bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxaliplatin/Capecitabine combination (Xelox) with or without targeted therapies in advanced colorectal cancer (ACRC) and pharmacokinetic analysis
Authors: Gil-Delgado M. , Bastian G. , Spano J. , Paule B. , Des-Guetz G. , Bardier-Dupas A. , Khayat D. 
Published: August 2020

e15068 From 04/2002 to 12/2004, and 03/2006 to 08/2008, two consecutive steps were conducted in ACRC patients with chemotherapy alone for the step 1 and with Cetuximab and Bevacizumab for the step 2. Treatment schedule: oxaliplatin (0) 130 mg/m2 D1 over 4 to 6 hours, capecitabine (X) 1000 mg/m2 bi daily D2 to 15, 1 week rest. Cetuximab D1 at cyle 1 and at D2 at cycle 2(400 mg/m2 loading dose, then 250 mg/m2 every week), bevacizumab 7.5 mg/Kg D2 at cycle 1 and at D1 for the cycle 2. At cycle 3 cetuximab and bevacizumab were given at D1. PK analysis were performed at cycles 1 and 2, days 1,2,15,22 and 23. In the step 1, 23 pts were included, M/F = 9/14, M. age 57, PS 0–1-2 = 14/6/3, 1st line /2/3 = 18/4/1. Eleven responses were obtained (4 CR and 7 PR) 2 pts were in CR after hepatectomy, ORR = 48 %( intent to treat). In the step 2, 18 pts were included, M/F = 11/7, M. age = 55, PS 0–1-2 = 8/7/3, 1st line/2 = 17/1.Status K-RAS mutated/wild = 2/13.Seven pts responded to therapy: 1 CR, 6 PR and 1MR for an ORR of 38 %(intent to treat) 3 pts were in CR after hepatectomy and 6 pts were in SD, tumor control in 16/18 pts=88 %.Toxicity was mild, only 1 pt had G3 diarrhoea, 1pt G3 acne, 1pt had G3 neurotoxicity with need oxaliplatin discontinuation after 14 cycles. One pt had fatal pulmonary embolism at first cycle. PK results in plasma ( 14 pts in step 1 and 12 pts in step 2):no statistical differences between X and its metabolites on D2 and 15. Urinary elimination is about 2 % of total dose administered over 4 hours for 5- FU and 8 to 22% for Fluoro β Alanine (FBAL). Plasma clearance of 1.73±1.22ml/h/m2 for 5FU, 53.76±25.36ml/h/m2 for FBAL. For O, residual level at D15 higher in erythrocytes than in plasma suggest an important irreversible binding with red cells without blood toxicity. Conclusions: Xelox with and without targeted therapies is an active and safe combination in ACRC. When O is administered over a long period of time and X is given at least 12 h later, neurotoxicity was mild and no hand-foot syndrome was observed. Important PK parameters variability mainly for 5FU and FBAL suggest posology adaptation on the basis of concentration ratio 5FU/FBAL in blood. No PK interaction between monoclonal antibodies and X or O were observed whatever the schedule of drug administration. No significant financial relationships to disclose.
Immune infiltrates in liver metastases of colorectal cancer and response to chemotherapy
Authors: Halama N. , Michel S. , Kloor M. , Zoernig I. , Pommerencke T. , Schirmacher P. , von Knebel-Döberitz M. , Weitz J. , Grabe N. , Jäger D. 
Published: August 2020

e15069 Background: Colorectal cancer (CRC) is a major cause of death from cancer. Patients with irresectable or metastasized CRC usually receive chemotherapy in combination with a monoclonal antibody, median overall survival time is around 20- 21 months with response rates of around 50%. Almost half of the patients experience treatment related side effects without benefit. K-ras mutation is the only (negative) predictive marker for response to therapy (for EGFR-targeting antibody treatment), no biomarkers are available that help to select patients most likely responding to chemotherapy. In primary colon cancer immune infiltrates in the tumor represent an important prognostic factor. High densities of tumor infiltrating lymphocytes (TIL) were shown to be correlated with an improved survival in patients with primary CRC. TILs therefore represent a valuable prognostic tool, a high density of immune cells being associated with good outcome independently of other established prognostic markers. Little is known about an association between these immune cells and the response to chemotherapy. Methods: Here the relation between infiltrates of immune cells in liver metastases of CRC and the response to chemotherapy (using immunohistochemical staining against CD8, GranB, FOXP3, CD45RO, etc.) was investigated. Samples from 33 patients with metastasized colorectal cancer (samples from 22 patients were used as training set and samples from 11 patients as validation set) were analyzed. Results: The evaluation of positively stained TIL in the invasive margin of the liver metastasis allowed to predict response to chemotherapy. This was also observed in the analysis of the time to progression, where higher numbers of positively stained cells were associated with longer intervals. The difference between the groups with either response or no response to chemotherapy in time to progression was statistically significant in the analyzed sets (Mann-Whitney- U, p<0.001, two-tailed, z=-3,961, n=33). In primary tumors no association between TIL densities and response to chemotherapy was observed. Conclusions: Our results suggest that the immune system has an important impact on the efficacy of chemotherapy and the presented data will have implications for the assessment of therapy options. No significant financial relationships to disclose.
Phase II study of bevacizumab in combination with capecitabine as first line treatment in elderly patients with metastatic colorectal cancer (MCC)
Authors: Vrdoljak E. , Omrcen T. , Hrabar A. 
Published: August 2020

e15074 Background: The aim of this prospective study was to evaluate efficacy and safety of bevacizumab in combination with capecitabine as first line treatment in elderly patients with MCC. Methods: 40 elderly patients (median age 75 years) with MCC have been treated with bevacizumab in combination with capecitabine as their first line therapy. Regimen consisted of bevacizumab 7.5 mg mg/kg on day 1 plus capecitabine 1000 mg/m2 on day 1–14 followed by 7 days rest. Results: The median follow up time at time of ASCO will be 12 months. Median number of 9 cycles was administrated, ranging from 1 to 23. 3 patients (7.5 %) had complete response, 19 patients (47.5 %) had partial response, 11 patients (27.5 %) had stable disease, 1 patient (2.5 %) progressed according to RECIST criteria and 6 patients (15%) were not evaluated yet. Until this report 15 of 40 patients progressed and 9 of 40 patients died. Median time to progression is 6.37 months. Median overall survival will be reported at ASCO 2009 meeting. The most common hematological adverse events were mild (grade I and II): anemia (27.5%) neutropenia (22.5%), and thrombocytopenia (20%). The most common non-hematological toxicity were mild as well (grade I and II): hand-foot syndrome (70%), arterial hypertension (52.5%), proteinuria (45%), hyperbilirubinemia (45%), diarrhea (25%), loss of appetite (23.5%), fever (22.5%), fatigue (17.5%), tearing (17.5%), and nail changes (12.5%). Grade 3 and 4 adverse events occurred rarely: hand-foot syndrome (12.5%), deep vein thrombosis (7.5%), fever (5%), and arterial hypertension (2.5%). Conclusions: This prospective phase II study has demonstrated that bevacizumab in combination with capecitabine as first line treatment in elderly patients with metastatic colorectal cancer is an effective and well-tolerated regimen. [Table: see text]
Capecitabine and irinotecan (XELIRI) in first-line treatment of metastatic colorectal cancer (mCRC): A systematic review of controlled clinical trials
Authors: Sukumaran S. , Pavlakis N. , Pittman K. B. , Patterson K. , Price T. J. 
Published: August 2020

e15100 Background: Irinotecan and 5-Fluorouracil based combination is an effective regimen for mCRC. Capecitabine, an oral fluoropyrimidine, is a convenient alternative to intravenous 5- Fluorouracil. This study aims to systematically review all published and unpublished controlled phase II and III trials of XELIRI combination, used in first line treatment of mCRC, reported from 2000–2008, to describe its efficacy and safety. Methods: A literature search of MEDLINE, EMBASE, CINAHL and proceedings from ASCO, ESMO and WGIC was conducted. The primary end point was response rate (RR), secondary endpoints include: time to progression (TTP), overall survival (OS) and toxicity. Results: Thirty non-randomised phase II trials (n = 1380) along with 6 randomised phase II and 3 phase III trials, were included (pooled n = 1478). The daily dose of capecitabine ranged from 1,800 mg/m2 to 2,500 mg/m2 for 7 to 14 days per cycle and the dose of irinotecan varied from 180mg/m2 to 350 mg/m2, over a 3 week period per cycle. Amongst the non-randomised studies, the median patient age was 61 years (53–72).The median RR was 46.75% (25–78%). The median reported TTP was 7.9 months (mo) (5- 9.9 mo) and the median OS was 15.6 months (7–24.8 mo). Grade 3–4 toxicity incidence was: diarrhoea (21.5%), neutropenia (12%), vomiting (12.5%), fatigue (6%) and Hand-foot syndrome (6%). The pooled incidence of febrile neutropenia was 2.5%. Amongst the randomised trials, the comparator regimens were XELOX or FOLFIRI. Median age was 65 years (61–74). RR for XELIRI was 39% (34–56%) compared to 47% (27–61.8%) for the non XELIRI comparator arms. Median reported TTP was 8.2 mo (5.7–12.5 mo) for the XELIRI arms and 9.2 mo for the comparator arms. Conclusions: XELIRI is an effective and feasible regime in the first line management of mCRC. However the optimal role of this combination remains to be established. No significant financial relationships to disclose.
Do predictive scoring systems have any role in determining treatment strategy for colorectal liver metastases at the individual patient level?
Authors: Malik H. , Poston G. 
Published: August 2020

e15104 Background: the literature contains four prognostic scoring systems from large volume series predicting survival after resection for colorectal liver metastases. Our aim was to directly compare these systems in terms of accuracy in predicting survival, and evaluate the role of such systems in determining therapeutic strategies on intention to treat at the individual patient level. Methods: the original published data were reviewed and the median survivals plotted against each point in the scoring system. The best fit line was drawn and the resultant plots enabled calculation of slope of the linear regression line and the square of the Pearson product moment correlation coefficient through data points allowing all four prognostic scoring systems to be directly compared. Results: when the prognostic scores were compared on a common scale, the R-squared values of all the scoring systems were similar with R-squared values of greater than 0.94 in all cases. The Basingstoke Predictive Index however produced the steepest gradient suggesting it can better distribute patients along a wider range of survival. Conclusions: none of the four scoring systems was perfect in their predictive value. It is not surprising that the risk score from MSKCC and Leeds are not as good as the others since they are meant to be preoperative prognostic scores and postoperative scoring system by their nature of having more information should be better. Clearly, future developments in this field must incorporate advances in our understanding of tumor biology. [Table: see text]
Evaluation of the distinction between responder and non-responder in FOLFOX/FOLFIRI based on the alteration of serum iron level
Authors: Ochiai T. , Nishimura K. , Watanabe T. , Kitajima M. , Nakayama N. , Mashiko S. , Yamazaki R. , Kaneko N. , Futagawa S. , Nagaoka I. 
Published: August 2020

e15110 Background: The alteration of serum-iron level during chemotherapy is already reported (Follezou, NEOPLASMA 1985). However, the correlation to prognosis has not been evaluated. The aim of this study was to evaluate the correlation between prognosis and serum-iron level in advanced / metastatic colorectal cancer (aCRC / mCRC) patients treated by FOLFOX / FOLFIRI. Methods: Serum-iron levels, hemoglobin, AST and ALT serum levels in immediately pre and post chemotherapy were analyzed in 58 aCRC / mCRC patients received FOLFOX-4 / FOLFIRI therapy between April 2005 and September 2008. 26 patients received FOLFOX-4 / FOLFIRI therapy as the final chemotherapy died by the time of analysis. These patients were categorized into the high increase group and the low increase group using 200% increase as cut-off value and the prognosis was compared. Results: Mean serum-iron levels in immediately pre and post chemotherapy were 71.7±29.0μg/dl and 186.8±83.2μg/dl, respectively, and significant increase after chemotherapy was observed (p<0.001). This increase was transient and returns to pre chemotherapy level by the start of next course. This alteration was always observed on the chemotherapy. The median survival times from the initiation of FOLFOX-4 / FOLFIRI therapy for the high increase group (n: 5) and the low increase group (n: 21) were 487 and 182 days, respectively, and was significantly better in the high increase group (p=0.004). The alterations of hemoglobin, AST and ALT serum levels in immediately pre and post chemotherapy were not observed. Conclusions: It is suggested that serum-iron increase is a biological response not attributed to leakage from erythrocyte and hepatocyte. Significantly better prognosis in high serum-iron group may suggest the usefulness of serum-iron level to distinguish responder and non-responder in FOLFOX-4/FOLFIRI therapy. No significant financial relationships to disclose.
A closer look at the number of lymph nodes examined in colorectal cancer: A VAMC experience
Authors: Kovar J. M. , Bui H. X. , Reynolds J. P. , Al-Ghawi H. , Luo G. , Abdel Karim N. , Samaan S. , Mehta A. , Molloy M. 
Published: August 2020

e15117 Background: Retrieval of 12 lymph nodes (LN) is a current benchmark in colorectal cancer (CRC) resections according to the National Quality Forum (NQF). Series of multiple institutions contain variability in surgical and pathologic techniques for lymph node retrieval. To ensure consistency in retrieving lymph nodes for satisfactory staging, we present a 12 year experience by a single surgeon and single pathology lab at one VAMC on 157 patients (mean age 67) undergoing CRC resection. Furthermore, the use of chemotherapy for Stage II patients <12 LN retrieved is controversial and yields only a small survival benefit. Methods: The records of 157 patients from one surgeon's case log from 1994–2007 were reviewed. Strict guidelines were applied to remove the same distribution of pericolonic fat. The lab followed a two step approach to LN dissection: Step 1 search for grossly identifiable LN; Step 2 overnight Carnoy's immersion to find smaller LN. Statview and SAS software analyzed 1)Overall survival (OS) and association with finding >12LN; 2)Number of LN identified and impact on AJCC tumor stage (TS) and overall survival; 3)Number of LN and WHO tumor grade (TG) with OS; 4)The impact of number of positive LN on OS. Results: Our mean LN found (14.75) is higher than the 12 recommended by the NQF and is not significantly associated with OS regardless of AJCC TS(p=0.06). The mean LN per TS was I=13.4(N=41)/II=16.3(N=56)/ III=14.3(N=38)/IV 14.2(N=22). Number of LN identified was not statistically significant in predicting TS(p=0.42) or OS(p=0.24). WHO TG is significantly associated to decreased OS, but only in AJCC TS II/III/IV and not stage I (Ip>0.05/IIp=0.008/ IIIp=0.01/IVp=0.025). Higher number of positive LN was associated with lower OS (per each +LN, survival decreases by 0.15 months p=0.001) Conclusions: Contrary to multicenter studies, total number of LN identified does not impact AJCC TS or OS. Higher WHO TG and higher number of positive LN is associated with worse OS. This suggests that the tumor biology is more indicative of OS rather than host response (reactive lymphoid tissue) to the tumor. Stage II patients <12 LN may not be ‘high risk’ and adjuvant chemotherapy based on this factor alone should be reconsidered. Further studies would be warranted. No significant financial relationships to disclose.
Randomized phase II trial of capecitabine versus capecitabine, low molecular weight heparin, and prednisone in refractory colorectal carcinoma
Authors: Mak E. , Townsley C. , Buckman R. , Chen E. , Lopez L. , Wang L. , Moore M. , Oza A. M. 
Published: August 2020

e15126 Background: Capecitabine is widely used in the treatment of advanced colorectal cancer. Continuous low dose chemotherapy has been postulated to have anti-angiogenic effects discrete from its anti-proliferative effects on tumors (metronomic therapy). Dalteparin and prednisone have also been implicated in inhibiting tumour angiogenesis and hypothesized to have additive benefit to chemotherapy. This randomized phase II study examined the additive effect of dalteparin and prednisone with capecitabine in metastatic colorectal cancer. Methods: Patients with metastatic colorectal cancer were randomized to either capecitabine (C) 2,500 mg/m2 in divided doses from days 1–14 in a 3-week cycle or capecitabine with dalteparin and prednisone (CDP). There was no restriction on previous treatment, other than no prior capecitabine. Dalteparin was given at 5,000 units once daily subcutaneously, and prednisone orally 10 mg daily, both on a continuous basis. Thirty patients were planned for accrual in each arm with interim analysis when accrual reached fifteen in each arm. The primary end-point was disease control defined as treatment response or stable disease >4 months. Radiological evaluation was performed every 6 weeks. Treatment was discontinued if patients had progressive disease or intolerable toxicity. Results: Thirty patients were recruited. Fourteen patients had received ≥3 previous regimens (median 3 (C), 2 (CDP)). Median performance statuses were ECOG 1 (C) and 0 (CDP). Nine patients achieved stable disease greater than 6 months (5 (C)/4 (CDP)). There was no statistical difference in the median survival time and time-to- progression for the two groups (11.1 mth (C)/15.8 mth (CDP); 3.2 mth (C)/2.8 mth (CDP)). The commonest toxicities overall were myelosuppression and hand-foot syndrome (HFS). The most common Grade 3+ adverse events were HFS (6 patients) and diarrhea (4 patients). Conclusions: The combination of dalteparin, prednisone and capecitabine did not improve disease control over that seen with capecitabine in refractory metastatic colorectal cancer. No significant financial relationships to disclose.
Protective role of silibinin on matrix metalloproteinase-2 and activator protein-1 on LoVo cells
Authors: Lin C. , Chen Y. 
Published: August 2020

e15136 Background: Silibinin, a flavonoid and the major active component of milk thistle, has been as a safe diet supplement for several decades. It has been proved with anti-hepatotoxic properties and pleiotropic anticancer capabilities. Current study aimed to investigate the role of silibinin as potential therapeutic target of colon cancer through antiangiogenesis and its related molecular mechanisms with matrix metalloproteinase- 2 (MMP-2) and activator protein-1 (AP-1). Colon cancer cell line, LoVo cells, treated with a major prognostic factor, interleukin-6 (IL-6), was studied. Methods and Results: By western blot analysis, silibinin suppressed MMP- 2 protein expression in time- and concentration-dependent manners. Furthermore, the inhibitors of JNK/AP-1 binding activity abolished the expression of MMP-2 in IL-6-stimulated LoVo cells, but not PI3K pathways. We also demonstrated that silibinin inhibited IL-6- stimulated LoVo cell migration and further tumor angiogenesis, which similar to the effects from addition with AP-1 inhibitor. By EMSA, the binding activity of AP-1 in LoVo cells was also decreased with silibinin treatment. In addition, the imaging of confocal microscopy revealed that AP-1 presentation was attenuated on IL-6-stimulated LoVo cells plus silibinin treatment. Conclusions: Taken together, these data indicated that silibinin inhibits angiogenesis through the suppression of MMP-2 expression and AP-1 binding activity in colon cancer cells. It suggests a novel anti-metastatic application of silibinin in colon cancer chemoprevention. No significant financial relationships to disclose.
Phase I study of preoperative (pre-op) short course chemoradiation (CRT) with proton beam therapy (PBT) and capecitabine (cape) for resectable pancreatic ductal adenocarcinoma (PDAC) of the head
Authors: Hong T. , Ryan D. P. , Blaszkowsky L. S. , Mamon H. J. , Mino-Kenudson M. , Adams J. , Yeap B. , Winrich B. , DeLaney T. F. , Fernandez-del Castillo C. 
Published: August 2020

e15536 Background: Standard adjuvant 6 week CRT may delay and reduce tolerability of adjuvant gemcitabine-based chemotherapy. We explore the feasibility of a one-week course of pre-op CRT with PBT and cape followed by pancreaticoduodenectomy (PD). Methods: 15 pts with radiographically resectable, biopsy-proven PDAC of the head were enrolled from May 2007- September 2008. Eligibility included no CT involvement of SMA or celiac artery; adequate renal, hepatic and hematopoetic function; and ECOG PS 0/1. Dose level 1 consisted of PBT delivered 3 Gy x 10 Monday to Friday. Pts in subsequent dose levels received 5 Gy x 5 in progressively shortened schedules: level 2 (wk 1 M W F, wk 2 T Th), level 3 (wk 1 M T Th F, wk 2 M), level 4 (wk 1 M-F). Radiation was targeted at pancreatic mass with elective nodal coverage. Pts received Cape 825 mg/m2 BID wk 1 and 2 M-F. PD was performed 1–6 wks after completion of chemotherapy. Results: 15 pts were enrolled on study. 3 pts were treated at each of dose levels 1–3. 6 pts were at dose level 4, which was selected as MTD. No dose limiting toxicities were observed. Gr 3 toxicity was noted in 4 pts (pain-1, GI-1, stent obstruction/infxn- 2). 11 pts underwent resection. Reasons for no resections were: metastatic disease-3 and unresectable tumor- 1. Mean time from last therapy to surgery was 28 d (10–44). Mean post-PD length of stay was 6 days (range 5–10). No unexpected 30-d post-op complications, including leak or infection, were noted in comparison to historical controls. 9/11 resected pts had R0 resection. 9/11 had positive nodes. Mean resected tumor diameter was 2.9 cm (2.2–4.3). Average percentage of fibrosis in tumor mass was 74%. Conclusions: Pre-op CRT with 1 wk of PBT and capecitabine followed by early surgery is feasible. A phase II study is underway. No significant financial relationships to disclose.