bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase III study of 5-fluorouracil continuous infusion (5FUci) versus methotrexate and 5-FU sequential therapy (MF) in gastric cancer with peritoneal metastasis (JCOG0106)
Authors: Shirao K. , Boku N. , Yamada Y. , Yamaguchi K. , Doi T. , Takiuchi H. , Nasu J. , Nakamura K. , Fukuda H. , Ohtsu A. 
Published: August 2020

4545 Background: Gastric cancer (GC) with peritoneal metastasis (PM) often complicates ascites or intestinal stenosis and the prognosis is still poor. Anti-cancer drugs generally can not be administered for such patients (pts) due to the risk of serious and prolonged adverse events. However, 5FU-based chemotherapy is reportedly relatively safe for PM. We conducted a phase III study to investigate the superiority of MF over 5FUci for GC with PM with a primary endpoint of overall survival (OS) and secondary endpoints of toxicities, ingestion-possible survival (IPS) in pts with initially possible ingestion and proportion of ingestive improvement (%II) in pts requiring nutrition support. Methods: Eligibility criteria included pts with histologically proven gastric adenocarcinoma; inoperable or recurrent GC; PM with radiologically confirmed intestinal stenosis or ascites; 20–75 years old; PS 0–2; no prior treatment except surgery or adjuvant chemotherapy. Treatment with 5FUci (800mg/m2/d, civ, d1–5, q4w) or MF (methotrexate, 100mg/m2, iv, followed 3 h later by 5FU, 600mg/m2, iv, with leucovorin rescue, q1w) were continued until disease progression or unacceptable toxicities. Projected sample size was 236 in total, which had 80% power to detect 40% increase of median OS in MF with 1-sided alpha 0.05. Results: A total of 237 pts were randomized between Oct 2002 and Apr 2007. Final analysis was performed in Dec 2008 when 224 pts (95%) were dead. Results of OS are shown in Table . Median IPS was 8.1M for 5FUci(n=102) and 9.0M for MF(n=103) (p=0.60). %II was 41%(7/17) for 5FUci and 57%(8/14) for MF (p=0.48). Frequencies (%) of grade 4 neutropenia, grade >3 febrile neutropenia, infection with neutropenia, anemia, anorexia, diarrhea, abdominal pain within 6M, and treatment related death (5-FUci/MF) were 0/9, 0/3, 0/5, 10/16, 27/34, 1/10, 5/10 and 2/1, respectively. Conclusions: MF could not become new standard therapy for GC with PM. [Table: see text] No significant financial relationships to disclose.
Effect of neoadjuvant combined modality therapy with weekly docetaxel (D) and cisplatin (P), 5-fluorouracil (5-FU) continuous infusion (c.i.), and concurrent radiotherapy (RT) on pathological response rate in esophageal cancers (EC): A phase II study
Authors: Pasini F. , de Manzoni G. , Stievano L. , Grandinetti A. , Maluta S. , Capirci C. , Durante E. , Bonetti A. , Zanoni A. , Cordiano C. 
Published: August 2020

4548 Background: The achievement of pathological complete response (pCR) seems essential to improve survival in EC. In a phase I study (Pasini et al, Ann Oncol 2005) we demonstrated the feasibility of a novel protocol of neoadjuvant chemoradiation. Based on these promising results, we have performed a phase II study. The primary end point was the pathological response rate, the secondary end points were survival and toxicity. Methods: 74 pts with stage II-III EC (37 adenocarcinomas) were enrolled; median age was 59 yrs (42–73). Treatment consisted of D 35 mg/m2 and P 25 mg/m2 d 1,8,15,29,36,43,50,57 plus 5-FU 180 mg/m2 c.i. d 1–21 and 150 mg/m2 c.i. d 29–64; concurrent RT (50 Gy) started on d 29. Surgery was performed 6 to 8 weeks after completion of RT. Results: 65/74 pts (88%) completed the planned chemo-radiation, while 9 required dose modification of chemotherapy. Median follow-up of living pts was 40 mo (18–75). Pathological findings: pT0 pN0 (pCR): 35 (47%); pTrm pN0:11 (15%)[residual microfoci]; Others: 28 (38%). The overall median survival was 50 mo; median survival times of Others, pTrm, and pCR subsets were 17, 42 months and not reached, respectively (p<0.001). The 3 years survival rates were 81%, 63.5% and 26% for pCR, pTrm and Othes subsets, respectively. During chemoradiation, grade 3–4 hematological toxicity occurred in 10 pts (13.5%); grade 3–4 non-hematological toxicities occurred in 22 pts (30%), mostly in the last 2 weeks. There were 3 toxic deaths (4%): one pulmonary embolism and 2 postoperative deaths. 67 pts underwent surgery, while 7 did not (4 progression, 3 refusal). Conclusions: High pCR rate (47%) and 3-yr survival rate of 81% were achieved. This weekly schedule allowed concomitant chemoradiation at cumulative doses impossible with three weeks protocols. Given the not negligible toxicity, this protocol requires management in dedicated institutions. [Table: see text] No significant financial relationships to disclose.
Phase II study of oxaliplatin combined with S-1 (SOX) as first-line therapy for patients with advanced gastric cancer (AGC)
Authors: Takiuchi H. , Koizumi W. , Yamada Y. , Boku N. , Komatsu Y. , Fuse N. , Muro K. , Tsuburaya A. 
Published: August 2020

4553 Background: Oral fluoropyrimidine S-1 is one of the standard 1st-line chemotherapy for patients with AGC in Japan, and oxaliplatin is active against AGC in combination with fluoropyrimidine. This study evaluates the efficacy and safety of oxaliplatin in combination with S-1 in AGC. Methods: Eligibility criteria were: pathologically confirmed AGC, no prior chemotherapy, age > 20, measurable lesions, ECOG PS < 2, adequate organ function, written informed consent. Oxaliplatin was administered intravenously at a dose of 100 mg/m2 on day 1, and S-1 was administered orally twice daily on days 1–14 at a dose of 80 mg/m2/day, repeated every three weeks. The primary endpoint was objective response with RECIST guidelines. The sample size of 52 patients has an 80% power to demonstrate a 60% response rate (RR) with a one-sided type I error of 2.5%. Results: Between Apr. and Dec. 2007, 55 patients were enrolled at 8 centers in Japan. 51 patients were assessable for efficacy and 54 were assessable for safety. Patient characteristics: male/female = 34/17; median age 63 (range 30–77); PS 0–1/2 = 50/1; diffuse type/intestinal type = 35/16; metastatic/recurrent = 47/4. Median cycles 6.5 (range: 1–16). Thirty patients achieved in PR, and RR was 58.8% (95%CI: 44.2–72.4). Disease control rate (CR+PR+SD) was 84.3% (43/51; 95%CI: 71.4–93.0). One patient received subsequent curative surgery and achieved pCR. Median progression free survival was 6.5 months (95%CI: 4.8–11.3). Median time to treatment failure was 4.8 months (95%CI: 4.0–5.6). Grade 3–4 major adverse reactions were neutropenia (22.2%), thrombocytopenia (13.0%), leucopenia (3.7%), anorexia (5.6%), nausea (1.9%), and sensory neuropathy (3.7%). No treatment-related death was observed. Conclusions: The SOX regimen was well-tolerated and showed promising activity. This regimen may become one of the standard chemotherapy for ACG. One-year overall survival rate will be present at the meeting. [Table: see text]
Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer
Authors: Kim C. , Lee J. , Choi Y. , Kang B. , Ryu M. , Chang H. , Kim T. , Kang Y. 
Published: August 2020

4559 Background: We conducted a phase I dose-finding study of sorafenib (S) in combination with capecitabine (X) and cisplatin (P) in patients with previously untreated metastatic or inoperable advanced gastric cancer. Methods: Four dose levels of S, X, and P combination were tested. The doses of S (p.o. daily), X (p.o. on days 1–14), and P (i.v. on day 1) were escalated at the following schedule; level 1: S 400 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 2: S 800 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 3: S 800 mg/d, X 2,000 mg/m2/d, P 80 mg/m2; level 1A: S 800 mg/d, X 1,600 mg/m2/d, P 60 mg/m2. The cycle was repeated every 3 weeks. Dose limiting toxicities (DLTs) were evaluated only in the first cycles and a standard 3+3 dose escalation design was implemented. Results: A total 21 pts were enrolled in the study. No DLTs were observed at dose level 1 (n=3). One DLT (grade 3 diarrhea) was noted at dose level 2 (n=6), and 2 DLTs (two grade 4 neutropenias longer than 5 days in duration) were observed at dose level 3 (n=6), which made the level 3 dose the maximum tolerated dose (MTD). However, at cycle 2 and thereafter at dose level 2, the relative dose intensity (RDI) of S and X could not be maintained (mostly below 80%) due to the frequent dose reductions and cycle delays. So, we explored a new dose level (1A) between dose level 1 and 2. Since no DLTs were found in 6 patients at level 1A with RDI mostly above 80% throughout the treatment period, level 1A was determined as recommended dose (RD). Most frequent grade 3 and 4 hematologic toxicities were neutropenia (25.0% of cycles), and most frequent grade 2 and 3 non-hematologic toxicities were hand-foot syndrome (9.4%), asthenia (7.0%), and anorexia (5.5%). The objective responses were confirmed in 10 out of 16 patients with measurable lesions (62.5%; 95% CI, 38.8–86.2%). With a median follow-up of 8.1 months, estimated median progression-free survival was 10.0 months (95% CI, 1.6–18.4 months) and median overall survival has not been reached. Conclusions: Diarrhea and neutropenia were DLTs in this S, X, and P combination. The dose schedule of sorafenib 400 mg po bid daily with capecitabine 800 mg/m2 po bid on days 1–14, and cisplatin 60 mg/m2 iv on day 1 in every 3 weeks is recommended for further development in AGC. [Table: see text]
Influence of age on outcome after radical treatment of esophageal cancer with surgery or chemoradiotherapy (dCRT)
Authors: Blackshaw G. , Davies L. , Escofet X. , Crosby T. , Roberts A. , Clark G. , Havard T. , Lewis W. 
Published: August 2020

4569 Background: To compare the outcomes of stage directed surgical therapy and dCRT, related to age, to determine if there is an age threshold or Age x Treatment Interaction, above which the risks of serious treatment related complications outweigh any potential survival benefit. Methods: Prospective study of 504 consecutive patients managed by a single regional upper GI cancer network with curative intent based on CT, EUS and performance status; 270 underwent surgical based therapy [104 neoadjuvant chemotherapy, 49 neoadjuvant chemoradiotherapy, median age 61 (31–79) yr], and 234 dCRT [68 (41–83) yr]. One hundred and forty- one patients (28%) were aged over 70 years, of whom 40 (28%) underwent surgery, and 101 (72%) dCRT. Analysis was based on intention to treat and the primary measure of outcome was survival. Results: Deaths within 30 days of surgery, median and 5 yr survival were 1%, 30 months and 37% in patients <70 years, compared with 8.1%, 20 months and 18% in patients >70 years. Deaths within 30 days of dCRT, median and 5 yr survival were 0%, 21 months and 20% in patients <70 years, compared with 0%, 21 months and 33% in patients >70 years. On multivariable analysis, EUS T stage (HR 1.33, 95% CI 1.021 to 1.747, p=0.035), EUS defined lymph node metastasis count (HR 1.169, 95% CI 1.044 to 1.308, p=0.007), and age (HR 1.556, 95% 1.095 to 2.211, p=0.014) were independently and significantly associated with survival. There was an age related stepwise incremental increase in the ratio of hazard of death following surgery and dCRT, with a hazard cross-over observed at 69 years of age (Age x Treatment Interaction, 95% CI 62 to 86 yr, p=0.047). Conclusions: Age was an important and significant prognostic indicator and the estimated tipping point at which dCRT conveyed better outcomes than surgery was in the region of 70 years. Elderly patients diagnosed with esophageal cancer are arguably better treated with dCRT than multimodal surgical therapy. No significant financial relationships to disclose.
Cetuximab in combination with chemoradiotherapy prior to surgery in patients with resectable, locally advanced esophageal carcinoma: A prospective, multicenter phase lb-ll trial of the Swiss Group for Clinical Cancer Research (SAKK 75/06)
Authors: Ruhstaller T. , Pless M. , Schuller J. C. , Kranzbühler H. , von Moos R. , Moosmann P. , Rauch D. , Montemurro M. , Schneider P. M. , Hess V. 
Published: August 2020

4570 Background: Cetuximab significantly enhances efficacy of radiotherapy and chemotherapy in head and neck cancer. We investigated the safety and feasibility of adding cetuximab to neoadjuvant chemoradiation of locally advanced esophageal cancer. Methods: Pts with resectable, locally advanced squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus or gastroesophageal junction (staged by EUS, CT and PET scan) were treated with 2 cycles of induction chemotherapy (docetaxel 75mg/m2, cisplatin 75mg/m2 q3w and weekly cetuximab 250mg/m2), followed by concomitant chemo- immuno-radiation therapy (CIRT: docetaxel 20mg/m2, cisplatin 25mg/m2 and cetuximab 250mg/m2 weekly five times concomitant with 45 Gy radiotherapy in 25 fractions); followed by surgery 4–8 weeks later. The phase I part consisted of 2 cohorts of 7 patients each, without and with docetaxel during CIRT, respectively. Interpatient dose-escalation (adding docetaxel during CIRT) was possible if < 2 out of 7 pts of the 1st cohort experienced limiting toxicity. Having finished the phase 1 part, 13 additional patients were treated with docetaxel-containing CIRT in a phase II part. Pathological response was evaluated according to the Mandard classification. Results: 27 pts from 12 institutions were included. As of today, results from 20 pts are available (cohort 1: 7, cohort 2: 7, phase ll : 6). Median age was 64yrs (range 47–71). 11 AC; 9 SCC. 19 pts (95%) completed CIRT (1 pt stopped treatment during induction therapy due to sepsis). 17 pts underwent resection (no surgery: 1pt for PD, 1pt for cardiac reasons). Grade 3 toxicities during CIRT included anorexia 15%, dysphagia/esophagitis 15%, fatigue 10%, nausea 10%, pruritus 5%, dehydration 5%, nail changes 5% and rash 5% .1 pt suffered from pulmonary embolism. 13 pts (65%, intention-to-treat) showed a complete or near complete pathological remission (cohort 1: 5, cohort 2: 4, phase II: 4). Conclusions: Adding cetuximab to preoperative chemoradiation for esophageal cancer is safe and feasible in a community-based multicenter setting. Antineoplastic activity is encouraging with 65% pathological responders. [Table: see text]
Phase II and fluorodeoxyglucose positron emission tomography (FDG-PET) study in patients with advanced biliary tract cancers (BTCs) receiving bevacizumab (B) in combination with gemcitabine (GEM) and oxaliplatin (OX)
Authors: Zhu A. X. , Meyerhardt J. A. , Blaszkowsky L. S. , Muzikansky A. , Abrams T. A. , Chan J. A. , Enzinger P. C. , Bhargava P. , Kwak E. L. , Sahani D. V. 
Published: August 2020

4578 Background: Vascular endothelial growth factor (VEGF) expression is present in BTCs and is associated with poor survival. We performed a phase II study to examine the efficacy and tolerability of GEM and OX in combination with B (GEMOX-B) in patients (pts) with advanced BTCs. We also assessed the use of FDG-PET as an early indicator of response following treatment. Methods: Eligibility criteria included unresectable or metastatic measurable BTCs, 0–1 prior chemotherapy regimens, performance status ≤ 2, and adequate organ functions. Pts were treated with all 3 drugs intravenously on days 1 and 15 every 28 days (one cycle): B was given first at 10 mg/kg, followed by GEM at 1000 mg/m2 as a dose-rate infusion at 10 mg/m2/minute, and OX at 85 mg/m2. Whole body FDG-PET scan was obtained at baseline and at the end of cycle 2. The primary endpoint of the study was progression-free survival (PFS). Results: The planned 35 pts (25 cholangiocarcinoma and 10 gallbladder carcinoma) were enrolled: median age = 60 (25–82), M/F = 21/14, median ECOG 1. All pts were evaluable for toxicity and 29 were evaluable for response. Treatment related grade 3–4 toxicities included neutropenia (20%), ALT (17%), neuropathy (14%), hypertension (11%), AST (9%), anorexia (9%), and thrombocytopenia (9%). 13 pts (45%) had a partial response (PR) and an additional 10 pts (34%) had stable disease (SD). With a median follow up of 9.9 months, the median overall survival was 13.2 months (95% CI, 7.3 to 20.5 months), and the median PFS was 7.0 months (95% CI, 5.4 to 9.6 months). The mean baseline SUVmax was 5.72±2.01 and post-treatment SUVmax was 3.73±1.88 with a median 36.4% decrease (n=32). The difference in SUV changes between the groups with PR/SD and progressive disease was statistically significant (p=0.006). An increase in adjusted post- to pre-treatment SUV increased the risk for tumor progression (hazard ratio=3.054). Conclusions: GEMOX-B demonstrated significant antitumor activity with tolerable safety profiles in patients with advanced BTCs. FDG-PET showed significant early decreases in SUVmax following treatment, and these changes correlated with tumor response and time to tumor progression. [Table: see text]
Randomized, phase I, and pharmacokinetic (PK) study of RAD001, an mTOR inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC)
Authors: Chen L. , Shiah H. S. , Chen C. Y. , Lin Y. J. , Lin P. W. , Su W. C. , Chang J. Y. 
Published: August 2020

4587 Background: RAD001, an orally administered, novel mTOR inhibitor has recently been extensively evaluated in cancer therapy. Up-regulation of mTOR expression has been noted in 40–45% of HCC, and preclinical studies suggest mTOR inhibitor can effectively inhibit proliferation of HCC cells as well as growth of HCC xenograft in mice. In addition, cytochrome P450 system is known to involve in metabolism of rapamycin analogues, and elimination of RAD001 is impaired in pts with hepatic dysfunction. The study aims to define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and PK of daily- and weekly-dosing RAD001 in advanced HCC pts. Methods: Advanced HCC pts who were not feasible for or progressed after local therapy (surgery, percutaneous ablation or transcatheter arterial chemoembolization), ECOG PS 0–2, Child-Pugh's score < 8, and adequate hepatic, renal and hematological functions were eligible. The doses of RAD001 for daily-dosing arm would be escalated from 2.5, 5.0, 7.5 to 10.0 mg, and from 20, 30, 50 to 70 mg in weekly-dosing arm. Four weeks of treatment was regarded as one cycle. PK samples were collected on days 1 of cycle 1 and 2. Results: A total of 36 pts (M/F 34/2; median age 58.5, range 28–75; Child-Pugh's class of A/B 31/5) were enrolled. Number of pts with DLT/enrollment for dose level I, II, III and IV in daily arm was 1/6 (grade 3 hyperbilirubinemia), 1/6 (grade 4 thrombocytopenia), 0/3 and 2/3 (grade 3 diarrhea and rectal bleeding in 1 and grade 3 diarrhea and cardiac ischemia in 1), respectively; whiles in weekly arm was 0/3, 1/6 (grade 3 ALT elevation), 0/3 and 1/6 (grade 3 infection), respectively. MTD for weekly- and daily- dosing schedule was 70 mg and <7.5 mg, respectively. Reactivation of HBV and HCV was observed in 4 and 1 pts, respectively. The disease control response (DCR) of 31 evaluable pts was 61% (10/16) and 46.7% (7/15, including one PR) of pts receiving daily and weekly treatment, respectively. However, the DCR for weekly-dosing pts received >50 mg was 75% (4/6). Conclusions: Patient accrual is ongoing to complete. However, preliminary data suggest RAD001 is moderately active in stabilizing the progression of HCC, and PK data will be important to determine the optimal dosing schedule of RAD001 for HCC pts. [Table: see text]
Randomized, phase II study comparing interferon combined 5-fluorouracil plus cisplatin hepatic arterial infusion with interferon combined 5-fluorouracil hepatic arterial infusion in patients with advanced hepatocellular carcinoma
Authors: Yamashita T. , Arai K. , Sunagozaka H. , Ueda T. , Terashima T. , Mizukoshi E. , Sakai A. , Nakamoto Y. , Honda M. , Kaneko S. 
Published: August 2020

4588 Background: This randomized phase II trial compared the response rate (RR) of interferon (IFN) combined 5-fluorouracil (5FU) plus cisplatin (CDDP) hepatic arterial infusion (HAI) with IFN combined 5FU HAI in advanced hepatocellular carcinoma. Methods: Patients (pts) with measurable histologically or radiologically confirmed advanced hepatocellular carcinoma (major vascular invasion and/or bilobular multiple ≥5 nodules) were randomized into 2 groups. Arm A (n=57): continuous 5FU HAI (300mg/m2 day1–5, day8–12), CDDP HAI (20mg/m2, day 1, day 8 for 1.5 hours). IFN alpha-2b (3M IU/body) was administrated intramuscularly 3 times per week for 4 weeks. The treatment cycles repeated for 6 weeks. Arm B (n=57): IFN combined 5FU HAI with same dose without CDDP infusion. Treatment was continued until disease progression. The primary endpoint was RR. The secondary endpoints were overall survival (OS), time to progression (TTP) and toxicity. Results: Results for responses are presented for 109 pts and toxicity for 114 pts. The best overall response rate (RR) was 46% for group A and 25% for group B. This included 1 (2% of group A) vs. 3 (6% of group B) complete responses, and 25 (44% of group A) vs. 11 (19% of group B) partial responses. Fifteen pts in group A (26%) vs. 19 pts (33%) in group B had stable disease and 13 pts (23%) vs. 22 (39%) in respectively group A and B progressed while on treatment. RR was significantly higher in group A (p=0.02). The median TTP was 6.5 ± 2.0 months (mo) for group A vs. 3.3 ± 2.0 mo for group B (p=0.005). The median OS was 17.6 ± 3.2 mo for group A vs. 10.5 ±2.3 mo for group B (p=0.38). The median OS was 13.7 ± 4.9 mo for both groups. Grade 3/4 toxicity occurred in 65.8% of pts. Hematological toxicity was common and occurred in 53.5%. The thrombocytopenia and infusion port-related toxicity occurred more frequently in group A. Conclusions: IFN combined 5FU plus CDDP HAI shows higher antitumor activity and longer TTP than IFN combined 5FU HAI. Although OS is also longer without significant difference, these results show the clinical efficacy of additional CDDP to IFN combined 5FU HAI. No significant financial relationships to disclose.