bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant chemotherapy for resectable adenocarcinoma of the panctreatic head - a prospective phase II trial
Authors: Pestalozzi B. C. , Heinrich S. , Schäfer M. , Pierre-Alain C. 
Published: March 2020

4610 Background: Pancreatoduodenectomy alone was considered the standard treatment for resectable adenocarcinoma of the pancreatic head in Europe. Recently adjuvant chemotherapy without radiation has become a new standard worldwide. Neoadjuvant chemotherapy has advantages over adjuvant chemotherapy. Methods: Patients (pts) with histologically or cytologically confirmed ductal adenocarcinoma of the pancreatic head judged to be resectable were entered into this single center prospective phase II trial. After written informed consent staging with thoracic/abdominal CT-scans, endoscopic ultrasound, PET-CT and diagnostic laparoscopy were performed. Preoperative chemotherapy consisted of 4 treatments with gemcitabine (1,000mg/m2) and cisplatin (50mg/m2) every 2 weeks. Re-staging was followed by (classic or pylorus-sparing) pancreatoduodenectomy about 8 weeks after the start of chemotherapy. CA 19- 9, prealbumin serum levels, and quality of life (QLQ-30) were also assessed before and after chemotherapy. The primary study end-point was the resectability rate. Results: Twenty-eight pts entered this trial between June 2002 and January 2007, 27 have completed chemotherapy. The resectability rate after chemotherapy was 93% (25/27). Neoadjuvant chemotherapy was well tolerated, although 7 episodes of transient Grade III/IV toxicities occurred in 5 pts. While median recurrence-free survival from diagnosis was 9.2 months (95% CI 7.7–10.8), median overall survival was an excellent 26.5 months (12.2–40.8). CA 19–9 serum levels decreased by 48% (p=0.01) after neoadjuvant chemotherapy, while overall quality of life increased by 24% (p=0.02). Nutritinoal status also improved: Prealbumin levels were normal in 89% after chemotherapy compared to 60% before (p=0.02). Conclusions: Neoadjuvant gemcitabine/cisplatin for two months is well tolerated and does not jeopardize surgical resectability in adenocarcinoma of the pancreatic head. Furthermore, it offers several advantages over primary surgery including patient selection, improvements in nutritional status and quality of life. We are currently planning a randomized study comparing the combination of neoadjuvant and adjuvant chemotherapy versus adjuvant treatment alone. No significant financial relationships to disclose.
A phase I study of erlotinib, bevacizumab and gemcitabine in patients with advanced pancreatic cancer
Authors: Gomez-Martin C. , Camara J. C. , Cortes H. , Jara C. , Gravalos C. , Rubio B. , Amador M. L. , Hidalgo M. 
Published: March 2020

4611 Background: Erlotinib is an EGFR TKI active in combination with gemcitabine in p with advanced pancreatic cancer (PC). The combination of gemcitabine and bevacizumab is also active in PC. A phase I of gemcitabine, bevacizumab and erlotinib in p with unresectable locally advanced or metastatic PC is being conducted. Methods: Two cohorts of 6 patients with advanced PC have been treated either with erlotinib (150 mg/day po), bevacizumab (5 mg/Kg iv, days 1 and 15, every 28 days), and either 10 mg/m2/min infusion of gemcitabine 850 mg/m2 or 1,000 mg/m2 days 1 and 15 every 28 days. P received a maximum of 6 cycles of 28 days. Cohort 1: Daily erlotinib 150 mg po + bevacizumab 5 mg/kg iv days 1 and 15 + gemcitabine 850 mg/m2 over 10 mg/m2/min infusion days 1 and 15. Cohort 2: daily erlotinib 150 mg po + bevacizumab 5 mg/kg iv days 1 and 15 + gemcitabine 100 mg/m2 over 10 mg/m2/min infusion days 1 and 15. Results: 12 p have been included in this study (6 cohort 1 and 6 cohort 2), being evaluable for toxicity. 11 p have concluded the study and 7 have received complete treatment as per protocol. Median age 62.6 yrs (range 38–71); male/female: 5/7 (42%/58%); stage III/IV: 3/9 (25%/75%); Karnofsky index 100%/80%: 2/10. 3 of 6 p in cohort 1 developed gr. 3 asthenia (50%), 2 p gr. 3 neutropenia (33.3%), whereas 1 p had grade 3 leucopenia and gr. 3 skin rash. In cohort 2, most severe adverse events were: 1 case of grade 4 GGT elevation, 1 p gr. 3 skin rash and 1 p. experienced asthenia gr. 3. No severe hematological toxicity in cohort 2 was reported. One p of each cohort required dose reduction of erlotinib, both due to skin rash. Mild diarrhea was reported in 11 of 12 p evaluated. No dose limiting toxicities has been reported. All p were available for response: 2 p reached partial response (both included in cohort 1) and 7 showed stabilization (3 and 4 in cohorts 1 and 2, respectively). No complete responses were observed. Overall disease control index was 75%. Conclusions: The combination of gemcitabine, erlotinib and bevacizumab is well tolerated. MTD has not been reached. Encouraging clinical activity in advanced pancreatic cancer has been observed. Phase I is still ongoing. Toxicity data for all the p will be presented. No significant financial relationships to disclose.
Phase II of trastuzumab and cisplatin in patients (pts) with advanced gastric cancer (AGC) with HER2/neu overexpression/amplification
Authors: Cortés-Funes H. , Rivera F. , Alés I. , Márquez A. , Velasco A. , Colomer R. , García-Carbonero R. , Sastre J. , Guerra J. , Grávalos C. 
Published: March 2020

4613 Background: Trastuzumab(T) exhibits activity in human gastric cancer cells that overexpress HER2/neu. We previously reported a 13.5% HER2/neu overexpression/amplification in AGC or gastroesofageal junction (GEJ) cancers (Grávalos C, et al. J Clin Oncol 24, 18S, 200s, abstr # 4089). We designed a phase II trial to determine the efficacy and tolerability of T and cisplatin(C) in pts with ACG with HER2/neu overexpression/amplification. Exploratory objectives include analysis of c-erbB-2 extracellular domain and correlation of the results with histological erB-2/neu overexpression and with clinical response Methods: Chemo-naïve pts with adenocarcinoma histopatologically confirmed, HER2/neu overexpression/amplification, measurable, no operable, locally advanced or metastatic AGC, age ≥ 18, ECOG ≤ 2, FEVI ≥ 50% and adequate organ function were eligible. Prior adjuvant radiotherapy or/and chemotherapy were allowed. Immunohistochemistry (IHC) was performed using herceptest. A fluorescence in situ hybridization (FISH) assay was done when IHQ was = 2. HER2/neu expression was considered negative if IHC= 0, 1 or IHC=2 and FISH -; and positive if IHC=2 and FISH + or IHC=3. T 8 mg/kg d1 (loading dose in first cycle) and 6 mg/kg (maintenance doses) and C 75 mg/m2 d1 were administered every 21 days until progression, unacceptable toxicity or withdrawal inform consent Results: 21 pts has been included. 17 are evaluable. 16 were men. Median age 66 (50–78). ECOG 0/1: 5/12. Histological subtypes were: 50% intestinal, 25% diffuse and 25% unknown. 56% had gastric localization and 44% GEJ. 16 pts had metastases (59% liver, 47% lymph nodes, 23% peritoneum, 17% lung, and 24% others). Prior treatment: 5 pts underwent surgery and 2 had adjuvant chemotherapy. Median cycles 2 (1–14). Efficacy: 6 (35%) pts achieved response (1/5 CR/PR), 3 (17%) stabilization (52% control disease = RC + PR+SD), 4 pts with progression disease, 4 pts too early Tolerance: There was no grade 4 toxicity. Main grade 3 adverse events included: asthenia (3 pts), nauseas/vomiting (3), diarrhea (2), hiporexia (2) and neutropenia (1) Conclusions: Trastuzumab and cisplatin is a well tolerated regimen with a promising activity. The study is ongoing and an update will be presented at the meeting. No significant financial relationships to disclose.
A 10-year retrospective analysis of risk factors, patterns of cancer recurrence, and survival after liver transplant for cirrhosis and hepatocellular carcinoma
Authors: Kaseb A. O. , Bansal M. , Wollner I. , Shah V. , Moonka D. , Divine G. , Abouljoud M. 
Published: March 2020

4617 Introduction: Determining eligible patients who are likely to have better outcomes following orthotopic liver transplant (OLT) for cirrhosis and hepatocellular carcinoma (HCC) is an ongoing challenge. In addition, tumor recurrence represents a major limitation of long-term survival in this setting. Patients and Methods: The study analyzed 72 OLT recipients for cirrhosis and HCC, between 1996–2006. The endpoints were frequency, patterns, localization, and risk factors of recurrence. Survival from time of OLT to recurrence was compared with primary tumor and patient characteristics, and type of treatment received pre- and post-OLT using univariate and multivariate analyses. Survival was estimated using Kaplan-Meier plots. Results: 13 recurrences (18%) occurred after a median of 33.4 months follow up (6–123 months). 11/13 (84.6%) were distant metastases. Using cox regression analysis and log-rank p-value; bilobar involvement, a tumor number of =3, tumor grade 2 or 3, size >3 cm, vascular invasion, and elevated AFP at diagnosis were all positively associated with recurrence (either distant or any). Tumors that met Milan criteria were associated with a lower likelihood of recurrence. In addition, Pre and post-OLT treatments were not found to be associated with significantly improved disease-free survival. Conclusions: Our analyses confirmed that advanced pathologic features are independently associated with significantly shorter disease-free survival. Pre- and post-OLT treatment modalities were not observed to improve disease-free survival for patients with bad prognostic indicators. However, this is limited due to our small sample size and our univariate anaylsis. We conclude that careful patient selection based on prognostic indicators would maximize benefit from use of this expensive and limited resource. [Table: see text] No significant financial relationships to disclose.
A randomized phase II trial of PEXG (cisplatin, epirubicin, capecitabine, gemcitabine) or PDXG (docetaxel) regimen in advanced pancreatic adenocarcinoma
Authors: Reni M. , Cereda S. , Passoni P. , Rognone A. , Mazza E. , Nicoletti R. , Arcidiacono P. G. , Zerbi A. , Balzano G. , Di Carlo V. 
Published: March 2020

4628 Background: Four-drug regimen significantly improved the outcome of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine in a phase III trial (Reni Lancet Oncol 2005). The current study was an attempt to further improve progression-free survival (PFS) by replacing epirubicin with docetaxel. Methods: Patients with stage III or metastatic PA, age 18–75y, Karnofsky performance status (PS) >50 were randomized to receive either D (arm A: 25 mg/m2 day 1 and 14) or E (arm B: 30 mg/m2 day 1 and 14) while P (30 mg/m2 day 1 and 14), G (800 mg/m2 day 1 and 14) and X (1250 mg/m2/day days 1 to 28) remained unmodified in the two arms. Cycles were repeated every 28 days. The primary endpoint of the study was PFS. The sample size was calculated on the probability of being PF at 6 months (PFS6) from treatment start. Assuming P0=25% and P1=45%, with a .05 and b.20, the study was to enroll 32 patients per arm. Results: Between July 2005 and January 2007, 64 patients were enrolled at a single institution, stratified by stage and randomized (32 per arm). Main patient characteristics were balanced (A/B): median age 61/58, PS > 70 93/84%, metastatic disease 69/69%. Treatment is ongoing in 6/7 patients; 16/15 patients concluded at least 6 cycles of chemotherapy while 9/10 interrupted treatment due to progressive disease (PD) and 1/0 due to consent withdrawal. To date, 51 patients are assessable for response and PFS6: 16 of 26 (62%) arm A patients and 12 of 25 (48%) arm B achieved a partial response. PFS6 was 54%/44%. Final results of toxicity, activity, PFS6 and survival will be available at time of meeting. Conclusion: PEXG regimen yielded similar results when compared to historical series treated by PEFG regimen, suggesting that the use of capecitabine instead of 5- fluorouracil did not compromise the outcome. The inclusion of D instead of E seems to be promising. The present trial further confirms the relevant impact on outcome of advanced PA of four-drug regimens. No significant financial relationships to disclose.
Normal esophageal mucosae adjacent to esophageal adenocarcinomas in both Japanese and U.S. patients have a field defect of methylation changes
Authors: Nasu M. , Orita H. , Gibson M. , Brock M. , Herman J. , Gabrielson E. , Tsurumaru M. , Forastiere A. 
Published: March 2020

4636 Background: Esophageal mucosae that reside next to gross cancer are often without histological premalignant changes. We hypothesized that DNA hypermethylation could be detected in “normal” tissues adjacent to esophageal adenocarcinomas (EAC). Methods: A cohort of patients from Japan (J, n=14) and the United States (US, n=41) with locally advanced EAC were evaluated for methylation status. Esophagectomy specimens provided a source of paired normal and tumor tissues. After DNA extraction, methylation specific PCR was used to evaluate the promoters of APC, p16 and MGMT in all samples. Methylation frequency was calculated for each patient and expressed as a percentage of total. Results: Age, gender, pathologic stage and epigenetic analyses of primary tumors were similar in each cohort. Methylation frequency of tumors was: APC (66% US; 70% J). p16 (39% US; 20% J). MGMT (63% US; 75% J). In adjacent histologically “normal” esophageal mucosae, the percentage of patients with methylation at 0, 1, 2 or 3 genes was 79%, 14%, 0%, 7% for the J group and 56%, 44%, 10% and 2% for the U.S. group. In both cohorts, the majority of the normal samples had no methylation changes. In over half of the total cohort, however, there was at least one gene in the adjacent histologically “normal” tissue positive for DNA hypermethylation. Very few samples in either group, however, had more than one gene methylated in histologically “normal” esophageal mucosae. In general, the same methylation pattern present in the “normal” tissue persisted in the primary malignancy. Conclusions: Histologically negative esophageal mucosae adjacent to cancer frequently show at least one hypermethylated gene in a multiple gene panel. These data suggest that for patients with EAC, regardless of nationality, there is a field defect of promoter hypermethylation changes in adjacent esophageal mucosae. These events reflect those of the primary malignancy, and are probably early and cumulative during carcinogenesis. No significant financial relationships to disclose.
Analysis of prostate-specific antigen decline as a surrogate for overall survival in metastatic hormone-refractory prostate cancer (HRPC)
Authors: Armstrong A. J. , Eisenberger M. A. , Garrett-Mayer E. S. , Ou Yang Y. , Carducci M. A. , de Wit R. , Tannock I. 
Published: March 2020

5009 Background: A 30% PSA decline following initiation of cytotoxic chemotherapy has been identified as a potential surrogate for overall survival in metastatic HRPC. We sought to examine whether various levels of PSA decline were surrogates for overall survival in TAX327, a randomized trial of q3w docetaxel and prednisone (DP), q1w DP, and q3w mitoxantrone and prednisone (MP). Methods: In this trial of 1006 men with HRPC, 943 men had sufficient data on 3-month post-treatment PSA decline for analysis, and 646 had sufficient data for analysis for a change in PSA kinetics with therapy. Surrogacy was examined for a range of PSA decline from 0% to 90% and PSA normalization, and for post-treatment changes in PSA kinetics. We investigated the Prentice Criteria for surrogacy using Cox proportional hazards models and calculated the proportion of treatment effect explained (PTE) by each surrogate marker. Results: In this analysis, a 30% or greater PSA decline with therapy was identified as the optimal cutoff that correlated with overall survival, based on the highest PTE point estimate (0.66, 95% CI 0.23–1.0), with 1.0 being a perfect surrogate. A 30% decline in PSA in the first 3 months after treatment occurred in 65% of subjects receiving q3w DP, 67% q1w DP, and 44% q3w MP, despite the significant survival benefits seen only with q3w DP. A 30% PSA decline was associated with a hazard ratio (HR) of 0.43 (95% CI 0.36–0.51) for overall survival after adjusting for treatment effect, while treatment effect itself lost significance, indicating surrogacy. Additionally, PSA normalization, changes in PSA kinetics, and pain response were significant prognostic variables, yet were only modest surrogates for the survival benefit seen with q3w DP therapy. Conclusions: In this trial of two schedules of DP as compared to MP for HRPC, a PSA decline of 30% in the first three months following initiation of cytotoxic chemotherapy was found to have the highest degree of surrogacy for overall survival, thus confirming data from the SWOG 9916 trial. However, given that the confidence interval for the estimate of this surrogate effect is wide, overall survival should remain the preferred endpoint for phase III trials of cytotoxic agents in HRPC. No significant financial relationships to disclose.
Correlation of low dose tamoxifen and its metabolites plasma level with Cyp 2D6, and SULT polymorphism; a pharmacogenetics study within a chemoprevention trial
Authors: Serrano D. , Macis D. , Gandini S. , Johansson H. , Guerrieri-Gonzaga A. , Mellgren G. , Lien E. A. , Mariett F. , Sandri M. , Decensi A. , Bonanni B. 
Published: March 2020

503 Background: Tamoxifen (T) is one of the most widely used drug for the treatment and prevention of estrogen receptor (ER) positive breast cancer. Individual genotype can modulate treatment efficacy. T metabolism is catalyzed by multiple enzymes: CYP2D6 is the main mediator for endoxifen, one of the most potent T metabolites. SULT may also play a role in T activation and can modulate hormone levels involved in breast cancer risk. Within a chemoprevention trial, we correlated T and its main metabolite concentration with polymorphisms (SNPs) of CYP2D6 and SULT genes. Methods: Premenopausal women (n 235) were randomly assigned in a double-blind four-arm trial to receive T 5 mg/d, fenretinide 200 mg/d, both agents, or placebo for 2 years CYP2D6 (*4–6) and SULT1A1*3 frequencies were determined using an Allelic Discrimination Assay, following a protocol for real time polymerase chain reaction. In the subjects receiving T, we measured plasma level of the drug, and its metabolites (endoxifen, 4-hydroxy-T, N-desmethyl-T, N-desdimethyl-T and Tnoxide) using a fluorescence detector at 12 and 24 months. Results: SNPs analysis was performed in 118 women; we found 65% wild type (WT), 31% heterozygous (H) and 5% mutated (M) for CYP2D6. The SNP frequency of SULT1A was A1, 61%; SULT1A2 36% and SULT1A3 3%. At one year a positive correlation was observed between CYP2D6 M and plasma level of N- desmethyl-T, the mean plasma level being 54.6, 62.4 and 108.5 ng/ml in WT, H and M, respectively, p=.001 (p=.01 at 24 months). Endoxifen was slightly increased in the WT compared to M (15.4 vs 12.9 ng/ml). SULT polymorphisms did not show any correlation with the drug and metabolite levels. Conclusions: CYP2D6 M mediates an increased level of N- desmethylT. This observation supports the role of CYP2D6 as an important enzyme in T metabolism, but more than one cytochrome P450 isoenzymes is required. to identify good or poor T metabolizers. No significant financial relationships to disclose.
Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): Interim results of a phase II randomized discontinuation trial (RDT)
Authors: Hutson T. E. , Davis I. D. , Machiels J. P. , de Souza P. L. , Hong B. F. , Rottey S. , Baker K. L. , Crofts T. , Pandite L. , Figlin R. 
Published: March 2020

5031 Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth & inhibits angiogenesis. This Phase II RDT determined effects of pazopanib on tumor growth in patients with adv/met RCC after 12 wks of treatment. Methods: Cytokine naïve and refractory (failed 1 prior cytokine or bevacizumab-containing regimen) patients with adv/met RCC, ECOG 1–2, were enrolled. Pazopanib 800 mg po qd was administered. Response (RECIST) assessed at wk 12: SD patients randomized to continue pazopanib or placebo (blinded); PR/CR patients continued pazopanib. Interim analysis (first 60 patients) endpoints: % randomized (SD) and % CR/PR at wk 12. Futility boundary was based on a randomization rate of <40%. Safety was analyzed in enrolled patients (n=161) at the time of interim analysis. Results: In the first 60 patients, response at wk 12 by independent review: PR in 24 (40%); SD in 25 (42%); PD in 5 (8%); unknown response in 2 (3%); and withdrawal prior to wk 12 (reasons other than PD/AE) in 4 (7%). 27 (45%) patients were randomized based on investigator review at wk 12. Total disease control rate was 82% (PR + SD). 67% of patients were treatment naïve, 33% had failed one prior treatment regimen (23% cytokine, 8% bevacizumab, 2% both). Most common AEs/lab abnormalities in all patients (n=161; 71% M, 29% F; mean 60.3 yrs; 81% Caucasian) were ALT/AST elevations, diarrhea, fatigue, nausea, hair depigmentation, & hypertension. Gr 3/4 AEs occurred in 26% of patients; most common were hypertension (8%) & ALT elevation (8%). One patient had Gr 5 AE due to large intestinal perforation. AEs led to discontinuation in 5% of patients. Conclusions: Interim analysis of this Ph II study demonstrated that pazopanib treatment resulted in a PR rate at wk 12 of 40% among patients with adv/met RCC and an acceptable toxicity profile. Based on these results, the Independent Data Monitoring Committee recommended discontinuation of randomization to placebo. Patients without PD were offered continued treatment with pazopanib beyond wk 12. At the time of publication, efficacy and safety data will be available for all 225 patients. [Table: see text]