bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase IV trial of dose-intense PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) in advanced pancreatic adenocarcinoma
Authors: Reni M. , Cereda S. , Passoni P. , Bonetto E. , Viganò M. G. , Balzano G. , Zerbi A. , Staudacher C. , Di Carlo V. 
Published: March 2020

4121 Background: In a phase III trial (Reni, Lancet Oncol 2005), PEFG regimen (cisplatin and epirubicin 40 mg/m2 day 1, gemcitabine 600 mg/m2 day 1 and 8, 5-fluorouracil (FU) 200 mg/m2/day continuous infusion) significantly improved the outcome of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. This regimen was subsequently modified by increasing dose-intensity (FU unmodified, cisplatin and epirubicin both at 30 mg/m2, and gemcitabine at 800 mg/m2 every 14 days; Dell’Oro, Ann Oncol 2004). The present study assessed activity and feasibility of dose-intense (DI) PEFG. Methods: DI-PEFG was administered to chemotherapy-naive patients with stage III-IV pancreatic adenocarcinoma, ≤ 75 years, performance status (PS) > 50, till progressive disease or for a maximum of 6 months. Analyses were conducted in the intent-to-treat population. Results: Between January ’04 and June ’05, 49 (31 or 63% metastatic) patients, median age 62 yrs, median PS 80, were treated with DI-PEFG at our institution. Partial response and stable disease was observed in 25 (51%) and 15 (31%) patients, respectively; 31 patients were progression-free at 6 months (PFS-6 = 63%). Median survival was 8.5+ months and 1-yr overall survival (OS) was 46%. 211 courses (range 1–6, median 5) of DI-PEFG were delivered. Main grade 3–4 toxicity was: neutropenia in 9% of cycles, anaemia, stomatitis, fatigue in 3%, nausea/vomit, deep venous thrombosis and diarrhoea in 2%, thrombocytopenia, febrile neutropenia and hand-foot syndrome in 1%. Dose intensity (mg/m2/week) was 13 for both epirubicin and cisplatin, 338 for gemcitabine and 1106 for FU. Conclusion: With respect to classical PEFG, DI-PEFG was not inferior in terms of PFS-6 (63% vs. 42%), 1-yr OS (46% vs. 38.5%) and response rate (49% vs. 38.5%); allowed to increase dose intensity for gemcitabine by 32%, for cisplatin and epirubicin by 36% (FU reduced by 3%), to reduce grade 3–4 hematological toxicity (neutropenia 9% vs. 43%; thrombocytopenia 1% vs. 28.5%) and to reduce by one third the number of outpatients accesses. No significant financial relationships to disclose.
Second-line therapy with pemetrexed after gemcitabine failure in patients with unresectable locally advanced or metastatic pancreatic cancer: A multicenter phase II trial
Authors: Boeck S. , Weigang-Koehler K. , Fuchs M. , Kettner E. , Quietzsch D. , Trojan J. , Stötzer O. , Mueller E. , Depenbrock H. , Heinemann V. 
Published: March 2020

4124 Background: There is no established second-line therapy for advanced pancreatic cancer after failure of standard first-line treatment with gemcitabine. In view of the urgent need of such therapy and the observation of clinically meaningful responses with pemetrexed in previously untreated pancreatic cancer, this phase II study evaluated pemetrexed as second-line therapy. Methods: This study was planned to evaluate the efficacy and safety of pemetrexed in 54 patients (pts) with unresectable locally advanced or metastatic pancreatic cancer (stage II-IV), ECOG performance status ≤2 and estimated life expectancy of ≥12 weeks (wks) after failure of first-line gemcitabine single agent or combination therapy. Pemetrexed was started at 500 mg/m2 q3w (10 min infusion), with vitamin B12 and folic acid supplementation. Dose escalation by 100 mg/m2 every other cycle and an unlimited number of cycles were allowed. Primary endpoint was the 3-month survival rate. Results: A total of 189 treatment cycles (median 2, range 1–20) was given to 52 pts (60% male, median age 63 yrs, median time since initial diagnosis 32 wks, 89% stage IV disease). Doses were escalated in 2 pts (4%) and reduced due to toxicity in 9 pts (17%); median dose per cycle was 500 mg/m2 (range 212–700 mg/m2). The 3-month survival rate was 75% (95% CI 63.2–86.8%). At a median follow-up of 20 wks, the median overall survival estimate was 20 wks, with 9 pts alive including 1 still on pemetrexed. Median TTP was 7 wks (range 1–62 wks). The overall response rate was 3.8% (0 CR, 2 PR); 12 pts (23%) had SD for ≥6 wks, 9 of them for ≥12 wks. CA 19–9 decreased at least once by ≥ 50% in 12 pts (23%). Grade 3/4 hematological toxicity rates per pt were as follows: neutropenia 17.3% (febrile neutopenia: 3.8%), leukopenia 15.4%, thrombopenia 5.8% and anemia 3.8%. Conclusion: Pemetrexed is a feasible option for second-line therapy with mild toxicity and encouraging activity in unresectable locally advanced or metastatic pancreatic cancer after gemcitabine failure. [Table: see text]
Gefitinib in advanced unresectable hepatocellular carcinoma: Results from the Eastern Cooperative Oncology Group’s Study E1203
Authors: O’Dwyer P. J. , Giantonio B. J. , Levy D. E. , Kauh J. S. , Fitzgerald D. B. , Benson A. B. 
Published: March 2020

4143 Background: Worldwide, hepatocellular carcinoma (HCC) is the most common cause of cancer death. Chemotherapy yields no survival benefit, and median survival is < 6 months. Up to 47% of HCCs express the epidermal growth factor receptor (EGFR), which predicts survival. Also, EGFR signaling activates c-Met, the hepatocyte growth factor receptor. Gefitinib is an oral selective EGFR inhibitor that has shown growth inhibition of HCC cell lines. Methods: E1203 was a single arm phase II study of gefitinib in advanced HCC. Eligibility requirements: unresectable measurable (by RECIST) HCC (diagnosed by histology or alpha-fetoprotein criteria); PS ≤ 2; total bilirubin ≤ 2× ULN; SGOT ≤ 5× ULN; INR ≤ 2.3; albumin ≥ 2.8 g/dl; Child Pugh Class < C; no prior systemic therapy. Gefitinib 250 mg taken daily. 1 cycle = 3 weeks. Tumor assessments done every 6 weeks. Objectives: 4.5 month PFS of 63%, OS, RR, toxicity. A two-stage design was used. Results: Thirty-one patients were accrued to the first stage. Median follow-up is 13.2 months. Med age = 64.8 yrs (46–86). M:F 87%:10%. PS 0/1/2: 39%/42%/16%. Med PFS = 2.8 months (95%CI: 1.5, 3.9). Med OS = 6.5 months (95% CI: 4.4, 8.9). Response #s (CR/PR/SD): 0/1/7. Selected grade 3 adverse events: neutropenia ×2; rash ×2; diarrhea ×1. There was only 1 grade 4 AE (neutropenia). The criterion for second-stage accrual was not met. Conclusion: Gefitinib as a single agent is not active in advanced HCC. No significant financial relationships to disclose.
Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein
Authors: Schwartz J. D. , Schwartz M. , Lehrer D. , Cohen E. , Sung M. , Kinkhabwala M. , Siegel A. , Holloway S. , Ocean A. , Wadler S. 
Published: March 2020

4144 Background: HCC is a vascular tumor in which angiogenesis contributes to pathogenesis. VEGF-inhibition has not been previously attempted in cirrhosis or HCC. Methods: We enrolled patients with unresectable HCC to treatment with bevacizumab at 5 mg/kg or 10 mg/kg every 14 days to assess safety and preliminary efficacy. Inclusion criteria were BR < 3.0 mg/dl, transaminases 75K and PT within 4 seconds of normal. Additional criteria included no history of myocardial infarction, stroke, or condition requiring ongoing antiplatelet or antithrombotic therapy. Results: Initial safety assessments for patients treated for at least 8 weeks indicate that 10 of 11 patients treated at 5 mg/kg and 7 of 8 patients treated at 10mg/kg tolerated therapy with acceptable toxicity. Of the first 28 patients treated at either dose, four have had therapy discontinued because of adverse events (including one grade 3 transient ischemic attack). Three patients had serious esophageal bleeding which was likely secondary to progression of HCC and liver disease (although contribution of drug to these events cannot be excluded). The protocol has been modified to identify and treat esophageal varices prior to enrollment. Other toxicities have included grade 2 fatigue, abdominal pain, gastric ulcer, hypertension, hyperbilirubinemia, rash and proteinuria and grade 1 gingivitis, diarrhea, vomiting and epistaxis. Of the initial 25 patients evaluable for efficacy, 5 had progressive disease within 16 weeks. Two patients had PR and 18 had SD. Median time-to-progression was 6.5 months (range 3.9–24.2). Nineteen of 25 (76%) patients had HCC that progressed following transplant, surgery, RFA or embolization procedures. Conclusions: Bevacizumab can be given safely at both 5 mg/kg and 10 mg/kg in HCC patients with localized, unresectable HCC, preserved liver function and no significant esophageal varices. Preliminary results suggest significant disease-modifying effect (80% disease-control rate); median time-to-progression to-date has exceeded 6-months. [Table: see text]
A non-randomized phase II study of sequential irinotecan (CPT) and flavopiridol (F) in patients (pts) with advanced hepatocellular carcinoma (HCC)
Authors: Abou-Alfa G. K. , Carvajal R. D. , Chung K. Y. , Ghossein R. A. , Capanu M. , Gonen M. , Jacobs G. , Kelsen D. P. , Schwartz G. K. 
Published: March 2020

4148 Background: F is a CDK inhibitor which potentiates CPT- induced apoptosis. In a phase I trial of CPT 100mg/m2 followed 7 hours later by F given over 1 hour weekly for 4 out of 6 weeks (Shah, Clin Can Res 2005), 2 pts with advanced HCC had stable disease (SD) for 14+ months. In the same phase I study, patients who were p53 wild-type (negative p53 staining), and whose p21 remained stable or was non-detectable on the post-treatment biopsy, were noted to have SD or a partial response. Methods: Pts with advanced HCC, no prior systemic therapy, Child’s-Pugh score A, B7 or B8, and KPS ≥ 70%, received 100 mg/m2 of CPT, followed 7 hours later by 60 mg/m2 of F over 1 hour weekly for 4 out of 6 weeks. The trial had a two stage design, with a planned accrual of 30 pts. The primary endpoint was TTP. Tumor response was assessed every 2 cycles using revised WHO criteria. p53 immuno-staining was performed on pre-treatment paraffin preserved tissues. A cut-off of 20% defined positive mutant versus negative wild-type p53 status. Results: 16 pts were enrolled: median age 64 (range 26–84), KPS 80% (70–90%), and 10 males/6 females. 13 pts received therapy, two progressed before starting, and one patient (pt) was excluded because pathology re-review did not confirm HCC. 1 pt was excluded because of consent withdrawal after first dose of therapy. This pt was included in the toxicity analysis. The median number of cycles given was 2 (range 1–8 cycles). Grade 3 and 4 toxicities included dehydration (4: 30%) diarrhea (2: 15%) febrile neutropenia (6: 46% - 4 events in one pt) and fatigue/weakness (3: 23%). Therapy had to be discontinued in 2 pts because of toxicity. TTP was 2.6 months (95% CI 2.43–8.42). One patient had SD for over a year, 8 had progression of disease (POD), and 4 came off study because of toxicity. Mutational p53 was evaluated in 7 pts. The pt with SD had wild type p53. Three pts with POD had mutant p53, while the other 3 had wild type 53. Conclusions: CPT followed by F is an ineffective therapy for HCC. This therapy was relatively poorly tolerated, likely contributed to by underlying cirrhosis in HCC, but similar to our experience of CPT in HCC. While p21 level pre and post therapy is lacking, the wild type p53 of the patient with SD maybe a predictor of response in HCC where p53 mutations are common. No significant financial relationships to disclose.
Phase I/II trial of the prostate-specific membrane antigen (PSMA)-targeted immunoconjugate MLN2704 in patients (pts) with progressive metastatic castration resistant prostate cancer (CRPC)
Authors: Milowsky M. I. , Galsky M. , George D. J. , Lewin J. M. , Rozario C. P. , Marshall T. , Chang M. , Nanus D. M. , Webb I. J. , Scher H. I. 
Published: March 2020

4500 Background: MLN2704 is an immunoconjugate that utilizes the PSMA-targeted monoclonal antibody MLN591 to deliver the maytansinoid antimicrotubule agent DM1 directly to prostate cancer cells. This multicenter trial was designed to determine the tolerability, optimal dosing schedule and efficacy of MLN2704 in pts with progressive metastatic CRPC. Methods: Pts aged ≥18 yrs with progressive metastatic CRPC received MLN2704 i.v. over 2.5 hr q1wk, q2wks or q3wks for 12 wks, with additional doses permitted in responders. Doses within a given schedule were escalated in 40% increments in the absence of excessive dose-limiting toxicity (DLT). Results: 61 pts have been treated. The most common adverse events (AEs) were nausea, fatigue, and schedule-dependent neurotoxicity. The only DLT was gr 3 hepatic transaminitis in 1/6 pts at 330 mg/m2 q2wks; the only gr 4 AE was transient neutropenia, in 2 pts (330 mg/m2 q2wks and q3wks). Declines in PSA were most frequent at 330 mg/m2 q2wks ( table ), including 49–88% PSA declines in 4/6 pts. However, given the frequency of grade 2–3 peripheral neuropathy an additional cohort is being treated with 330mg/m2 on days 1 and 15 of a 6-wk cycle. Initial results with this 6-wk schedule indicate PSA declines with a lower incidence of gr 2–3 toxicities, particularly neuropathy. Conclusions: Accrual to the dose-escalation phase is complete. Dose-dependent antitumor effects were seen. Peripheral neuropathy has limited continuous dosing at higher dose levels prompting a schedule change. Accrual to the 6-wk schedule is continuing. [Table: see text] [Table: see text]
Efficacy of lapatinib in patients with high tumor EGFR expression: Results of a phase III trial in advanced renal cell carcinoma (RCC)
Authors: Ravaud A. , Gardner J. , Hawkins R. , Von der Maase H. , Zantl N. , Harper P. , Rolland F. , Audhuy B. , Machiels J. , El-Hariry I. 
Published: March 2020

4502 Background: Lapatinib is an orally-active, reversible inhibitor of EGFR/ErbB2 tyrosine kinases. In Phase I/II trials, lapatinib has demonstrated activity in patients (pts) with advanced breast cancer. We report the first results of a randomized open-label Phase III trial ( EGF20001 ) of lapatinib vs. hormone therapy (HT) in pts with advanced RCC that express EGFR and/or ErbB2 by immunohistochemistry (IHC). The main endpoints were time to progression (TTP) and overall survival (OS). Methods: Pts with advanced RCC of any histology who had failed first-line cytokine therapy were stratified by Karnofsky performance score (KPS) and number of metastatic sites. Pts were randomized to receive oral lapatinib 1250 mg OD or HT. The primary efficacy endpoint was TTP, with 90% power to detect a 50% increase (i.e. 4 vs. 6 months) at a two-sided 5% significance level. All pt scans were interpreted by independent radiologic review. Results: At the time of the TTP analysis, 417 pts were randomized and 298 TTP events were reported. Demographic and baseline characteristics were similar between both arms; pooled results were: median age: 61 yrs; Stage IV disease: 97%, KPS 90–100: 59%, metastatic sites >2: 49%, prior nephrectomy: 94%, prior interferon therapy: 64%. No unexpected toxicities were observed, and drug-related AE (all grades) for lapatinib vs. HT included rash (44%:3%), diarrhoea (40%:3%). When results from all pts were analysed, median TTP was 15.3 weeks for lapatinib vs. 15.4 weeks for HT (hazard ratio (HR) = 0.94; p = 0.60), and median OS was 46.9 weeks for lapatinib vs. 43.1 weeks for HT (HR=0.88; p=0.29). In the major subgroup of 241 pts with EGFR overexpressed disease (3+ by IHC), median TTP was 15.1 weeks for lapatinib vs. 10.9 weeks for HT (HR = 0.76; p = 0.06), and median OS was 46.0 weeks for lapatinib vs. 37.9 weeks for HT (HR = 0.69; p = 0.02). These results were confirmed by Cox Regression analysis, and additional biomarker evaluation, including FISH, is underway. Conclusions: The EGFR/ErbB2 dual targeted inhibitor, lapatinib, appears to prolong overall survival compared to hormone therapy in advanced RCC pts with overexpressed EGFR who failed prior therapy. [Table: see text]
Systems pathology for building predictive models: The androgen receptor as a prototype biomarker in prostate cancer progression and targeted therapeutic response assessment
Authors: Donovan M. J. , Scher H. , Scardino P. , Kotsianti A. , Cordon-Cardo C. 
Published: March 2020

4504 Background: A functional androgen receptor (AR) signaling axis plays a critical role in prostate cancer (PCA) development and progression across the clinical spectrum of the illness. Following diagnosis, most prostate cancers respond to treatments that block circulating androgen levels or block AR action. The measurement of AR levels in tumor tissue samples has the potential to provide prognostic information, to treatment selection, and a measure of the pharmacodynamic effect of a therapeutic agent(s) designed to reduce AR levels or block AR action. Existing methods to assess AR antigen levels in tissue are subjective, we have developed a systems pathology strategy for interrogating biomarker assessment in a predictive model by integrating clinical data with histological and quantitative antigen profiles. Methods: Tissue microarrays from 366 MSKCC patients were stained with H&E, images captured, analyzed and quantitative cellular features produced. Immunohistochemistry (IHC) was performed for AR and a staining index generated. A multiplex immunofluorescent (IF) assay using DAPI, CK18 and AR was performed on a subset of patients. IF mages were acquired and specific IF scripts were used to generate quantitative features of AR which were compared with AR IHC data. Results: Androgen Receptor levels by IHC in PCA demonstrated that a high-level of expression was associated with a greater risk of PSA-relapse within 5 years. (P < 0.0001; cut point 100). The correlation of AR IF with AR IHC established that all derived AR-IF measurements were statistically associated with the AR-IHC data. Furthermore, in a very preliminary model using machine learning and feature selection to predict PSA recurrence, 1AR-IF feature (epithelial and stromal AR) along with 2 clinical variables was selected with a concordance index of 0.80. Conclusion: AR levels in newly diagnosed localized prostate cancer are associated with clinical outcome. The levels can be assessed accurately and in a standardized manner using quantitative multiplex antigen methods. Such approaches are critical for evaluating biomarkers, especially when determining therapeutic response and clinical endpoints. [Table: see text]
Predicting the outcome of salvage radiotherapy for recurrent prostate cancer after radical prostatectomy
Authors: Stephenson A. J. , Pollack A. , Kattan M. W. , Scardino P. T. 
Published: March 2020

4514 Background: Salvage radiotherapy may potentially cure patients with recurrent prostate cancer after radical prostatectomy (RP). However, the outcome is highly dependent on patient selection factors and current diagnostic modalities for locally recurrent prostate lack acceptable sensitivity and specificity. We developed a model to predict the likelihood of a durable response to salvage radiotherapy for patients with post-RP biochemical recurrence (BCR). Methods: Using multivariable Cox proportional hazards regression analysis, we modeled the clinical data for 1540 patients who received salvage radiotherapy at 1 of 17 North American tertiary referral centers for post-RP BCR. The primary endpoint was disease progression after salvage radiotherapy, defined as a serum prostate-specific antigen (PSA) value ≥ 0.2 ng/mL followed by another increase, initiation of systemic therapy, or clinical recurrence. The median follow-up was 53 months. Results: Disease progression was observed in 866 patients and the 5- and 10-year progression-free probability was 38% (95% CI, 35–40) and 19% (95% CI, 15–23), respectively. Significant variables in the nomogram were: pre-radiotherapy PSA (P < .001), RP Gleason score (P < .001), neoadjuvant androgen-deprivation therapy (P< .001), negative surgical margins (P < .004), PSA at BCR (P = .011), PSADT (P = .029), and regional lymph node metastasis (P = .034). The nomogram was accurate and discriminating with a concordance index of 0.68. Published models predicting the probability of metastasis progression or PCSM for BCR patients based on disease-free interval, prostatectomy Gleason score, and/or PSA doubling time discriminated poorly for a durable response to salvage radiotherapy among patients in our cohort (concordance index, 0.56–0.61). Conclusions: A nomogram has been developed that predicts the 5-year progression-free probability after salvage radiotherapy for men with post-RP BCR. This represents the first model to predict the outcome of salvage therapy for BCR and is useful for quantifying the anticipated benefit of salvage radiotherapy for prostate cancer recurrence. Published predictive models for metastasis progression or PCSM are of limited clinical utility in selecting patients for salvage radiotherapy. No significant financial relationships to disclose.
Absolute PSA value after androgen deprivation (AD) is a strong independent predictor of survival in new metastatic (D2) prostate cancer (PCa): Data from Southwest Oncology Group Trial 9346 (INT-0162)
Authors: Hussain M. , Tangen C. M. , Schellhammer P. F. , Crawford E. D. , Higano C. S. , Wilding G. , Akdas A. , Small E. J. , Donnelly B. , Raghavan D. 
Published: March 2020

4517 Background: PSA is a biomarker for monitoring disease activity in PCa. It is not well established if absolute PSA values achieved after AD is prognostic in patients (pts) with new D2 PCa. Methods: Hormone naive D2 pts with baseline PSA ≥ 5ng/mL are treated with 7 months (ms) AD induction. Pts achieving PSA-n (PSA ≤ 4.0 ng/ml that is stable or declining on ms 6 and 7) are randomized to continuous vs. intermittent AD on month 8. To be eligible for this analysis (approved by Data Safety Monitoring Committee), pts had to have a prestudy PSA with at least 2 subsequent PSAs during induction and be registered at least 1 year prior to analysis date. Survival was defined from 8 months to death due to any cause. Associations were evaluated by proportional hazards regression models. P≤0.05 was statistically significant. Results: Of the first 1,395 registered pts, 1345 were eligible for this analysis. Median age was 70 years, median baseline PSA 76.1 ng/mL, 38% had bone pain (BP) and 47 % had Gleason sum (GS) > 7. Median number of on-study PSAs during induction was 5 (range: 2 -18). Of the 1,345 pts, 1134 achieved PSA-n with 965 maintaining PSA-n at end of induction. Of those achieving PSA-n, 604 (45% of all pts) had an undetectable PSA (PSA-u, ≤ 0.2 ng/mL) at end of induction. In multivariate analysis, 4 significant independent risk factors were associated with post-induction survival: Performance status, GS, BP, and being randomized. After adjustment for these factors, pts who had a PSA-n at the end of induction but not PSA-u had less than half the risk of death (RoD) as those who did not have PSA-n (HR: 0.41; 95% CI 0.32, 0.54, p < 0.001), and pts with PSA-u had about one-quarter the RoD as pts with no PSA-n (HR: 0.26; 95% CI 0.20, 0.35, p < 0.001). After adjustment for covariates, pts with PSA-u had significantly better survival than those with only PSA-n at end of induction (p < 0.001). The median overall survival was 13 ms for the 383 not normalized (95% CI: 11 to 16 ms), 44 ms for the 360 pts normalized but not undetectable (95% CI: 39 to 55 ms), and 75 ms for the 602 pts with PSA-u (95% CI: 62, 91 ms). Conclusion: Achieving a PSA-n or PSA-u after 7 ms of AD is a strong predictor of survival and should be used to tailor future trial design in new D2 pts. [Table: see text]