bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxaliplatin, irinotecan, and cetuximab in advanced gastric cancer. First efficacy results of a multicenter phase II trial (AGMT Gastric-2) of the Arbeitsgemeinschaft Medikamentoese Tumortherapie (AGMT)
Authors: Woell E. , Greil R. , Eisterer W. , Fridrik M. , Grünberger B. , Zabernigg A. , Mayrbäurl B. , Russ G. , Thaler J.
Published: August 2020

4538

Background: Patients (pts.) suffering from advanced gastric cancer have still a poor prognosis and treatment options are limited. In our previous phase II trial (AGMT-Gastric-1) we could show that the combination of oxaliplatin and irinotecan was well tolerated and showed an objective response rate of 58% (Anticancer Res 28:2901–2906, 2008). This chemotherapy regimen was tested in combination with cetuximab in a multicenter phase II trial. Methods: Oxaliplatin 85 mg/m2 biweekly and irinotecan 125 mg/m2 biweekly were combined with cetuximab 400 mg/m2 loading dose and subsequently weekly 250 mg/m2. 51 patients with histological proven unresectable and/or metastatic gastric adenocarcinoma were treated in a first line setting. Median age: 62 years (range 19–79 years), PS 0: 25 patients, PS 1+2 26 patients, single metastatic site: 24 patients, multiple metastases: 27 patients. Results: Frequently reported adverse events (more than 20% of pts.) were predominantly grade 1 or 2 and included neutropenia (35% of pts.), thrombocytopenia (33%), anemia (73%), nausea (45%), diarrhea (57%), alopecia (22%), and fatigue (37%). Grade 3 and 4 toxicities included neutropenia in 9/1 pts., thrombocytopenia in 1/0 pts., anemia in 3/1 pts., nausea in 2/0 pts., and diarrhea in 7/2 pts. Sensory neuropathy occurred mostly as grade 1 and 2 in 37% of pts., in 7 pts. grade 3 neurotoxicity was observed. Acneiform skin rash grade 1 / 2 / 3 / 4 was reported in 31% / 20% / 6% / 2% of pts. respectively. 16 pts. went off-study due to neutropenia (n=5), nausea/vomiting (n=1), diarrhea (n=1), progressive disease (n=3), toxic colon (n=2), and allergic reaction to cetuximab at first (n=2), second (n=1) or third infusion (n=1). 35 patients are assessable for response with 1 pt. (3%) showing a CR, 21 pts. (60%) a PR, 7 pts. (20%) a SD and PD in 6 pts. (17%). A disease control rate was achieved in 83%. Median time to progression was 24.8 weeks (n=29), median overall survival 38.1 weeks (n=32). Conclusions: The combination of oxaliplatin and irinotecan with cetuximab is feasible, safe and active in advanced gastric cancer.

[Table: see text]
Irinotecan versus best supportive care (BSC) as second-line therapy in gastric cancer: A randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Authors: Thuss-Patience P. C. , Kretzschmar A. , Deist T. , Hinke A. , Bichev D. , Lebedinzew B. , Schumacher G. , Gebauer B. , Maier V. , Reichardt P.
Published: August 2020

4540

Background: Up to now the value of 2nd-line therapy for metastatic gastric cancer is unclear. So far there are no randomized phase III data comparing 2nd-line chemotherapy to BSC. Irinotecan has proven activity in 1st-line therapy. In this randomized phase III study we compared irinotecan to BSC to evaluate the value of 2nd- line chemotherapy for gastric cancer. Methods: Prospective multicenter randomized phase III study, open label. Eligibility: Metastatic or locally advanced gastro-esophageal junction or gastric adenocarcinoma. Objective tumor progession (PD) within 6 months after 1st- line chemotherapy. ECOG PS 0–2. Statistics: Primary endpoint: Overall survival (OS). Hypothesis: H1: OS(Irinotecan)>OS(BSC). Calculated number of pts needed (power 80%, alpha error 5%): 60 pts per arm. Stratification for a) PD less versus (vs) more than 3 months after 1st line chemotherapy, b) ECOG PS 0/1 vs 2. Treatment: Arm A: Irinotecan 250mg/m2 q3w (1st cycle) to be increased to 350 mg/m2, depending on toxicity. Arm B: BSC Results: Between Oct 2002 and Dec 2006 40 pts were randomized. The study was closed prematurely due to poor accrual. Arm A:21 pts, arm B 19 pts. Median age A: 58 yrs (43–73), B: 55 yrs (35–72); PD less vs more than 3 months after 1st-line chemotherapy: A: 18 / 3, B: 17 / 2pts. ECOG PS 0/1 vs 2: A: 17/ 4, B: 14/ 5pts. Pre-treatment with cisplatin: A: 21, B:19 pts. Arm A: 68 cycles administered in 21 pts. Toxicity: (main CTC grade 3/ 4): Nausea 1 pt, vomiting 1 pt, diarrhoea: 5 pts, neutropenic fever: 2 pts, data incomplete 6 pts. In 37% of 19 evaluable pts irinotecan dose was escalated to 350mg/m2. Response (19 pts evaluable): No objective responses, SD 58%, PD 42%. Improvement of tumor related symptoms: 44% of pts in arm A, 5% in arm B. Survival: (evaluable pts arm A 21, arm B 18): median survival arm A: 123 days (95%CI 95–216), arm B 72.5 days (95%CI 41–106); OS: HR=2.85 (95%CI 1.41–5.79), Logrank test (two-sided): p=0.0027. Conclusions: To our knowledge this is the first randomized phase III study investigating 2nd- line chemotherapy in gastric cancer. Irinotecan as 2nd-line chemotherapy significantly prolongs overall survival compared to BSC. 2nd-line chemotherapy can now be considered as a proven option in gastric cancer.

[Table: see text]
Second-line chemotherapy with FOLFIRI in patients with metastatic gastric cancer (MGC) not previously treated with fluoropyrimidines
Authors: Di Lauro L. , Fattoruso S. I. , Giacinti L. , Vici P. , Sergi D. , Lopez M.
Published: August 2020

4549

Background: No established second-line chemotherapy exists for patients (pts) with MGC failing to respond or progressing after first-line chemotherapy. This study was designed to determine the efficacy and safety of FOLFIRI combination used as second-line therapy in pts with MGC not previously treated with regimens containing fluoropyrimidines. Methods: Pts with measurable distant metastases, previously treated with a combination of epirubicin, docetaxel and cisplatin or oxaliplatin as first-line therapy, received irinotecan 180 mg/mq (150 mg/mq in pts >70 ys old) as a 1-h infusion day 1; leucovorin 100 mg/mq/day followed by bolus fluorouracil (FU) 400 mg/mq and a 22-h infusion of FU 600 mg/mq day 1–2, every 2 weeks for a maximum of 12 cycles or until disease progression, unacceptable toxicity or patients refusal. Endpoints were response rate (RR), time to progression (TTP), overall survival (OS) and safety. Results: 38 pts were enrolled: M/F 23/15; median age 66 ys (34–75); median ECOG PS 1 (0–2); number of metastatic sites 1/2/≥3: 9/18/11 pts, respectively. A total of 223 cycles was performed (median 6, range 2–12). One CR and 8 PR were observed for an overall RR of 24% (95% CI, 11–39 %). Disease remained stable in 11 pts. Median TTP was 4.0 months (95% CI, 2.9–5.1) and median OS was 6.2 months (95% CI, 4.7–7.7). Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 29%, 3% and 8% of pts, respectively. Febrile neutropenia was seen in 2 pts (5%). Other grade 3 toxicities included diarrhea in 5 pts (13%), mucositis in 2 pts (5%) and vomiting in 2 pts (5%). There were no treatment related deaths. Conclusions: FOLFIRI is an active and well tolerated second-line regimen for MGC pts not previously treated with fluoropyrimidines.

No significant financial relationships to disclose.
Meta-analyses of randomized trials assessing the influence of chemotherapy and prognostic factor in advanced/recurrent gastric cancer
Authors: Pozzo C. , Ohashi Y. ,   on behalf of the GASTRIC project
Published: August 2020

4550

Background: Advanced or recurrent stomach cancer remains an incurable disease. Several drugs and different combinations of chemotherapy have been investigated but very often with small sample sizes making definitive conclusions difficult. The GASTRIC project is an individual-patient-data (IPD) based meta-analysis in the advanced disease setting to quantify the potential benefit of various chemotherapies. We used this large database to study the role of various prognostic factors and potential interactions with chemotherapy. Methods: All randomized clinical trials (RCT) closed to patient accrual at the end of 2004 were eligible. Radiotherapy, intraperitoneal chemotherapy, or immunotherapy was excluded. The primary endpoint was overall survival (OS). Baseline variables included sex, age, performance status (PS), diseases status at entry, prior surgery, number of organs involved at entry, location of metastasis, TNM stages, histology, operative procedures, and geographic area. The hazard ratio (HR) and 95% confidence interval (CI) was calculated by the multivariate Cox analysis to assess of the prognostic factors for their relationship to OS. Results: Fourty-nine eligible RCTs (7,120 patients) were identified. As of December 2008, IPD from 21 trials (3,619 patients) with a median follow- up of 7.3 months were available for OS. There was no statistically significant difference between 5FU-based, anthracycline-based, platinum-based, taxane-based, or irinotecan-based regimens versus any other CT. In the multivariate Cox regression analysis stratified by trial and treatment arm, PS of 2 (HR, 2.43; 95%CI, 2.02 to 2.94) compared to PS of 0, metastatic (HR, 1.29; 95%CI, 1.01 to 1.64) compared to local advanced, many number of organs, and location of metastasis (especially with peritorium; HR, 1.75; 95%CI, 1.23 to 2.48) compared to none were strongly associated with lower survival. Conclusions: Our interim results could not show an overall survival benefit in favour of 5FU-, anthracycline-, platinum-, taxane-, or irinotecan-based regimens compared with a regimen without the specific chemotherapy. We confirm the impact of PS, diseases status at entry, number of organs involved, and location of metastasis on OS.

No significant financial relationships to disclose.
Phase II study of S-1 monotherapy in taxane, cisplatin refractory gastric cancer
Authors: Cho S. , Lee S. , Hwang J. , Bae W. , Shim H. , Park C. , Park M. , Chung I.
Published: August 2020

4551

Background: S-1 is a fourth-generation oral fluoropyrimidine that was developed to mimic protracted continuous infusion of 5-fluorouracil (5-FU). In previous study, S-1 demonstrated promising activity which is comparable to combination chemotherapy in advanced gastric cancer. This phase II study evaluated the efficacy and safety of S-1 salvage chemotherapy, in patients with taxane and cisplatin refractory gastric cancer. The primary end point was progression free survival and secondary end points were overall survival, safety and clinical benefit. Methods: Patients were eligible if they had histologically documented gastric adenocarcinoma previously treated with taxane (docetaxel or paclitaxel) and cisplatin; age≥18; Eastern Clinical Oncology Group (ECOG) performance status of 2 or less; adequate organ function; no evidence of gastrointestinal obstruction or passage disturbance. S-1 treatment was performed according to BSA as followed; < BSA 1.25, 80 mg/day, 1.25 ≤ BSA < 1.5, 100 mg/day; BSA ≥ 1.5, 120 mg/day. Every dosage was delivered divided two times and administered for 4 weeks followed by 2 weeks of resting period. Treatment continued until progression of disease or life-threatening adverse events were occurred. Results: Fifty-four patients were enrolled in this study and of the patients, forty-eight patients were evaluable. A total 194 chemotherapy cycles were administered and median number of cycles was three. Four (8.3%) patients had a partial response and 18 (37.5%) patients had stable disease. The median progression free survival and overall survival were 3.8 and 10.2 months, respectively. Grade III/IV hematologic toxicities included neutropenia in 6 patients (12.5%) and there was no febrile neutropenia. Most of nonhematologic toxicities were diarrhea, asthenia, and mucositis, and there was no grade 3 or grade 4 except two patients, who developed grade 3 anorexia and diarrhea, respectively. The clinical benefit response was observed in 16 patients (33.3%). Conclusions: This results showed that S-1 monotherapy was active and safe salvage chemotherapy in patients with advanced gastric cancer previously treated with taxane and cisplatin.

No significant financial relationships to disclose.
Preoperative cetuximab and radiation (XRT) for patients (pts) with surgically resectable esophageal and gastroesophageal junction (GEJ) carcinomas: A pilot study from the Hoosier Oncology Group and the University of Texas Southwestern
Authors: Agarwala A. K. , Hanna N. , McCollum A. , Bechar N. , DiMaio M. , Yu M. , Tong Y. , Becerra C. R. , Choy H.
Published: August 2020

4557

Background: Pre-operative chemoradiotherapy (CRT) followed by surgical resection is a standard treatment option for pts with resectable esophageal or GE junction (GEJ) carcinomas (CA). Cetuximab, when combined with XRT is effective treatment for locally advanced cancers of the head and neck. We conducted this study to evaluate this regimen in pts with esophageal and GEJ CA. Methods: This is a single arm, open label pilot study combining cetuximab with XRT for pts with resectable esophageal and GEJ CA. The primary objective is to determine the pathologic complete response rate (pCR) (null hypothesis: p=0.20; alternative hypothesis: p=0.35) and determine the feasibility and toxicity of this regimen when given prior to esophagectomy. Key eligibility criteria are: squamous cell (SC)or adenoCA of the esophagus or GEJ, ECOG PS 0–2, clinical stage II -IVa, and eligible for esophagectomy. Pts received a loading dose of cetuximab at 400mg/m2 2 weeks prior to XRT, then weekly at 250 mg/m2 starting one week prior to XRT until completion of 50.4 Gy XRT. After satisfactory recovery, pts had esophagectomy. Results: Patient characteristics (n=40): median age 65 years (range, 54–82); 92% male; PS 0/1 63%/32%; esophageal/GEJ 65%/35%; adenoCA/SC 78%/22%; 36 pts have completed cetuximab and radiation and 26 pts have undergone esophagectomy. Of the 26 pts that have undergone esophagectomy, 13 obtained a pCR. 5/13 SC had pCR and 8/13 adenoCA had pCR. 10 pts did not undergo surgery for various reasons including disease progression (n=7), AE unrelated to treatment (n=2), and personal decision to forgo esophagectomy (n=1). 4 patients are still completing cetuximab/XRT. The most common G3 adverse event was rash (56%). Other G3 toxicities were infrequent and included dysphagia (6%), infection (6%), and GI bleed (3%). There have been no treatment or surgery related deaths. Conclusions: Cetuximab and XRT results in pCR's in pts with esophageal and GEJ CA (rate of pCR 13/36), including patients with either SC or adenoCA histologies. G3/4 toxicities, including dysphagia were generally uncommon. Further study of this combination prior to esophagectomy is warranted.

[Table: see text]
Metastatic gastroesophageal cancer and long-term survival
Authors: Power D. G. , Jhawer M. , Feilchenfeldt J. W. , Kelsen D. P. , Shah M. A.
Published: August 2020

4560

Background: Despite modest therapeutic improvements, resistance to systemic chemotherapy develops in most pts with advanced gastric/GEJ (GE) adenocarcinoma. Median OS rarely exceeds 10 mo. However, a subgroup of pts(5–10%) have substantial benefit from chemotherapy, living >2 years. We describe clinicopathological characteristics of a large cohort of long term survivors(LTS) with metastatic GE adenocarcinoma. Methods: Our institutional database of pts with GE adenocarcinoma who received chemotherapy between 1999–2008 identified 103 pts with metastatic disease (M1) surviving >2 years from M1. We evaluated clinicopathologic characteristics for correlation of LTS with chemotherapy. Results: From Jan 1999–2008, 1,140 pts with metastatic GE cancer received systemic therapy. Male:female 1.9:1 and median age 66 yrs(22–89). From the time of M1, 103 pts (9%) lived >2 yrs. Of this cohort, median follow up is 51 mo and median OS from M1 is 33 mo (24–106 mo); 44 pts remain alive (43%), 9 pts ≥5 yrs. Demographics: M:F 1.8:1, median age 61 yrs (22–84). Tumors were located at GEJ/cardia (n=52), body/fundus (n=29), antrum/pylorus (n=22), and were mainly poorly differentiated (n=61). Laurens subtype was reported in 33 cases (17=diffuse, 15=intestinal). 77 pts presented with M1 and 26 developed recurrence after resection. Sites of M1 are: peritoneum(35), single visceral organ(19), M1 lymph nodes (24), >1 site (25). 52 pts received 2–3 treatment regimens, range 1–7. Common regimens were docetaxel/fluoropyrimidine (26), cisplatin/irinotecan (21), and DCF (11); intraperitoneal chemotherapy (5). Surgery was performed in 28 pts, 26 gastrectomies (15 with occult peritoneal M1, 11 once peritoneal M1 cleared) and 2 metastatectomies; 7 pts received RT(6 to primary, 1 to M1 site). No distinct clinicopathologic correlates were identified as associated with prolonged survival with systemic chemotherapy. Conclusions: Although systemic chemotherapy has modestly improved survival in advanced GE cancers, long term control is possible. The lack of clinicopathologic correlates for LTS suggests that molecular/genomic characteristics may distinguish LTS and predict chemo-sensitivity. We are now exploring tumor and normal tissue from LTS versus matched controls (survival <1 year) for molecular/genomic correlates for LTS

No significant financial relationships to disclose.
Lymph node ratio and survival for gastric cancer: A retrospective analysis of the SEER database
Authors: Shridhar R. , Dombi G. W.
Published: August 2020

4561

Purpose: To determine the prognostic significance of the lymph node ratio (ratio of number of positive lymph nodes to number of dissected lymph nodes) in gastric cancer patients. Methods: We retrospectively analyzed 10,176 gastric patients from 1990–2003 who underwent curative gastrectomy from the SEER database. Survival curves were calculated according to the Kaplan-Meier method and analyzed with log-rank test. Multivariate analysis of prognostic factors related to survival was performed by the Cox proportional hazard model. Results: The lymph node ratio (LNR) was a strong predictor of survival. LNR was equally predictive of survival whether the analysis was restricted to patients with <15 lymph nodes dissected or >15 lymph nodes dissected. Survival of patients with a LNR of 0.1–5% was not significantly different than node negative patients; however, survival of patients with a LNR of 5–10% was significantly different than node negative patients. Multivariate analysis showed that LNR, T-stage, tumor size, and number of lymph nodes positive were independent prognostic predictors of death and that LNR was the strongest predictor for death. Multivariate analysis showed that the number of lymph nodes dissected was an independent prognostic factor for survival. Moreover, LNR was an independent prognostic factor for N1 and N2 patients by AJCC staging. LNR trended toward significance in AJCC N3 patients. Conclusions: LNR was the strongest predictor of death in gastric cancer patients when compared to T-stage, number of lymph nodes positive, and tumor size. LNR is equally predictive regardless of the adequacy of the lymph node dissection.

No significant financial relationships to disclose.
Stemness signature of BMI1 and clinical outcome in esophageal cancer patients undergoing neoadjuvant chemoradiotherapy
Authors: Fujiwara Y. , Yoshikawa R. , Tao L. , Tsujimura T. , Sasako M.
Published: August 2020

4572

Background: The polycomb group (PcG) family BMI1, acting downstream of the hedgehog (Hh) pathway, plays an essential role in the self-renewal of hematopoietic, neural, and intestinal stem cells, and is dysregulated in many types of cancer. Our recent report has demonstrated that Gli-1 nuclear expression indicative of Hh signalling activation can predict very poorer prognosis of esophageal squamous cell carcinomas (ESCCs)(Br J Cancer 2008). As data were not available on the clinical role of BMI1 expression, we analyzed whether it could be also used to predict disease progression and prognosis in ESCC patients undergoing neoadjuvant chemoradiotherapy (CRT). Methods: BMI1, Gli-1, and p16INK4A expressions were evaluated in 78 ESCC patients by immunohistochemical staining. All patients underwent preoperative chemoradiotherapy; 40 Gy irradiation plus FP (5- FU and CDDP) regimen. Results: In total, 24 out of 78 patients (30.8%) showed BMI1 positive expression. All Gli- 1 nuclear positive cancers expressed BMI1. There was no significant correlation between p16INK4A expression and BMI1 expression. Overall survival (OS) was significantly correlated with the absence of BMI1 expression. The patients with BMI1-positive cancers showed significantly poorer prognoses than those without (mean disease-free survival (DFS) time 16.8 vs 71.2 months, P<0.005; mean OS time 21.8 vs 76.6 months, P<0.001). Conclusions: We demonstrated that BMI1 expression indicative of PcG protein chromatin silencing pathway activation was significantly correlated with esophageal cancer recurrence and poor prognosis after CRT, and that it was not inversely correlated with the presence of the downstream target p16INK4A. These findings suggest that the stemness signature including components of Hh and PcG pathways might be involved in promoting cancer regrowth and progression after CRT, and is thus a potential prognostic biomarker and rational therapeutic target for attacking the “more aggressive” cancer cells causing recurrence.

No significant financial relationships to disclose.
Phase II trial of preoperative bevacizumab (Bev), irinotecan (I), cisplatin (C), and radiation (RT) in esophageal adenocarcinoma: Preliminary safety analysis
Authors: Ilson D. , Bains M. , Rizk N. , Rusch V. , Flores R. , Park B. , Shah M. , Kelsen D. , Miron B. , Goodman K.
Published: August 2020

4573

Background: Preo chemoRT with weekly I/C and 5040 cGy followed by surgery is well tolerated [JCO 24: Abstract 4032; 2006]. ECOG trial E1201recently reported a median survival of 34 months with this preop regimen [JCO 26: Abstract 4532; 2008]. Bev + chemo improves response rate (RR) and time to progression (TTP) when added to weekly I/C in advanced esophagogastric cancer but does not increase chemo toxicity [JCO 24: 5201; 2006]. We are now combining in a Phase II trial Bev/I/C with concurrent radiotherapy (RT) in esophageal adenocarcinoma (EA) with the primary endpoint of safety. Methods: Patients (pts) with resectable Siewert's I or II EA were staged by EUS, PET, and CT. Induction chemo consisted of I-50–65 mg/m2 and C-30 mg/m2 weeks 1,2,4,5, Bev-7.5 mg/kg weeks 1 and 4; and, during RT (180 cGy daily to 5040 cGy), I/C was given weeks 7,8,10,11 and Bev weeks 7,10. Esophagectomy was 6–8 weeks after RT. A planned toxicity analysis was made in 10–15 pts completing chemoRT, and in 10 pts undergoing surgery: toxicity was acceptable if grade 3 / 4 hematologic toxicity remained < 72% and non hematologic toxicity < 40% during combined chemoRT (based on our prior phase II trial of I/C/RT [JCO 24: Abstract 4032; 2006]); and if pts undergoing surgery had no surgical complication related to Bev. Results: 18 pts have been enrolled, 12 male: 6 female; 7 Siewert I: 11 Siewert II; T3N1 12: T3N0 5: T2N0 1. 14 are evaluable for toxicity, 2 are too early, one progressed prior to RT, and one was taken off due to a CVA from a patent foramen ovale. Grade 3/4 neutropenia occurred in 4 pts (29%). Grade 3/4 non heme toxicity occurred in 5 pts (36%), including esophagitis 2 pts (14%), neutropenic fever 1 pt (7%), and pulmonary embolism 1 pt (7%). No grade 3 / 4 hypertension was seen, and 3 pts (21%) developed grade 1 proteinuria. Ten pts underwent surgery, and there were no unexpected surgical or wound complications; there were 2 anastomotic leaks. Pathologic responses: 1 pathologic CR and 1 T0N1. Conclusions: In a preliminary analysis of pts treated with Bev + preop chemoRT in EA, there was no increase in hematologic/non hematologic toxicity or Bev related surgical complications. Accrual will continue to 33 patients. Supported by Genentech.

[Table: see text]
Multimodality treatment for distal esophageal (DE) and gastroesophageal junction (GEJ) adenocarcinoma (ACA) with celiac lymph node (CLN) involvement
Authors: Khan G. , Adelstein D. J. , Rice T. W. , Rybicki L. A. , Videtic G. M. , Saxton J. P. , Murthy S. C. , Mason D. P. , Rodriguez C. P. , Ives D. I.
Published: August 2020

4574

Background: CLN involvement is a predictor of poor outcome in patients (pts) with DE or GEJ ACA. Pre-treatment identification of such patients depends on clinical staging including endoscopic ultrasound (EUS), computerized tomography (CT), and positron emission tomography (PET). This review of our CLN positive pts was undertaken to define the impact of clinical staging on prognosis after concurrent chemoradiotherapy (CCRT) and surgery. Methods: We retrospectively identified all pts with DE or GEJ ACA, CLN involvement by EUS, CT or PET, and no evidence of distant hematogenous metastases, who were treated with the same CCRT and surgery protocol at the Cleveland Clinic. Pts not staged with all three modalities were excluded. Induction CCRT consisted of radiation (30 Gy at 1.5 Gy bid), and chemotherapy with cisplatin (20 mg/m2/d) and fluorouracil (1000 mg/m2/d) both given as continuous intravenous infusions during the first 4 days of radiation. Surgery was performed in 4–6 weeks and identical CCRT was planned 6–10 weeks post-operatively. Outcomes examined included locoregional control (LRC), distant metastatic control (DMC), freedom from recurrence (FFR) and overall survival (OS). Results: Between 2/00 and 12/07, 54 pts with clinically staged CLN involvement were treated with this protocol. CLN involvement was found by EUS in 70%, CT in 69% and PET in 54% of pts. No single or combination of clinical staging tests proved predictive of outcome except for LRC which was worse in pts with all 3 tests positive (p = 0.008). With a median follow-up of 27 (range 8–71) months, the 2-year Kaplan-Meier projected LRC is 87%, DMC 18%, FFR 18%, and OS 28%. DE (vs. GEJ) primary site predicted for better DMC (p < 0.001), FFR (p = 0.002), and OS (p = 0.025). Negative surgical margins predicted for better DMC and FFR (p=0.005 both outcomes). Only tumor location remained significant in multivariable analysis. Conclusions: CLN involvement portends a poor but not hopeless prognosis after multimodality therapy. Despite excellent LRC, distant failure predominates. DMC, FFR, and OS were worse in pts with GEJ primaries, but were independent of how the CLN involvement was clinically identified.

No significant financial relationships to disclose.
A randomized study of gemcitabine/cisplatin versus single-agent gemcitabine in patients with biliary tract cancer
Authors: Furuse J. , Okusaka T. , Miyazaki M. , Taniai H. , Nimura Y. ,   BT22 Study Group
Published: August 2020

4579

Background: Biliary tract cancers (BTC) are not common but increasing in the US and Europe, and more prevalent in South America and Asia including Japan. Gemcitabine (G) and cisplatin (C) are now deemed as key drugs based on the accumulated literature. This is the first study to compare GC combination with G alone in Japan, even though one phase 3 trial (ABC-02) is ongoing in UK. Methods: 84 Japanese pts, aged ≥ 20 years, with histologically or cytologically confirmed advanced BTC, Performance Status 0 - 1, with adequate bone-marrow, hepatic and renal function were randomized. 83 pts received either C 25 mg/m2 plus G 1000 mg/m2 on days 1, and 8 of each 21-day cycle (GC-arm) or G 1000 mg/m2 on days 1, 8 and 15 of each 28-day cycle (G-arm). Treatments were repeated up to a maximum of 16 cycles of GC or 12 of G until disease progression or unacceptable toxicity occurred. Tumor response was evaluated using RECIST criteria by an independent review committee. The primary end-point of the study was 1- year survival rate. Safety, response rate, duration of progression-free survival were also evaluated. Results: A total of 83 pts (19 extrahepatic bile duct cancer, 28 intrahepatic bile duct cancer, 32 gallbladder cancer and 4 ampullary carcinoma) were eligible for the study protocol defined analysis set (Full Analysis Set, FAS); GC-arm n=41 and G-arm n=42. Baseline characteristics were similar between the two arms: median ages were 65.0 vs 66.5, females were 56.1 vs 50.0%. All pts completed at least one cycle of therapy, yielding a total of 247 cycles (median 6) in GC vs 203 (median 4) in G. The overall response rates were 19.5% (95% CI: 8.8, 34.9) vs 11.9 (95% CI: 4.0, 25.6). The results on survival will be determined and presented at the meeting. The most commonly reported grade 3 or 4 toxicities were: neutropenia (56.1 vs 38.1%), thrombocytopenia (39.0 vs 7.1%), leukopenia (29.3 vs 19.0%), hemoglobin decrease (36.6 vs 16.7%) and γ-GTP increase (29.3 vs 35.7%). Grade 3 acute renal failure was reported in 1 pt on GC. Conclusions: The combination therapy of GC would be an effective and well-tolerated chemotherapy regimen for Japanese pts with advanced BTC.

[Table: see text]
A phase II study of sorafenib in combination with tegafur/uracil (UFT) for Asian patients with advanced hepatocellular carcinoma (HCC)
Authors: Shen Y. , Hsu C. , Hsu C. , Lin Z. , Chen P. , Shao Y. , Huang T. , Ding Y. , Cheng A.
Published: August 2020

4589

Background: Sorafenib, a multikinase inhibitor with antiangiogenic activity, has recently been approved for the treatment of unresectable HCC. Combination of sorafenib with metronomic chemotherapy has theoretic advantage in improving antitumor activity without increasing toxicities. UFT (tegafur: uracil = 4:1 in molar ratio), an oral fluoropyrimidine, is active in various gastrointestinal cancers. We conducted a phase II study to evaluate the efficacy and safety of sorafenib plus low-dose UFT in advanced HCC patients (pts). Methods: Pts with histologically or cytologically proven unresectable/metastatic HCC, ECOG PS 0–2, Child-Puch class A, platelets ≥ 100 K/μl, transaminases ≤ 5 × ULN, bilirubin ≤ 3 mg/dl, INR ≤ 2.3 and creatinine ≤ 1.5 × ULN were enrolled. Prior systemic therapy for advanced disease is not allowed. Sorafenib (400 mg bid) and UFT (125 mg/m2 based on tegafur bid) were taken per os continuously. Tumor assessment was performed q8w by RECIST criteria. Primary endpoint is progression-free survival (PFS). Results: Between April 2007 and April 2008, 53 pts were enrolled. Baseline pts characteristics were: M/F, 47/6; median age 57 (range, 31–83); CLIP score 0–3/4, 48/5; extrahepatic spread/macroscopic vascular invasion, 33/30; and HBsAg(+)/anti-HCV(+)/both(+), 38/13/4. 89% of pts were BCLC stage C. Pts received a median of 3.7 (range 0.3- 18.9+) months of treatment. There were 3 (6%) PR and 27 (51%) SD. The median PFS and OS were of 3.7 months (95% C.I., 1.9- 5.5) and 7.4 months (95% C.I., 3.4- 11.4), respectively. Adverse events (AEs) were summarized in Table . Hand-foot skin reaction (HFSR), fatigue, and diarrhea were most common AEs. HFSR was the major AE resulting in dose reduction (19%) or treatment delay (21%). Grade 3/4 neutropenia occurred in 2 pts (4%). Conclusions: Adding metronomic UFT chemotherapy to sorafenib may improve therapeutic efficacy of the latter in pts with advanced HCC. The toxicity profile of the combination is similar to that of sorafenib alone.

[Table: see text]

[Table: see text]
A phase II (PhII) trial of sorafenib (S) in combination with 5-fluorouracil (5FU) continuous infusion (c.i.) in patients (pts) with advanced hepatocellular carcinoma (HCC): Preliminary data
Authors: Petrini I. , Lencioni M. , Ricasoli M. , Iannopollo M. , Orlandini C. , Oliveri F. , Filipponi F. , Bartolozzi C. , Del Tacca M. , Ricci S.
Published: August 2020

4592

Background: S, an oral multi-kinase inhibitor that targets Raf-kinase and receptor tyrosine kinases, improved overall survival (OS) and time to progression (TTP) versus placebo in a randomized phase III study in HCC (SHARP study). The safety of S in association with infusional and bolus 5FU regimens was established in a previous PhI study, with no clinically relevant pharmacokinetic interaction between S and 5FU. The present trial was designed to evaluate the safety and efficacy of S with infusional 5FU in HCC pts. Methods: Patients with advanced HCC (not eligible to surgical or locoregional therapies), age≥18 years, Child-Pugh Class A or B, ECOG PS 0–1, without prior systemic treatment for HCC and adequate bone marrow, liver and renal function, were eligible for the study. The primary endpoint is the Disease Control Rate (DCR). Secondary endpoints included response rate, TTP, OS and safety. According to a two-step Simon's model 46 pts were to be accrued. Pts were treated with oral S 400 mg bid continuously and c.i. 5FU 200 mg/sqm/day day 1–14 every 3 weeks. Tumour response was assessed according to RECIST criteria every 9 weeks. Results: Between October 2006 and October 2008 38 pts were enrolled: M-F: 32–6, median age (range): 68(47–83) years, ECOG-PS 0–1: 28–10, Child-Pugh A-B: 35–3, extrahepatic spread: 14 pts, macroscopic vascular invasion: 6 pts. Grade 3/4 (%) toxicities (NCI CTC v 3.0 criteria) included diarrhoea 5/0, stomatitis 21/3, hand foot syndrome 21/0, skin rash 11/0, hypertension 11/0; hyperbilirubinemia 5/3, AST 11/0, ALT 8/0, cardiac toxicity (one cardiac failure, one atrial fibrillation) 5/0 and bleeding (melena) in 3/0. One partial response was observed. Stable disease was obtained in 45% of pts with a median duration of 9.6 months (range 5–18+). Median TTP was 7.6 months (CI 95%=5.3–9.9) and median OS 12.2 months (CI 95%=4.45–19.8). Conclusions: Preliminary results of this PhII study show encouraging disease control rate, TTP and OS in pts with advanced HCC. The S+5FU association is feasible, well tolerated and AEs were predictable and manageable.

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Randomized phase II/III study of docetaxel/S-1 (DS-1) versus CDDP/5FU (FUP) in advanced or recurrent gastric cancer: Updated phase II results
Authors: Ikeda R. , Yoshida K. , Satou Y. , Takahashi M. , Une Y. , Yamamoto W. , Tanimoto K. , Hiyama K. , Sasaki Y. , Nishiyama M.
Published: August 2020

4595

Background: Our previous single arm phase II trial demonstrated that the combination of DS-1 was one of the most powerful candidates to become a standard regimen for metastatic gastric cancer (K. Yoshida, et al: Clin Cancer Res 2006). This trial evaluated DS-1 and FUP in advanced or recurrent gastric cancer, and the primary objective of the phase II part was to evaluate activity and safety of the 2 regimens. Methods: Patients with advanced or recurrent gastric cancer, who had not received any chemotherapy except one regimen (not including taxanes), were eligible for this trial. Patients were randomized to either: DS-1, intravenous administration of 40 mg/m2 docetaxel on Day1 and oral administration of 80–120 mg/m2/day S-1 on Days 1 to 14 every 3 weeks, or FUP, intravenous continuous administration of 800 mg/m2/day 5-FU on Day 1 to 5 and intravenous administration of 80 mg/m2/day CDDP on Day 2 every 4 weeks. Results: Between June 2005 and August 2008, forty-nine of 54 patients (ECOG PS 0–2) were randomized to DS-1 (n=24) or FUP (n=25). Response rates (CR+PR) assessed by RECIST were 88.3% (CI;62.6–95.3) vs 52.0% (CI; 31.3–72.2, P=0.032), median times to treatment failure (TTF) were 122 days (CI; 75.2–168.8) vs 85 days (CI;67.9–102.1, P=0.003), median progression free survivals (PFS) were 198 days (CI;117.8–278.4) vs 105 days (CI;90.3–119.7, P=0.066). Median overall survival times (MSTs) were 369 days (CI; 359.6–378.4) vs 371 days (CI; 297.2- 444.8, P=0.281), but as of today, 14 pts (8 in DS-1 and 6 in FUP) are still alive. Grade 3/4 adverse events assessed by CTCAE v3.0 occurring in ≥20% patients, were neutropenia (58.3% vs 28.0%), nausea (4.2% vs 20.0%), leucopenia (33.0% vs 4.0%), fatigue (0% vs 20.0%) and anorexia (8.3% vs 32.0%). All treatment-related adverse events were resolved and no toxic death was reported. Conclusions: DS-1 significantly improved the RR and TTF in advanced or recurrent gastric cancer patients. To clarify the survival benefit, a phase III continuation of the study is in preparation.

No significant financial relationships to disclose.
Phase I radiation dose-escalation trial of intensity-modulated radiotherapy (IMRT) with concurrent fixed dose-rate gemcitabine (FDR-G) for unresectable pancreatic cancer
Authors: Ben-Josef E. , Griffith K. , Francis I. R. , Khan G. , Lawrence T. S. , Abrams R. , Leslie W. , Zalupski M.
Published: August 2020

4602

Background: Current treatments of non-metastatic, unresectable pancreatic cancer result in poor survival and nearly uniform local persistence of disease. We hypothesized that intensification of local therapy would result in better local control and improve survival. The primary objective of this trial was to determine maximum tolerated radiation dose delivered with IMRT and concurrent FDR-G. Methods: Eligibility included tissue diagnosis of adenocarcinoma, unresectable by radiological criteria, Zubrod performance of 0–2, ANC of ≥ 1500/mm3, platelets ≥ 100,000/mm3, creatinine < 2 mg/dl, bilirubin < 3 mg/dl, ALT and AST ≤ 2.5 x ULN, and informed consent. Patients (pts) received FDR-G (1000 mg/m2, 100-minute infusion) on days -22 and -15. IMRT started day 1 (radiation dose levels [L2-L6] 50, 52.5, 55, 57.5 and 60 Gy, all in 25 fractions) with concurrent FDR-G on days 1, 8, 22, and 29. GTV was defined on pancreas protocol CT in the treatment position. PTV was GTV plus 1 cm expansion. Active Breathing Control was used to reduce breathing motion, except in 3 pts, in whom 4D CT was used to generate an ITV. Post IMRT, up to 4 cycles of FDR-G were given. DLT was defined as GI toxicity ≥ G3, neutropenic fever, or deterioration in Zubrod to ≥3 between day 1 and 126. IMRT dose level was assigned using the Time-to-Event Continual Reassessment Method. With a sample size of 50, the design allows concurrent assessment of efficacy. Results: From 8/06, 27 pts have been accrued. DLTs have been observed in 6 (G3 anorexia, nausea vomiting, and/or dehydration [5 pts]; duodenal bleed [1 pt]). The posterior estimates of probability of DLT are 0.17, 0.21, 0.24, 0.27, and 0.28 for L2 to L6, respectively. The response rate is 52.4% (95% CI 29.8% to 74.3%). The median overall survival and progression-free survival are 23.1 months (95% CI 9–23.1) and 7.2 months (95% CI 5.0–8.0), respectively. Only 1 patient (4%) progressed locally. Two patients have undergone resection (R0), and demonstrated near- and complete pathological responses. Conclusions: High dose radiotherapy and concurrent FDR-G, utilizing the techniques above, is well tolerated and results in highly encouraging response rates, local control rates and overall survival.

No significant financial relationships to disclose.
Use of amolecular mimicry approach to identify effective agents in pancreatic cancer
Authors: Tan A. , Jimeno A. , Garrido-Laguna I. , Uson M. , De Oliveira E. , Wilson A. , Rubio-Viqueira B. , Rajeshkumar N. V. , Hidalgo M.
Published: August 2020

4603

Background: We proposed a molecular mimicry approach (prêt-à-porter), based on pathway-expression signatures that systematically connect a query case with the most similar profile from a reference profile database and extrapolates the most effective drug for personalized medicine. Here we report the pre-clinical and clinical validation of this concept in pancreatic cancer treatment. Methods: Baseline gene expression profiles of 24 patients that received gemcitabine as adjuvant chemotherapy were collected. A patient is defined as sensitive and resistant to gemcitabine if the disease free survival (DFS) is more and less than 300 days, respectively. We also performed a small scale pre-clinical study on comparing patient-derived xenografts refractory to gemcitabine in a second-line treatment of prêt-à-porter choice of drugs vs. one-size-fits-all choice of drug (erlotinib). Four gemcitabine resistant xenografts were randomly assigned into control, erlotinib and the prêt-à-porter choice of drug groups. Tumor growth inhibition values (TGI) were calculated at the end of the experiment. Results: Using the molecular mimcry concept, where a patient is connected to a sensitive cell line, s/he will be predicted as sensitive to gemcitabine and vice versa. The prêt-à-porter achieved an overall prediction accuracy of 71% on these retrospective patient samples. Our approach correctly classified 67% and 75% of the patients that were sensitive and resistant to gemcitabine as adjuvant chemotherapy, respectively. The median DFS for the sensitive and resistant groups are 491 and 162 days, respectively. This difference was statistically significant (log-rank test, p = 0.04). Furthermore, the mean TGI% for the prêt-à-porter is about 10-fold lower than the erlotinib arm (3% vs. 30%, Chi-square test, p = 0.02) in the pre-clinical study. This demonstrates that prêt-à-porter approach can be used to tailor personalized medicine and achieved better clinical response as compared to the current treatment approach. Conclusions: We comprehensively validated the prêt-à-porter approach in pre-clinical and clinical data and demonstrated that this approach can be used as a powerful translation research tool in enriching patient selection of novel drugs in clinical trials and realizing personalized medicine.

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Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine: Interim toxicity analysis of a multicenter, randomized, cross-over phase III trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Authors: Heinemann V. , Vehling-Kaiser U. , Waldschmidt D. , Kettner E. , Marten A. , Winkelmann C. , Klein S. , Kojouharoff G. , Gauler T. , Boeck S.
Published: August 2020

4604

Background: To date, only limited toxicity data are available for the combination of erlotinib (E; 150 mg/d) with either gemcitabine (G) or capecitabine (C) as first-line therapy for advanced pancreatic cancer (PC). Methods: Within a prospective multicenter phase III trial, 281 patients (pts) with histologically confirmed advanced exocrine PC were randomly assigned to first-line treatment with either C (2000 mg/m2/d, d1–14 q3w) plus E (150 mg/d, arm A) or G (1000 mg/m2 over 30 min weekly x 7, then d1, 8, 15 q4w) plus E (150 mg/d, arm B). In case of treatment-failure (e.g. disease progression or toxicity), pts were “crossed-over” to second-line treatment with the comparator cytostatic drug without E. The primary study endpoint was time to treatment failure of second-line therapy (TTF2). Results: While the trial has completed recruitment, toxicity data (secondary endpoint) are available from the first 127 randomized pts. Sixty pts were randomized to arm A (55% male, 83% metastatic PC), 67 pts to arm B (55% male, 82% metastatic PC); median age was 64 years. During first-line therapy, pts received a median number of 3 treatment cycles (range 0–13) in both arms; overall 456 treatment cycles were applied (arm A: 218, arm B: 238). Regarding chemotherapy, a treatment delay was observed in 12% of the cycles in arm A and in 22% of the cycles in arm B. Dose reductions of the cytostatic drug were performed in 18% and 27% of treatment cycles, respectively. E dose reductions were performed in 6% and 11% of all cycles. Grade 3/4 hematological toxicity was <15% in both arms; in arm A, grade 3/4 diarrhea was observed in 9% of pts (arm B: 7%), grade 3/4 skin rash in 4% (12%) and grade 3/4 hand-foot syndrome in 7% (0%), respectively. Nine pts in arm A (7 of them due to PC) and 8 pts in arm B (6 due to PC) died within 60 days after randomization. Conclusion: G/E and C/E were both tolerated well and toxicity was manageable. This first analysis suggests that treatment with E 150 mg/d is feasible in combination with G or C.

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Multicenter randomized controlled phase III clinical trial using TNFerade (TNF) with chemoradiation (CRT) in patients with locally advanced pancreatic cancer (LAPC): Interim analysis (IA) of overall survival (OS)
Authors: Chang K. J. , Fisher W. , Kenady D. , Klapman J. , Posner M. , Reid T. , Rosemurgy A. , Shah R. , Zervos E. , Laheru D. ,   PACT Study Group
Published: August 2020

4605

Intro: Local control of LAPC with CRT has historically demonstrated survival benefit vs. RT alone. TNF is a nonreplicating adenovirus vector delivering human tumor necrosis factor (TNF-α). Results from a phase II study with TNF in LAPC indicated a possible survival advantage. To confirm these findings, a randomized, open-label, controlled Pancreatic Cancer Trial with TNF (PACT) study was developed. Methods: The TNF arm received a 5 wk treatment of qw intratumoral inj of 4x1011 PU TNF, cont. iv 5-FU and 50.4Gy radiation. The standard of care (SOC) arm received CRT alone. Both groups received adjuvant gemcitabine(G) with the option of erlotinib(E). An IA of OS (primary efficacy endpoint) was planned after the first third (92) of the expected 276 total death events (from a total patient n=330). Nonparametric logrank of OS was planned; in addition, a lognormal model was used to account for an evident separation of the survival curves after the median. Results: 185 pts were available for OS analysis (117-TNF+SOC and 68-SOC). Survival in the TNF+SOC group demonstrated a HR of 0.753 (CI [0.494 - 1.15]) relative to SOC. Best fit parametric lognormal analysis indicated a median survival of 11.1 mo with TNF+SOC and 8.7 mo with SOC; nonparametric methods indicated a MS of 9.9 mo for both arms, with a pronounced “late effect” (75th percentile 19.4 mo with TNF+SOC and 11.8 mo with SOC). Prognostic information (G and E use, stage, etc) indicated equivalent distribution between groups. Conclusions: HR results of the OS IA indicate an encouraging trend in favor of the TNF treated group. Parametric medians may better reflect the true HR than nonparametric methods since the latter do not reflect the shape of the OS distribution. A second IA is planned after 2/3 total events.

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A randomized phase II trial of two different four-drug combinations in advanced pancreatic adenocarcinoma: Cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel
Authors: Cereda S. , Rognone A. , Ghidini M. , Rezzonico S. , Passoni P. , Mazza E. , Nicoletti R. , Zerbi A. , Villa E. , Reni M.
Published: August 2020

4614

Background: The combination of cisplatin (P), epirubicin (E), 5-fluorouracil (F) and gemcitabine (G) (PEFG regimen) yielded a progression-free survival at 6 months from treatment start (PFS6) of about 50% and a 1-year overall survival (OS) around 40% in patients with advanced pancreatic adenocarcinoma (PA). The current trial was aimed to assess whether the replacement of E with docetaxel (D) may improve PFS6. Methods: Chemo-naive patients with stage III or metastatic PA, age 18–75y, Karnofsky performance status (PS) >50 received P (30 mg/m2 day 1), G (800 mg/m2 day 1) and capecitabine (1250 mg/m2/day days 1 to 14) and were randomized to receive either D at 25–30 mg/m2 day 1 (arm A: PDXG regimen) or E at 30 mg/m2 day 1 (arm B: PEXG regimen). Cycles were repeated every 14 days for a maximum of 6 months. Tumor was assessed by CT scan every 8 weeks. The Fleming design was used to calculate the sample size on the probability of being PFS6 (primary endpoint). Assuming P0=40% and P1=60%, α .05 and β.10, the study was to enroll 52 patients per arm. The regimen had to be considered of interest with > 26 patients being PFS6. Results: Between July 2005 and September 2008, 105 patients were enrolled at a single institution, stratified by stage and randomized (53 arm A). Patients’ characteristics were (A/B): median age 61/59, PS > 70 92/88%, metastatic disease 66/65%; CA19.9 > upper limit of laboratory normal (ULN) 87/90%, median CA19.9 820/755 UI/mL. To date, 46 patients per arm are assessable for the primary endpoint: PFS6 was 58/54%. One- year OS was 41% in both arms. A partial response was observed in 61/37% of patients. Among assessable patients with basal CA19.9 value > ULN (37 per arm), a major biochemical response (reduction >89%) was observed in 46/35% and a minor biochemical response (reduction between 50 and 89%) in 43/35% of patients. Main per cycle G3–4 toxicity was: neutropenia 4/13%, thrombocytopenia 3/2%, anemia 4/3%, fatigue 6/4%. Conclusions: PEXG yielded similar results when compared to prior series treated by PEFG, suggesting that capecitabine may replace F. The inclusion of D instead of E seems to be promising. The present trial confirms the relevant impact on outcome of advanced PA of four-drug regimens.

No significant financial relationships to disclose.