bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I trial of gefitinib with concurrent radiotherapy and fixed dose-rate gemcitabine infusion, in locally advanced pancreatic cancer
Authors: Maurel J. , Martin-Richard M. , Conill C. , Sanchez M. , Petriz L. , Ginés A. , Gallego R. , Cajal R. , Navarro S. , Fernandez-Cruz L. 
Published: March 2020

4105 Background: Pancreatic cancers are resistant to radiotherapy (RT) and current chemotherapy agents. Epidermal growth factor receptor (EGFR) is over-expressed in pancreatic cancer and in vitro studies have shown that EGFR inhibitors can overcome radio- and chemo-resistance. The aim of the study was to determine the maximally tolerated dose of gefitinib, in combination with RT and gemcitabine for patients with locally advanced pancreatic carcinoma (LAPC). Methods: Eighteen patients with pathological proven LAPC, due to major vascular invasion based on helical computed tomography and endoscopic ultrasound, were entered. The targeted irradiated volume included the tumor and 2 cm-margin. Prophylactic irradiation of regional nodes was not allowed. Patients with >500 cc of planned tumor volume (PTV) were excluded. An initial cohort of 6 patients was treated with RT (45 Gy/25 fractions/5 weeks) plus concomitant gefitinib (250 mg/day). Successive cohorts of patients received 100, 150 and 200 mg/m2/day of gemcitabine in a 2 hour infusion over weeks 1,2,3,4, and 5 with gefitinib (250 mg/day) and RT. Gefitinib was continued after RT until progression. A pharmacodynamic study of angiogenic markers (VEGF and IL-8) was also performed. Results: Mean PTV was 293cc (range 137–462 cc). There were no dose-limiting toxicities on study. Common toxicities were mild neutropenia, asthenia, diarrhea, cutaneous rash and nausea/vomiting. One patient showed a partial response of 13 months in duration, and 7 patients showed disease stabilization. Median progression free survival (PFS) was 3.7 months and median overall survival (OS) was 7.5 months. No patients have a reduction in VEGF levels >50%. Reduction in VEGF serum levels >25% and IL-8 levels >50% had no impact on PFS and OS. Conclusion: Our results support thatthe combination of gefitinib, RT and gemcitabine showed an acceptable toxicity but with modest activity in LAPC. [Table: see text]
Use of pre-trial EBV titres as a measure of immune status: Further support for independence from health status of immunological response to G17DT in gemcitabine—G17DT combination pancreatic cancer trial patients
Authors: Broome P. , Mudde G. , Kircheis R. , Takhar A. , Watson S. A. 
Published: March 2020

4108 Background: In a Phase III pancreatic cancer trial combining G17DT with gemcitabine (Gem) vs Gem alone [ASCO 2005, Abstract 4012], a significant survival effect, independent of baseline KPS, was seen in patients with gastrin antibody response (Placebo + Gem 178 days vs 264 for antibody responders > 16U, p = 0.03). A consistent criticism of such analyses of vaccine trials in cancer patients is that the immuno-responders reflect a fitter sub-population. To show that response to G17DT was at least partially independent of health status, pre-trial EBV titres, which can be considered as a marker of immunological status, were shown to be predictive of survival in the placebo group. However, in the G17DT treated group, antibody responders and non-responders had similar distributions of anti EBV titres. Methods: Baseline PC4 patient sera from both Gem alone (placebo) and Gem + G17DT groups were examined for antibodies against EBV by ELISA. The placebo patients were assigned high or low EBV status if they were respectively above or below the mean titre. Kaplan-Meier curves for these sub-populations were compared using the log rank statistic. G17DT-treated patients were grouped into high, low and non-responders. Mean EBV titres of the G17DT subgroups were compared with each other and with the placebo group using the t-test. Results: HighEBV titre was shown to predict improved survival in the placebo arm of the Phase III trial (Gem treatment only, p = 0.049). However, mean EBV titres were similar in high G17DT antibody responders cf non-responders (EBV titre 125 vs 159, p = 0.13) and in placebo patients cf non-responders (160 vs 159, p = 0.98). Conclusions: Pre-trial EBV titre, found to be predictive of survival in pancreatic cancer patients treated with gemcitabine, was similar between G17DT responders and non-responders, adding further weight to the hypothesis that G17DT response is substantially independent of health status. [Table: see text]
A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy (PROSPECT - CONKO 004)
Authors: Pelzer U. , Hilbig A. , Stieler J. , Roll L. , Stauch M. , Opitz B. , Scholten T. , Hahnfeld S. , Dörken B. , Riess H. , Oettle H. 
Published: March 2020

4110 Background: Approximately 20% of patients (pts) diagnosed with pancreatic adenocarcinoma (PA) develop venous thromboembolism, which may contribute to the dismal prognosis of PA. A small phase II trial suggested an improved survival by the addition of low molecular weight heparin (LMWH) to chemotherapy (Icli et al., ASCO 2003). We conducted a small pilot study which indicated that the addition of enoxaparin to chemotherapy GFFC chemotherapy (see below) is safe and feasible in pts with advanced PA. Furthermore, results of several phase III studies suggest that pts in good performance status may benefit from more intensive chemotherapy regimen (Riess et al; Heinemann et al; ASCO 2005). Based on these considerations we started the multicenter phase III study CONKO 004. Methods: 540 patients are to be recruited into this study. Primary stratification takes place according to Karnowsky performance status and kidney function. Patients with KPS > 80% and normal kidney function receive GFFC ± LMWH (gemcitabine 1 g/m2 (30 min), cisplatin 30 mg/m2 (90 min), 5-fluorouracil 750 mg/m2 (24 h), folinic acid 200 mg/m2 (30 min), d1, 8; q3w ± Enoxaparin 1mg/kg daily s.c.). Pts with KPS < 80 % and increased creatinin plasma levels (>1.3 mg/dl) receive the current standard therapy (gemcitabine 1 g/m2 (30 min), d1, 8, 15; q4w) ± LMWM ± Enoxaparin 1mg/kg daily s.c. After 12 weeks of initial chemotherapy all patients who have not progressed received the standard therapy (gemcitabine 1 g/m2 (30 min), d1, 8, 15; q4w) ± Enoxaparin 40mg daily s.c. Results: From April 2004 to Dezember 2005 140 pts have been recruited in this study. Until now no unexpected serious adverse events concerning severe bleedings were observed in the enoxaparin treatment group. No heparin induced thrombocytopenia (HIT II) was documented. The first interim analysis per protocol is planned after 12 pts. with deep vein thrombosis or thromboembolic events. This interim analysis is expected to be completed in May 2006. Conclusions: Our observations indicate that the addition of enoxaparin—given the dosage mentioned above—to GEM/GFFC is safe, does not change toxicity and maintains activity of chemotherapy in pts with advanced PA. This study is open to recruitment. No significant financial relationships to disclose.
A phase II study of S-1 in gemcitabine-refractory metastatic pancreatic cancer
Authors: Morizane C. , Okusaka T. , Furuse J. , Ishii H. , Ueno H. , Ikeda M. , Najima M. , Hirokawa S. , Nakachi K. , Ogura T. 
Published: March 2020

4115 Background: Gemcitabine (Gem) monotherapy or Gem-containing chemotherapy is the standard first line therapy for advanced pancreatic cancer. After disease progression, there is no standard regimen available. In a previous phase II trial (J. Furuse et al, Proc ASCO 2005: # 4104), S-1 has been reported to show considerable efficacy, achieving a response rate of 37.5% in chemo-naïve patients with pancreatic cancer. This study evaluated the efficacy and toxicity of S-1 in patients with Gem-refractory metastatic pancreatic cancer. Methods: Eligibility criteria were pathologically-proven pancreatic cancer with confirmation of progressive disease while receiving Gem-based chemotherapy, Karnofsky performance status 80 to 100%, age 20 to 74 years, with measurable metastatic lesions, adequate hematological, renal and liver functions, and written informed consent. S-1 was administered orally at 40 mg/m2 twice daily for 28 days with a rest period of 14 days as one course. Administration was repeated until the appearance of disease progression or unacceptable toxicity. The primary study end point was objective response, secondary end points included toxicity, progression-free survival (PFS) and overall survival, as well as clinical benefit response in symptomatic patients. Results: Forty patients (pts) from two institutions were enrolled between September 2004 and November 2005. Thirty-three pts are currently evaluable for response in this ongoing trial. There have been 5 confirmed partial responses (12.5%), and 14 pts (35%) with stable disease. Median survival has not been reached. Median PFS was 2.1 months. Toxicity data were available for 28 patients. Grade 3 and 4 toxicities were anemia (1 pts), appetite loss (2 pts), and fatigue (2 pts). Conclusions: Preliminary results demonstrated the safety and activity of S-1 in Gem-refractory metastatic pancreatic cancer. Efficacy and toxicity analysis are ongoing. Final results will be presented at the meeting. No significant financial relationships to disclose.
Proposal of a new staging system for hepatocellular carcinoma based on the treatment strategy: An analysis of 1,084 patients
Authors: Ishii H. , Furuse J. , Kinoshita T. , Nakachi K. , Suzuki E. , Yoshino M. , Konishi M. , Nakagohri T. , Takahashi S. , Gotohda N. 
Published: March 2020

4137 Background: Although several prognostic models have been proposed for hepatocellular carcinoma (HCC), they are not useful for conducting treatment strategy. Methods: Between July 1992 and May 2005, consecutive 1084 patients (pts) with naïve HCC were treated in our hospital. Based on our treatment strategy, we set our own HCC stage as follows: stage 1; Child-Pugh A or B, N0M0, solitary tumor without vascular invasion (VI), stage 2; Child-Pugh A or B, N0M0, multiple tumors without VI, stage 3; Child-Pugh A or B, N0M0, solitary tumor with VI, stage 4A; Child-Pugh A or B, N0M0, multiple tumors with VI, stage 4B; Child-Pugh A or B, N1 or M1, any T, stage 4C; Child-Pugh C, any TNM. Generally, treatments for stage 4C, 4B, & 4A were observation, chemotherapy trials or aggressive local therapies in selected pts, & hepatic arterial infusion chemotherapy. For the pts with stage 1–3, the priority of treatment options was hepatectomy first, percutaneous ablation (PA) second, and transcatheter arterial chemoembolization third. PA was indicated for 3 or fewer HCC nodules without VI, of which the largest diameter were smaller than 3 cm. Treatment outcomes were retrospectively analyzed according to the above staging system. Results: The overall survival rate was 50% at 3 yrs, 33% at 5 yrs, 24% at 7 yrs & 13% at 10 yrs. The median survival in stage 1, 2, 3, 4A, 4B & 4C was 5.5 yrs (N = 444), 2.9 yrs (N = 397), 0.8 yr (N = 36), 0.5 yr (N = 109), 0.3 yr (N = 76) & 0.2 yr (N = 22), respectively. Most of the definitive local therapy (91% of 371 hepatectomies with curative intent & 99% of 191 PAs) were classified in stage 1 or 2. The prognosis was also well predicted by the other 6 staging systems (Okuda, AJCC, CLIP, JIS, Tokyo and BCLC). However, hepatectomy with curative intent & PA were distributed into a CLIP score of 0–5 & 0–3, respectively, & into a JIS score of 0–4 & 0–3, respectively. Conclusions: The present staging system was simple & predicted prognosis well. Although other scoring systems caused various heterogeneities (hepatic reserve & tumor status) in each score, our staging system consisted of homogenous hepatic reserve & simple tumor status, so it might be useful for conducting treatment plan. Validation study is warranted in other population. No significant financial relationships to disclose.
Molecular analysis for new kinase mutations in imatinib resistant gastrointestinal stromal tumor patients
Authors: Ling K. , Liu C. , Tsen C. , Hsieh R. , Huang M. 
Published: March 2020

4155 Background: Gastrointestinal stromal tumors (GISTs) are characterized by expression of activated mutation of KIT or platelet-derived growth factor receptor alpha (PDGFRA). Imatinib had now been widespread used for treatment of unresectable or metastatic GISTs. However, most patients developed resistant to imatinib in a period of 1∼2 years. We have recently found the resistance to imatinib in GIST might be related to additional mutations in the kinase domain and we intend to identify the secondary mutation in imatinib resistant GISTs in Taiwanese patients. Patients and Methods: From April 2001 to November 2005, 20 advanced GIST patients were treated in Taipei MMH. Within 32 months, 10 patients with initial near-complete response to imatinib developed disease progression and resistant to imatinib. Nine harbored mutations in KIT exon 11, and one harbored mutation in KIT exon 9 before imatinib treatment. Five patients expired and the other (residual) five patients received excision or biopsy of progression lesions. Genomic DNA extracted from paraffin-embedded specimens from alive patients, were analyzed by sequencing for KIT (exon 9, 11, 13, 17) and PDGFRA (exon 10, 12 14, 18) gene mutation. Results: Molecular analysis revealed two patients harbored KIT exon 13 mutation Val654Ala substitution in their progression lesion. The other three patients harbored KIT exon 17 mutation Asn822Lys substitution. Conclusion: The novel missense mutation of KIT exon 17 N822K has never been reported before. The finding of an association between new mutation and disease progression is very impressive. The relationship between secondary mutation in these kinases and clinical response to imatinib will require further investigation. No significant financial relationships to disclose.
Long-term non-cancer mortality among 39,657 one-year testicular cancer survivors (TCSs)
Authors: Fosså S. D. , Chen J. , Dores G. M. , McGlynn K. A. , Schonfeld S. J. , Travis L. B. 
Published: March 2020

4508 Background: Multiple reports address the incidence of second cancer (SC) and long-term morbidity in TCSs, yet few data analyze the impact of non-malignant late sequelae on mortality. Methods: 39,657 one-year TCSs were identified in 14 population-based cancer registries in North America and Europe, with 17,856, 13,084 and 6,298 men followed for 10, 20 and 30 years, respectively. Standardized mortality ratios (SMRs), comparing TCSs to the general population, were calculated for deaths due to all non-cancer causes (n = 2,942) and specific sites. Further, absolute mortality due to TC, non-TC SC and all non-cancer disorders was estimated. Results: The SMR for all non-malignant diseases combined was 0.99 (95% CI: 0.95–1.02), with a significant reduction of deaths due to circulatory diseases (SMR: 0.92, n = 1,117). However, following initial treatment with chemotherapy and radiotherapy, the SMR for circulatory diseases was significantly elevated (SMR: 1.76), with a non-significant 29% excess after chemotherapy alone. Mortality due to digestive diseases was significantly increased (SMR: 1.32, n = 222), including gastric and duodenal ulcers (SMR = 1.52; excess deaths were observed between 10 and 25 years after initial radiotherapy). For the first 20 years after TC diagnosis, deaths due to infection were significantly elevated (SMR: 1.52, n=211). Absolute mortality due to non-cancer disorders always exceeded that due to SC, and was 15% after 30 years in a TCS diagnosed at age 35 compared with about 11% for SC. Conclusions: Compared with the general population, the overall risk of mortality due to all non-cancer causes combined does not appear to be increased in TCSs. However, they experience excess non-cancer deaths due to infection and digestive diseases, but not circulatory diseases. Additional analytic studies with detailed data on treatment and co-morbidities are required to further evaluate associations with specific causes of death. No significant financial relationships to disclose.
A phase II study of sunitinib administered in a continuous daily regimen in patients with cytokine-refractory metastatic renal cell carcinoma (mRCC)
Authors: De Mulder P. H. , Roigas J. , Gillessen S. , Srinivas S. , Pisa P. , Vogelzang N. , Fountzilas G. , Peschel C. , Baum C. , Escudier B. 
Published: March 2020

4529 Background: Renal cell carcinomas are known for their vascularity and production of high levels of VEGF. Sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor of multiple receptors including VEGFR, PDGFR, KIT, RET, and FLT3, has previously demonstrated significant efficacy in 168 patients (pts) with mRCC, with a 42% objective response rate (ORR) at 50 mg/day in 6-week (wk) cycles of 4 wks on treatment followed by 2 wks off. This study sought to determine the efficacy and safety of single-agent sunitinib in mRCC when administered in a continuous 37.5 mg/day regimen. Methods: Pts with histologically proven mRCC, refractory to a cytokine-based regimen, were enrolled in this open-label, multicenter, phase II study. Eligibility criteria included measurable disease, ECOG PS 0/1, and adequate organ function. Pts were randomized to receive sunitinib in the morning (AM) or in the evening (PM) at a dose of 37.5 mg/day, with individual doses subsequently titrated based on tolerability. The primary endpoint was RECIST-defined ORR. Secondary endpoints includedprogression-free survival, adverse events (AEs) and quality of life measures. Results: A total of 88/100 planned pts have been randomized to date: AM (43) and PM (45), and enrollment will be completed by end January 2006. 44 pts have been on continuous sunitinib treatment at 37.5 mg/day for >16 wks (3), >12 wks (9), >8 wks (12), and >4 wks (20). 2 pts (2.3%) discontinued (colon perforation and renal insufficiency) and 9 (10.2%) dose reduced to 25 mg/day due to grade 2/3 AEs: mucositis (2), hand-foot syndrome (2), thrombocytopenia (2), asthenia (1), nausea/diarrhea (1), and neutropenia (1). Preliminary efficacy data show some tumor shrinkage in the majority of patients evaluated at 4 wks, with 3 initial partial responses. There has been no significant difference between pts who received AM or PM doses. The most commonly reported AEs were mucositis, fatigue, hair/skin discoloration, and hand-foot syndrome. Conclusions: Sunitinib administered at a continuous dose of 37.5 mg/day was generally well tolerated; only a few patients required treatment breaks and/or dose reduction. Preliminary efficacy data are encouraging. Mature data will be presented. [Table: see text]
CD8+ tumor-infiltrating lymphocytes as a statistically significant marker of disease recurrence and survival in transitional cell carcinoma patients
Authors: Sharma P. , Sato E. , Bajorin D. , Shen Y. , Wen S. , Reuter V. , Jungbluth A. , Gnjatic S. , Old L. 
Published: March 2020

4544 Background: Superficial transitional cell carcinoma (TCC) is an immune-responsive tumor evidenced by immunotherapy trials with BCG demonstrating improved survival. In contrast, more advanced muscle-invasive TCC is not considered an immunologically active tumor. Yet, host immune functions that may have a clinical impact on the biologic activity of these more invasive tumors have not been systemically evaluated. CD8+ T-cells are responsible for cytotoxicity and potential tumor eradication by interaction with antigen plus human leukocyte antigens (HLA). A clear association between intratumoral CD8+ T-cells and clinical outcome has not been established in TCC. Methods: We performed pathological, immunohistochemical and RT-PCR analyses of 69 TCC patient samples that were obtained with appropriate informed consent on an Institutional Review Board (IRB)-approved protocol. The samples were studied for pathological stage, tumor-associated antigen expression, class I HLA expression, and CD8+ intratumoral T-cells. Systemic CD8+ T-cells from one patient with positive CD8+ intratumoral T-cells were studied by tetramer analyses for reactivity against the NY-ESO-1 tumor antigen expressed on the patient’s tumor. Results: In a subset analysis, advanced TCC (pT2, pT3 and pT4) patients who had higher numbers of CD8+ tumor infiltrating lymphocytes (TILs) had a greater disease-free survival (p = 0.0002) and overall survival (p = 0.011) than similarly staged TCC patients with lower numbers of CD8+ TILs. In the multivariate analyses, CD8+ TILs (p = 0.04) and tumor stage (p < 0.001) were significant risk factors to predict overall survival. Furthermore, a CD8+ T-cell clone derived from one patient demonstrated strong recognition of the tumor antigen NY-ESO-1. Conclusions: This is the first report, to our knowledge, that CD8+ TILs is an important prognostic indicator for patients with advanced TCC. Investigational immunotherapy strategies to evoke CD8+ T-cell responses are warranted in patients with advanced TCC. [Table: see text]
Toremifene citrate increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer
Authors: Smith M. R. , Chu F. , Forrest J. , Malkowicz S. B. , Price D. , Sieber P. , Barnette K. G. , Segal S. , Steiner M. S. 
Published: March 2020

4553 Background: In men with prostate cancer, androgen deprivation therapy by either surgical orchiectomy or treatment with a gonadotropin releasing hormone agonist decreases bone mineral density (BMD) and increases clinical fracture risk. In postmenopausal women, selective estrogen receptor modulators (SERMs) increase BMD and decrease fracture incidence. We conducted a multicenter randomized controlled trial to evaluate the efficacy of the SERM toremifene citrate in men with prostate cancer. Methods: In a 24-month prospective study, 1392 men with prostate cancer who have been treated with ADT for at least 6 months and are at increased risk of fracture based on either being older than 70 years of age or having evidence of osteopenia by baseline dual energy X-ray absorptiometry (DEXA) scan were assigned randomly (1:1) to receive either toremifene citrate 80mg or placebo (by mouth daily). The primary study endpoint is proportion of men with one or more fracture at 24 months. Secondary endpoints include changes in BMD of the hip and spine. Here we report the results of a planned interim analysis of 12-month changes in BMD for the first 200 subjects. Results: As summarized in the table below, toremifene citrate significantly increased BMD of the lumbar spine, total hip, and femoral neck compared to placebo. Conclusions: In men receiving ADT for prostate cancer, toremifene citrate significantly increased BMD of the hip and spine. In randomized controlled trials of SERMs in postmenopausal women, similar BMD improvements translated into statistically and clinically significant decreases in fractures risk. These interim results of BMD effects suggest toremifene citrate has the potential to provide a fracture reduction benefit in men with prostate cancer, the hypothesis being tested in the ongoing study. [Table: see text] [Table: see text]