bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant chemotherapy including bevacizumab in potentially curable metastatic colorectal cancer
Authors: Gruenberger B. , Scheithauer W. , Tamandl D. , Puhalla H. , Kornek G. , Zielinski C. , Gruenberger T. 
Published: March 2020

3546 Background: the addition of targeting therapies to combination chemotherapy have dramatically improved outcome in metastatic colorectal cancer (mCRC). Special issues have been raised regarding the sequence of bevacizumab (bev) administration and surgery in mCRC. Methods: a pilot series of non-optimal resectable mCRC patients was initiated including a neoadjuvant protocol with bevacizumab 5mg/kg every two weeks plus XELOX (capecitabine 3500mg/m2/day days 1–7 plus oxaliplatin 85mg/m2 day 1 of a 2-week cycle) for six cycles (3 months). The sixth cycle did not include bev resulting in a gap of 5 weeks between last bev and surgery. Additional 6 cycles were started 5 weeks after surgery. Primary end points were feasibility of the regimen, possibility of curative surgical approach and morbidity of the surgical procedure including liver resection. Results: we have enrolled 22 patients of whom 12 are evaluable for all primary endpoints today. Median age of the patients was 61.5 years (± 8.8), 83% had a lymph node positive primary, 67% had synchronous liver metastases (LM), 33% had bilobar LM. The neoadjuvant treatment regimen was safely administered resulting in 2 CR, 8 PR and 2 SD; XELOX was dose reduced to 75% due to HFS, diarrhoe or PNP ≥ 3 in 3 patients (25%). Potentially curative surgery was performed in all but one patient (92%) including liver resection in 11 patients, involving additional resection of the primary in 3 patients. No patient required perioperative blood transfusions, morbidity consisted of one bile leak from the resection edge and one wound infection. No patient experienced bleeding complications or showed postoperative liver dysfunction. Median postoperative hospital stay was 7 days (± 1.7). All patients started adjuvant treatment within 5 weeks. Liver regeneration as evaluated during staging CTs confirmed no abnormalities. Conclusions: these data suggest that bevacizumab can be administered prior and after potentially curative surgery including liver resection without appearing to adversely effect surgical wound healing, bleeding or liver regeneration. However we would like to emphasize that patients need to be treated by an experienced multidisciplinary team including a liver surgeon qualified in dealing with chemotherapy altered livers. [Table: see text]
Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing low (1–9%) or negative (<1%) levels of epidermal growth factor receptor (EGFr)
Authors: Hecht J. , Mitchell E. , Baranda J. , Malik I. , Richards D. , Navale L. , D’Avirro P. , Amado R. 
Published: March 2020

3547 Background: Panitumumab is a fully human monoclonal antibody directed against EGFr. We investigated the antitumor activity of panitumumab in pts with mCRC who failed prior therapy and had low or negative EGFr tumor expression. Methods: In this multicenter, phase 2 study of 150 planned pts, pts had documentation of disease progression (PD) during or after adequate doses of fluoropyrimidine, irinotecan, and oxaliplatin (centrally confirmed refractory disease [CCRD]), 2–3 prior regimens, ECOG score 0–2, and low or negative EGFr staining (by IHC) in evaluable tumor cells. Pts received panitumumab at 6 mg/kg Q2W until PD or drug intolerability. Tumor assessments (modified WHO, blinded central review) were taken periodically from wk 8 until PD. Endpoints were objective response (OR) through wk 16 (+ ≥ 4 wk confirmation; primary) and OR throughout study, response duration, progression-free survival (PFS) time, survival time, and safety (secondary). Results: In this interim analysis (6/05), 88 pts were enrolled and had ≥ 1 dose of panitumumab (safety set); 23 pts had ≥ 20 wks before the cutoff and CCRD (efficacy set). The efficacy set consisted of 16M/7W, median age of 65 (range: 46, 85) yrs, 83% white, 100% with ECOG ≤ 1, 74% colon cancer and 26% rectal cancer; all received ≥ 2 prior regimens (equivalent characteristics for safety set). 2/11 (18%) pts with EGFr-negative tumors and 1/12 (8%) with low EGFr staining had a partial response. Duration was up to 16 wks. 7/23 (30%) of all pts had SD. Median (95% CI) PFS was 7.9 (7.0, 23.0) wks. In the safety set, all pts had a treatment-related adverse event; 19% grade (gr) 3; 2% gr 4. Integument and eye toxicities were: 92% skin, 17% eye, 28% nail, 8% hair, and 2% chelitis. 20 (23%) had diarrhea (1 gr 3); 7 (8%) had hypomagnesemia (2 gr 3/4). Three pts had an infusion reaction-1 gr 3 (led to panitumumab discontinuation) and 2 gr 1/2. In 65 pts with both a baseline and post-baseline sample, no human anti-human antibodies to panitumumab were detected. Updated data will be presented. Conclusions: Responses to panitumumab were seen in pts with mCRC with both low and negative EGFr levels. Efficacy appears similar to that in other studies with panitumumab in pts with higher EGFr tumor levels. [Table: see text]
Cetuximab plus irinotecan for metastatic colorectal cancer (mCRC): Safety analysis of 800 patients in a randomized phase III trial (EPIC)
Authors: Abubakr Y. , Eng C. , Wong L. , Pautret V. , Scheithauer W. , Maurel J. , Kroening H. , Lutz M. , Zubel A. , Sobrero A. 
Published: March 2020

3556 Background: EPIC is a randomized phase III study comparing cetuximab plus irinotecan to irinotecan in second-line metastatic, EGFR-expressing mCRC patients (pts) (target N=1,300 pts). Following an independent Data Safety Monitoring Board (DSMB) review of 400 pts., the pooled safety data was presented at ASCO 2005 (#3580). The DSMB has recently reviewed safety data on the first 800 patients. Methods: Patients with EGFR-expressing mCRC who had failed first-line oxaliplatin in combination with a fluoropyrimidine and an ECOG performance status ≤ 2 were randomized to either Arm A (cetuximab 400 mg/m2 followed by 250 mg/ m2 weekly and irinotecan 350 mg/ m2 q 3 weeks) or to Arm B (irinotecan 350 mg/ m2 q 3 weeks). A pooled safety analysis is presented. Results: Eight hundred patients were randomized from May 2003 to March 2005 in Europe, Australia, Asia, and the US: 309 women and 491 men, with a median age of 61 years (range 21–90) and ECOG performance status (PS) of: 0= 53%, 1= 42%, 2= 5%. Seventeen pts received no study therapy and are excluded from the analysis. A total of 3,629 chemotherapy cycles were administered to the 783 pts with a median of 4 cycles per pt (range 1–23). Four (0.5%) subjects experienced severe infusion reactions: 2 grade 3 and 2 grade 4, none were fatal. In this pooled analysis, 59 deaths occurred within 30 days of last study therapy: 45 disease-related, 5 study drug related, 6 due to other causes, and 3 with unknown etiology. A summary table of adverse events (AE’s) is included. Conclusions: The DSMB raised no concerns after reviewing the safety data from 800 pts. In this pooled analysis characteristic toxicities of cetuximab and irinotecan do not appear to be increased, incidences and severities are similar to the earlier safety report based on the initial 400 patients. The study is currently nearing completion of accrual. [Table: see text] [Table: see text]
cT3N0 rectal cancer: Potential overtreatment with preoperative chemoradiation (CRT) is warranted
Authors: Guillem J. G. , Diaz-Gonzalez J. , Minsky B. , Rodriguez-Bigas M. , Jeong S. , Coco C. , Hernandez J. L. , Valentini V. , Riedel E. , Pucciarelli S. 
Published: March 2020

3568 Background: Although CRT has emerged as the preferred treatment for T3 and/or lymph node (LN) positive rectal cancer, Sauer et al (NEJM 2004) demonstrated that 18% of patients deemed suitable for preop CRT via endorectal ultrasound (ERUS) were overstaged and therefore received unnecessary preoperative CRT. Since data also suggest that LN negative rectal cancer s/p TME may not need adjuvant therapy, it is reasonable to consider the omission of radiotherapy for the cT3N0 subset. We therefore determined the accuracy of pre-CRT ERUS/MRI staging in order to explore the validity of a non-radiation approach for cT3N0 disease. Methods: 188 ERUS/MRI staged T3N0 rectal cancer patients from 6 insitutions in the US, Europe and Asia received preoperative CRT (5-FU based and 45–52.5 Gy) followed by radical resection. Rates of pathologic complete response (pCR) and mesorectal LN involvement were determined. Results: Tumors were located a median of 5 centimeters from the anal verge. Sphincter-preserving surgery was performed in 135 (81%) patients. Overall pCR was 19%. Median number of LN sampled was 9 (range 0–38). Rate of positive LN was significantly associated with T-stage: pT0: 3%, pT1: 7%, pT2: 20%, pT3–4: 36%(p=0.001). 41 patients (22%) had pathologically positive mesorectal LN. There was no significant difference in rate of positive LN between those staged by ERUS and MRI(25% vs 16%, p=0.19). Conclusions: Accuracy of preoperative ERUS/MRI for identifying mid to distal T3N0 rectal cancer is limited, as 22% will have undetected mesorectal LN involvement despite CRT. Therefore, ERUS/MRI staged T3N0 patients should continue to receive preoperative CRT. Although 19% are overstaged and therefore overtreated, our data suggest that an even larger number would be understaged and require postoperative CRT, which is associated with inferior local control, higher toxicity, and poor functional outcome. No significant financial relationships to disclose.
Genome-wide expression profiling and tissue array analysis for prediction of recurrences in stage II-III colorectal cancer (CRC)
Authors: Boige V. , Svrcek M. , Michiels S. , Pocard M. , Laville V. , Drusch F. , Sabourin J. , Dessen P. , Ducreux M. , Lazar V. 
Published: March 2020

3572 Background: Despite substantial progress in molecular pathogenesis of colon cancer (CC), no reliable biomarkers of outcome have yet been identified in patients with resected stage II-III CC. Methods: We analyzed genome-wide mRNA expression profiles in 20 stage II or III left side CC from 10 patient who developed metastasis (M+) and 10 disease free patients followed up for at least 4 years (M-) using high-density oligonucleotide microarrays (Agilent technology). RNA from tumor tissue (T) was hybridized against normal tissue (NT) from the same patient and each experiment was replicated 4 times (with 2 dye-swaps). The goal was to select genes both differentially expressed between T and NT and between M+ and M-. A tissu-array was constructed using 212 stage II and III resected CRC (164 CC, 64 rectal cancers) and their matched NT. For survival analysis, immunohistochemistry (IHC) data was dichotomized at the median value. Results: Analysis of microarray data yielded 27 genes that had a 2-fold difference between the expression in T and NT in at least 5 out of 20 patients and for which the average expression was significantly different between M+ and M- (p<0.01, t-test). Among the 6 most differentially expressed genes between M+ and M- in T, 4 of them were found to be involved in interferon γ pathway and could be evaluated by IHC: CXCL9, CXCL13, PPARγ, THSD. In order to assess macrophage and natural killer (NK) cell infiltration, CD68 and CD57 were also analyzed. Intensity was measured by semi-quantitative scores for the first 4 genes and by the number of infiltrating cells for the others. CXCL9, PPARGγ, CXCL13, CD57 and CD68 were significantly underexpressed in T as compared to NT (p<0.0001, paired t-test). The logrank test stratified by cancer site indicated that high IHC expression of CD57 possessed a significantly better recurrence-free survival (RFS) than those low expression (p=0.004). Multivariate Cox analysis identified tumor site (p=0.001), node stage (p<0.001) and CD57 (p=0.002) as independent predictors of RFS. Conclusions: NK cell infiltration within colorectal cancers is associated with prolonged recurrence-free survival in stage II and III CRC. No significant financial relationships to disclose.
Randomized phase III trial of the TTD Group comparing capecitabine and oxaliplatin (XELOX) vs. oxaliplatin and 5-fluorouracil in continuous infusion (FUFOX) as first line treatment in advanced or metastatic colorectal cancer (CRC)
Authors: Massuti B. , Gómez A. , Sastre J. , Tabernero J. M. , Chaves M. , Carrato A. , Abad A. , Aparicio J. , Díaz-Rubio E. , Aranda E. 
Published: March 2020

3580 Background: OX plus CI 5-FU is one of the standard chemotherapy regimens for first-line treatment in patients (p) with advanced CRC. Phase II trials have shown XELOX as a convenient combination, with a high activity and a favourable safety profile. This study is a phase III trial comparing both schedules. Methods: Multicenter, randomized and open labeled study was designed to include p withadvanced/metastatic CRC adenocarcinoma, measurable disease, PS ≥70% and adequate bone marrow, renal and hepatic functions. Previous adjuvant chemotherapy was allowed. Primary endpoint is time to progression (TTP). The study was designed to determined non-inferiority when the median time to progression in the XELOX arm was not lower than 5.5 months (hazard ratio no larger than 1.27). A sample size of 348 p (174 per arm) was necessary (0.05 level test; 80% power). Treatment: P were randomly assigned to receive either Arm A: oral XEL 1000 mg/m2 twice daily from day 1 to day 15, plus OX 130 mg/m2, iv, 2h, day 1 (in 3-week treatment cycles) or Arm B: biweekly 85 mg/m2, OX, iv, 2h, plus weekly CI 5-FU 2250 mg/m2, in 48h (TTD schedule). Treatment was continued, until progressive disease, unacceptable toxicity or consent withdrawal. Results: 340 (170/170) p have been included in the interim analysis over 348 enrolled, (M/F, 61%/39%), median age: 65.6 years (32.3–81.6), PS 90–100%: 62%. Primary tumour sites were colon (66.4%), rectum (28.3%) and both (5.3%). Median relative dose intensity was 90% for XEL and 92% for OX in arm A and 78% for OX and 78% for 5-FU in arm B. Efficacy: overall response rate in each arm (A/B) was 37.1/43.0% (p=0.824). With a median follow up of 12.6 months, median TTP was 8.8/9.6 months (p=0.130). Main grade 3–4 toxicity per p in each arm (A/B) was: paresthesia (17.7/15.9%), asthenia (12.4/17.1%), diarrhea (14.1/23.6%), neutropenia (8.3/10.0%) and vomiting (4.1/7.6%). Mature data on TTP and OS will be presented at the meeting. Conclusions: Efficacy and safety results suggest a similar toxicity profile, response rate and TTP for both regimens. No significant financial relationships to disclose.
A phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)
Authors: Fakih M. G. , Pendyala L. , Toth K. , Creaven P. , Soehnlein N. , Litwin A. , Trump D. 
Published: March 2020

3592 Background: Vorinostat is a novel histone deacetylase (HDAC) inhibitor that potentiates 5-FU and platinum antitumor activity. This potentiation is associated with ∼ 40 fold decrease in thymidilate synthase (TS) expression, the main target of 5-FU, in preclinical models. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design. FOLFOX was administered at a fixed dose every 2 weeks: leucovorin 400mg/m2 and oxaliplatin 85mg/m2 over 2 hours followed by 5-FU bolus 400mg/m2 and 5-FU infusion 2400mg/m2 over 46 hours. Vorinostat started 3 days prior to FOLFOX and was given twice daily for 1 week followed by 1 week break. Investigated dose levels of vorinostat (twice daily) include 100, 200, and 300 mg. Tumor biopsies were obtained from patients with accessible liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 9 patients (pts) enrolled (M/F: 8/1; median age: 57, ECOG 0/1: 5/4). All pts had failed prior FOLFOX, irinotecan, and cetuximab therapy. One pt at dose level (DL) 1 was not evaluable due to rapid clinical progression. No dose-limiting toxicities were noted among the 8 evaluable pts. No grade (G) 3 toxicities were noted on the first cycle of treatment (within 2 weeks after 1st FOLFOX) and accrual continues on DL3. Cycle 1 toxicities were attributed to FOLFOX and consisted of 1 G2 neutropenia, 1 G2 mucositis, and 2 G2 nausea/vomiting. Responses were evaluable in 6 pts: 1 pt with peritoneal carcinomatosis on DL 1 has stable disease 5 months + along with a stable CEA; 3 patients at DL2 have stable disease at 2 months along with declining CEA in 2/3 pts. Two pts (DL1) with liver metastases biopsies had a major decrease in TS expression by IHC after 4 days of vorinostat. Conclusions: Vorinostat at 100–200mg PO BID × 1 week every 2 weeks in combination with FOLFOX is well tolerated. The lowest DL of 100 mg PO BID is associated with down-regulation of TS. Disease stabilization in highly refractory patients is promising. The investigation of this regimen in the first or second-line treatment of metastatic CRC is warranted. No significant financial relationships to disclose.
Patupilone in chemotherapy-pretreated patients with advanced colorectal cancer (CRC) receiving nutritional support and intensive diarrhea management: A phase I multicenter trial
Authors: Casado E. , Tabernero J. , Melichar B. , Bridgewater J. , Bennouna J. , Delord J. , Sopala M. , Sklenar I. , Cheung W. , Johri A. 
Published: March 2020

3593 Background: In previous clinical studies, a positive effect was noted in patients with CRC heavily pretreated with chemotherapy who received the novel microtubule stabilizer patupilone (EPO906; epothilone B) once-weekly or q3wk; however, susceptibility to diarrhea was high and response rates were modest. This dose-escalation trial examined the safety/efficacy of 3 patupilone regimens in chemotherapy-pretreated patients with CRC who received nutritional support and intensive diarrhea management. Methods: Patients with histologically confirmed CRC, without ileo- or colostomy or history of abdominal/pelvic irradiation, and who relapsed or were refractory after ≤4 prior chemotherapy regimens received nutritional support, intensive diarrhea management if needed, and patupilone as IV bolus q3wk or 1-or 5-day continuous IV (CIV) q3wk at doses of 6–10 mg/m2. Additional inclusion criteria: ≥1 measurable lesion; age ≥18 years; WHO performance status <2; no hepatic, renal, or hematologic impairment. Nutritional supplementation: ω-3 fatty acids, pre- and probiotics, antisecretory factor, and glutamine. Diarrhea management: appropriate clinical care, loperamide, opium tincture, codeine, and octreotide. Dose escalation was per protocol following a 3+3 design. The primary objective of this trial was to determine the maximum tolerated dose of the 3 patupilone treatment schedules in these patients. Results: Forty-four patients were enrolled: bolus, n = 22; 5-day CIV, n = 3; 1-day CIV, n = 19. Mean age 58.8 years; 95% Caucasian; 54% men. In the 5-day CIV arm, enrollment was closed at the 6.5-mg/m2 dose level since 2 dose-limiting toxicities (severe diarrhea) were reported. With bolus and 1-day CIV, the current doses are 10 and 9 mg/m2, respectively. The most common adverse events in the 43 patients evaluable for safety were diarrhea (70%), asthenia (23%), and nausea (21%). Grade 3 diarrhea occurred in 9 patients (21%). Overall response: 4 partial responses and 13 stable disease. Conclusions: Preliminary results suggest that patupilone monotherapy administered q3wk + intensive diarrhea management may prove beneficial in patients with CRC who progressed after 2–3 chemotherapy regimens. [Table: see text]
A randomized phase II non-comparative study of Ispinesib given weekly or every three weeks in metastatic colorectal cancer. A California Cancer Consortium Study (CCC-P)
Authors: El-Khoueiry A. B. , Iqbal S. , Singh D. A. , D’Andre S. , Ramanathan R. K. , Shibata S. , Yang D. Y. , Lenz H. J. , Synold T. , Gandara D. R. 
Published: March 2020

3595 Background: Ispinesib(SB-715992) is a polycyclic, nitrogen-containing heterocycle that inhibits the mitotic kinesin spindle protein (KSP). KSP is essential for mitotic spindle assembly and function during mitosis, and is a rational target of anti-cancer therapy. This phase II study used two different dosing schedules; the primary objective was to determine the response rate (RR) and the secondary objectives were to determine time to tumor progression (TTP), progression free survival (PFS), overall survival (OS) and toxicity. Methods: Patients (pts) were randomized to receive (Arm A) ispinesib 7 mg/m2 every week for 3 weeks, every 28 days or (Arm B) 18 mg/m2 every 21 days. Response was assessed every 6 weeks. Chemotherapy was administered until disease progression or intolerance. Results: A total of 64 pts were accrued. The median number of cycles was 2 for both arms. Five pts had stable disease and 48 had progressive disease. PFS was 49 days in Arm A (44 to 51) and 37 days in Arm B (35 to 42 days). The most common grade 3/4 toxicities in arms A and B respectively included neutropenia (3 and 20), nausea and vomiting (3 and 1), neurologic (1 and 2). Of these, only 1 pt had febrile neutropenia and 1 pt had peripheral sensory neuropathy. The toxicity data is not available on 2 patients. Eleven pts are not evaluable for response yet. Conclusions: Ispinesib did not demonstrate significant activity in heavily pretreated patients with advanced/metastatic colorectal cancer at the dose and schedule employed in this trial. Correlative studies are in progress. Supported by NO1 CM17101 [Table: see text] No significant financial relationships to disclose.
A genetic UGT1A1 polymorphism oriented phase I study of irinotecan (CPT-11) and doxifluridine (5’-DFUR: An intermediate form of capecitabine for metastatic colorectal cancer (MCRC)
Authors: Hazama S. , Nagashima A. , Kondo H. , Shimizu R. , Araki A. , Yoshino S. , Okayama N. , Hinoda Y. , Oka M. 
Published: March 2020

3602 Background: 5-Fluorouracil plus CPT-11 is one of the standard 1st-line therapies in patients (pts) with metastatic colorectal cancer (MCRC). Although it has been reported that individuals carrying the (TA) 7 allele in the TATAA promoter of UGT1A1 increased risk of severe toxic event occurrence after CPT-11 administration, there is no report about phase I study based on the polymorphism of UGT1A1. Here we report the results from a genetic UGT1A1 polymorphism oriented phase I study of CPT-11 and 5’-DFUR to determine the maximum tolerated dose (MTD) and the recommend doses (RD) for each UGT1A1 genotypes. Methods: Eligibility criteria were as follows; histologically proven CRC with unresectable metastatic lesions, PS 0–2, age<76, adequate organ functions, and written informed consent. CPT-11 was infused (level 1, 2, 3 and 4: 70, 100, 120, 150 mg/m2, respectively) biweekly and 5’-DFUR was administered orally (800 mg/body, <1.39 m2; 600 mg/body) on 5 consecutive days with 2 days’ rest for more than 12 weeks. DLT were determined as grade 3 hematological and non-hematological toxicities. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from pts. Results: Eighteen pts with wild 6/6 allele and 9 pts with mutated 6/7 allele were registered. In pts with 6/6 allele, MTD was not observed up to level 4 (150 mg/m2). In pts with mutated 6/7 allele, on the other hand, MTD was observed at level 2 (100 mg/m2). We recommend doses of 70 mg/m2 of CPT-11 for pts with mutated 6/7 allele and 150 mg/m2 of CPT-11 for pts with wild 6/6 allele, respectively. Conclusions: The recommended phases II/III starting doses of biweekly CPT-11 administration are 150 mg/m2 for pts with wild 6/6 allele and 70 mg/m2 of CPT-11 for pts with mutated 6/7 allele, and 5’ -DFUR 800 mg/body on every 5 days per week. This combination therapy may be administered safely for all pts according to the TATAA promoter polymorphism of UGT1A1. The gene polymorphism should be taken into consideration to provide more precise information to guess the individual toxicities. No significant financial relationships to disclose.