mCRC pts with ECOG PS = 2 who had refractory disease to all three active chemotherapeutic drugs were enrolled. Determination of EGFR status was not mandatory. Cetuximab was given at an initial dose of 400mg/m2, then 250mg/m2 iv weekly; Bevacizumab was administered at a dose of 10 mg/kg on d1 every 2 weeks. Results: From June 2005 to November 2006, 14 pts were enrolled. Median age was 65 years, and median PS was 1. Treatment was 3rd-line in 5 pts, and = 4th-line for 7 patients. 12 pts had received prior treatment with Cetuximab and 6 were Bevacizumab. Thirty-nine cycles were administered with a median of 3 cycles/patient. All pts were evaluable for toxicity and response. No grade 3–4 hematological toxicity was observed. Non-hematological toxicities included grade 3 fatigue (7.1%), grade 2 diarrhea (7.1%), grade 2 allergic reactions (14.1%). Amongst the 14 patients evaluable for response, there was 1 objective PR (7.1%; 95% CI: 6- 24%), and 2 (14.2%) SD (tumor growth control rate, TGCR: 21.3%). The median time to progression was 2.4 months and the median survival has not yet been reached. The estimated probability for 1-year survival was 65.7%. Conclusions: The combination of Cetuximab plus Bevacizumab in patients with mCRC refractory or resistant all active chemotherapeutic drugs is safe and has promising activity.

No significant financial relationships to disclose.
Correlation of bone marrow micrometastases with nodal status in gastrointestinal tumors
Authors: Chivu S. , Saha S. , Patel G. M. , Wiese D. , Bassily N. , Henke A. , Sankaran H. , Misra A. , Singh T. , Arora M.
Published: March 2020

14577

Background: Presence of bone marrow micrometastases (BMM) is an important prognostic factor for patients (pts) with solid tumors. Sentinel lymph node (SLN) mapping (M) has been found to upstage pts with gastrointestinal (GI) malignancies. However, a direct correlation between the presence BMM and nodal metastases (mets) is lacking. Hence, a retrospective study was undertaken to determine the relationship between BMM and nodal status in various GI malignancies. Methods: A total of 159 consecutive pts with GI malignancies were analyzed. Of these, 6 pts with non-epithelial tumors were excluded. All pts underwent bilateral posterior-superior-iliac spine bone marrow (BM) aspiration. BM samples were examined for micrometastases by Automated Cellular Imaging System using ChromaVision Cytokeratin Detection Kit to detect cells expressing CK8 as defined by CAM 5.2 monoclonal antibody. When feasible, SLNM was performed followed by standard oncologic resection (n=105). The SLN were examined by H&E and immunohistochemical (IHC) staining. Results: A total of 153 pts were analyzed in the study. Of these 13.72% (21/153) were found to have BMM (CI 8.70–20.21, p=0.05). When analyzed by sites, the incidence of BMM was 33.3% (4/12) for stomach cancer, 9.1% (1/11) for pancreatic cancer, 12.36% (11/89) for colon cancer and 16.13% (5/31) for rectal cancer. No BMM were detected in pts with cancer of esophagus (n=7), small bowel (n=2) and liver (n=1). The BMM was positive bilaterally in 61.9% (13/21), and unilaterally in 38.1% (8/21). In pts who underwent SLNM (n=105), BMM were detected in 11.11% of SLN positive pts vs. 10.14% for SLN negative pts (p=0.87). For a subgroup of pts with colorectal cancer who underwent SLNM (n=97), BMM were detected in 9.67% of SLN positive pts vs. 9.09% for SLN negative pts (p=0.92) Conclusions: BMM did not correlate with nodal status for GI malignancies suggesting a possible different mechanism for metastases. Detection of BMM may have a significant clinical value in SLN negative pts who may benefit from adjuvant therapy.

[Table: see text]

No significant financial relationships to disclose.
Efficacy of FUFOX regimen in the treatment of a selected population with metastatic colorectal cancer (MCC)
Authors: Garassino M. C. , Borgonovo K. , La Verde N. , Sburlati P. , Bianchi C. , Cobelli S. , Rovej R. , Tomirotti M. , Torri V. , Farina G.
Published: March 2020

14596

Background: FOLFOX is usually employed as first line treatment of MCC. Some patients (pts), for both clinical reasons and poor compliance, are not eligible for CVD insertion. At the moment, it is not clear if FUFOX (with 5-FU bolus) is less active than FOLFOX (with 5-FU infusion). We evaluated the outcome of MCC pts treated, as first line, with FUFOX. Primary end-point is efficacy. Secondary endpoints are time to progression (TTP) and overall survival (OS). Toxicity is also reported. Materials and Methods: We analysed all consecutive MCC patients who referred to our centre, without CVD, treated with the Hochster regimen: Oxaliplatin 85 mg/m2 days 1, 15; Leucovorin 20 mg/m2 and 5-FU 500 mg/m2 bolus days 1, 8, 15 - every 28 days. Response rate was evaluated with RECIST criteria. TTP and OS were analysed with Kaplan-Meier methods. Results: From July 2003 to October 2006 we treated 25 MCC pts. Main characteristics were: median age 71 years (range 46–79), 12 males, 13 females; PS 0–1; metastatic sites: liver 15 pts; lung 6; abdominal 10. 2 pts are early. A total of 128 courses were administered (5,4 median courses/pt, range 3–9). 5/23 pts (21.7% 90%CI: 9.0%-40.4%) had a PR and 2 achieved a secondary complete surgery. 15/23 pts (65.2%: 90%CI: 46.0%-81.4%) had a SD and 3 pts (13.0%: 90%CI: 3.7%- 30.4%) had a PD. At the moment of analysis 14 pts are still alive with a median follow up of 25 months; the median time to progression is 7.2 months. This combination was well tolerated with no grade 3–4 toxicities observed. G1-G2 peripheral neurotoxicity is reported in 15/25 pts (60%). Other common toxicities are: G1–2 haematological in 10 pts (40%); G1–2 gastrointestinal in 7 pts (28%); asthenia 5 pts (20%). Conclusions: We observed a low response rate, but high number of stable disease. Toxicity was acceptable. Although this is a not controlled study, this regimen seems to be less effective than infusional regimens but, due to the high control rate of disease (86.9%) we can consider it an alternative choice for patients that refuse or cannot receive continuous infusion.

No significant financial relationships to disclose.
First-line chemotherapy with irinotecan plus capecitabine for advanced colorectal cancer
Authors: Michalaki V. , Gennatas C. , Gennatas S. , Vasiliou J. , Smyrniotis V.
Published: March 2020

14602

Background: The effective, oral fluoropyrimidine capecitabine is increasingly replacing intravenous (IV) 5-FU/LV in colorectal cancer treatment. The aim of this study was to evaluate efficacy and safety of the combination chemotherapy with irinotecan plus capecitabine (XELIRI), in patients with advanced colorectal adenocarcinoma. Methods: Patients with advanced colorectal adenocarcinoma received a first-line chemotherapy with capecitabine (1000 mg/m2 twice daily) on days 1–14 and irinotecan (240 mg/m2) on day 1 of a 21-day cycle. Results: Twenty-eight patients were evaluable for response. Baseline characteristics: 18men, 10 women; median age 65.5 years (range, 49–73); colon cancer (71%), rectal cancer (29%). Most common metastatic sites were the liver (53.5%), lymph nodes (43%), lung (21%) and bones (18%). There were 7 partial responses (25%), 8 cases of stable disease (28.5%), and 13 cases of disease progression (46.5%). The median survival was 14 months (range, 2–28.8 months) and median progression-free survival was 7 months (range, 6- 26 months). The median number of cycles received was 7 (range, 3–15 cycles). Frequently encountered therapy-related events were leukopenia and gastrointestinal side effects including diarrhea. Conclusions: First-line capecitabine/ irinotecan is an active combination for the treatment of metastatic colorectal cancer achieving high efficacy with a good safety profile.

No significant financial relationships to disclose.
Phase II trial to evaluate combination of folfox6 + bevacizumab in initially unresectable liver metastases from colorectal cancer (crc)
Authors: Malavasi N. , Dealis C. , Depenni R. , Zironi S. , Bertolini F. , Losi L. , Gerunda G. E. , Colucci G. , Luppi G. , Conte P. F.
Published: March 2020

14603

Introduction: The gold standard treatment of CRC liver metastases is surgical resection. Bevacizumab has proved efficacy in advanced disease. Primary objective of the study is to evaluate resecability rate of liver metastases and incidence of major surgery complications. Secondary objective is to relate tumor and serum biomarkers (EGFR, VEGF, TS, Ki67, ERCC1, MSH2, MLH1 and VEGF ) to clinical outcome Methods: Baseline requires evaluation by CT-PET scan, biopsy of metastases; PET scan is needed after first administration to describe preliminary response. The treatment consists of FOLFOX6 regimen associated to Bevacizumab, 5mg/Kg, every two weeks; elective surgery is planned after 6 cycles (the last one excludes Bevacizumab dose) by CT-PET scan; if resection is appropriate, it will be performed, otherwise the treatment will continue to 12 cycles. Biomarkers are assessed at baseline, following the first administration and before surgery Results: Up to now 11 patients have been enrolled (M/F:6/5; median age:64, range:46–72); ECOG: 0/1. 10 patients reached surgical step while 1 patient is still on chemotherapy. Three patients (27%) were not suitable for resection and received further chemotherapy: 1 had PR, 1 PD and 1 became resectable after 12 cycles. In the other 7 patients (63%): 2 CR (18%) histologically confirmed; 4 macroscopic and curative resection of liver metastasis; 1 is receving two stage epathectomy (portal vein occlusion before major liver resection). Life threatening toxicities: 1 TVP causing discontinuation of Bevacizumab, 1 hospitalization for gastro-intestinal and G4 neutropenia both causing discontinuation of the whole therapy. Bevacizumab complications before major surgery did not occurred; 1 patient reported post operative delay wound healing. Less severe toxicities: haematological G3 in 2 patients (18%), G1 in 1 patient (9%); 3 gastrointestinal G2 (27%); neuropathic in 1 patient (9%). The VEGF serum decreased after the first dose of Bevacizumab in all specimens Conclusions: Systemic chemotherapy with combination regimens may downstage liver metastases and thus increase resecability rate without important surgery complications; biomarkers related to clinical outcome are in evaluation.

No significant financial relationships to disclose.
Glufosfamide (GLU) plus gemcitabine (GEM) in pancreatic adenocarcinoma: Preliminary results of a phase 2 trial
Authors: Chiorean E. G. , Dragovich T. , Hamm J. , Barrios C. H. , Gorini C. F. , Langmuir V. K. , Kroll S. , Tidmarsh G. T. , Colowick A. B. , Loehrer P. J.
Published: March 2020

15005

Background: Glufosfamide is glucose linked to isophosphoramide mustard, the active metabolite of ifosfamide. Cancer cells use glucose at a higher rate than normal cells, which may lead to preferential metabolic targeting by GLU. The Phase 1 study established a GLU dose of 4500 mg/m2 for the GLU + GEM regimen. The objectives of the Phase 2 part of this study are to evaluate the safety and efficacy of GLU+GEM in pts with pancreatic adenocarcinoma. Methods: Eligible pts had metastatic and/or locally advanced pancreatic adenocarcinoma previously untreated with chemotherapy, Karnofsky Performance Status =70, creatinine clearance (CrCL) =60 mL/min and acceptable hematologic and liver function. Pts received GLU 4500 mg/m2 iv over 4 hours on Day 1 and GEM 1000 mg/m2 iv over 30 minutes on Days 1, 8 and 15 of every 28-day cycle. CT scans were obtained every 8 weeks. Primary endpoint was response rate. Results: Twenty-nine pts were enrolled. One patient with ineligible histology was excluded from efficacy analyses. The 14 male/15 female pts had a median age of 59 years. Median cycles on treatment was 4 (range 1–10+) and 9 pts completed all 6 cycles. Six of 28 (21%; 95% CI: 8- 41%) pts had a partial response (duration 1.0+ to 5.8+ months), one unconfirmed. Ten of 28 (36%) pts had stable disease (median duration 5.3 months). Median progression-free survival was 3.7 months. Six-month survival was 54% (95% CI: 38–78%). Grade 3/4 neutropenia and thrombocytopenia occurred in 21/29 (72%) and 8/29 (28%) pts. Five pts (18%) had a GLU-related serious adverse event (SAE). Two pts died due to SAE unrelated to GLU. Three pts developed renal failure; two were GLU-related with evidence of renal tubular acidosis (RTA). One pt developed GLU-related SAE of RTA without renal failure. The CrCL fell below 60 mL/min in 7 of 27 (26%) pts with CrCL =60 at baseline. Conclusions: Preliminary data indicate that GLU + GEM may benefit pts with chemotherapy naïve pancreatic adenocarcinoma.

[Table: see text]
Response evaluation with endoscopic ultrasound (EUS) measuring maximum tumor thickness to predict pathological response after neoadjuvant chemoradiation therapy (CRT) in patients with locally advanced esophageal cancer (EC)
Authors: Jost C. , Schuller J. C. , Meyenberger C. , Bauerfeind P. , Moosmann P. , Frossard J. L. , von Moos R. , Koeberle D. , Metzger U. , Ruhstaller T.
Published: March 2020

15009

Background: EUS does not accurately assess T-stage after neoadjuvant CRT due to inflammation, necrosis and fibrosis. We evaluated whether maximum tumor thickness (MTT) can predict pathological response (tumor regression grade, TRG) after CRT. Methods: Patients (pts) with resectable, locally advanced EC, were treated with 2 cycles of docetaxel/cisplatin (DC) q3w followed by CRT (DC weekly x5 with concomitant 45 Gy radiation therapy) and surgery. Radial scan EUS (7.5MHz) measured MTT at baseline and 3–5 weeks after CRT completion. We prospectively hypothesized that MTT =6mm in the second EUS predicts complete and subtotal pathological response (TRG1 and 2), tested by logistic regression. The effect of >50% reduction of MTT was analysed as well. Results: 66 pts from 11 institutions were treated; median age 61y (35–70y); adenocarcinoma (AC) 53%; squamous cell carcinoma 46%; 40 pts were eligible for the EUS project (10 no surgery, 10 tumor stenosis prohibiting EUS, 5 MTT not measured, 1 intolerant to EUS). Initial EUS staging: 9 uT2N1, 3 uT3N0, 27 uT3N1, 1 uT3Nx; Siewert-type-1 in 13 of 22 AC. Reduction of MTT to =6mm correctly predicted TRG1/2 with sensitivity (sens) 45%, specificity (spec) 90%, negative predictive value (NPV) 62%, and positive predictive value (PPV) 82%, the Iogistic regression model showed a trend predicting response only (OR 0.80; C.I. 0.62–1.03; p=0.082). Reduction of MTT >50% predicted TRG1/2 with sens 40%, spec 75%, NPV 56% and PPV 62%. Conclusions: The absolute value of maximum tumor thickness =6mm in the second EUS correctly predicts a good response to CRT in 82% (spec 90%) - rather than the relative reduction of MTT >50% -, but does not identify all responders. Feasibility in this multicenter setting was limited by exclusions due to tumor stenosis and incomplete measurements.

[Table: see text]

No significant financial relationships to disclose.
Cancer stage at diagnosis, treatment, and survival among US- and foreign-born Asians and Pacific Islanders with gastric cancer
Authors: DaCosta Byfield S. , Earle C. C. , Li D. , Ayanian J. Z. , McCarthy E. P.
Published: March 2020

15018

Background: Asians and Pacific Islanders (APIs) have increased risk of developing gastric cancer, but whether cancer treatments and outcomes vary by birthplace is unknown. We examined the association between birthplace and cancer stage at diagnosis, treatment, and survival comparing API and non-Hispanic white (NHW) patients. Methods: We studied 6840 NHW and 4485 API patients diagnosed with gastric cancer from the Surveillance, Epidemiology and End Results Program between 1992 and 2003. We used bivariable analyses to compare stage, receipt of adequate lymph node assessment and surgery across groups: US-born APIs, foreign-born (FB) APIs and NHWs. We used multivariable polychotomous logistic and proportional hazards regression models to determine differences between US-born and FB APIs compared to NHWs in cancer stage and survival, respectively. Models included age, marital status, tumor grade, location, and stage (survival only). Results: Of API patients, 29% were US-born, 49% FB and 22% of unknown birthplace. APIs were more likely than NHWs to present with earlier-stage diagnoses and receive surgery and adequate lymph node assessment (p<0. 001). After adjustment, US-born [aOR=0.86 (0.75–0.93)] and FB APIs [aOR=0.76 (0.68–0.84)] were less likely to present at later stages than NHWs. Among APIs, FB patients had fewer lymph node assessed than US-born (p<0.001), but were as likely to present with earlier stage disease and receive surgery. After adjustment, US-born [aHR= 0.90 (0.85–0.98)] and FB APIs [(aHR= 0.85 (0.78–0.92)] had higher survival rates than NHWs. Results were similar after adjusting for treatment. *p <0.001 for comparison with NHW +p>0.05 for comparison among API Conclusions: Compared to US-born APIs, FB API patients with gastric cancer present at later stages and are less likely to receive adequate surgical lymph node assessment. However, both US-born and FB API patients present at earlier stages and experience better survival than non-Hispanic white patients.

[Table: see text]

No significant financial relationships to disclose.
A study of the pharmacokinetics of 5-FU when S-1 was administered orally as an adjuvant agent in gastric cancer patients
Authors: Matsumoto H. , Hirai T. , Hirabayashi Y. , Kubota H. , Murakami H. , Higashida M. , Kawabe Y. , Urakami A. , Yamashita K. , Tsunoda T.
Published: March 2020

15024

Background: S-1 is an effective oral anti-cancer drug which is formulation of 5-FU, and it is widely used for gastric cancers in Japan. However, the compliance of S-1 treatment is not satisfactory due to its side effects. We hypothesized that the plasma concentration of 5-FU could be verified individually, because the drug is administered orally. Therefore, we investigated the pharmacokinetics of 5-FU when it was administered orally in the form of S-1. Methods: The plasma concentration of 5-FU after S-1 oral administration for adjuvant chemotherapy was measured in 22 advanced gastric cancer patients (Stage II or III). Total gastrectomy was performed in 12 patients and distal gastrectomy was performed in 10 patients. All patients were given S-1 (80mg/m2) orally at 8:00 and 20:00, daily. Blood samples were collected at 10:00, 12:00, 14:00 and 16:00 on the 7th day after S-1 administration and we measured 5-FU concentration of plasma. Results: Pharmacokinetic parameters of plasma concentration of 5-FU were as follows: Cmax, 157.92 ± 42.9 ng/ml; Tmax, 2.36 ± 0.79 h; T1/2, 2.90 ± 2.36 h; and AUC 0–8 ,731.8 ± 236.4 ng ·h/ml in all patients given the usual dosage. The plasma concentration of 5-FU was quite different between patients. The difference of Cmax and AUC was 3∼ 4 times. The AUC0- 8 in the total gastrectomy patients (752.6± 273.3 ng·h/ml) was higher than that in distal gastrectomy patients (714.5±211.7 ng·h/ml), however this difference did not reach significance. Adverse events of more than grade 3 were observed in 7 patients. AUC0–8 of 4 of 7 patients were more than 800 ng·h/ml and those of 2 other patients were more than 750 ng·h/ml. The patients with high AUC0–8 levels had a tendency to show more severe adverse events. Conclusions: We conclude that physicians should pay close attention to individual differences in the plasma concentration of 5-FU in postoperative gastric cancer patients when this drug is given orally as S- 1.

No significant financial relationships to disclose.
Cumulative false-positives (FP) in the prostate, lung, colorectal, ovarian (PLCO) cancer screening trial
Authors: Miller J. H. , Kramer B. S. , Kreimer A. R. , Prorok P. C. , Xu J. , Baker S. G. , Fagerstrom R. , Berg C. D. , Gohagan J. K.
Published: March 2020

1503

Background: Multiple cancer screening tests have been advocated for the general population. However, providers and patients are not always well-informed of the burdens incurred by screening. We sought to determine the cumulative risk of a FP screen, and resulting diagnostic procedure risk, for an individual in a multiple modality screening program. Methods: Data were analyzed for a 3-year period from the intervention arm of the randomized PLCO Cancer Screening Trial. Eligible individuals were 55 to 74 years of age with no prior history of prostate, lung, colorectal, or ovarian cancer. Additional exclusion criteria were: 1) death before/refusal to take/missing all screens, and 2) less than 3-year follow-up. 68,415 participants were included. The control arm received “usual care.” Women randomized to screening were offered annual CA-125, transvaginal ultrasound, CXR, and baseline plus 3- or 5-year sigmoidoscopy (FSG). Men randomized to screening were offered annual digital rectal exam, PSA, CXR, and baseline plus 3- or 5-year FSG. Fourteen exams were possible for each sex over the study period. We defined a FP as a positive screen with no target cancer diagnosis after at least 3-years follow-up. Advanced adenomas (villous histology, severe cellular dysplasia, or =1cm in diameter) were considered true positives. Results: 42.6% (N=29,152) of participants had at least one FP. Using a geometric distribution model, the cumulative risk of a FP after 1 screen was 5.7% for men, and 2.2% for women. After 14 tests, the risk was 62.2% for men and 50.7% for women. Sensitivity analysis for FP risk after 14 tests by Kaplan-Meier method demonstrated a cumulative FP risk of 61.5% for men and 54.5% for women. The consequent cumulative risk of a diagnostic procedure was about 27% for men and 18% for women after 14 tests. Conclusions: For an individual participating in a multiple modality cancer screening trial, the risk of a FP exceeded 50% by the 14th test. Physicians should educate patients about the risks of FP tests and resulting diagnostic interventions when counseling about cancer screening regimens.

[Table: see text]
Improved survival with radiation therapy in early pancreatic adenocarcinoma
Authors: Artinyan A. , Hellan M. , Mojica-Manosa P. , Ellenhorn J. , Kim J.
Published: March 2020

15036

Background: Although chemoradiation is often used following pancreatic cancer resection, recent studies have questioned the role of radiation therapy in this setting. The objective of this study was to determine the effect of adjuvant radiation therapy following pancreatectomy in patients with node-negative (N0) pancreatic cancer. Methods: The Surveillance, Epidemiology, and End Results (SEER) registry was used to identify patients with N0 pancreatic adenocarcinoma who had undergone curative-intent resection between 1988–2003. Kaplan-Meier survival curves were constructed to compare overall survival between patients ± adjuvant radiation therapy. Multivariate Cox regression analysis was performed to determine the prognostic significance of radiation therapy when additional clinicopathologic factors were assessed. The analysis also examined the potential treatment selection bias of patients with survival <3 months. Results: Query of the SEER database identified 2342 surgical patients with N0 disease. The median survival for these patients was 18 months. 889 (60.1%) patients were treated with radiation. There was no difference in gender or grade between radiation and non-radiation groups; however, radiation patients were younger (63 vs. 67 years, p<0.001) and had a greater proportion of T3 lesions (p=0.002). Radiation patients had significantly improved survival compared to non-radiation patients (20.0 vs. 15.0 months, p<0.001). On multivariate analysis, radiation therapy (HR 0.72, p<0.001), age, grade, T-stage, and tumor location were independent predictors of survival. When patients with survival <3 months were excluded from analysis, no difference in survival between radiation and non- radiation was noted (20.0 vs. 19.0 months, p=0.096). However, on subset analysis, patients with T3 tumors demonstrated improved survival with the addition of radiation (24.0 vs 16.0 months, p=0.002) and on multivariate analysis radiation therapy was an independent predictor of improved overall survival (HR 0.87, p=0.027). Conclusions: Radiation treatment is associated with improved survival in operable N0 pancreatic cancer and its use should be considered in patients with early stage N0 disease. The greatest impact of radiation therapy use appears to occur with T3 tumors.

No significant financial relationships to disclose.
Detection of circulating tumor cells (CTCs) in patients with hepatocellular carcinoma (HCC)
Authors: Zee B. C. , Wong C. , Kuhn T. , Howard R. , Yeo W. , Koh J. , Hui E. , Chan A. T.
Published: March 2020

15037

Background: Allard et al. (2004) has established the accuracy, sensitivity, reliability and linearity of circulating tumor cells (CTCs) detection using the CellSearch System. 57% prostate cancers, 37% breast cancers, 37% ovarian cancers, 30% colorectal cancers, and 20% lung cancers specimens had >= 2 CTCs per 7.5 mL of blood. Only 0.3% healthy non-malignant disease subjects had >= 2 CTCs per 7.5 mL of blood. Cristofanilli et al.(2004,2005) have shown that CTCs at baseline and first follow-up were a significant prognostic factor for survival in metastatic breast cancer patients. However, HCC data on CTCs are not available. Methods: 20 locally advance or metastatic HCC patients who had not received prior treatment had been recruited after informed consent and 7.5 mL of blood were collected using the CellSave Preservative tubes (Veridex LLC, Raritan, NJ) that prevents CTCs degradation. The CellSearch system (Veridex LLC) similar to the previous studies was used to analyze the specimen. The CellSearch system consists the CellPrep system, the CellSearch Epithelial Cell Kit, and the CellSpotter Analyzer. All the procedures and interpretation of results followed closely with the quality control procedure of Veridex LLC including accreditation of trained laboratory personnel. Results: 13/20 (65%) had locally advanced disease and the rest had metastatic HCC. All patients had multiple lesions. 9/20 (45%) patients had detectable CTCs, 7/20 (35%) had >= 2 CTCs, and about 5/20 (20%) had 5 or more CTCs. For locally advanced HCC 4/13 (31%) patients had >= 2 CTCs per 7.5 mL of blood. For HCC patients with metastatic diseases 3/7 (43%) patients had >= 2 CTCs per 7.5 mL of blood. Conclusions: HCC patients with locally advance or metastatic disease had detectable CTCs in 7.5 mL of blood. We expected that the performance of CTCs in HCC is similar to that of breast cancer. Future study of using CTCs as prognostic factor at baseline and during treatment for HCC is being planned.

No significant financial relationships to disclose.
Magnetic resonance imaging versus mammography for diagnosing ductal carcinoma in situ
Authors: Kuhl C. K. , Schrading S. , Wardelmann E. , Braun M. , Kuhn W. , Schild H. H.
Published: March 2020

1504

Background: Mammographic screening is considered the mainstay for diagnosing pre-invasive breast cancer (DCIS). However, (over)diagnosis of DCIS has become a major concern. We investigated the sensitivities of high-resolution MRI and of state-of-the-art mammography (Mx) for diagnosing pure DCIS, and compared the biologic profile of MRI-detected versus Mx-detected DCIS. Methods: Prospective study on 5960 consecutive women who were referred to a dedicated breast unit for screening or for diagnostic assessment. Women underwent bilateral mammography with at least 2 views, plus spot compression views where appropriate, and high-resolution bilateral MRI. A total 137 women received the final pathologic diagnosis of having DCIS (no invasion). Of these, 108 (79%) had been referred for regular screening, 14 (10%) for high risk screening, 10 (7%) for follow up after breast cancer, and 5 (4%) for clinical symptoms. We investigated the mode of detection, and the biologic profile of the DCIS (size, nuclear grading, ER/PR and HER2-receptor status). Results: Overall, Mx was positive in 79/137 patients (58%), MRI was positive in 123/137 (90%). In 68/137 (50%), Mx and MRI were concordantly positive. In 3/137 (2%), Mx and MRI were both false-negative. In 11/137 (8%), only Mx was positive, MRI was false- negative. In 55/137 (40%), only MRI was positive, Mx was false negative. Of the 11 DCIS which were only detected by Mx, 1 was high grade, none was ER negative or HER2 positive. Mean VNPI was 4.2. Of the 55 DCIS which were only MRI detected, 41 (78%) were high grade, 14 (27%) were ER negative, 17(33%) HER-2 positive. Mean VNPI was 6.5. Conclusions: Compared to mammography, MRI offers a significantly higher sensitivity for DCIS, in particular for DCIS with adverse biologic profile: Half of the high grade or HER2-positive DCIS were only MRI detected. In turn, DCIS which was only mammography detected had a relatively benign biologic profile. We propose that MRI is helpful for diagnosing biologically (i.e. possibly prognostically) relevant DCIS

[Table: see text]

No significant financial relationships to disclose.
Preferential inhibition of Sp1 expression in growing tumors by mithramycin-A (MIT) directly correlates with its potent antiangiogenic effects in human carcinoid xenograft model
Authors: Xie K. , Jia Z. , Zhang J. , Wang L. , Li Q. , Le X. , Yao J. C.
Published: March 2020

15041

Background: MIT, also known as aureolic acid and plicamycin (Mithracin), is an aureolic acid-type polyketide produced by various soil bacteria of the genus Streptomyces. Previous studies have shown that MIT exhibits antitumor activity. In the present study, we examine the antiangiogenic effect of MIT and its underlying mechanisms. Methods: Cohorts of 10 athymic BALB/c nude mice were implanted with 1.5 million human H727 carcinoid cells. Mice were treated with subcutaneous or intraperitoneal 0.2 mg/kg of mithramycin twice weekly once implanted tumor reached 4 mm in size. Results: Both subcutaneous and intraperitoneal MIT significantly suppressed the growth of carcinoid cells in nude mouse models (median tumor weight in PBS, s.c., i.p. groups 790 mm3 vs 280 mm3, 480 mm3; P < 0.01). We also evaluated the Sp1 expression in growing tumors and various organs. We found that the liver expressed the highest level of Sp1 among normal organs (including liver, stomach, large intestine, and small intestine, spleen, kidney, brain and lymph node). However, Sp1 expression in the growing tumors was more than 10 times higher than that in a normal liver. Treatment with MIT reduced the Sp1 expression in the tumors, while no discernible effect on Sp1 expression in normal tissues was observed. This is the first demonstration that MIT selectively inhibited the Sp1 expression in the growing tumors. Consistent with the expression of Sp1, a substantial suppression of VEGF, PDGF, EGFR, and IGFR expression was evident. Finally, treatment with MIT reduced the microvessel formation in tumors by 80% (MVD count; P < 0.01). This antiangiogenic activity was confirmed by in vitro tubulogenesis assay and in vivo Matrigel plug assay. Conclusions: Collectively, our studies strongly indicate that MIT is a potent antiangiogenic agent and its mechanism of action involved suppression of Sp1 expression and its consequent downregulation of its downstream targets including VEGF, PDGF, EGFR, and IGFR that are key to tumor angiogenesis.

No significant financial relationships to disclose.
Adjuvant chemoradiation therapy for pancreatic adenocarcinoma: Impact of family history on outcome
Authors: Herman J. M. , Pawlik T. J. , Swartz M. , Yu H. M. , Schulick R. , Winter J. , Laheru D. , Hruban R. , Klein A. P.
Published: March 2020

15044

Background: The objective of the current study was to examine the impact of a family history of pancreatic adenocarcinoma (PCA) on the outcome of patients receiving adjuvant chemoradiation therapy (CRT) following pancreaticoduodenectomy (PD). Patients and Methods: Between August 1993 and February 2005, 902 patients underwent PD for pancreatic adenocarcinoma. Following PD, 405 patients received no adjuvant CRT, while 346 patients received CRT. Another 151 patients were excluded because they received protocol treatment, neoadjuvant CRT, or were lost to follow-up. Patients who received adjuvant CRT were treated with 5-FU (97.4%) based CRT (median dose 50 Gy) and maintenance 5-FU or gemcitabine. Survival was estimated using the Kaplan-Meier method and differences in survival were examined using the log-rank test. Cox regression analysis was used to control for family history. Results: Of the 751 patients included in the study, 158 (21%) patients had a known family history of pancreatic adenocarcinoma (only one family member n=119; >=2 either first or second degree relatives, n=39). Clinicopathologic characteristics of patients with a family history of PCA were similar to those of patients who did not have a family history (age, race, positive lymph node status, primary tumor size, and proportion receiving adjuvant CRT; all P>0.05). In an analysis of the entire patient cohort, adjuvant CRT was associated with an improvement in median overall survival compared with no adjuvant CRT (21.0 months vs. 14.6 months, respectively; P= 0.001). Family history of PCA (>=1 family member) was not associated with overall survival (positive family history, 20.0 months vs. negative family history, 17.3 months; P = 0.12). Family history of PCA also did not modify the effect of CRT on overall survival. Specifically, on multivariate analysis, after stratifying on family history (>=1 family member), CRT remained significantly associated with an improved survival (Hazard ratio=0.71; P=0.001). Conclusion: Adjuvant 5-FU based CRT improves the median survival of patients with resected pancreatic adenocarcinoma. The improvement in median survival associated with adjuvant CRT was independent of a familial history of pancreatic adenocarcinoma.

No significant financial relationships to disclose.
Portal vein and systemic thromboses in hepatocellular carcinoma
Authors: Connolly G. C. , Khorana A. , Mantry P. , Bozorgzadeh A. , Abt P. , Chen R. , Hyrien O.
Published: March 2020

15048

Background: Hemostatic activation may be important for tumor growth and metastasis. Hepatocellular carcinoma (HCC) is commonly associated with portal vein thrombosis (PVT). Very little is known about factors predictive for PVT in patients with HCC or its correlation with systemic venous thromboembolism (VTE). Methods: We conducted a retrospective chart review of 194 patients diagnosed with HCC at the University of Rochester between 1998 and 2004. The primary endpoints of this study were presence of PVT and any systemic VTE. The secondary endpoint was overall survival calculated from time of diagnosis. Univariate and multivariate logistic regression analyses were conducted to assess the association of PVT with a set of clinical covariates, and the survival curve was estimated using the method of Kaplan-Meier. Results: The mean age of the total population was 60.4 ± 11.9, and one-third of the patients underwent liver transplant. The incidence of PVT in the total population was 31% (60/194) with a higher incidence in the non-transplant group compared to transplanted patients (34% vs. 24%; p= 0.08). In univariate analysis, advanced stage, major vessel involvement, higher MELD score, higher Child-Turcotte-Pugh (CTP) classification, lower serum albumin, elevated serum bilirubin, elevated serum alpha-fetoprotein (AFP) level, and elevated INR were associated with development of PVT (p <0.05 for each). In multivariate analysis CTP class, stage, major vessel involvement, serum albumin, and serum AFP were independently and significantly associated with PVT (p <0.05 for each). The presence of PVT was associated with reduced survival (median survival 4.61 months for those with PVT versus 17.55 months for those without PVT, HR 2.01, p <0.001). The incidence of systemic VTE in the total population was 6.7%, and patients with PVT had a higher rate of systemic VTE compared to patients without PVT (11.5% vs. 4.4%; p 0.044). Conclusions: PVT is common in patients with HCC and is associated with worse outcomes. The correlation between PVT and systemic VTE suggests a common mechanism of hemostatic activation. Advanced stage, higher CTP class, major vessel involvement, and serum albumin and AFP levels are predictive of PVT. Identifying patients at high-risk for PVT and instituting prophylaxis may affect HCC outcomes.

No significant financial relationships to disclose.
Phase II study of sequential chemotherapy with cisplatin (P) in combination with infusional 5FU/LV (PFL) followed by irinotecan (Ir) + 5FU/LV (IrFL) followed by docetaxel (T) + 5FU/LV (TFL) in patients (pts) with metastatic gastric carcinoma (MGC) by the Gruppo Oncologio Nord-Ovest (GONO)
Authors: Loupakis F. , Masi G. , Bursi S. , Picone V. , Mentuccia L. , Granetto C. , Fea E. , Murr R. , Antonuzzo A. , Falcone A.
Published: March 2020

15059

Background: 5FU in combination with P can be considered a standard treatment for MGC. Ir and T are active agents with not complete cross-resistance with P and 5FU. The combination of Ir or T with P and 5FU is feasible but with substantial toxicities. A different way to include Ir and T in the first-line treatment of MGC is to use them sequentially to a P and 5FU containing regimen. Methods: we conducted a phase II study of first-line sequential chemotherapy in MGC pts with measurable disease (RECIST criteria). Treatment consisted of: 3 cycles of PFL (biweekly P 50 mg/sqm d1, LV 200 mg/sqm d1 and 5FU 3200 mg/sqm 48-h c.i. starting on d1) followed by 3 cycles of IrFL (biweekly Ir 180 mg/sqm d1 and 5FU/LV) followed by 3 cycles of TFL (biweekly T 50 mg/sqm d1 and 5FU/LV). Evaluation of disease was performed every 3 cycles. Results: 46 pts have been enrolled. Pts characteristics are: median age = 60 years (37–75), M/F = 36/10, sites of disease (single/multiple) 9/37, ECOG PS 0/1 = 27/19. Treatment was well tolerated. Grade 3–4 non-haematological toxicities were: diarrhea in 2,5% pts with PFL; diarrhea and asthenia in 2,5% and stomatitis in 5% pts with IrFL; stomatitis in 5,7% pts with TFL. Grade 3/4 neutropenia was observed in 14% pts with PFL, 15% with IrFL and 22,9% pts with TFL. Nor febrile neutropenia neither toxic deaths have occurred. Two pts had not evaluable disease and 6 are still receiving treatment. We observed 1 CR and 8 PR with PFL (RR 24%) among the 38 evaluable pts. IrFL improved responses in 10 pts while 4 pts progressed and TFL further improved responses in 6 pts while 5 pts progressed. Response rate at the end of the planned 9 cycles was 40% (4 CR, 11 PR; 95% CI 25–58%). At a median follow-up of 15.5 mos median TTP is 6.8 mos and median OS is 13.5 mos. Conclusions: this sequential treatment is feasible with a very favourable safety profile and produces encouraging results in terms of activity and efficacy in a population of unselected MGC patients. Final data will be presented at the meeting. Partially supported by A.R.C.O. Foundation.

No significant financial relationships to disclose.
Lack of concordance between I-111 pentreotide (PEN) status and immuno-histochemistry (IHC) status for somatostatin receptors type 1, 2, and 3 in neuroendocrine tumors (NET)
Authors: Palhares A. C. , Costa F. P. , Belfer A. J. , Bacchi C. E. , Jokh S. H. , Hoff P. M. , Buzaid A. C. , Maluf F. C. , Marques R. J. , Dzik C. , Lopes L. F.
Published: March 2020

15060

Background: The use of somatostatin analogues (ST) in the treatment of NET is recommended for functional and non- function slow progressing tumors that present with positive PEN. The goal of the study was to determine if expression of ST receptors type 2, 3 and 1 in NET tumors by IHC predict the PEN status and response to ST. Methods: Retrospective analysis of paraffin blocs from primary or metastatic sites and PEN imaging from 39 patients with a diagnosis of NET confirmed by independent pathology review. IHC analysis was performed in a central laboratory using antibody ST receptor type 1 from Neomarkers and type 2 and 3 from Affinity Bio Reagents. Status for each receptor type was reported as positive or negative, diffuse or focal and by % of positive cells. All slides were reviewed by the same pathologist. PEN images were submitted to an independent radiology review and reported as positive or negative and the signal intensity was graded from 1 to 4. Investigators were blinded to receptor and PEN status. This concordance analysis study was designed with a power to detect at least 60% correlation between receptor and PEN status with type I error of 5% and a type II error of 20%. Results: There was no correlation between receptor and PEN status ( Table ). Furthermore, there was no significant correlation between PEN and receptor types 3 and 1 in receptor type 2 negative patients (p=0,54, p=0,14, respectively). There was no correlation between receptor type status and PEN positive intensity. No independent or multivariate characteristics by IHC can correlate to PEN status in this cohort. Conclusions: Commonly used antibodies for IHC detection of receptors type 2, 3 and 1 used in this study failed to correlate with PEN. These results do not support the use of IHC as a substitute for PEN with respect to prediction of ST activity in NET.

[Table: see text]

No significant financial relationships to disclose.