bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic alterations of primary tumor and metastatic site of colorectal carcinoma (mCRC)
Authors: Tommasi S. , Silvestris N. , Petriella D. , Pinto R. , Pilato B. , Lacalamita R. , Gernone A. , Paradiso A. , Zito F. A. , Colucci G.
Published: August 2020

4128

Background: K-ras gene mutation detection is essential to set a therapy with anti-EGFR antibodies (cetuximab, panitumumab) in mCRC and NCCN guidelines for treatment with cetuximab foresees that only lack of mutations permits the treatment. However, recent studies demonstrated that the presence of BRAF mutations could also indicate an ineffective anti-EGFR therapy. Furthermore, k-ras and BRAF mutations resulted to be mutually exclusive. Aberrant DNA promoter methylation frequently occurs as early event in carcinogenesis as important mechanism of inactivation of tumor suppressor genes. Our hypothesis states a potential role of tumor suppressor methylation in inhibiting EGFR signaling cascade thus blocking anti-EGFR therapeutic effect. Our further aim was to evidence the role of epigenetic alterations in metastatic progression. Methods: Fifty consecutive patients affected by mCRC have been enrolled in this study. Primary tumor and liver metastatic tissues have been characterized for k-ras and BRAF mutations and for promoter methylation of p16, RASSF1A and RARbeta suppressor genes by Quantitative Methylation-Specific PCR (QMSP). Results: k-ras resulted mutated in 32% of cases while BRAF in 5%. The two genes conserved their characteristics in both site of disease: primary tumor and liver metastasis. RARbeta, RASSF1A and p16 genes resulted methylated in 50%, 60% and 30% of primary tumors, respectively. RARbeta promoter methylation mean content resulted significantly higher in k-ras mutated with respect to k-ras wt tumors (209.96 vs 0.44 respectively, p<0.01). Interestingly, the percentage of RARbeta methylation in metastatic sites of k-ras wt tumors is significantly higher than that of the related primary tumors (20% vs 100% respectively, p<0.05). RASSF1A and p16 genes resulted less methylated in k-ras wt patients and significantly higher methylated in metastatic than in primary site (p<0.01). Conclusions: These results might suggest that genetic and epigenetic changes specifically interact to promote tumorigenesis of colon carcinoma and that epigenetic events have to be taken into account when setting biological therapy mainly in metastatic disease.

No significant financial relationships to disclose.
Phase Ib study of recombinant human Apo2L/TRAIL plus irinotecan and cetuximab or FOLFIRI in metastatic colorectal cancer (mCRC) patients (pts): Preliminary results
Authors: Yee L. , Burris H. A. , Kozloff M. , Wainberg Z. , Pao M. , Skettino S. , Novotny W. , Durbin B. , Weston J. , Hurwitz H.
Published: August 2020

4129

Background: Preclinical data suggest that recombinant human Apo2 ligand/TNF-related apoptosis-inducing ligand (rhApo2L/TRAIL) induces tumor cell death through pro-apoptotic receptors DR4 and DR5. In specific mouse xenograft colon cancer models, tumors regressed in the majority of mice given rhApo2L/TRAIL and irinotecan. In this ongoing study of rhApo2L/TRAIL in previously treated mCRC pts, the primary objectives are to assess the safety and pharmacokinetics of rhApo2L/TRAIL combined with irinotecan and cetuximab or FOLFIRI. Methods: As of 12/12/08, 30 pts have received rhApo2L/TRAIL (on Days 1–5) with irinotecan (on Day 1) and cetuximab (on Days 1, 8, and 15) in 21-day cycles; rhApo2L/TRAIL dose cohorts range from 1.5–8 mg/kg/day. 5 pts have received rhApo2L/TRAIL 9 mg/kg (on Days 1–3) with FOLFIRI (leucovorin, 5-FU, and irinotecan on Day 1) in 14-day cycles. Results: In the first cohort, rhApo2L/TRAIL was given at 4 mg/kg/d with irinotecan (350 mg/m2) and cetuximab; the first 3 pts developed Grade 3–4 neutropenia. The study was amended to allow irinotecan dose reductions to 300 mg/m2 for pts at risk for irinotecan-related toxicities and patients were started on a lower dose of Apo2L/TRAIL at 1.5 mg/kg/d. An additional 32 pts received rhApo2L/TRAIL at 1.5–9 mg/kg/d. The most common adverse events thus far are diarrhea, fatigue, and nausea. A pt with anemia at screening developed Grade 4 anemia DLT. 2 pts (1 with progressive liver disease) discontinued therapy due to elevated ALT. Conclusions: Preliminary data indicate that rhApo2L/TRAIL can be safely combined with irinotecan-based regimens. Full data will be available by June 2008. A phase II study of rhApo2L/TRAIL with FOLFIRI should provide more information on safety, efficacy, and a potential diagnostic for rhApo2L/TRAIL.

[Table: see text]
Prognostic impact of allelic losses in 1p32–36 (HYTM1), 4p15.2 (D4S2397), 5q22.2 (D5S346), 8p22 (D8S254), 18q12.3 (D18S474), and microsatellite instability for colorectal cancer
Authors: Melcher R. , Kudlich T. , Luehrs H. , Katzenberger T. , Illert B. , Al-Taie O. , Einsele H. , Scheppach W. , Scheurlen M.
Published: August 2020

4132

Background: The aim of this prospective study was to analyse the prognostic impact of allelic losses in the chromosomal regions 1p32–36 (HYTM1), 4p14–16 (D4S2397), 5q22 (D5S346), 8p21–22 (D8S254), 18q12.3 (D18S474) and microsatellite instability (MSI) in colorectal cancer (CRC). The microsatellite markers HYTM1, D4S2397, D8S254, and D18S474 were previously shown to have prognostic relevance in retrospective studies. The National Cancer Institute (NCI) microsatellite panel (BAT25, BAT26, D2S123, D5S346 and D17S250) was used for MSI-Analysis. Methods: Between July 1999 and February 2004, the data from a total of 165 patients, preoperatively diagnosed with colorectal cancer, and operated on in the Department of Surgery, University of Wuerzburg were collected. Inclusion criteria were: (a) electively operated primary adenocarcinomas; (b) obtainment of fresh paired normal mucosa-tumor samples; (c) no postoperative death (survival < 1 month); and (d) availability of follow-up data. Allelic loss (LOH) was determined by comparing the PCR-patterns of tumor DNA with corresponding normal tissue (signal reduction of at least 50%). MSI-L (low microsatellite instability) was defined as one marker out of five NCI-markers, MSI-H (high microsatellite instability) as more than two markers to display microsatellite instability. MSI-H tumours were excluded for further LOH-analysis. The endpoint of the study was tumour specific death. Kaplan-Meier survival curves were compared using the log-rank test. Results: We found expected frequencies in age, gender, tumour stage, and tumour grading. Tumour stage, grading, and an allelic loss of D18S474 was confirmed to be of prognostic significance for UICC I-IV, I-III, and II cancer in univariate analysis. Tumour stage and LOH D18S474 were also independent prognostic variables in stage I-IV and I-III. There was no significant prognostic impact of a loss of the markers HYTM1, D4S2397, D5S346, D8S254, MSI-L and MSI-H in either UICC stage I-IV, I-III, and II colorectal cancer patients. Conclusions: A loss of D18S474 defines a high-risk subgroup of patients with stage I-IV, I-III and stage II colorectal cancers.

No significant financial relationships to disclose.
A phase Ib study to evaluate the safety and efficacy of AMG 655 in combination with gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (PC)
Authors: Kindler H. L. , Garbo L. , Stephenson J. , Wiezorek J. , Sabin T. , Hsu M. , Civoli F. , Richards D.
Published: August 2020

4501

Background: AMG 655 is an investigational, fully human agonist monoclonal antibody (IgG1) that binds human death receptor 5 (DR5), activates caspases, and induces apoptosis in sensitive tumor cells. In preclinical PC models, cooperative activity is observed when G is added to AMG 655. We performed a multi-center phase I trial to evaluate AMG 655 + G in metastatic PC pts. The primary endpoint was dose-limiting toxicity (DLT). Secondary endpoints included toxicity, pharmacokinetics, antibody formation, objective response rate, progression-free survival (PFS), 6-month and overall survival. Methods: Eligible pts had previously untreated metastatic PC and ECOG PS 0 or 1. Pts enrolled into sequential cohorts and received AMG 655 3 or 10 mg/kg IV days (D) 1 and 15 and G 1000 mg/m2 IV D 1, 8, and 15 every 28 D. CT scans were obtained Q8 weeks. Results: 13 pts (3 mg/kg cohort = 6; 10 mg/kg cohort = 7) enrolled from 7/07–11/07. Pt characteristics: females 61%; ECOG PS 1 69%; median age 65 (range 35–81); liver metastases 77%. Median number of cycles: 6 (range 2–12). There were no DLT. Nine (69%) pts had grade 3–4 toxicity, the most common were: thrombocytopenia (4 pts), neutropenia (2 pts), and abdominal pain (2 pts). No anti-AMG 655 antibodies were detected. After one 3 or 10 mg/kg dose of AMG 655 after G, the Cmax and AUC of AMG 655 were similar to those in the first- in-human single-agent study (LoRusso JCO 2007; 25: abstract 3534). Preliminary data indicate no effect of AMG 655 on PK of G. Partial response 31% (4 pts, 2 unconfirmed); stable disease 38%. Median PFS: 5.3 months (95% CI, 3.5, 6.2); 6-month survival rate: 76.2% (95% CI: 42.7%-91.7%). Conclusions: AMG 655 + G is well-tolerated and may have activity in metastatic pancreatic cancer. A randomized phase II trial of G ± AMG 655 at 10-mg/kg is currently enrolling.

[Table: see text]
Assessment of two dosing schedules of GSK1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in metastatic gastric cancer (GC): Interim results of a multicenter phase II study
Authors: Jhawer M. , Kindler H. L. , Wainberg Z. , Ford J. , Kunz P. , Tang L. , McCallum S. , Kallender H. , Shah M. A. ,   on behalf of the MET111643 Investigators and GlaxoSmithKline
Published: August 2020

4502

Background: GSK089 is an oral, small-molecule inhibitor of cMET and VEGFR2/KDR, and has potent antitumor activity in cMET-amplified cell lines and xenografts. cMET is reportedly amplified, overexpressed and/or activated in GC, making it an attractive therapeutic target. This phase II study examines the safety and efficacy of 2 dosing schedules of GSK089 as a single agent in patients (pts) with metastatic GC. Methods: Pts with distal esophagus, GE junction or stomach adenocarcinoma, 0–2 prior chemotherapy regimens, adequate organ function, measurable disease, and ECOG PS 0–2 are sequentially enrolled in 2 cohorts: 1) Intermittent 5 days on/9 off - GSK089 240 mg/d on D1–5 repeated every 14 days, and 2) Daily - 80 mg/d. Primary study endpoint (response) is assessed every 8 weeks. cMET amplification by FISH (≥2 copies of cMET per copy of chromosome 7) is not an entry criterion, but is determined on archival tissue for all pts. Pre- and on-treatment tumor biopsies in select pts and plasma samples in all pts are analyzed for GSK089 effects on direct and downstream drug targets. GSK089 pharmacokinetics (PK) are also evaluated. Results: As of 12/19/08, enrollment to the 5 on/9 off cohort is complete with 41 evaluable pts, and 14 evaluable pts have enrolled on the daily cohort. cMET amplification was seen in 3/43 (7%) pts tested; all 3 were in 5 on/9 off cohort. Best response of stable disease (SD), was noted in 6/41 (15%) pts in the 5 on/9 off cohort (none were cMET-amplified), with 2 pts SD >6 months, 1 ongoing; and in 3/14 (21%) pts in the daily cohort. Among all-enrolled pts (48 pts in 5 on/9 off, 16 pts in daily cohort), LFT abnormalities (9%), fatigue (5%), and venous thromboembolism (3%) were the most common GSK089 related grade 3- 4 adverse events (AE). Only 1 possibly related grade 5 AE, death due to unknown cause, was noted. Conclusions: GSK089 is well tolerated on both dosing schedules. cMET amplification in metastatic GC is rare. Single agent GSK089 demonstrates minimal antitumor activity in a cMET-unselected gastric population on the 5 on/9 off schedule. Enrollment on the daily dosing schedule continues, now with mandatory pre- and on-treatment biopsies to better define cMET pathway and target inhibition with GSK089.

No significant financial relationships to disclose.
Multicenter phase III comparison of cisplatin/S-1 (CS) with cisplatin/5-FU (CF) as first-line therapy in patients with advanced gastric cancer (FLAGS): Secondary and subset analyses
Authors: Ajani J. A. , Rodriquez W. , Bodoky G. , Moiseyenko V. , Lichinitser M. , Gorbunova V. , Vynnychenko I. , Garin A. , Lang I. , Falcon S.
Published: August 2020

4511

Background: The primary analysis of FLAGS (ASCO-GI-2009) showed that CS and CF had similar overall survival (OS) but CS had a significantly superior safety profile. Methods: 1,053 (1,029 treated; CS=521/CF=508) patients with untreated, advanced gastric/gastroesophageal adenocarcinoma were randomized to either S-1 (25 mg/m2 bid, d 1–21)/cisplatin (75 mg/m2 d 1) q 28 d or 5-FU (1,000 mg/m2/d 5-d infusion)/cisplatin (100 mg/m2 d 1) q 28 d. OS analyses for non-inferiority (NI), by pre-specified stratifications, and by the largest histologic subset (diffuse type histology) were performed. Results: OS for NI: OS from CS compared to CF had a HR=0.92 (two-sided 95% CI, 0.80–1.05). HR=1.05 being much lower than HR=1.22 derived from the literature. Using a stringent HR non-inferiority margin of 1.10, CS remains statistically significantly non-inferior (p=0.0068) to CF. The 74% preserved control effect by CS is well above the suggested 50% by Rothmann et al. (Statist-Med2003;22:239–264). OS by stratifications: Of 12 stratification sub-categories, CS produced OS HR=<1.0 in 9 and HR=>1.0 in 3. Subset analysis: OS analysis for diffuse type histology (n=590) showed that CS (median survival=9.0 months) resulted in a superior OS (Log rank p=0.0413; HR, 0.83 [95% CI, 0.70 to 0.99]) than CF (median survival=7.1 months). Conclusions: CS is statistically non-inferior to CF while proving much safer for the patients. CS resulted in a HR=<1.0 in the majority of pre-specified stratifications and CS produced statistically superior OS for patients with diffuse type histology (needs prospective studies). CS is an optimum substitute for CF. Supported by Taiho Pharma, USA.

No significant financial relationships to disclose.
Results of a phase II multicenter study of minimally invasive esophagectomy (Eastern Cooperative Oncology Group Study E2202)
Authors: Luketich J. , Pennathur A. , Catalano P. J. , Swanson S. J. , de Hoyos A. L. , Maddaus M. A. , Nguyen N. , Benson A. B. , Fernando H. C.
Published: August 2020

4516

Background: The incidence of esophagogastric adenocarcinoma (EAC) is increasing at an alarming rate in the United States. Definitive treatment may require a combination of surgery (esophagectomy), chemotherapy and radiation. Operative mortality rates after esophagectomy have been reported as high as 8–23% (NEJM 2003). Minimally invasive esophagectomy (MIE) may decrease morbidity and mortality. Previous single institution studies have demonstrated successful outcomes with MIE. The primary aim of this cooperative group protocol ECOG 2202 was to assess the feasibility of MIE in a multi-institutional setting. Methods: We conducted a prospective phase II trial with a two-stage design. Thirty-five patients entered the first stage, followed by an interim analysis. Next, the study continued to the second stage and full accrual. The primary endpoint was 30-day mortality. Secondary endpoints included complications, duration of intensive care unit (ICU) stay, lymph node (LN) count and clinical outcomes at 3 years. Results: We entered 106 patients (men 84%; women 22%; median age 64, range 36–83) into the study from 16 institutions in the United States (ECOG, CALGB, ACOSOG). Neoadjuvant chemotherapy was administered in 35 (33%) and radiation in 26 (25%). MIE was performed in 99 patients. Final pathology included high-grade dysplasia (n=11), and EAC (n=88). Complications included an overall 30-day mortality rate of 2% (2/106),. Other major complications included pneumonia (4.9%) and anastomotic leak (7.8%). Median ICU stay was 2 days; median LN count was 20. At a mean follow-up of 19 months, the estimated 3-year overall survival for the entire cohort was 50% (95% Confidence interval 35–65%). Stage specific survival was similar to open series. Conclusions: This phase II study demonstrates that MIE is safe and feasible in a multi-center trial, with low perioperative mortality rate and morbidity. Oncologic outcomes are similar to open esophagectomy. This is the first report of a multicenter trial of minimally invasive esophagectomy.

No significant financial relationships to disclose.
Biological activity of bevacizumab and erlotinib in patients with advanced hepatocellular carcinoma (HCC)
Authors: Kaseb A. O. , Iwasaki M. , Javle M. , Onicescu G. , Garrett-Mayer E. , Abbruzzese J. L. , Thomas M. B.
Published: August 2020

4522

Purpose: HCC is the fifth most common solid tumor worldwide and the incidence is rising in western countries. Current standard of care for advanced HCC is sorafenib based on median survival (MS) of 10.7 months (mos), median time to progression 5.5 mos. HCC are highly vascular tumors, and due to the prevalence of vascular endothelial growth factor and epidermal growth factor receptors in HCC, a phase II single-arm open-label trial of B and E in patients (pts) with HCC has been completed. Patients and Methods: Eligibility criteria include biopsy-proven unresectable HCC, Child-Pugh class A or B cirrhosis, bilirubin ≤2.0 mg/dL, transaminase (TA) levels ≤5 times the upper limit of normal, platelets ≥50,000/μL and Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2. Prior allowed therapies are surgery, external radiotherapy, ablation, transarterial chemoembolization (TACE) and 1 systemic therapy. Pts received B 10 mg/kg every 14 days plus E 150 mg orally daily. Results: The primary endpoint was the percent of pts alive and progression-free after 16 weeks of therapy (PFS16) based on historic median PFS of 3 to 5 mos. Response was evaluated by RECIST. 57 pts have been enrolled and were evaluable for analysis on an intent to treat basis. For all pts, the median age was 62.8 years (range 29–82), 44 (77%) male, 25 (43.9%) Caucasian; 25 (43.9%); ECOG PS of 0, 31 (54.4%) pts PS of 1. 14 pts (24.6%) had prior therapy (6 sorafenib). Of the 57 pts enrolled, 14 (28%) had confirmed partial responses, 31 (62%) had stable disease and 5 (10%) had progressive disease. PFS16, was 73% (95% CI 60%, 84%). The median PFS is 7.9 mos (95% CI 5.7, 9.5) and the OS is 12.8 mos, 95% CI (9.5, 17.9). 6 pts were removed for toxicity; there was one on-study death. The most common grade 1 or 2 toxicities are folliculitis, anorexia, diarrhea, dry skin, and epistaxis. Grade 3 or 4 toxicities were transaminase elevation, diarrhea, fatigue, hyperkalemia, hypertension, proteinuria, pulmonary embolus, leukoencephalopathy and gastrointestinal bleed. Conclusions: The combination of B and E appears to have significant clinically meaningful activity in HCC. A multi-institution randomized phase II trial is planned.

[Table: see text]
Phase III trial of adjuvant capecitabine/cisplatin (XP) versus capecitabine/cisplatin/RT (XPRT) in resected gastric cancer with D2 nodal dissection (ARTIST trial): Safety analysis
Authors: Lee J. , Kang W. , Lim D. , Park J. , Park Y. , Lim H. , Sohn T. , Noh J. , Bae J. , Kim S.
Published: August 2020

4537

Background: Although the adjuvant chemoradiation therapy has gained popularity and has become the standard of care in patients with resected gastric cancer in U.S., the role of chemoradiation therapy after extended D2 dissection has been questioned. We conducted a phase III trial to compare capecitabine/cisplatin (XP) vs XP + radiotherapy (RT) in curatively D2 resected gastric cancer patients in terms of disease free survival and overall survival. Methods: Eligibility criteria were as follows: stage Ib (T1N1, T2bN0) - IV (M1 excluded), curatively ≥ D2 resected gastric adenocarcinoma. XP only: X 2,000 mg/m2/d D1∼14, CDDP 60 mg/m2 D1 repeated every 3 weeks, 6 cycles; XP + RT: X 2,000 mg/m2/d D1∼14, CDDP 60 mg/m2 D1 x 2 cycles ⋄ RT 45 Gy (25 fractions) + X 1,650 mg/m2/d during RT ⋄ X 2,000 mg/m2/d D1∼14, CDDP 60 mg/m2 D1 x 2 cycles. The primary endpoint is 3-year disease-free survival. Results: From October 2004 to April 2008, 458 patients (XP arm: 228 patients; XP/RT arm: 230 patients) were enrolled. In XP arm, 172 (75%) of 228 enrolled patients completed 6 cycles of chemotherapy. In XP + RT arm, 188 (82%) of 230 patients completed the full course of XP 2 cycles - X + RT - XP 2 cycles. Conclusions: Safety and feasibility analysis of the two arms will be reported at the meeting.

No significant financial relationships to disclose.
Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis
Authors: Ishigami H. , Kitayama J. , Kaisaki S. , Hidemura A. , Kato M. , Otani K. , Kamei T. , Soma D. , Miyato H. , Yamashita H. , Nagawa H.
Published: August 2020

4542

Background: A phase II study to evaluate the efficacy and tolerability of weekly intravenous and intraperitoneal paclitaxel combined with S-1 was performed in gastric cancer patients with peritoneal metastasis. Methods: Gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8. S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. The primary endpoint was the 1-year overall survival rate. Secondary endpoints were the response rate, efficacy against malignant ascites and safety. Results: Forty patients were enrolled, including 21 with primary tumors with peritoneal dissemination confirmed by staging laparoscopy, 13 with peritoneal recurrence, and 6 with positive peritoneal cytology only. The median number of courses administered was 7 (range 1–23). The 1-year overall survival rate was 78% (95% CI, 65–90%). The overall response rate was 56% (95% CI, 32–79%) in 18 patients with target lesions. Malignant ascites disappeared or decreased in 13 of 21 (62%) patients. The incidences of grade 3/4 hematological and non- hematological toxicities were 40% and 15%, respectively. The frequent grade 3/4 toxicities included neutropenia (38%), leukopenia (18%), anemia (10%), and nausea (8%). Catheter obstruction observed in one patient was the only complication related to the peritoneal access device or intraperitoneal infusion. There were no treatment-related deaths. Conclusions: Combination chemotherapy of intravenous and intraperitoneal paclitaxel with S-1 is well tolerated and active in gastric cancer patients with peritoneal metastasis.

No significant financial relationships to disclose.
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.

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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.

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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.

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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.

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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.
Phase II trial of nemorubicin hydrocloride (nemorubicin) in combination with cisplatin (cDDP) in patients (pts) with hepatocellular carcinoma (HCC): First step results
Authors: Izzo F. , Catino A. M. , Vogl T. J. , Middleton M. , Valle J. W. , Fiore F. , Gadaleta C. D. , Pirotta R. M. , Martignoni M. , Laffranchi B.
Published: August 2020

4593

Background: Nemorubicin is a novel DNA-intercalator, mainly metabolized in liver by CYP3A4 enzyme and showing synergic antitumor activity with cDDP. The objective of this study was to evaluate the efficacy and adverse effects of nemorubicin administered by intra-hepatic artery in combination with cDDP to unresectable HCC pts. Methods: The study was in two HCC pt populations: intermediate risk (IRP) (CLIP 0–1, bilirubin < 1.5 x upper normal limit, no portal vein thrombosis [PVT]) and advanced risk (ARP) (CLIP 2, bilirubin < 2.5 mg/dL, PVT admitted). Treatment was repeated every 4–6 weeks for a maximum of six courses, if no toxicity and disease progression occurred. A single-arm, Simon's minimax two-stage design was adopted to evaluate the primary endpoint of tumour response (WHO criteria). In the first step >5/18 responses (IRP) and >2/10 responses (ARP) are needed to proceed with the second step. Results: Twenty-three IRP pts (13 evaluable) and 13 ARP pts (10 evaluable) were enrolled. The median number of treatments was 3 (range 1–6) in IRP (dose 600 mcg/m2 nemorubicin and 60 mg/m2 cDDP) and 4 (range 1–4) in ARP (dose 400 mcg/m2 nemorubicin and 60 mg/m2 cDDP). In IRP, so far 1 pt (8%) achieved complete response, 3 pts (23%) had partial response (PR), 5 pts (38%) had minor response (MR)/disease stabilization (SD) >3 months. In ARP, 2 pts (20%) had PR, satisfying the first step efficacy criteria. Also, 2 ARP pts (20%) had MR/SD. Overall, the main grade 3 and 4 hematological toxicities were thrombocytopenia (47%), leukopenia (42%), anemia (12%) and neutropenia (6%). Grade 3 and 4 biochemical alterations were aspartate aminotranferase (29%) alanine transferase (24%) and bilirubin increase (12%). The most frequent adverse events were fatigue (35%), vomiting (29%), diarrhoea (24%) and nausea (18%). Conclusions: Hepatic arterial infusion of nemorubicin with cisplatin showed promising activity in the first step of the study and it was a well tolerated regimen. These encouraging results warrant further development in HCC pts.

No significant financial relationships to disclose.