bluuebunny/crossref_metadata_2025 huggingface dataset:
Selection of a phase 3 dose regimen for denosumab based on pharmacokinetic (PK), pharmacodynamic (PD), and safety data from multiple subcutaneous (SC) dosing regimens in breast cancer patients (pts) with bone metastases (BM)
Authors: Peterson M. C. , Jang G. , Kim W. , Gurrola E. , Kinsey A. , Dansey R.
Published: March 2020

3086

Background: Receptor activator of NF-κB ligand (RANKL) is essential for osteoclast formation, function, and survival. PK and PD of denosumab (AMG 162), a fully human monoclonal IgG2 antibody to RANKL, from a randomized, double-blind, active-controlled, multidose study in breast cancer pts with BM were evaluated and modeled to assist in dose selection for the pivotal phase 3 study. Methods: Five dosing cohorts (∼40/cohort) received 30-, 120-, or 180-mg denosumab SC Q4W; 60- or 180-mg denosumab SC Q12W. Data through 12 weeks were used for PK/PD modeling and dose decisions. Validated methods were used to quantify all serum and urine analytes. The bone resorption marker uNTx (reported as uNTx/Cr ratio) was used as the PD endpoint, and population PK/PD model parameters were estimated using nonlinear mixed effects modeling methods (NONMEM). A combination of PK/PD trial simulation (TS), clinical chemistries, and safety profiles was utilized for phase 3 dose selection. Results: Exposure to denosumab increased approximately dose-proportionally for both the Q4W and Q12W schedules, and accumulation (3rd vs 1st Q4W dose) ranged from 2.37- to 2.56-fold. The population typical half-maximal inhibitory concentration (IC50) for denosumab to affect uNTx and the typical maximum suppression were estimated to be 12.2 ng/mL and 77.8%, respectively. While denosumab in all cohorts caused rapid and sustained suppression of uNTx from baseline (>60%), TS showed that for a dose of 120 mg Q4W, 97% of subjects would be expected to attain denosumab serum concentrations above their individual IC90 at steady state. TS did not suggest that higher doses (180 mg Q4W) would result in further uNTx suppression, and more asymptomatic decreases in calcium were noted in pts dosed above 120 mg Q4W. Conclusions: The PK and PD of denosumab in pts with BM are consistent with those in other pt populations and demonstrate rapid and substantial suppression of uNTx. Population PK/PD analysis and TS suggests a dose of 120mg Q4W is appropriate for use in a phase 3 program in this study population.

[Table: see text]
A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of MN-029, a novel vascular disrupting agent (VDA), in patients (pts) with advanced solid tumors
Authors: Ricart A. D. , Cooney M. , Sarantopoulos J. , Brell J. , Locke K. W. , Gammans R. E. , Medina G. , Zambito A. , Tolcher A. W. , Remick S. C.
Published: March 2020

3096

Background: MN-029 is a novel VDA that binds reversibly to the colchicine-binding site on tubulin and inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor endothelial cells (EC). Disruption of the tumor EC cytoskeleton ultimately leads to a temporary reduction in tumor blood flow. Methods: MN-029 is administered IV as a 10–20 min infusion, at 3-wk intervals in pts with advanced cancer. The study has followed an accelerated titration design, with intrapatient dose escalation. PD effects on tumor blood flow are evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: 28 pts were enrolled (13M/15F), median age 56 (range 35 - 76) and tumor types: colorectal (5), renal (5), hepatocellular (3), ovarian (2), melanoma (2), soft tissue sarcoma (2), carcinoid (2) and others (7). A total of 110 cycles of MN-029 were given, median 3/pt (range 1–20), over 9 dose levels (4, 8, 16, 24, 36, 54, 80, 120 and 180 mg/m2). Escalation proceeded until an initial dose-limiting toxicity (DLT) was observed in 1 pt in the 180 mg/m2 cohort, consisting of a reversible episode (3 hours post dose) of acute coronary ischemia (without sequelae and with preservation of myocardial function) probably due to coronary vasospasm. Therefore, this cohort was expanded to 6 pts, with no further DLTs observed. Common mild to moderate toxicities included nausea, vomiting (which appears dose-related), hypotension, fatigue and diarrhea. There was no significant myelotoxicity, stomatitis or alopecia. Seven pts had stable disease after 3 cycles, including 2 pts with carcinoid tumor (+21 cycles and +17 cycles). PK data generally indicated dose-related increases in Cmax and AUC values, although substantial inter-patient variability was observed. Tumor blood flow reduction assessed by DCE-MRI was recorded at 120 and 180 mg/m2, but not at 80 mg/m2. Conclusions: MN-029 produced reductions in tumor blood flow at doses that were well tolerated. Accrual continues at 225 mg/m2. [Supported in part by grants from MediciNova, Inc. and M01 RR-000080]

[Table: see text]
Sphincter preserving surgery after preoperative treatment for ultra-low rectal carcinoma. A French multicenter prospective trial: GRECCAR 1
Authors: Rouanet P. , Rivoire M. , Lelong B. , Rullier E. , Dravet F. , Mineur L. , Vanseymortier L. , Pocard M. , Faucheron J. , Gourgou S. , Saint Aubert B.
Published: March 2020

3527

Background: GRECCAR 1 is a phase III randomised multicenter trial which compared two preoperative treatments for low rectal carcinoma which should be classicaly treated by abdominoperineal resection (Eligibility: distance between the tumor [T] and the levator ani [LA] less than 2 cm). Methods: Between 2001 and 2005, 207 patients with rectal adenocarcinomas were included in 13 French centers. The average distance between the tumor and the levator ani was 0.8 cm. 72% of the tumors were classified T3 with 60% of N1 on pre treatment endorectal ultrasonography. The mean lenght of the tumors was 5 cm on colonoscopy. Preoperative treatment randomisation was made between high dose radiation (HDR: 45 + 18 Gy: 106 patients) and radio-chemotherapy (RTCT: 45 Gy + 5FU continuous infusion: 101 patients). All surgeons performed homogeous technique for intersphincteric resection. Results: Conservative rate was 83% (HDR) and 86% (RTCT) (p: 0.64) with 84% (140/168) of intersphincteric resection. Conservative rate did not differ according to the distance T-LA: 0 cm: 84% / 1–2 cm: 84% and 3 cm: 91%. No post operative mortality was noticed with a 15% post operative morbidity rate, same in the two arms. Sterilized specimen rate was respectively 7% and 12.5% (p: 0.29), the mean inferior safety margin and radial margin was 1 cm and 4 mm, same in the two groups as the 90% R0 resection rate. On specimen, nodal involvement rate was 5.6% for pT0–1, 29% for pT2 and 56% for pT3–4. No difference was seen for down-staging between the two groups (p: 0.59). With a 22 months follow up, we noticed 92% rate of stoma closure in the conservative group. Seven patients had a local recurrence and 25 metastases with 12 patient’s death. Conclusions: GRECCAR 1 is the first prospective randomized trial which shows an 85% rate of sphincter conservative surgery due to down staging induced by preoperative tretament. No significant difference was seen between HDR and RTCT with a trend for more morbidity in the first group. Intersphincteric resection is a safe technical procedure in order to preserv the striated sphincter with sufficient lateral and inferior margins.

No significant financial relationships to disclose.
Cetuximab + capecitabine + irinotecan (CCI) versus cetuximab + capecitabine + oxaliplatin (CCO) as first line therapy for patients with metastatic colorectal cancer (CRC): Preliminary results of a randomized phase II trial of the AIO CRC Study Group
Authors: Heinemann V. , Fischer Von Weikersthal L. , Moosmann N. , Vehling-Kaiser U. , Stauch M. , Oruzio D. , Schulze M. , Walther J. , Weiss J. , Dietzfelbinger H.
Published: March 2020

3550

Background: Combinations of infusional 5-FU/FA with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) have become standards of care in the treatment of metastatic colorectal cancer. In this trial, 5-FU/FA was replaced by capecitabine, an oral fluoropyrimidine. In addition, cetuximab, an antibody directed against the EGF-receptor was added to further improve treatment efficacy. Methods: Patients (pts) with metastatic CRC (age 18 to 75 years) and measurable disease were randomized to 3-week cycles of therapy. In the CCI-arm, pts received cetuximab (400 mg/m2 iv on day 1 of cycle 1 and 250 mg/m2 iv subsequently), capecitabine (2 × 800 mg/m2 po on days 1 to 14), and irinotecan (200 mg/m2 iv on day 1). In patients >65 years doses of irinotecan and capecitabine were reduced by 20%. In the CCO arm, cetuximab (as described above) was combined with capecitabine (2 × 1000 mg/m2 po on days 1 to 14) and oxaliplatin (130 mg/m2 iv on day 1). Both treatment arms were planned separately according to the optimal design described by Simon (p0 = 0.3, p1 = 0.5, α = 0.1, β = 0.1) with objective response rate (ORR) according to RECIST) as the primary endpoint. Results: The recruitment goal of 92 patients has been achieved. Among evaluable patients, median age in the CCI arm was 63 yrs (range 38–72) and 58 yrs (range 38–74) in the CCO arm. Median Karnofsky performance status was 90% (range 70–100) and 100% (range 70–100), the EGFR-status was positive in 64% and 69% of pts, respectively. The ORR in the CCI arm was 41% (11/27) (95%-CI: 22% to 61%), while in the CCO arm an ORR of 71% (15/21) (95%-CI: 48% to 89%) was documented. Toxicity data were available for 25 pts in each arm. The most common grade 3–4 CTC- toxicities observed in the CCI and the CCO-arm respectively were skin toxicity (4 vs 5 pts), allergic reactions (0 vs 5 pts), diarrhea (5 vs 3pts), neurotoxicity (1 vs 3 pts), and leucopenia (4 vs 5 pts). Conclusion: The preliminary evaluation of this randomized phase II trial suggests the feasibility of both treatment arms. Updated results regarding response rate and progression-free survival will be presented at the meeting.

[Table: see text]
The impact of cetuximab on the capecitabine plus oxaliplatin (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC): A randomized phase II trial of the Swiss Group for Clinical Cancer Research (SAKK)
Authors: Borner M. , Mingrone W. , Koeberle D. , Von Moos R. , Rauch D. , Saletti P. , Herrmann R. , Dietrich D. , Lanz D. , Roth A.
Published: March 2020

3551

Background: XELOX is a valuable alternative to continuous infusion FOLFOX type regimens in the treatment of MCC (Borner et al, JCO 2002, 1759). Cetuximab is an EGFR antibody, which has been shown to improve the efficacy of chemotherapy. A phase II study in first-line treatment of MCC has demonstrated a high response rate combining cetuximab with FOLFOX (Tabernero et al, Proc ASCO 2004, 3512). Methods: Multicenter, randomized two-arm phase II trial: OXA 130 mg/m2 day 1 and oral CAP 1000 mg/m2 bid days 1–14 every 21 days alone or in combination with cetuximab 250 mg/m2 weekly after a loading dose of 400 mg/m2. Treatment was limited to a maximum of 6 cycles. With 37 patients in each arm, the power was 90% to select the truly better arm if the true between-arm difference in response rate (RECIST) is at least 15%. The study was open for accrual until October 2005. Results: We present here the results of 74 patients included in the study. In 67 patients the first response data are available (investigators’ assessment after 3 cycles). The two arms are well balanced for relevant patient, disease and treatment characteristics. The study treatment was well tolerated with grade 3/4 toxicities in < 10% of the cycles in each arm. The frequency of side effects was balanced, but with more frequent skin toxicity in the cetuximab arm (6% versus 0% grade 3/4). Conclusions: Cetuximab seems to positively interact with XELOX in terms of efficacy but not toxicity. The cetuximab/XELOX combination appears to be a valuable option in first-line treatment of MCC especially if high response rates are a primary objective. This trial was supported in part by Merck KGaA and Sanofi-Aventis Switzerland.

[Table: see text]

No significant financial relationships to disclose.
Cetuximab + FOLFOX6 as first line therapy for metastatic colorectal cancer (An International Oncology Network study, I-03–002)
Authors: Dakhil S. , Cosgriff T. , Headley D. , Boccia R. V. , Badarinath S.
Published: March 2020

3557

Background: Cetuximab, an IgG1 monoclonal antibody targeting the EGFR, is currently approved for second line treatment of metastatic colorectal cancer (CRC). This phase II trial was designed to evaluate the safety and efficacy of cetuximab combined with FOLFOX6 as first line therapy in this patient population. Promising results have been reported at ESMO in a similar small pilot study. Methods: Eligibility: Age ≥ 18, locally advanced or metastatic CRC, no prior therapy for advanced disease, EGFR expression positive or undetectable. Regimen: Cetuximab 400 mg/M2 (2 hour infusion) day 1; 250 mg/M2 day 8 (and 250 mg/M2 for all subsequent doses); and modified FOLFOX 6 (2 hour infusion); and 5FU bolus 400 mg/M2 day 1 followed by 5FU-CI 2400 mg/M2 over 46 hours (days 1 and 2). Cycles were repeated every 14 days. Results: 82 patients were enrolled in the study. The median number of treatment cycles administered was 8. (range 1–28) At the time of this report, 23 patients are still on study. Reasons for discontinuation of therapy included: Toxicity (14 patients), disease progression (20), investigator /patient decision (11), planned therapy completed (3). Five patients (6%) died on study. Causes of death included: PD (2 patients), acute MI (1), respiratory failure secondary to pneumonia (1), sudden death of unknown cause (1). The most frequently observed toxicity was neutropenia. Grade 3/4 toxicities are listed in the table below. At this early analysis time point, 32 of 60 patients evaluable for response have documented CR/PR (3 CR, 29 PR, overall response rate of 53%). A pre-meeting update is planned for presentation purposes. Conclusion: These findings suggest that the combination of cetuximab with FOLFOX6 is safe and active in first line treatment of patients with metastatic CRC. Updated efficacy and safety data will be presented.

[Table: see text]

No significant financial relationships to disclose.
Molecular determinants of capecitabine efficacy in colorectal cancer
Authors: Vallbohmer D. , Kuramochi H. , Shimizu D. , Danenberg K. D. , Nielsen J. N. , Lindebjerg J. , Jakobsen A. , Danenberg P. V.
Published: March 2020

3606

Background: Capecitabine offers physicians a more convenient treatment for advanced colorectal cancer (CRC), with manageable toxicity and antitumor activity comparable to that of continuous-infusion therapies with 5-fluorouracil (5-FU). However, there are no validated and established predictive factors for clinical outcome of capecitabine efficacy in CRC. Therefore we investigated whether intratumoral mRNA expression levels of genes involved in the capecitabine/5-FU metabolism (cytidine deaminase (CDA), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), thymidine phosphorylase (TP), thymidylate synthase (TS)) and in angiogenesis (cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)) are associated with the clinical outcome of patients with metastatic CRC treated with first-line capecitabine. Methods: Thirty-seven patients with metastatic CRC were enrolled in this study and treated with single agent capecitabine.The intratumoral mRNA levels of CDA, COX-2, DPD, EGFR, FPGS; GGH, TP, TS, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture-microdissection methods and quantitative real-time PCR. Results: There were20 women and 17 men with a median age of 61 years (range 49–74). The median progression-free survival was 6.7 months (95% CI, 4.8–11.6 months), with a median follow up of 14.4 months (range: 1.3 to 18.7 months). Complete response was observed in 1 (3%), partial response in 6 (20%), stable disease in 14 (47%) and progressive disease in 9 (30%) patients (response was inevaluable in 7 patients). Higher gene expression levels of DPD were associated with resistance to capecitabine (P= 0.032; Kruskal-Wallis test). Patients with a lower mRNA amount of DPD (≤0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test). Conclusions: This pilot study suggests that intratumoral gene expression levels of DPD may be useful to predict the clinical outcome of patients with metastatic CRC with first-line single agent capecitabine treatment. Our data are hypothesis generating and should be validated in larger and prospective clinical trials.

[Table: see text]
Prophylactic treatment of irinotecan-induced diarrhea with neomycin (a randomized, placebo-controlled, double-blind study)
Authors: Mathijssen R. H. , De Jong F. A. , Kehrer D. F. , Van Schaik R. H. , Verweij J. , Sparreboom A. , De Jonge M. J.
Published: March 2020

3626

Background: Delayed-type diarrhea is a common side-effect of irinotecan, and is associated with a bacterial-mediated formation of the active irinotecan metabolite SN-38 from its glucuronide conjugate in the intestines. We hypothesized that concomitant administration of the aminoglycoside antibiotic neomycin would diminish exposure of the gut to SN-38, ameliorating the incidence of diarrhea. Methods: Patients were treated with irinotecan in a randomized, placebo-controlled, double-blind trial. In arm A, patients received irinotecan (350 mg/m2 i.v. for 90 minutes once every 3 weeks) combined with neomycin (660 mg orally 3 times daily for 3 consecutive days, starting 2 days before chemotherapy). In arm B, patients received the same irinotecan regimen with placebo. To detect a 50% reduction to less than grade 2 diarrhea (power=.80; P=.05), 60 patients had to be studied. Blood samples for additional pharmacokinetic and pharmacogenetic analyses were obtained after separate informed consent. Results: Sixty-two patients were evaluable for toxicity analysis. Relevant baseline patient characteristics (P>.06), SN-38 plasma concentrations (P=.80; N=43), and UGT1A1*28 genotype status (P=.58; N=52) were similar in both arms. Distribution, severity, and duration of diarrhea did not differ significantly between both arms (P>.32), although grade 3 diarrhea tended to be less frequent in the neomycin arm (45% reduction; P=.19). Grade 2 nausea was more common in this arm (39% vs. 9%; P<.01). The presence of at least one UGT1A1*28 allele was strongly related to the incidence of grade 2–3 diarrhea (69% vs. 34%; P=.01). Conclusions: Our results do not suggest a role for neomycin in the prophylactic treatment of irinotecan-induced diarrhea. In addition, neomycin does not influence systemic SN-38 pharmacokinetics. Also, it is suggested that each patient’s UGT1A1*28 genotype status could be used as a prospective screening tool to prevent severe diarrhea.

No significant financial relationships to disclose.
Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced non metastatic pancreatic cancer: A FFCD-SFRO study
Authors: Chauffert B. , Mornex F. , Bonnetain F. , Triboulet J. P. , Bouche O. , Rougier P. , Bosset J. F. , Aparicio T. , Masskouri F. , Bedenne L.
Published: March 2020

4008

Background: The GITSG studies have shown a greater survival after 5 FU-based chemoradiotherapy (CHRT) than radiotherapy or polychemotherapy alone in patients (pts) with locally advanced non metastatic pancreatic cancer. This randomized trial evaluated whether initial CHRT adds to modern gemcitabine in term of Overall Survival (OS). Methods: Pts with WHO status 0–2, proven adenocarcinoma of the pancreas, without metastasis at CT-scan, and deemed non resectable, were randomized 1:1 between CHRT ( 60 Gy in 6 weeks, 2 Gy/fraction, concomitant with 5-FU, 300 mg/m2/24 h as a continuous infusion, day 1–5 every week and cisplatin, 20 mg/m2/d, day 1–5 at week 1 and 5) or gemcitabine (G) (1000 mg/m2 weekly 7q8w) as induction treatment. Maintenance treatment was G (1000 mg/ m2 weekly 3q4w) in both arms until progression or limiting toxicity. Stratification criteria were: center, WHO status and initial surgery. It was required to include 176 pts to detect an expected change in median OS from 6 to 12 months (bilateral α = 1% and β = 10%). Intent to treat survival analysis used the Logrank test. Results: Between 03/00 and 07/05, 59 pts were randomized to CHRT and 60 to G. Median follow-up at the 05/05 was 16 months. Pt characteristics were well balanced (CHRT/G) with mean age (60.1/62.7 year), sex ratio (1/ 1.4) and WHO status ( 0–1: 88%/73%, 2: 9%/23%). During the induction phase, more than 75% of the planned dose was completed in 81.4% of pts for radiotherapy, 52.5% for 5-FU and 50.8% for cisplatin and 76.7% of pts in the G arm. In CHRT and G arms, OS at 6 and 12 months were respectively 78/82% and 24/51%, with a median survival of 8.4/14.3 months (stratified log-rank p = 0.014). CHRT or G related toxicities during induction phase were grade 3/4 leukopenia (17%/10%), thrombopenia (8.5%/0%), non-haematological toxicity (37%/ 17%) with diarrhea (7%/0% ), cutaneous toxicity (0%/3%). One treatment-related death was observed in the CHRT arm (aplasia). Conclusion: Study was stopped before the planned inclusion due to lower survival with initial CHRT when compared to G alone. Reasons explaining this difference are under investigation.

No significant financial relationships to disclose.
Tumor VEGF expression and serum VEGF levels are independent prognostic factors in curatively resected gastric cancer patients
Authors: Pera M. , Vidal O. , Elizalde J. , Soriano A. , Volant A. , Palacin A. , Molina R. , Castells A. , Pique J. , Metges J.
Published: March 2020

4021

Background: Increased serum and/or tumor vascular endothelial growth factor (VEGF) and urokinase-type plasminogen activator (uPA) have been shown to predict poor survival in several neoplasms, but their prognostic value in gastric cancer (GC) remains unknown. Methods: Serum VEGF (S-VEGF) and uPA concentrations were measured by commercially available ELISA in 20 healthy controls and 97 GC patients (70% I-II stages) before an R0 gastric resection. Tumor expression of VEGF and uPA were assessed by immunohistochemistry. Additional variables, including demographic, histological and therapeutic data were also evaluated. Univariate (Kaplan-Meier, log-rank test) and multivariate (Cox regression) analyses were performed to select prognostic factors regarding survival and tumor recurrence. Results: S-VEGF, but not uPA levels were significantly higher in GC patients than in controls. After a mean follow-up of 47 ± 3 months, the probability of cancer-related survival at 2, 5, and 10 years was 86%, 69% and 59%, respectively. Univariate analysis identified tumor VEGF expression (p=0.001) and high (> 289 pg/ml) S-VEGF levels (p=0.045), along with pTMN stage, grade of curability, perineural invasion, lymph node ratio, and extent of lymphadenectomy as variables associated with cancer-related survival. The mean disease-free survival was 20 ± 3 months, the probability of tumor recurrence being 78%, 62% and 62% at 2, 5 and 10 years, respectively. Prognostic variables for recurrence were the same as those identified for survival. Multivariate analysis identified tumor VEGF expression and high S-VEGF levels as independent prognostic survival factors. Conclusions: After a long follow-up, tumor VEGF expression and S-VEGF levels are independent prognostic factors for recurrence and survival in curatively resected gastric cancer patients. Such markers for increased angiogenic activity might help to identify patients at high risk of recurrence that could mostly benefit from adjuvant therapies. It is tempting to speculate that trials assessing the potential benefit of a.ntiangiogenic agents might be particularly warranted in patients with resected GC and a highly angiogenic phenotype.

No significant financial relationships to disclose.
Differences in the patterns of presentation and treatment between proximal and distal gastric cancers
Authors: Wilkinson N. W. , Howe J. , Patel-Parekh L. , Smith B. , Scott-Conner C. , Donohue J.
Published: March 2020

4022

Background: While the overall incidence of gastric cancer has declined in the United States, the incidence of proximal gastric cancers has increased. Understanding the differences between proximal and distal gastric cancer, may enable us to identify important risk factors and treatment patterns. Methods: Data on 6099 patients diagnosed with gastric adenocarcinoma were collected as a Patient Care Evaluation under the auspices of the American College of Surgeons Commission on Cancer. Clearly defined proximal and distal cancers were compared using the Pearson chi-square test and logistic regression. Results: The proximal cancer group included 1924 patients (87% cardia; 13% fundus) and the distal cancer group included 1312 patients (85% antrum; 15% pylorus). Proximal gastric cancers occurred more often in men (p<0.0001), whites (compared to Black, Hispanic, Native American and Asian races) (p<0.0001), and at younger age (p<0.0001) compared to distal cancers. Risk factors for proximal presentation included tobacco use (Hazard ratio (HR) 1.9, p= 0.002) alchohol use (HR 1.5, p= 0.038) and Barretts (HR 2.7, p<0.0001). Risk factors for distal presentation included H. Pylori (HR 2.3, p= 0.001). Despite increased use of multi-modality therapy, fewer proximal gastric cancers underwent resection compared to distal cancers (p<0.0001). Conclusions: Different risk factors can be identified for proximal and distal gastric cancers, which can impact on risk reduction, screening efforts and help define the pathogenesis of gastric cancer. While proximal cancer patients receive more aggressive multimodality treatments, including adjuvant and neoadjuvant therapy, fewer undergo surgical resection. Long term survival based upon proximal and distal tumor differences will be explored when follow-up data become available.Key Words: gastric adenocarcinoma, proximal gastric cancer, distal gastric cancer, risk factors, treatment.

[Table: see text]

No significant financial relationships to disclose.
Impact of pre-operative chemoradiotherapy on post-esophagectomy morbidity and mortality
Authors: Rizk N. P. , Bains M. , Flores R. , Park B. , Minsky B. , Ilson D. , Rusch V.
Published: March 2020

4025

Background: While multimodality therapy prior to surgical resection for locally advanced esophageal cancer is increasingly utilized, there remains the perception in the literature that its use may contribute to increased peri-operative morbidity and mortality. The purpose of this study was to compare our experience with the use of pre-operative chemoradiation with surgery (CRT) to patients who underwent surgery alone (S). Methods: We performed a retrospective review of a prospectively maintained database of all patients in our institution who underwent either (S) or (CRT) between 1/96 and 5/05. Data collected included demographics (age, sex), co-morbidities (cardiac, pulmonary, diabetes), pre-operative treatment details (chemotherapy type, radiation dose), procedure type, post-operative complications (pneumonia, anastomotic leak), length of stay (LOS), and hospital mortality. Statistical analysis included chi-square analysis for categorical variables and analysis of variance for continuous variables, and multivariate analyses was done using a logistic regression model. Results: There were 701 patients who were appropriate for this analysis, 332 (47.3%) (CRT) and 369 (52.7%) (S). 76% of CRT patients received 5040cGy of radiation and 90% received concurrent cisplatin based chemotherapy. CRT patients were younger (p<0.001) and more often male (p=0.003). Univariate analysis indicated a similar incidence of pneumonia (p=0.78), leak rate (p=0.41), hospital length of stay (0.97), and hospital mortality (0.48). Multivariate analysis, controlling for demographics, co-morbidities, procedure type, and tumor location showed no significant difference in hospital mortality (p=0.84). Conclusions: The use of CRT does not appear to result in increased peri-operative morbidity or mortality.

No significant financial relationships to disclose.
Dihydropyrimidine dehydrogenases (DPYD), and cytidine-deaminase (CDA) gene polymorphisms as genomic predictors of clinical outcome in resected gastric cancer patients (GCP) treated with fluoropyrimidine-based adjuvant chemotherapy
Authors: Grau J. J. , Monzo M. , Muñoz C. , Bombi J. A. , Domingo-Domenech J. , Jansa S. , Lema L. , Palmero R.
Published: March 2020

4052

Background: Single nucleotide polymorphisms (SNPs) of DPYD gene induces DPD deficiency resulting in decreased activity of 5-fluorouracil derivatives in treatment of colorectal cancer patients (pts). In GCP has not been previously analysed. Methods: We analysed paraffin-embedded biopsies from 50 consecutive resected GCP who received adjuvant chemotherapy with four cycles of Mitomycin C (MMC), 20 mg/m2 iv day 1 plus oral Tegafur (TG), 500 mg/m2 day 1 to day 45 every six weeks, for SNPs of genes DPYD1 (A/G; Ile/Val), DPYD2 (C/T; Arg/Cys) and CDA (A/C; Lys/Gin). The status of alleles (wild type or at least 1 polymorphism) was correlated with outcome, overall survival (OS) and toxicity. Results: The status of SNPs frequencies according to the classification between wild type/non-wild type, were 36/14 in DPYD1; 26/24 in DPYD2; and 17/23 in CDA or between homozygous/heterozygous were 39/11 in DPYD1; 33/17 in DPYD2 and 26/24 in CDA respectively. After 77 months of median follow-up, 18 pts died of tumor relapse, (7 in peritoneum and 11 in distant organs). Difference in survival was observed in DPYD1 pts only, for non wild-type over wild-type (p = 0.0283) and in any of the 3 genes tested heterozygous over homozygous pts (p = 0.0463). In 10 pts (20%) total dose was reduced by toxicity (5 diarrhea, 2 neutropenia, 2 hepatotoxicity, 1 vomiting), only 3 of them were homozygous. Conclusions: SNPs of DPYD1, DPYD2 and CDA predict outcome, survival and toxicity of GCP treated with 5-FU-based adjuvant chemotherapy.

No significant financial relationships to disclose.
CONKO-101: Results of a multicenter phase II study of an outpatient regimen consisting out of gemcitabine, 5-FU (24h CI), folinic acid and cisplatin for patients with inoperable esophageal cancer
Authors: Stieler J. M. , Hilbig A. , Pelzer U. , Roll L. , Dörken B. , Riess H. , Oettle H.
Published: March 2020

4066

Background: Standard therapy for inoperable esophageal cancer is a combination of cisplatin and 5-FU combined with radiation for locally advanced stages. As gemcitabine shows synergy with cisplatin and 5-FU, we evaluated the combination of cisplatin 30 mg/m2 (90 min), Gemcitabine 1000 mg/m2 (30 min), FS 200 mg/m2 (30 min) and 5-FU 750 mg/m2 24h CI) d1,8 q d22 for patients with inoperable esophageal cancer. For locally advanced stages, patients received sequential radiochemotherapy with 5-FU CI. Methods: 89 (75 m/14 w) pts. were included into this multicentrical phase 2 study. 58 had SCC, 30 AC, 1 pt. had undifferentiated carcinoma. Median age was 61 (22–86), Median KI 90 (60–100). 2 pts. had stage IIa, 4 stage IIb, 30 stage III, 16 stage IVa and 37 stage IVb. Results: 71 pts. are so far evaluable for response and 84 for toxicity. 2 pts. (2.8%) had CR (1 pathologically confirmed), 27 pts. had PR (38.1%), 33 pts. had SD (46.5%) and 9 pts. had PD (12.6%) as best response. MS was 10.7 months (13.1 for stage II/III and 9.1 for stage IV). Median TTP was 6 months, and PFS was 6 months. Observed toxicity was low and predominantly hematologic with Leukopenia Grade III/IV in 10% of cycles, Hb Grade III/IV in 5.3% of cycles and Thrombopenia Grade III/IV in 2.4% of cycles. Conclusion: This regimen is well tolerable and can easily be applied on an outpatient base. The remission rates and survival data are within the range previously reported in other phase II studies.

No significant financial relationships to disclose.
Mature data on capecitabine (X) + fractionated cisplatin (P) as first-line therapy in patients (pts) with advanced gastric carcinoma (AGC)
Authors: Jin M. , Shen L. , Hu B. , Yu J. , Wen Z. , Su Y. , Wang B. , Chen L. , Ying H. , Chen L.
Published: March 2020

4075

Background: Gastric cancer is one of the most common malignancies in Asia with an adjusted mortality rate above 20/100,000 population. 5-FU + fractionated P is a standard treatment for AGC in China. In a Korean study by Kim et al., X + P produced a response rate of 55% in pts with previously untreated AGC. Here we present mature efficacy/safety results in Chinese pts with AGC. Methods: 154 pts of a planned population of 120 pts were enrolled between Jun 2002 and Aug 2004. All had measurable AGC (WHO), Karnofsky performance status ≥60, adequate bone marrow, renal and hepatic functions. Prior radiotherapy or adjuvant chemotherapy was permitted. Pts received × 1000 mg/m2 orally bid on days 1–14 + P 20mg/m2/day i.v. on days 1–5, every 3 weeks for 6 cycles. The primary endpoint was time to disease progression (TTP). Results: Baseline characteristics of the 141 evaluable pts (104 men, 37 women) are: median age 54 years (range 23–80), main sites of metastases: lymph nodes 45%, liver 40%, stomach 18%, skin 6%, other 6%, lung 5%, abdomen 4%. The overall response rate was 36%, including 13 complete responses and 38 partial responses. After a median follow-up period of 12 months, the median TTP is 9 months (95% CI, 9–12 months) and the median overall survival is 12 months (95% CI, 12–15 months). Median treatment duration was 6 cycles (range 3–6). The most common treatment-related clinical adverse events (all grades >5%) were: hand-foot syndrome (HFS) 25%, leucopenia 13%, and SGOT abnormality 12%. The most commongrade 3 adverse events were SGPT abnormality 3%, HFS 2%, and anemia 2%. There were no grade 4 adverse events. Most grade 3 adverse events improved or resolved after treatment or interruption except in 1 pt with anemia who withdrew after 2 cycles. Conclusions: X combined with fractionated P is highly active and very well tolerated as first-line treatment for AGC, with comparable results to 5-FU + P.

No significant financial relationships to disclose.
SP1049C as first-line therapy in advanced (inoperable or metastatic) adenocarcinoma of the oesophagus: A phase II window study
Authors: Armstrong A. , Brewer J. , Newman C. , Alakhov V. , Pietrzynski G. , Campbell S. , Corrie P. , Ranson M. , Valle J. W.
Published: March 2020

4080

Background: SP1049C (a block co-polymer incorporating doxorubicin) has demonstrated broad in vitro activity and superior anti-tumour activity in 9/9 in vivo animal tumour models compared to doxorubicin. Methods: Chemotherapy- or radiotherapy-naïve patients with measurable, inoperable, recurrent or metastatic adenocarcinoma of the oesophagus; KP ≥60; normal cardiac LVEF; adequate swallowing and adequate renal, hepatic and bone marrow function were eligible. SP1049C 75mg/m2 IV 30-minute infusion was given q3w, for up to 6 cycles. Radiological response was assessed after cycles 2, 4 and 6. Upon disease progression (PD) patients were offered standard chemotherapy. QoL (by QLQ-C30 and QLQ-OES24 questionnaires), toxicity, disease-related symptoms and cardiac function were also prospectively assessed. Results: From February 2002 to December 2004, 21 patients (all male), median age 62 years (range 38–78) with stage 3 (n = 1) of stage IV (n = 20) disease were enrolled. Response rate (WHO criteria) in 19 patients eligible for efficacy analysis (radiologically re-assessed after ≥2 cycles of treatment) included: PR 9/19 (47%), SD (8/19) 42% and PD (2/19) 11% by investigator assessment (confirmed PR 41%, unconfirmed PR 12% and SD 29% by independent review, RECIST criteria). One responding patient underwent salvage resection of a pT2N0 (Stage 2A) tumour. All patients are evaluable for toxicity. Toxicity (Gd 1–2/3–4, by patient) included: neutropaenia 24%/62%, leucopaenia 19%/29%, anaemia 38%/5% and thrombocytopaenia 9.5%/0% (resulting in 9 (43%) patients being dose-reduced to 55 mg/m2 at cycle 2), nausea 81%/19%, vomiting 62%/24%, anorexia 52.4%/14%, lethargy 81%/14%, febrile neutropaenia -/29%, mucositis 48%/5%, and Gd 1–2 alopecia in 67%. Grade I cardiotoxicity (fall in LVEF by 10–19% from baseline, CTC v2.0) was seen in 4 (19%) patients. The median overall survival (all patients) is 10 months; four patients received 2nd-line chemotherapy. Conclusions: SP1049C appears to have activity in monotherapy in this patient group and combination studies with other active agents are warranted.

[Table: see text]
The prognostic role of the WHO classification, urinary 5-hydroxyindoleacetic acid (u5HIAA) and liver function tests (LFTs) in metastatic neuroendocrine carcinomas (NECs) of the gastroenteropancreatic (GEP) tract
Authors: Formica V. , Norman A. R. , Cunningham D. , Wotherspoon A. , Sirohi B. , Oates J. , Chong G.
Published: March 2020

4092

Background: The aim of this study was to assess the prognostic value of the revised neuroendocrine tumour (NET) WHO classification (2000) and to identify additional prognostic factors. Methods: 119 pts with metastatic NET arising from the GEP tract treated at the RMH were eligible for this retrospective study. All were classified according to WHO guidelines into well-differentiated and poorly-differentiated neuroendocrine carcinomas (WDNEC and PDNEC). Demographic, clinical and biochemical data at diagnosis were recorded as potential prognostic factors. The hazard ratios (HRs) between subgroups of patients were estimated by Cox regression analysis; survival curves were generated by Kaplan-Meier method. Approval for the study was obtained from the local ethics committee. Results: 8% of pts had PDNECs, 92% had WDNECs. Histological differentiation had the most impact on overall survival (OS) (HR = 4.02, 95%CI 1.26–12.82, p = 0.02, using WDNECs as the reference). In a WDNEC-restricted multivariate analysis, significantly abnormal LFTs and elevated u5HIAA were independent prognostic factors for survival (HR = 2.65, 95% CI 1.33–5.30, p = 0.006 and HR = 2.51, 95% CI 1.35–4.63, p = 0.003, respectively). Radiological evidence of liver metastases was not predictive of survival. These variables were used to create a WDNEC-specific prognostic model (low-risk = both normal, intermediate-risk = one abnormal, high-risk = both abnormal) (see table ). Statistically distinct median OS (mOS) were identified for each of the 3 risk groups. High-risk WDNECs had similar poor survival to PDNECs. Conclusion: This analysis supports the prognostic value of the WHO classification for metastatic NETs arising from the GEP tract. Risk stratification using readily available u5HIAA and LFTs may give additional prognostic information for WDNECs, although these observations need to be confirmed in an independent dataset.

[Table: see text]

No significant financial relationships to disclose.
Relation of tumor vascularity to effect of gemcitabine in pancreatic carcinomas: Value of contrast-enhanced harmonic ultrasonography
Authors: Kitano M. , Sakamoto H. , Suetomi Y. , Nishio T. , Nishio T. , Takeyama Y. , Kudo M.
Published: March 2020

4114

Background: Most ductal adenocarcinomas of the pancreas are hypovascular as compared with the surrounding parenchyma on dynamic CT. Coded phase-inversion harmonic ultrasonography more clearly depicts fine vessels in pancreatic tumors after the infusion of ultrasound contrast than dynamic CT. In the present study, we observed the vascularity of pancreatic tumors by means of this technique and investigated its usefulness for evaluation of response to gemcitabine. Methods: Thirty-three patients with inoperable pancreatic carcinomas were enrolled in this study. They received gemcitabine (1 g/m2) 3 times in a cycle (4 weeks). Contrast-enhanced harmonic ultrasonography (CE-US) was performed immediately before the fist cycle and after completing each cycle, by the use of a GE LOGIQ 9 Series unit. We classified patients into 2 groups according to the changes of tumor vascularity observed by CE-US. Group A represents those with tumors in which tumor vascularity was increased during a certain period after the chemotherapy. Group B represents those with tumors in which tumor vascularity was not increased throughout the observation period. Tumor makers (serum CEA, CA19–9, Span-1 and Dupan-2) and median survival time (MST) were employed for the evaluation of therapeutic response and compared between the 2 groups. Results: CE-US demonstrated the increase of tumor vascularity after the chemotherapy in 17 of 33 patients (Group A). MST in the Group A (306 days) was significantly longer than that in the Group B (187 days). The reduction of tumor makers (reduction by 50 % of either serum CEA, CA19–9, Span-1 or Dupan-2) was observed in all patients (17/17) in the group A and in 25 % of patients (4/16) in the group B. The increase of tumor vascularity was noted when the tumor makers were reduced. The increased vascularity turned to decline in parallel with the tumor progression. Conclusion: CE-US is useful for the evaluation of chemotherapeutic response in terms of vascularity. The increased vascularity in pancreatic carcinomas after the chemotherapy may represent the improvement of vascular sclerosis and tumor invasion in small arterioles.

No significant financial relationships to disclose.
A phase III trial of virulizin plus gemcitabine vs. gemcitabine alone in advanced pancreatic cancer: Results of subgroup analysis
Authors: Wright J. A. , Osterlee J. , Fekete S. , Lee Y. , Young A. H.
Published: March 2020

4116

Background: Virulizin (V) is a novel antitumor immune modulator that improves survival in pancreatic cancer patients (pts) as monotherapy. A double-blind, multicenter, randomized, phase III study was conducted to evaluate the survival benefits and safety of V in combination with gemcitabine (G) in pts with advanced pancreatic cancer. Methods: Chemo-naive pts with locally advanced or metastatic pancreatic cancer with ECOG Performance Status (PS) of 0, 1 or 2 were enrolled. Pts were randomized to receive intramuscular injections of either V or placebo (P) 3 times weekly + G (1,000 mg/m2 weekly ×7 with 1 week rest, then weekly ×3 q4w). Randomization was stratified according to ECOG PS (0 or 1, and 2) and extent of disease (locally advanced and metastatic). Pts who showed no clinical benefit or were intolerant to G entered 2nd-line therapy (stage 3), in which pts continued to receive either V or P alone or with 5-FU, or best supportive care. The primary endpoint was survival, defined as time from baseline/treatment day 1 to time of death from any cause. Results: The intent to treat (ITT) population comprised 434 pts, of which 377 were efficacy evaluable (EE). Median overall survival for V + G was 6.3 months for the ITT population (6.8 months for EE pts) and 6 months for P + G for both ITT and EE pts. While differences in survival times were not statistically significant, exploratory analysis showed encouraging results in specific subgroups treated with V + G ( table ). Importantly, a significant difference was found in stage 3 pts who received V in a salvage setting compared to pts who received P. Conclusions: Pancreatic cancer pts with either low ECOG PS or metastatic cancer showed a survival benefit when treated with V + G, which was significant in pts who continued to receive V as a salvage therapy. Further studies in these targeted patient populations are being considered.

[Table: see text]

No significant financial relationships to disclose.
Gemcitabine hepatic arterial chemoembolization (TACE) in the treatment of unresectable HCC
Authors: Carr B. I.
Published: March 2020

4141

Background: Hepatocellular carcinoma (HCC) generally arises in the presence of cirrhosis and is typically multifocal and bilobar and thus not often resectable. A major limitation of chemotherapy is due to the damaged underlying liver as a result of cirrhosis. A non-hepatotoxic drug such as Gemcitabine is thus potentially useful in patient management. Methods: 57 patients with biopsy-proven HCC were evaluated for response, survival and toxicity after treatment with gemcitabine via hepatic arterial chemoembolization. Patients were treated with 1250 mg/m2, given in 150 ml of normal saline over 30 min to either the right or left hepatic artery at any one treatment session. Treatments were repeated every 8 to 10 weeks. Embospheres (Embogold, Biosphere Medical) 100–300 micron size were also injected to vascular slowing but not to occlusion of the same hepatic artery during the chemotherapy infusion. A CT scan was performed at baseline and just prior to each repeat treatment, which was continued until tumor progression. CBC, liver function tests and AFP were performed at baseline and monthly. Results: There were 19 partial responses (PR) (33%), 2 minor responses (4%), 24 patients with stable tumors (42%), 9 with tumor progression (16%) and 3 unevaluable (diffuse) (5%). Survival was: median 12 mo (range 1–36 mo). 23 patients survived 24 mo. There were no hepatotoxicities greater than grade 1 and no myelotoxicities greater than grade 2 (NCI common toxicity criteria). Conclusions: Gemcitabine chemoembolization (TACE) in unresectable HCC patients with normal bilirubin and without ascites appears to be entirely safe with a minimal clinical or laboratory toxicity and is associated with encouraging responses and survival.

No significant financial relationships to disclose.
Phase II study of lenalidomide in patients (pts) with metastatic renal cell cancer (MRCC)
Authors: Marsh L. , Khan M. , Needle M. , Amato R.
Published: March 2020

4533

Background: Immunomodulatory drugs are compounds that originated via the deliberate structural modification of thalidomide. Lenalidomide (Revlimid) is a derivative with enhanced immunological and anti-angiogenic properties lacking toxicities associated with thalidomide. Objectives were to determine response rate, time to progression (TTP), one-year survival, and toxicity in patients with progressive MRCC. Methods: Eligibility included: progressive measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) ≤ 2, ≤ 1 prior therapy, and no active CNS involvement. Lenalidomide is administered orally at a dose of 25mg daily for 21 days with 7 days rest (28-day cycle), with dose modifications for toxicity. Re-evaluation is done every 3 cycles (12 weeks). RECIST criteria is utilized to determine response rate. TTP is determined from entry into study. Results: 40 pts enrolled. 30 male/10 female, range 38–73 (median 63) years. 38 pts had clear cell carcinoma; 2 pts with papillary. 24 pts received prior immunotherapy and/or chemotherapy. 3 pts met criteria for good prognosis, 33 intermediate and 4 poor. Sites of disease included: lung, nodal, bone, adrenal, kidney, and liver. 17 pts had 1 metastatic site, 13 pts 2 metastatic sites, and 10 pts 3 or more metastatic sites. 36 pts completed at least 12 weeks of therapy. 4 pts had early progressive disease. 1 pt had a CR, 2 pts achieved a PR. 52% of pts had a prolonged TTP ≥ 6 months and 25% ≥ 12 months. Median overall survival of 14.8 months (4.1− 22.2+). Treatment related adverse events included: reversible grade 1/2 non-hematologic toxicity consisting of: nausea, diarrhea, constipation, myalgia and fatigue. 19 pts with grade 3/4 neutropenia and 9 pts with grade 3/4 thrombocytopenia. Median duration of therapy is 6 months (2 - 22). Conclusion: Lenalidomide was well tolerated. Anti-tumor activity has been demonstrated by the following: tumor regression and delayed TTP. The tumor effect was also demonstrated as a second line therapy following cytokine failure.

[Table: see text]