bluuebunny/crossref_metadata_2025 huggingface dataset:
NVP-TAE226, a potent dual FAK/IGF-IR kinase inhibitor, prevents breast cancer metastasis in vivo
Authors: Kawahara E. , Ohmori O. , Nonomura K. , Murakami Y. , Tomioka D. , Niwa S. , Meyer T. , Mestan J. , Honda T. , Hatakeyama S.
Published: March 2020

13163

Background: Focal Adhesion Kinase (FAK) and Insulin-like Growth Factor-1 Receptor (IGF-IR) kinase are attractive anti-cancer drug targets because they are both drivers of tumor cell proliferation, migration, and survival. Although virtually every cell type expresses FAK, it is generally overexpressed in tumor cells. FAK levels are greatest in highly metastatic tumors. A selective FAK inhibitor would be expected to halt or kill invasive tumor cells, and potentially interfere with normal cell migration (e.g. endothelial cells). IGF-IR function is required for tumor cell survival, but dispensable for survival of normal cells. Therefore, a dual inhibitor of both kinases may selectively block the growth, migration, and survival of FAK- and IGF-IR- expressing tumor cells compared to proliferating and migrating normal cells. Methods: NVP-TAE226, a novel small molecule developed as an inhibitor of FAK, was evaluated in kinase enzymatic assays, cell-based kinase assays and 4T1 metastatic breast carcinoma in vivo model. Results: NVP-TAE226 inhibits FAK with low nanomolar IC50 values in a purified kinase enzymatic assay. In cell-based kinase assays, FAK and IGF-IR kinase were inhibited with an IC50 range of 100 to 300 nM compared to the other kinases tested which were >10-fold less sensitive. Oral administration of NVP-TAE226 inhibited 4T1 murine breast tumor growth and metastasis to the lung in a dose-dependent manner. The compound was well tolerated in mice as determined by measuring changes in body weight. The highest dose of 100 mg/kg, qd, 5x/week showed T/C value of 18%. Inhibition of FAK autophosphorylation at Y397 and Akt phosphorylation at Serine473 was observed in a dose-dependent manner in 4T1 breast carcinoma. Conclusions: NVP-TAE226 represents a novel class of selective and small molecule kinase inhibitors that have potential clinical applications with a potent in vivo activity.

[Table: see text]
Antitumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases
Authors: Morelli M. P. , Cascone T. , Troiani T. , Tuccillo C. , Bianco R. , Romano M. , Eckhardt S. G. , De Pacido S. , Tortora G. , Ciardiello F.
Published: March 2020

13170

Background: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor A (VEGF-A) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. ZD6474 (ZACTIMA™) is an orally available, small molecule inhibitor of VEGF receptor-2 (VEGFR-2), EGFR and RET tyrosine kinase activity. We investigated the activity of ZD6474 in combination with cetuximab, an anti-EGFR blocking monoclonal antibody, to determine the antitumor activity of EGFR blockade through the combined use of two agents targeting the receptor at different molecular sites in cancer cells and of VEGFR-2 blockade in endothelial cells. Methods: The antitumor activity in vitro and in vivo of ZD6474 and/or cetuximab was tested in human cancer cell lines with a functional EGFR autocrine pathway. Results: In vitro, the combination of ZD6474 and cetuximab produced synergistic growth inhibition in all cancer cell lines tested as assessed by the Chou and Talalay method. In vivo, 4 weeks of treatment with ZD6474 (75 mg/kg p.o., days 1–5 each week) or cetuximab (1 mg i.p., days 2 and 5 each week) produced a tumor growth delay of 21–28 days (P < 0.001) in nude mice bearing established human colon carcinoma (GEO) or lung adenocarcinoma (A549) cancer xenografts compared with untreated controls. Combination treatment with ZD6474 and cetuximab for 4 weeks resulted in a more marked tumor growth delay of 120–140 days compared with controls, and this was significantly greater than with either single agent therapy (P < 0.001). Following combination treatment, 3/10 A549 xenograft-bearing mice and 4/10 GEO xenograft-bearing mice had no histologic evidence of tumor at the end of the experiment. Immunohistochemical analysis of tumor samples obtained from mice treated with the two drugs in combination demonstrated a cooperative inhibition of cancer cell proliferation and an almost complete suppression of tumor angiogenesis. Conclusions: This study provides a rationale for evaluating in a clinical setting the double blockade of EGFR in combination with inhibition of VEGFR-2 signaling as cancer therapy.

[Table: see text]
Capecitabine (X) vs. bolus 5-FU/LV as adjuvant chemotherapy for patients (pts) with Dukes’ C colon cancer: economic evaluation in an Italian hospital setting
Authors: Di Costanzo F. , Sobrero A. , Twelves C. , Douillard J. , Giuliani G. , Patel K. , Garrison L. P. , Cassidy J.
Published: March 2020

13518

Background: In the X-ACT adjuvant trial, X showed consistent benefits over bolus 5-FU/LV, with at least equivalent disease-free survival (DFS) and an improved safety profile [Twelves et al. 2005]. In addition, X demonstrated superior relapse-free survival (65.5% vs. 61.9% at 3 years follow-up; p=0.0407) and improved covariate-adjusted overall survival (p=0.0208). We used the results from X-ACT to assess the cost-effectiveness of X from the Italian hospital and societal perspective. Methods: Trial-based data were collected on treatment period medical resource use. Unit costs for drug administration, hospitalizations, emergency room visits, and concomitant medications were considered using published sources in Italy. Cost for physician consultation visits, pt time and travel were also considered in the societal perspective. A health-state transition model was used to estimate incremental cost impact and the effectiveness in terms of gains in quality-adjusted life months (QALMs). Costs and effectiveness were discounted at 3.5%. Results: Mean duration of treatment was similar with X and 5-FU/LV; pts received 92% and 93% of planned treatments, respectively. Administration of X required fewer clinic visits per pt (7.4 vs. 28.0 with 5-FU/LV). Acquisition costs of X were higher than 5-FU/LV, approximately 2533 vs. 231€, but this difference was more than fully offset by the difference in administration cost of 5-FU/LV (4338 vs. 152€ for X). Total hospital days for treatment-related adverse events (AEs) and medication costs for treating AEs were higher for 5-FU/LV than X. The cost of emergency room visits for treating AEs and physician consultation did not differ. Compared with 5-FU/LV, X is projected to increase QALMs by 6.5 months, with overall treatment period cost savings of 2234€ for the hospital. From a societal perspective, the cost savings increase to 3976€. These findings show that X is a dominant (cost-saving and more effective) treatment in this setting. Conclusions: X as adjuvant treatment for pts with colon cancer is clinically effective with an improved safety profile vs. 5-FU/LV and is also a dominant choice from an economic perspective.

[Table: see text]
Gefitinib and irinotecan in patients with fluoropyrimidine-refractory irinotecan-naïve advanced colorectal cancer (CRC): dose-finding, pharmacokinetics, safety and efficacy
Authors: Hickish T. , Chau I. , Massey A. , Higgins L. , Osborne R. , Botwood N. , Swaisland A. , Cunningham D. C.
Published: March 2020

13520

Background: Gefitinib (IRESSA) is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has shown supra-additive activity in human CRC xenografts when combined with irinotecan. We have previously established that the recommended dose level (RDL) to be irinotecan 225mg/m2 q3 weeks and gefitinib 250mg daily (Chau et al ASCO 2004). The dose limiting toxicities were neutropenia and diarrhoea. The continuation phase of this study aimed to evaluate the efficacy and safety of this combination. Patients and Methods: Between Jun 2002 and Feb 2005, patients (pts) with advanced CRC progressing on or within 12 weeks of fluoropyrimidines-based chemotherapy, irinotecan-naïve and performance status ≤2 were recruited. Thirty-nine pts were treated with irinotecan and gefitinib in total with 27 treated at the RDL. Results: Median age was 61 years (range: 31–79) and 13 (33.3%) pts were females. All pts were Caucasians (94.9%) and non-oriental Asians (5.1%). Thirteen (33.3%) pts had received (neo)adjuvant chemotherapy and 16 (41.0%) pts had prior oxaliplatin-based chemotherapy for metastatic disease. Grades 3–4 toxicities were anaemia 2.6%, neutropenia 15.4%, febrile neutropenia 10.3%, diarrhoea 35.9%, nausea 2.6%, vomiting 5.1%, lethargy 15.4% and skin rash 7.7%. For the pts treated at RDL, the objective tumour response rate was 11.1% (3 partial responses [PRs]; 95% confidence interval [CI]: 2.4–29.2%) and the disease control rate was 40.7% (3PRs, 8 stable diseases lasting for ≥12 weeks). The median time to progression was 4.2 months and median survival was 9.3 months. Six-month progression free survival was 22.2% (95% CI: 6.5–37.9%) and 6-month overall survival was 73.4% (95% CI: 56.5–90.3%). Preliminary pharmacokinetic data suggested that the addition of irinotecan to gefitinib resulted in an average of 14–33% increase in exposure to gefitinib (p<0.05). Conclusions: Irinotecan and gefitinib at this dose schedule was tolerable. Gefitinib did not appear to add substantial efficacy to irinotecan. The relative low dose of irinotecan at the RDL and the rarity of EGFR somatic mutation in CRC may be contributory to the modest activity of irinotecan and gefitinib combination.

[Table: see text]
Induction chemotherapy (ICT) followed by pre-operative chemoradiotherapy in locally advanced rectal cancer
Authors: Elkerm Y. , Elrewiny M. , Al-Batran S. , Jager E. , Elsaid A.
Published: March 2020

13531

Background: Preoperative radiotherapy (RT)with or without chemotherapy (CRT) for patients (ptns) with T3,4 rectal carcinoma is increasingly accepted.We presented, 3 yrs ago, our experience with Cisplatin-5FU-Folonic(FA)regimen (FOLFC) in patns with metastatic CR carcinoma.We proved it is comparable to other regimens with lower cost. Methods: Between 10/99 & 8/04, 104 ptns between 18 and 65 year old (PS 0–1) were assessed retrospectively (24 T3 & 80 T4). Ptns received 2 months of ICT Cis(40mg/m2 D1)+FA(200mg/m2 2hrs infusion D1,2)followed by 5FU bolus(400 mg/m2 D1,2)+5FU cont inf(1200 mg/m2 D1–2)this cycle repeated q 2 wks for 8 wks. Starting on wk 9, 5 FU-FA was given as in Mayo-clinic regimen (D1–5, D21–25) with concomitant RT 45Gy in 25 fractions followed by 9 Gy boost to primary tumor. TME was planned at 4–6 wks from completion of ICT. 2 more cycles of FOLFC was given post-operatively. Results: All ptns (104) undergoing CRT completed therapy as planned, with no treatment-related interruptions. No GIII-IV toxicity. The radiological RR (after ICT) was 75% and (4 wks after CRT) was 89% (20CRs, 73PRs). 92% of ptns had subjective R in a median of 24 days from start of ICT in terms of improvement of diarrhea/constipation (90.4%), in obstructive symptoms (40/ 50 ptns)&weight gain in 100% of ptns.Reduced rectal bleeding (100%) & pelvic pain (100%). 17 of 20 ptns who were considered to be inoperable prior to the treatment underwent TME with negative radial margins. Anastomotic leakage occurred in 8 ptns (7.7%). Wound infection occurred in 4 ptns (3.8%). Delayed complications occurred in 3 ptns one required surgery for a stomal stricture. All ptns underwent R0 resection with clear CRM. Pathological CR was found in 32 ptns and in an additional 41 ptns, only microscopic tumor foci were found on surgical specimens. After a median follow-up of 16 months, two ptns had developed LR. Conclusions: ICT followed by synchronous CRT and TME results in marked tumor regression, rapid symptomatic response and achievement of R0 resection. The majority of ptns considered inoperable prior to receiving this treatment underwent successful excision. Given the low toxicity and promising activity, this regimen is being compared to standard synchronous 5FU- pelvic chemoradiation in a randomized study.

No significant financial relationships to disclose.
Evaluating carcinoembryonic antigen (CEA) and tumor size as predictors of outcome in patients receiving capecitabine (X) plus oxaliplatin for metastatic colorectal cancer (MCRC): findings from a retrospective analysis
Authors: Jonsson F. , Twelves C. , Tabernero J. , Schoffski P. , Sobrero A. , Van Cutsem E. , Díaz-Rubio E. , Cassidy J. , Claret L. , Zuideveld K.
Published: March 2020

13534

Background: The oral fluoropyrimidine X has superior efficacy and improved safety compared with bolus 5-FU/LV in CRC. Twice-daily oral X is replacing 5-FU as the backbone of combination regimens. The combination of X and 3-weekly oxaliplatin (XELOX regimen) has demonstrated similar efficacy to FOLFOX with some safety advantages and enhanced convenience in phase II/III clinical trials. The objective of this retrospective study was to investigate the use of CEA as an early predictor of outcome. Methods: The data used in this analysis came from a previously published large phase II study (n=96) of XELOX as first-line treatment for patients with MCRC [Cassidy et al. J Clin Oncol 2004]. A population-based pharmacodynamic analysis of CEA and tumor size progressions was performed. The resulting data were linked to hazard models for the secondary clinical endpoints: time to disease progression (TTP) and overall survival. As we were interested in early prediction, model-predicted time courses of CEA and tumor size (up to 10 weeks) were examined as covariates in the hazard models. The resulting predictions for TTP and survival based on either measure were tested and compared using stochastic simulations. Results: An indirect effect model provided the best description of CEA progression. For tumor size, a similar indirect effect model with an added resistance term gave the best description. CEA performed marginally better than tumor size in predicting survival and less well in predicting TTP. For survival the misclassification rate decreased from 0.426 to 0.404 when using tumor size and to 0.396 when using CEA as predictors. Conclusions: CEA and tumor size were found to have clinically equivalent power as early phase predictors of clinical outcome.

[Table: see text]
Bevacizumab (BV) induced hypertension (HT): A manageable toxicity
Authors: Pande A. U. , Lombardo J. C. , Fakih M. , Wong M. K. , Iyer R. V. , Kuvshinoff B. W. , Javle M. M.
Published: March 2020

13539

Background: BV inhibits angiogenesis by targeting vascular endothelial growth factor (VEGF). Anti-VEGF therapy blocks nitric oxide and causes relative vasoconstriction leading to HT in some patients (pts). Guidelines for anti-hypertensive (anti-HT) therapy in this setting are not well-established. Methods: Medical records of pts treated with BV from Oct. 2003 to Sep. 2005 were reviewed to document the incidence and treatment outcomes of BV induced HT. Grading of HT was as per CTC version 3.0. Institutional review board approval was obtained for this investigation. Results: One hundred fifty-four pts were treated with BV during study period. Fifty-five (35%) pts with colon (n=44), pancreatic (n=8), renal cell (n=2) and small cell lung cancer (n=1) had HT: 11 developed new-onset HT, 41 experienced exacerbation of pre-existing HT & 3 with prior HT became normotensive. BV was given with FOLFOX (n=38), FOLFIRI (n=5), gemcitabine & capecitabine (n=8) or interferon (n=4). Median dose of BV was 10 mg/kg (range=5–15 mg/kg). HT occurred after a median of 11 weeks after BV therapy (range=3–33 weeks). HT grading: grade 1 (n=1), grade 2 (n=29) & grade 3 (n=22). HT was controlled (BP≤140/90) in 44 (80%) and BP was >140/90 in 8 pts (BV was discontinued in 3). Complications of HT were chest tightness (n=1) and TIA (n=1). Anti-HT therapies are described in table 1 . Quinapril was commonly used (n=31): median dose of 20mg qd (range 5–40 mg). Renal function abnormalities occurred in 13 pts (creatinine 1.3–3.3), and proteinuria occurred in 7/27 pts. Conclusion: Exacerbation or new onset HT occurred in 35% of BV-treated pts after a median of 11 weeks. BV-induced HT is controllable in most cases with standard anti-HT therapy such as ACE-I. BV interruption and serious complications from HT are uncommon. [Table: see text]

[Table: see text]
Phase-2 study of neoadjuvant chemoradiation in locally advanced rectal adenocarcinoma: The Radio-Xelox study
Authors: Salimichokami M. , Vafai M. , Derakhshani S. , Aminian S. , Vaheed A. A.
Published: March 2020

13549

Background: Neoadjuvant Radiation treatment has been shown in many studies to decrease the incidence of loco-regional relapse in pts with locally-advanced Rectal Adenocarcinoma. Capecitabine and Oxaliplatin are both effective antineoplastic drugs in Colorectal Adenocarcinoma. They also have radiosensitizing effects. Hence,it is rational to combine these agents in association with radiotherapy,to achieve local controle and prevent systemic spread of the cancer. Methods: Thirty-eight pts with Rectal Adenocarcinoma (T3-T4 and/or N+) received radiation treatment (2.0 Gy, 5days a wk over 5 wks,total dose 50 Gy) plus oral Capecitabine at 600 mg/m2 twice a day and iv Oxaliplatin at 35 mg/m2 once weekly × 5wks. Surgery was performed 6wks post completion of XRT. Our end points were safety/feasibility and response/efficacy as demonstrable by the rate of pathologic complete remission (path-CR). Results: Seven pts (20%) acheived path-CR. Diarrhea was the most important severe adverse effect (in 25% of pts). fourteen pts (40%) showed good regression (very few cancer cells in fibronecrotic tissue Dworak grade 3). The remaining 17 pts showed less favorable regression or no significant change. Conclusions: Preoperative Radiation treatment plus chemotherapy with XELOX regimen is feasible, safe and effective with an impressive rate of path-CR in locoregionally advanced Rectal Adenocarcinoma.

No significant financial relationships to disclose.
First-line bolus IFL and second-line FOLFOX: A retrospective review of two hundred thirty patients
Authors: Heng D. , Kennecke H. , Gill S. , Kollmannsberger C. , Lohrisch C. , Shah A. , Melosky B.
Published: March 2020

13555

Introduction: The IFL regimen (irinotecan, 5-fluorouracil bolus and leucovorin) is active in metastatic colorectal cancer. Early treatment-related deaths in N9741 led to the utilization of a dose-reduced schema. An infusional regimen (FOLFIRI) replaced IFL because of superior tolerability. FOLFOX can be used as second-line therapy in patients treated previously with IFL. Methods: A retrospective review was performed at the British Columbia Cancer Agency to evaluate both the safety and outcome of all patients given IFL as first-line treatment for metastatic colorectal cancer. Data on second-line FOLFOX was also collected. Between March 31/2002 and April 1/2004, 230 patients were treated. Results: The mean number of IFL cycles delivered was 4.6 (18 doses) for a mean duration of 7.1 months. Toxicity was manageable with only 1 treatment-related death. 17% of patients had grade 3/4 toxicities that included neutropenia and diarrhea. Only 6% of patients required hospitalization during IFL treatment. The median survival of the entire group was 16.6 months (95% CI 14.3–18.6). One hundred twelve patients received second-line therapy. Forty-nine of these patients (44%) received infusional oxaliplatin (mFOLFOX 6) as second-line therapy. 27% had grade 3/4 toxicities and 10% required hospitalization. The median survival of these patients was 25.2 months (95% CI 20.1–30.3). Conclusion: This population-based study demonstrated that bolus IFL played a significant role in the treatment of metastatic colorectal cancer and had a manageable toxicity profile. Lastly, the sequence of IFL followed by FOLFOX resulted in a very meaningful patient survival of over 25 months.

No significant financial relationships to disclose.
Efficacy of systemic chemotherapy (CT) for the patients (pts) with unresectable liver metastasis (LM) of colorectal cancer (CRC)
Authors: Mera K. , Ohtsu A. , Doi T. , Muto M. , Sano Y. , Takahashi S. , Yoshida S.
Published: March 2020

13567

Background: Surgical resection of colorectal LM is the only treatment which provides long-term survival for pts with advanced disease confined to the liver. However, most of LM are initially unresectable. The aim of this retrospective study was to evaluate the efficacy of systemic CT for the pts with initially unresectable LM from CRC. Methods: Subjects of this study were advanced CRC with unresectable LM treated by systemic CT at our institution between Aug ’92 and Dec ’03, and fulfilled the following criteria; Age ≤ 75, PS ≤ 2, histologically confirmed colorectal adenocarcinoma, no extrahepatic disease, no prior CT and no serious complication. Results: A total of 349 pts with metastatic CRC were managed by systemic CT between the period. Among these, there were 47 pts who met the recruitment criteria. Their characteristics were; male/female: 32/15, median age (range): 59 (34–75), PS 0/1/2: 33/12/2, primary tumor: colon/rectum: 26/21, sinchronous/metachronous: 26/21, number of LM: 4 ≥ / 5 ≤: 9/38. Regimens of CT were; 5FU/5FU+LV/CPT-11+5FU/CPT-11+5FU+LV/Others: 4/11/7/18/7. In all 47 pts, response rate was 53%, median survival time and 3-year survival rate were 14.6 month and 14.6%, respectively, at a median follow-up of 43.4 month. Seven of 47 (15%) could be secondarily resected after response to CT and all had R0 resection. Estimated 3-year survival rates in resected and non-resected pts were 57.1% and 0%, respectively. Prior CT before liver resection was CPT-11+5FU+LV (IFL)/CPT-11 alone: 6/1. Of the 7 resected pts, 2 pts are alive with no evidence of disease for 38 and 40 month after initiation of CT. Five of 7 pts relapsed (liver 3, liver and lung 2) and all treated with systemic CT for recurrence. Although recurrent disease is persisting, 2 of 5 are still alive for 34 and 48 month by continuing CT. Conclusions: Effective systemic CT allows some pts with unrsectable colorectal LM to be rescued by hepatic resection and provides a chance of long-term survival.

No significant financial relationships to disclose.
Outcome of rectal carcinoma patients receiving adjuvant chemoradiotherapy in Marmara University Hospital
Authors: Dane F. , Gumus M. , Iyikesici S. , Yumuk F. , Basaran G. , Atasoy B. M. , Abacioglu U. , Cabuk D. , Teomete M. , Turhal S.
Published: March 2020

13584

Background: Surgical resection is the cornerstone of curative therapy for rectal cancer. Relapse rate following potentially curative resection is high in patients with stage II/III disease. Thus, chemoradiotherapy is the standard adjuvant treatment in resected stage II/III rectal carcinoma. There are limited studies, if any, analyzing the outcome of rectal cancer patients with stage II/III who received adjuvant chemoradiotherapy after curative resection in Turkey. Therefore, we aimed to analyze the treatment outcome, and the prognostic significance of various parameters in these patients. Methods: 106 patients with stage II/III rectal cancer treated with adjuvant chemoradiotherapy since 1997 until present were analyzed retrospectively. Patients received 5-fluorouracil (370–425mg/m2/day × 5days) and calcium leucovorin (20mg/m2/day × 5days), q4weeks, two courses before and two courses after radiotherapy. The 5-fluorouracil dose was reduced to, 225mg/m2/day given continuously as protracted short-term infusion during radiotherapy. 45–50.4 Gy radiotherapy was given to the pelvic region. Patients were followed-up every 3 months for the first 2 years and every 6 months thereafter. Age, gender, T stage, N stage, histological grade, lymphatic, vascular, and perineural invasion were analyzed as prognostic factors. Results: The median follow-up was 34 months. Median age was 59.5 years. Forty-four percent of the patients were node-negative. Lymphatic, vascular, and perineural invasion rate were 50.5%, 47.3%, and 32.3% respectively. Five-year disease-free and overall survival rates were 68.8% and 72.2%, respectively. Median survival time and median disease free-survival time were not reached at the time of analysis. In multivariate Cox regression analysis; T stage (p: 0.022), nodal stage (0.019), presence of lymphatic invasion (p: 0.0001), and the presence of vascular invasion (p:0.01) were independent prognostic factors. Conclusion: The adjuvant treatment outcome in Turkish patients in our department with stage II/III rectal cancer is similar to those reported in the Western studies.

No significant financial relationships to disclose.
A phase II pilot trial with RP101 in advanced pancreatic carcinoma
Authors: Fahrig R. , Quietzsch D. , Heinemann V. , Liebert A. , Haenel M.
Published: March 2020

14000

Background: (E)-5-(2-bromovinyl)-2’-deoxyuridine (BVDU, RP101), which supports apoptosis and prevents the acquisition of chemoresistance, was tested in cultured human pancreatic tumor cells. RP101 down-regulated uridine phosphorylase, a marker of poor prognosis, and APEX1, which is involved in DNA repair, and repressed Stat-3 and its target VEGF. Furthermore, RP101 activated antitumor immunity. These results encouraged us to investigate the effect of RP101 in combination with gemcitabine (GEM) and cisplatin (CIS) in patients with advanced pancreatic cancer. Methods: A phase II pilot trial was designed to compare the GEM/CIS/RP101 combination to historical GEM/CIS combination. The primary endpoint was survival. 13 pts with histological documented pancreatic carcinoma received GEM 1.000 mg/m2 plus CIS 50 mg/m2 on days 1 and 15 of a 28-day schedule. RP101 treatment was on the same day and for four days after chemotherapy (500 mg/day). Results: All patients showed at least a stable disease, and 33% of them a PR. As a historical control, 22 pts were selected by random generator from 98 patients enrolled in a previous Phase III study performed in the same centers, 15 with stage IV and 7 with stage III disease, resulting in a similar proportion of stage III to IV patients as in the RP101 co-treatment group (nine stage IV and four stage III). In the RP101-co-treatment group the median survival was significantly longer than that of the historical control group (447 days vs. 186 days, p=0.007). Time to progression (TTP) was also prolonged (280 days vs. 104 days, p=0.004). Ten of the 13 pts lived longer than one year, 4 nearly two years after first treatment. Conclusions: The combined use of GEM/CIS/RP101 prolonged progression-free and overall survival in locally advanced and metastatic pancreatic cancer when compared to all published studies with all combinations of drugs. A repeat study with GEM/RP101 shows similar promising results indicating that the combination of RP101 with GEM should be explored in larger studies in patients with advance pancreatic cancer.

[Table: see text]
Long-term outocomes of preoperative chemoradiation therapy with gemcitabine and accelerated hyperfractionated radiation for respectable pancreatic cancer
Authors: Nakamori S. , Nakahira S. , Miyamoto A. , Marubashi S. , Nagano H. , Dono K. , Sakon M. , Monden M.
Published: March 2020

14004

Background: Gemcitabine (GEM) is recognized as an effective chemotherapeutic agent for non-curative pancreatic cancer and has an activity for radiosensitizer. Although preoperative chemoradiation therapy (preCRT) with GEM is one of the promising adjuvant therapies for potentially curative pancreatic cancer, the clinical significance of the treatment remains to obscure. Methods: Potentially resectable pancreatic cancer patients were recruited in this study from September 2001 through August 2004. Patients were randomly divided into preCRT group and a control group. Patients in preCRT group received GEM (400 mg/m2 or 800 mg/m2 on day 1 and 7) and concomitant accelerated hyperfractionated irradiation (1.5 Gy ×2/day, 5 days/weeks, total dose 30Gy or 36 Gy). After 3–4 weeks’ rest of the preCRT, patients were re-evaluated for resectability. Patients who underwent R0 resection did not received any postoperative adjuvant treatment until recurrence. Results: There were 23 patients in preCRT group and were 19 patients in control group. After re-evaluation, 4 patients (17%) were considered as unresectable due to the progressed disease. 19 patients (83%) in preCRT group and 19 patients (100%) in control group underwent laparotomy. Sixteen patients (70%) in preCRT group and 17 patients (89%) in control group underwent R0 resection. Median survival times were 17.6 months in preCRT group and 16.7 months in control group, respectively (p=0.65). Among patients underwent R0 resection, one and three-years survival rate were 81.2% and 27.1% in preCRT group, while these were 70.6% and 15.4% in the control group (p=0.26). Local recurrence was observed in 4 (25%) of 16 patients who underwent R0 resection in preCRT group and in 7 (41%) of 17 patients who underwent R0 resection in control group, while recurrence at distant organs (liver, lung, peritoneum, bone) were observed in 8 patients (50%) of preCRT group and 8 patients (47%) in control group. Conclusions: Although the preoperative chemoradiation therapy with GEM and accelerated hyperfractionated radiation for potentially curative pancreatic cancer is likely to be promising against local recurrence after R0 resection, survival benefit of the therapy was unsatisfactory.

No significant financial relationships to disclose.
Pre-operative chemotherapy with epirubicin, cisplatin and 5FU/capecitabine in patients with operable oesophageal cancer
Authors: Boleti E. , Sharland D. , Weeden D. , Bailey I. , Bateman A. , Geldart T. , Crabb S. , Copson E. , Darby A. , Iveson T.
Published: March 2020

14011

Background: The MRC OE02 study demonstrated pre-operative chemotherapy in patients with potentially operable oesophageal cancer improved survival. Pre-operative chemotherapy has been widely adopted in the UK. At our institution for the past 5 years patients with operable oesophageal cancer have routinely been given pre-operative chemotherapy with 3 cycles of Epirubicin, Cisplatin and Protracted Venous Infusion (PVI) 5FU (ECF). Recently, PVI 5FU has been replaced by Capecitabine (ECX). Methods: From March 2000 to October 2005, patients with operable oesophageal carcinoma have received 3 cycles of ECF or ECX (Epirubicin 50mg/m2, Cisplatin 60mg/m2, and PVI 5FU 200mg/m2 per day or Capecitabine 625mg/m2 po bd for 21 days). Disease response was assessed by CT scan and surgery was performed 4–6 weeks after completion of chemotherapy. Results: 59 patients received neo-adjuvant chemotherapy (48 received ECF, 11 ECX). Median age was 64. Fifty-three patients (89.8%) completed the planned 3 cycles of chemotherapy. WHO grade 3 or 4 toxicity occurred in 7 patients (11.8%): 6 haematological with 1 toxic death among them (1.7%) and 1 mucositis. Forty-four of 49 patients (89.7%) with dysphagia reported improvement of their symptoms as a result of chemotherapy. Fifty-two patients (88.1%) proceeded to surgery of which 47 (90.3%) underwent complete tumour resection, 4 patients (7.7%) were found to have inoperable/metastatic disease and 1 patient had incomplete excision (1.9%). Median follow-up was 26.8 months with overall median survival of 36.2 months and a 2-year survival of 63.2%. Thirty-four (57.6%) patients remain alive to date of which, 30 are disease-free and 4 are alive with recurrent disease. Conclusions: These encouraging results demonstrate that 3 cycles of preoperative ECF/ECX chemotherapy in patients with operable oesophageal cancer allow surgery to be safely performed in the vast majority of patients and our 2-year survival compare favourably with previously reported series. These results suggest that 3 cycles of pre-operative treatment with ECF/ECX chemotherapy may improve survival in this group of patients and is worthy of further research.

No significant financial relationships to disclose.
Gemcitabine and oxalipaltin (Gemox) in advanced/unresectable gall baldder cancer: A phase II study
Authors: Sharma A. , Raina V. , Shukla N. K. , Deo S. V.
Published: March 2020

14027

Background: Adenocarcinoma of gall bladder is common in females in northern part of India with rising incidence. In Delhi incidence is 5.5 per 1,00,000 population in females (4th most common cancer in females after breast, cervix, and ovary). Majority of patients present in unresectable stage and are offered palliative treatment by placing a stent and/or using chemotherapy. Gemcitabine and Oxaliplatin as single agents or in combinations with others have shown some activity in adenocarcinoma of pancreas, gall bladder, and biliary tracts. There is in vitro evidence about synergism between gemcitabine and oxalipaltin. To investigate efficacy of this combination in advanced/ inoperable gall bladder cancer this study was started. Method: A phase II study. Eligible patients were started on Gemcitabine and oxaliplatin combination as: Inj Gemcitabine 900 mg/m2 IV 30 minutes infusion day 1 and 8, Inj Oxaliplatin 80 mg/m2 2 hours infusion in Dextrose 5% Day 1 and 8 All every 3 weeks. For a maximum of 6 cycles/ disease progression which ever is early. Protocol was approved by local ethics committee. Results: Thirty two recurrent/ unresectable patients, twenty two of them females, with an age range of 31–72 years (median 48 years) were enrolled for the study after obtaining written consent. With median of 3 total of 98 cycles (range 1–6) have been delivered. 3 patients received 6 cycles and another 8 are at various stages of therapy. Grade III/IV toxicity was seen in 4 patient; no toxic death. Responses have been assessed on intent to treat basis using RECIST criteria: CR 2 (6.3%) including one pathological, PR 3 (9.4%), SD 10 (31.3%), 13 (40.6%) progressed (PD) on chemotherapy, and in 4 (12.5%) patients response evaluation is being done. Even in a worst case scenario about 16% patient had documented response and another 31% stable disease. On follow up 18 (56.2%) patients have died. Median survival is 6 months and 10 patients survived more than 6 months and 10 months survival is 12% (4 patients). Updated results will be presented during meeting. Conclusion: This combination is feasible, well tolerated and may be viable option in treatment of such patients where otherwise median survival is about 3 months. These results warrant further evaluation in a large trial.

No significant financial relationships to disclose.
Immunological evaluation of personalized peptide vaccination with gemcitabine for advance pancreatic cancer patients
Authors: Yanagimoto H. , Mine T. , Yamamoto K. , Satoi S. , Honma S. , Mizoguchi J. , Yamada A. , Oka M. , Kamiyama Y. , Itoh K. , Takai S.
Published: March 2020

14029

Background: A phase I clinical study was performed to determine safety and immunogenicity of personalized peptide vaccination with gemcitabine (GEM) in advanced pancreatic cancer patients (APC). Methods: Thirteen human histocompatibility leukocyte antigen (HLA)-A24+ or A2+ patients with unresectable (n=10) or recurrent (n=3) pancreatic cancer were treated with GEM plus up to four peptides that were positive for pre-vaccination measurement of peptide-specific IgG antibodies and/or cytotoxic T lymphocyte (CTL) precursors in the circulation (personalized peptide vaccine). GEM was administered at 1000mg/m2 as a 30-min intravenous infusion once a week for three week, followed by 1 week of rest. All patients were treated on outpatient basis. The cycle was repeated every 8 weeks. Results: Peptide doses of vaccination per week were planned as follows: level 1, 1mg; level 2, 2mg; and level 3, 3mg. The main grade 3 toxicities observed during the first cycle in each level were neutropenia (15%), anemia (23%) and thrombocytopenia (15%). No significant differences in the toxicities were found between each level. There was no dose limiting toxicity (DLT) observed in each level. Augmentation of peptide-specific CTL responses in the post-vaccination peripheral blood mononuclear cells was observed in each level, while increased titer of peptide-specific IgG antibodies was observed in the post-vaccination plasma in level 2 and level 3. Applicable responses were no complete response, two partial responses (15%), and 7 stable diseases (55%). Nevertheless 7 patients of them (54%) were under the second-line chemotherapy, disease control rate was 70%, the median TTP (time to progression) was 18.5 weeks and the MST (median survival time) was 7.6 months in this study. Conclusions: The combination therapy of personalized peptide vaccination with GEM for APC patients is feasible and safe. Because of positive immune responses under a full dose of GEM, the peptide vaccination of 3 mg is recommended.

No significant financial relationships to disclose.
Late toxicity after adjuvant radiochemotherapy for gastric adenocarcinoma
Authors: Wysocka B. , Kassam Z. , Lockwood G. , Brierley J. , Dawson L. , Ringash J.
Published: March 2020

14042

Background: There is limited late toxicity data following adjuvant radiochemotherapy for resected gastric cancer. Methods: We reviewed radiation dose volume histograms (DVHs) and toxicity outcomes for gastric cancer patients (stage Ib to IV) who received adjuvant conformal radiochemotherapy between November 2000 and May 2005. Charts were reviewed to determine survival, late clinical toxicity, and biochemical markers of renal or hepatic toxicity (creatinine, bilirubin, ALP, AST, ALT). DVHs for kidneys and liver were correlated with toxicity outcomes. Overall (OS), disease-free (DFS) and event (death or late toxicity) -free (EFS) survival were calculated. Results: 80 of 88 patients’ DVHs were available for review. Mean age was 58 years (range: 22 - 75), with 53 (66%) males and 27 (34%) females. Stage distribution was: IB - 13 (16%), II - 32 (40%), IIIA - 24 (30%), IIIB - 4 (9%) and IV - 7 (9%). 3D conformal radiotherapy (45 Gy/25 fractions) was used. In 69 patients, chemotherapy was standard as per the INT-116 study; 11 study patients received infusional 5FU (200mg/m2/day for 12 weeks) and cisplatin in escalating dose (4 cycles q 2 weeks, 0–30 mg/m2). All treatment was completed in 56 (70%) patients; 9 (11%) did not complete radiotherapy and 22 (27.5%) had chemotherapy dose omissions. Median follow up is 30 months (range 6–62). At 2 years, OS was 84% (95% CI 73%-90%), DFS was 66% (95% CI 53%-75%) and EFS was 61% (95% CI 49–72%). Clinical late toxicity occurred in 6 patients 9 to 53 months following treatment: bowel obstruction/perforation (2) and anastomotic stricture (4), in volumes treated to 45 Gy. No clinical symptoms of renal or hepatic toxicity were reported. Grade 1 (CTCAE v3.0) elevation of creatinine was observed in 8 (10%) patients; at least one liver test was altered in 22 (27.5%) patients, (grade 1–17; 2–4; 3–1). Abnormal bloodwork occurred 9 days to 55 months following treatment and did not correlate with higher kidney and liver doses. Conclusions: In our cohort of patients treated with conformal radiochemotherapy, small bowel and anastomotic toxicity was most common, with no clinical renal or hepatic toxicity observed. Biochemical renal and hepatic changes were not related to clinical toxicity or dose delivered. Further assessment with longer follow-up in a larger sample is planned.

No significant financial relationships to disclose.
Usefulness of FDG-PET in predicting the prognosis of advanced pancreatic carcinoma with chemotherapy
Authors: Ueno M. , Ohkawa S. , Miyakawa K. , Amano A. , Masaki T.
Published: March 2020

14043

Background: 18F-fluorodeoxyglucose (FDG) PET is a new diagnostic imaging technique that takes advantage of increased glucose metabolism by the tumor cells. High uptake of FDG is reportedly associated with poor survival in head and neck cancer (Heikki et al., 1997, Nuclear Oncology). FDG uptake diminishes with elevated levels of plasma glucose. We herein evaluated the usefulness of FDG-PET in predicting the prognosis of advanced pancreatic carcinoma (APC). Methods: FDG-PET was performed on 32 consecutive patients with APC between July 2001 and April 2004. The patients fasted for at least 5 hr before the study. The plasma glucose level was controlled under 150 mg/dl by using oral antidiabetic or insulin therapy in advance. FDG-PET images were acquired 45 min after intravenous injection of FDG. We did not measure the plasma glucose level directly before imaging. The FDG uptake in the primary tumor was quantitated as the standardized uptake value (SUV), and the maximum SUV (SUVmax) was measured in the regions of interest. All of the 32 APC patients received chemotherapy (26: gemcitabine, 1: gemcitabine + UFT, 5: TS-1). We analyzed the correlation between SUVmax and the overall survival. Then, we excluded the diabetics (n = 8) and compared SUV in the non-diabetic patients (n = 24). The overall survival curve was plotted according to the method of Kaplan and Meier. The difference in the overall survival was calculated using the log-rank test, and a multivariate analysis was conducted. Results: 32 patients were examined. All cases showed FDG uptake in the pancreatic tumor (SUVmax ranged from 2.73 to 9.67). The overall survival ranged from 38 to 945 days with a median of 261 days.These patients were classified into two groups at a median SUVmax value of 4.81. There was no significant difference in the overall survival between these two groups (p > 0.05). The non-diabetic patients (n = 24) were classified into two groups at a median SUVmax value of 5.51. The high SUVmax group had shorter overall survival than the low SUVmax group (p = 0.039). The multivariate analysis using Cox hazard model also revealed that SUVmax was a significant, independent factor that influenced the survival (p = 0.043) in the non-diabetic patients. Conclusions: FDG-PET may be a useful modality in determining the prognosis of APC.

No significant financial relationships to disclose.
A phase I/II study of oxaliplatin, docetaxel, and capecitabine in advanced carcinoma of the esophagus and stomach
Authors: Evans D. L. , Miner T. , Ng T. , Akerman P. , Harrington D. , Martel D. , Maia C. , Benton D. , Saba N. , Safran H.
Published: March 2020

14046

Background: The Brown University Oncology Group has attempted to modify the regimen of docetaxel, cisplatin and fluorouracil (DCF) to reduce toxicity, simplify administration and maintain efficacy. We have a completed a phase I/II study of weekly doxetaxel, carboplatin and capecitabine for patients with advanced esophagogastric cancer (Safran et al, Am J Clin Oncol, 2006). In this phase I study we have substituted oxaliplatin for carboplatin to determine the maximum tolerated dose (MTD) of weekly docetaxel and oxaliplatin with capecitabine. Methods: Patients with metastatic esophageal and gastric cancers received docetaxel and oxaliplatin on days 1 and 8 and capecitabine in divided doses, twice daily, on days 1–10, with each cycle repeated every 21 days. Patients were treated at 4 dose levels as shown in the table. Results: Fourteen patients have been enrolled. The median age was 58.5 years. Eight patients had esophageal cancer and six had gastric cancer. Grade 3/4 dose limiting toxicities (DLTs) of diarrhea, nausea, and febrile neutropenia occurred in three of four patients at dose level 3. An intermediate dose level was added (2A), reducing the capecitabine dose. Conclusion: Oxaliplatin 50 mg/m2 and docetaxel 35 mg/m2 day 1 and 8 with capecitabine 750 mg/m2 BID × 10 days in 21 day cycles may represent a promising, easily administered regimen for metastatic esophageal and gastric cancer. Enrollment continues at dose level 2A. [Table: see text]

[Table: see text]
A phase I multicentric trial of combined chemotherapy with gemcitabine plus S-1 in patients with advanced pancreatic cancer
Authors: Ohkawa S. , Amano A. , Ueno M. , Miyakawa K. , Sugimori K. , Tanaka K. , Kida M.
Published: March 2020

14047

Background: While gemcitabine (GEM) is the standard drug for chemotherapy against advanced pancreatic cancer, the development of multidrug therapies for improved outcome is important. We conducted multicentric combined chemotherapy with GEM and S-1 and report the results of the phase I trial. Methods: The subjects had unresectable pancreatic ductal cancer. The method of administration was single administration of GEM on the first day of the week from Level 1 to Level 4 at 400 to 1000 mg/m2, with concurrent administration of S-1 at 40 to 100 mg/day × 7 days, repeated every other week as a collaborative trial conducted at 3 facilities. The purpose was to determine the optimal dose with adverse events as an indicator. Results: Eighteen patients were enrolled (3 each at Levels 1, 2, 3 and 4’, 6 at Level 4). Average age was 60.9 years (38 - 71 years). There was no dose limiting toxicity (DLT) up to Level 3. Level 4 was the maximum tolerated dose since DLT was observed in 4/6 patients (mucositis 2, rash 1, anorexia 1), and no DLT was observed in 3 additional patients at Level 4’. The resulting recommended dose was Level 4 (GEM 1000 mg/m2, S-1 100 mg/day). For reference, partial response was observed in 5 patients, and median survival time at this stage is 336±39 days. Conclusions: The recommended dosage of GEM + S-1 combined chemotherapy for unresectable advanced pancreatic cancer was determined in a phase I trial. We intend to proceed to a phase II trial.

No significant financial relationships to disclose.
A phase II study of oxaliplatin with biweekly, low dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFOX-4) as first line therapy for patients with advanced or metastatic gastric cancer
Authors: Kim H. , Kwon H. , Oh S. Y. , Seo B. G. , Kim S. G. , Kim S. , Kim J.
Published: March 2020

14052

Background: To determine the activity and toxicities of low dose leucovorin (LV) plus fluorouracil (5-FU) regimen, combined with oxaliplatin every two weeks (modified FOLFOX-4), as a first-line therapy for patients with advanced or recurrent gastric cancer. Methods: Between January 2003 and March 2005, forty-five patients were enrolled in this study. Patients were treated with oxaliplatin 85 mg/m2 as a 2-hour infusion at day 1 plus LV 20 mg/m2 over 10 minutes, followed by 5-FU a 400 mg/m2 bolus and 22 hour continuous infusion of 600 mg/m2 5-FU at day 1–2. This treatment was repeated in 2 week intervals. Results: There was one patient (2.2%) demonstrated a complete response. Twenty patients (44.4%) showed a partial response. Overall response rate was 46.6%. Ten patients (22.2%) showed a stable disease and fourteen patients (31.1%) progressed during the course of the treatment. The median time to progression and overall survival time were 7.73 months (95% CI: 3.6–11.86 months) and 11.17 months (95% CI: 9.06–13.28 months) from the start of the chemotherapy, respectively. A total of 247 cycles were analyzed for toxicity. Major hematologic toxicities included grade 1–2 anemia (39.7%), neutropenia (30.4%), grade 3–4 neutropnenia (10.9%) and thrombocytopenia (9.3%).There were 12 cycles of neutropenic fever. The most common non-hematological toxicities were grade 2 nausea/vomiting (20%), grade 1–2 neuropathy (13.4%) and grade 3 diarrhea (2.2%). There was no treatment related death. Conclusions: The modified FOLFOX-4 regimen is safe and effective regimen as a first line therapy in advanced or metastatic gastric cancer.

No significant financial relationships to disclose.