bluuebunny/crossref_metadata_2025_split huggingface dataset:
Irinotecan-induced neutropenia and UGT1A1*28: Does dose matter?
Authors: Hoskins J. M. , Goldberg R. M. , McLeod H. L. 
Published: March 2020

4023 Background: On July 7 2005, the Food and Drug Administration (FDA) of the U.S.A. and Pfizer Pharmaceuticals changed the package insert information for irinotecan to include a patient’s UGT1A1*28 genotype as a risk factor for severe neutropenia. This change resulted from the findings of four pharmacogenetic studies that identified a 2.5 to 17-fold risk of toxicity in homozygous UGT1A1*28 patients receiving irinotecan. Notably, a total number of 34 patients in the four studies were homozygous for the UGT1A1*28 allele. Subsequent studies on larger patient cohorts treated with other dosage regimens have failed to consistently replicate the UGT1A1*28 genotype-toxicity associations, thus confounding the development of dosing recommendations. This has contributed to confusion on how best to select a safe dose of irinotecan for a patient who is homozygous for UGT1A1*28. Methods: We reviewed the data presented in ten irinotecan pharmacogenetic studies (825 patients) and assessed the correlations between the incidence of irinotecan-induced hematological toxicities (grade III/IV) in UGT1A1*28/*28 patients, irinotecan dose, and overall toxicity. Results: We found that the incidence of grade III/IV hematological toxicities in UGT1A1*28/*28 patients was positively related to both irinotecan dose (Spearman Rank correlation rS=0.68; P=0.04; N=10 studies) and the overall incidence of toxicity of a regimen (rS=0.88; P=0.002; N=10 studies). The incidence of severe hematological toxicity amongst all patients was not related to irinotecan dose (rS=0.44; P=0.20, N=10 studies). Conclusions: Our results suggest that the risk of experiencing irinotecan-induced hematological toxicity for UGT1A1*28/*28 patients is a function of the dose of irinotecan administered. In the spirit of maximizing patient safety, we support the use of genotype-based dosing of irinotecan for high doses of irinotecan, but believe it may not be as useful for lower doses and suggest strategies for dosing patients with irinotecan. [Table: see text] No significant financial relationships to disclose.
18F-FDG PET changes management and improves prognostic stratification in patients with colorectal cancer: results of a prospective, multi-centre study
Authors: Scott A. M. , Gunawardana D. , Kelly B. , Stuckey J. , Byrne A. , Ranshaw J. , Fulham M. 
Published: March 2020

4025 Background: The aims were to: 1) examine the impact of PET in changing management in patients with proven or suspected recurrence of colorectal cancer and, 2) assess the impact of management change on disease free survival. Methods: Symptomatic patients (Group A) with a residual structural lesion suspicious for recurrent tumour, or patients (Group B) with pulmonary or hepatic metastases, which were potentially resectable as determined by conventional imaging, underwent PET scans. Pre- and post-PET management plans were documented blinded to PET results. Patients were followed for 12 months to determine actual management and to assess clinical outcomes. Results: A total of 191 patients (118M:73F, mean age 66 yrs) were recruited. PET detected additional sites of disease in 48.4% of Group A and 43.9% of Group B patients. Importantly, a change in planned management was documented in 65.6% of Group A and 49.0% of Group B patients. Follow-up confirmed implementation of management plans in 96% of patients. Analysis of follow-up data to 12 months post- PET showed that in Group A progressive disease was identified in 60.5% of patients with additional lesions detected on PET compared with conventional imaging, and 36.2% patients with no additional lesions detected by PET (p=0.0364); in Group B progressive disease was identified in 65.9% of patients with additional lesions detected on PET and 39.2% patients with no additional lesions detected by PET (p=0.0198). Patient follow-up also showed that PET provided valuable prognostic information in patients stratified into curative/palliative intent groups. Conclusions: These data unequivocally demonstrate the significant impact of PET on management and outcomes in patients with suspected recurrent colorectal cancer. No significant financial relationships to disclose.
Updated results of BICC-C study comparing first-line irinotecan/fluoropymidine combinations with or without celecoxib in mCRC: Updated efficacy data
Authors: Fuchs C. , Marshall J. , Mitchell E. , Wierzbicki R. , Ganju V. , Jeffery M. , Schultz J. , Richards D. A. , Soufi-Mahjoubi R. , Barrueco J. 
Published: March 2020

4027 Background: This multicenter, randomized study assessed efficacy & safety for irinotecan/fluoropyrimidines combinations in previously untreated mCRC. Methods: Pts were randomized to: infusional FOLFIRI, modified bolus IFL (mIFL), or CapeIri; and concurrent celecoxib or placebo in a double-blind fashion. The protocol was amended in April 2004: bevacizumab (bev) was added to the FOLFIRI and mIFL arms, whereas CapeIri was discontinued. Period 1 (P1) and Period 2 (P2) designate subjects enrolled before or after the amendment. Initial efficacy & safety analyses were reported at ASCO ’06. We now report follow-up of 46 months for P1 and 31 months for P2. Results: 430 pts were treated in P1 and 117 pts in P2. Baseline characteristics and post-study treatment were balanced. P1 results: Median progression free survival (PFS) was 7.6 mos for FOLFIRI; 5.9 mos for mIFL (p=0.004); and 5.8 mos for CapeIri (p=0.015). Median overall survival (OS) was 23.1 mos for FOLFIRI; 17.6 mos for mIFL (p=0.087); and 18.9 mos for CapeIri (p=0.27). One-year survival rate favored FOLFIRI (75%) compared to either mIFL (65%) or CapeIri (66%). Overall Response Rate (ORR) was 47% in FOLFIRI, 43% in mIFL, 39% in CapeIri (not significantly different). P2 results: Median PFS was 11.2 mos for FOLFIRI+bev and 8.3 mos for mIFL+bev (p=0.28). Median OS was not reached for FOLFIRI+bev but was 19.2 mos for mIFL+bev (p=0.007). One-year survival rate favored FOLFIRI+bev (87%) when compared to mIFL+bev (61%). ORR was 58% for FOLFIRI+bev and 54% for mIFL+bev (p=0.73). Common grade = 3 AEs are listed below. Celecoxib did not impact safety or efficacy. Conclusions: First line FOLFIRI or FOLFIRI+bev were superior to their comparators and show favorable results in survival and tolerability in untreated mCRC. Median survival for FOLFIRI+bev has not been reached. [Table: see text] No significant financial relationships to disclose.
Final results of CONFIRM 2: A multinational, randomized, double-blind, phase III study in 2nd line patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo
Authors: Kohne C. , Bajetta E. , Lin E. , Valle J. W. , Van Cutsem E. , Hecht J. R. , Moore M. , Germond C. J. , Meinhardt G. , Jacques C. 
Published: March 2020

4033 Background: PTK/ZK, a novel, oral, anti-angiogenic compound that inhibits all VEGF receptors has been investigated in two multinational randomized phase 3 studies in 1st (CONFIRM 1) and 2nd line (CONFIRM 2) mCRC. Interim analyses (IA) have been presented at ASCO 2005 and 2006, respectively. Methods: In CONFIRM 2, 855 pts were randomized to FOLFOX4 plus PTK/ZK (1250 mg, qd), or placebo. Eligibility included histologically documented mCRC, pre-treatment for metastatic disease with irinotecan-/fluoropyrimidine- based therapy, measurable disease by RECIST, PS of 0–2 and adequate organ function. Pts were stratified based on PS (0 vs. 1–2) and baseline serum Lactate Dehydrogenase (LDH = vs. >1.5 × ULN). The primary endpoint is overall survival (OS). Secondary endpoints included OS and PFS in high LDH pts (LDH > 1.5 × ULN). Results: At the time of IA in July 2005, OS was 12.1 mo in the PTK/ZK and 11.8 mo in the placebo arm (HR: 0.94; p=0.511). PFS was significantly longer in the PTK/ZK arm (5.5 mo vs. 4.1 mo; HR: 0.83; p=0.026). LDH, a marker for poor prognosis in mCRC, is predictive of the outcome in the PTK/ZK arm. When treated with PTK/ZK, high LDH pts showed a strong improvement in PFS (5.6 mo vs. 3.8 mo; HR: 0.63; p<0.001) and in OS (9.6 mo vs. 7.5 mo; HR: 0.78; p=0.10). Adverse events (AE) were similar to that of the CONFIRM 1 trial. Final analysis for OS, PFS and safety is planned for Feb. 2007 after 732 events (compared to 413 in the IA) and will be presented at the meeting. Conclusions: While the primary endpoint for OS was not met in the IA, PTK/ZK improves PFS significantly in the overall population, and shows strong activity (improved PFS and OS) in patients with high baseline serum LDH. Final results of the study will be presented at the meeting. No significant financial relationships to disclose.
Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the first-line treatment of metastatic colorectal cancer (mCRC): OPUS, a randomized phase II study
Authors: Bokemeyer C. , Bondarenko I. , Makhson A. , Hartmann J. T. , Aparicio J. , Zampino M. , Donea S. , Ludwig H. , Zubel A. , Koralewski P. 
Published: March 2020

4035 Background: FOLFOX-4 is a standard first-line treatment for patients (pts) with mCRC. The IgG1 monoclonal antibody cetuximab has proven activity in combination with cytotoxic chemotherapy. Excellent response rates (RRs) have been reported with first-line cetuximab and FOLFOX-4. This randomized, controlled study was conducted to compare RRs of FOLFOX-4 + cetuximab vs FOLFOX-4. Methods: Pts with previously untreated epidermal growth factor receptor (EGFR)-expressing mCRC not resectable with curative intent were eligible. They were randomized 1:1, stratified by ECOG performance status (PS) (0–1 vs 2), to either Group A (cetuximab 400 mg/m2 initial dose then 250 mg/m2/week plus FOLFOX-4 every 2 weeks [oxaliplatin 85 mg/m2 day (d) 1; FA 200 mg/m2 d1, 2; 5-FU 400 mg/m2 bolus + 600 mg/m2 infusion over 22 h, d1, 2]) or Group B (FOLFOX-4 only). The primary objective was the best confirmed RR assessed by independent review; secondary objectives were progression- free survival (PFS), overall survival (OS), the R0 resection rate after metastatic surgery of curative intent and safety. Results: Between July 2005 and March 2006, 337 pts were randomized and treated in more than 70 centers in Europe. 181 (53.7%) pts were male; the median age of all pts was 61.0 years [24–82]; 305 (90.5%) pts had an ECOG PS of 0 or 1, and 32 (9.5%) of 2. The best overall confirmed RR was 45.6% in A and 35.7% in B. For pts with ECOG PS 0–1, RR was 49.0% in A and 36.8% in B (Odds Ratio 1.648, 95%CI [1.043- 2.604]). PFS and OS results are not yet available. The most common grade 3/4 adverse events were neutropenia (27.6% in A; 31.5% in B), diarrhea (7.1 and 6.0%), leucopenia (7.1 and 5.4%) and rash (9.4%, in A only). Conclusions: The addition of cetuximab increased the RR of FOLFOX-4 in first-line treatment of mCRC. Grade 3/4 adverse events, with the exception of skin rash, were not significantly more frequent in the cetuximab arm. No significant financial relationships to disclose.
Treatment patterns and outcomes of patients with pT3N0 rectal cancer in a population-based setting
Authors: Johal B. S. , Phang P. , McGahan C. , Hay J. , Brown C. , Kennecke H. 
Published: March 2020

4039 Background: Adjuvant radiation (R) and chemotherapy (C) is generally recommended for patients (pts) with pT3N0 rectal cancer. Patterns of adjuvant therapy and outcomes among pts with pT3N0 rectal cancer referred to the British Columbia Cancer Agency (BCCA) were determined. Methods: The BCCA Colorectal Cancer Outcomes Unit database was used to identify referred pts with pT3N0 rectal carcinoma diagnosed between 2000–2004. During this period, “short course” R (25Gy/5, surgery within 10 days) was recommended for resectable cT3 tumors followed by 6 months of C. If not treated pre-operatively (pre-op), guidelines specified post-op “long course” (45Gy/25) R and C. Three treatment groups were identified: Surgery alone (S), S and R (SR), and S, R and C (SRC). Eligible pts had complete surgical resection with or without Total Mesorectal Excision (TME). Pts treated with “downstaging” pre-op long course R, with S and C only (13 pts) or with R2 resection were excluded. Locoregional Recurrence (LR) and Distant Recurrence (DR) rates determined. Reasons for non-treatment were determined by chart review. Results: 303 pts were identified, with median follow-up of 33.5 months. Significant differences in age, tumor height, grade, and R therapy existed between groups ( Table I ). TME status, R status and Radial Margin positivity were similar. LR rates were 15% (S), 2% (SR) and 1.4% (SRC). DR rates were 11.7% (S), 7.9% (SR) and 8.5% (SRC). Median Overall Survival (OS) and Disease Free Survival (DFS) was not reached. Conclusions: Treatment of pT3N0 rectal cancer was variable and significant heterogeneity existed between groups receiving S, SR and SRC. Nevertheless, LR rates were very low in pts receiving R and substantially higher in pts who did not. DR rates were similar across groups, irrespective of C history. Reasons for not receiving R or C were primarily patient related (medical/post- operative considerations, patient refusal). Potential physician related factors (non-referral) accounted for 28% of lack of C treatment in the SR group. [Table: see text] No significant financial relationships to disclose.
Preoperative FU-based chemoradiation with or without weekly oxaliplatin in locally advanced rectal cancer: Preliminary safety findings of the STAR (Studio Terapia Adiuvante Retto)-01 randomized trial
Authors: Aschele C. , Pinto C. , Cordio S. , Rosati G. , Bonetti A. , Alabiso O. , Siena S. , Pucciarelli S. , Boni L. , Cionini L. 
Published: March 2020

4040 Introduction: Oxaliplatin (OXA) significantly enhances the efficacy of 5-Fluorouracil (FU)-based chemotherapy (CT) in metastatic and radically resected, early stage colon cancer. Weekly OXA, at systemically active doses, can be added to preoperative FU-based pelvic chemoradiation (CRT) (Aschele, Ann Oncol 2005). Methods: An open-label, multicenter, randomized, phase III trial was launched to compare the efficacy (disease-free and overall survival) and activity (pathological response rate) of infused FU (225 mg/msq/day) concomitant to external-beam pelvic radiation (50.4 Gy in 28 daily fractions) (Arm A) to that of the same regimen plus weekly OXA (60 mg/msq weekly x 6) (Arm B). TME surgery is scheduled 6–8 weeks after completing CRT. FU-based adjuvant CT (4 cycles) is planned in both arms. Eligible patients (pts) have resectable tumors located within 12 cm from the anal verge and radiological evidence of perirectal fat or regional nodes involvement. Results: 410 pts (median age 63 years; males/females: 66/34 %; cT3/cT4: 66/18 %; cN+: 56 %; median distance from the anal verge: 6 cm) were randomized between 11/2003 and 10/2006 at 40 Italian centers. Toxicity data from the first 250 randomized pts are reported in the table . CRT was completed by 89 % and 74 % of pts in arm A and B, respectively. The median cumulative dose of delivered radiotherapy was 50.4 Gy in both arms. 120 of 123 pts in arm A and 109 of 112 pts in arm B were operated with a median interval from the end of treatment to surgery of 7.3 and 7.4 weeks, respectively. Conclusions: This analysis provides the first comparative toxicity data showing that OXA, at systemically active doses, can be safely added to standard FU-based CRT with an increased frequency and severity of acute toxicity but without major unexpected adverse events and without affecting the ability to deliver full RT doses and to perform surgery. [Table: see text] No significant financial relationships to disclose.
Bevacizumab, a vascular endothelial growth factor (VEGF) specific antibody reduces interstitial fluid pressure (IFP) in human rectal cancer xenograft (HT29) by day 5: Is this evidence for rescheduling its timing relative to chemotherapy?
Authors: Dani M. , Vojnovic B. , Newman R. , Honess D. , Wilson I. , Mitchell I. , Glynne-Jones R. 
Published: March 2020

4043 Background: Interstitial fluid pressure (IFP) of most solid tumours is increased relative to normal tissues; this is thought to be associated with the development of structurally and functionally abnormal blood and lymphatic vessels and interstitial fibrosis. Such interstitial hypertension creates a barrier for tumour transvascular transport, consequently compromising the delivery and efficacy of chemotherapy. We investigated the effect of Bevacizumab on IFP of a human rectal cancer xenograft. Methods: SCID mice bearing subcutaneous HT29 tumours of =8.5 mm diameter received a single dose of 10 mg/kg Bevacizumab intraperitoneally; controls received saline. Tumour IFP was measured in sedated mice (Hypnorm) on days 1, 3 and 5 post injection, using the wick-in-needle technique. Experiments were conducted under Home Office licence and approved by the local ethical committee. Results: Groups of 8 treated and control tumours were examined on days 1, 3 and 5 (n = 48). IFP was significantly lower (p<0.0001) on day 5 in treated than control tumours (mean ± SD 15.1 ± 4.7 cf 36.9 ± 5.6 mm Hg). No significant differences (p>0.05) between treated and control groups were seen on day 1 (31.8 ± 3.5 cf 30.6 ± 3.1 mm Hg) or day 3 (33.4 ± 5.5 cf 31.5 ± 3.2 mm Hg). No data were acquired on day 7 as the tumours ulcerated. Conclusions: Our data show that Bevacizumab causes a significant reduction of tumour IFP, but not until 5 days after treatment. Reduced IFP could augment uptake of cytotoxic drugs into tumour cells, hence timing of Bevacizumab relative to the first dose of chemotherapy could be of critical importance. No significant financial relationships to disclose.
Delayed start of adjuvant 5-FU/leucovorin based chemotherapy in colon cancer is safe up to 12 weeks postoperatively
Authors: Carlsson G. , Albertsson P. , Gustavsson B. 
Published: March 2020

4056 Background: Postoperatively adjuvant chemotherapy with 5-Fluorouracil modulated by leucovorin alone or in combination with Oxaliplatin significantly reduce the risk of recurrence and prolong the disease free survival (DFS) in patients with a radical resection for colonic carcinoma. In all reported studies the chemotherapy has started within 6–8 weeks after surgery. Due to complications following surgery it is not always possible to start adjuvant chemotherapy within this time frame. The aim of the present retrospective study was to investigate the effect on risk of recurrence and effect on DFS in patients treated in clinical routine practice in one single institution. Methods: Between 1992 and 2004, 234 patients (121 females, 113 males) with a median age of 66 years (range 25–84 years) received weekly bolus 5-FU/leucovorin postoperatively for 6 months. 211 (90.2%) had a Dukes′ C tumour and 23 (9.8%) high risk Dukes′ B tumour. The median time from surgery and start of adjuvant therapy was 71 days (range 30–190 days). Patients were divided in three groups, where chemotherapy started within 6 weeks, 8 weeks and 12 weeks after surgery and the frequency of recurrent disease and DFS were compared between these groups. Results: Medium follow-up was 35.6 months (range 2,7- 140.6 months). Five patients (21.7%) with Dukes′ B tumours and 76 patients (36.0%) with Dukes′ C tumours recurred during the follow-up period. There were no differences in the proportion of Dukes′ B and C tumours between the three groups. Recurrent disease was more frequent but no significant difference in patients that started within 6 weeks (52.6%) compared with patients that started within 8 weeks (45.5%) and 12 weeks (35.5%). In all three groups there was a tendency to better DFS in patients that started later than 6 or 8 weeks, but these differences were not significant. Conclusions: Starting adjuvant 5-Fluorouracil/leucovorin alone later than 6–8 weeks do not negatively effect the risk of recurrent disease or DFS. No significant financial relationships to disclose.
Preliminary efficacy of bevacizumab with first-line FOLFOX, XELOX, FOLFIRI and monotherapy for mCRC: First BEATrial
Authors: Kretzschmar A. , Van Cutsem E. , Michael M. , Rivera F. , Berry S. , DiBartolomeo M. , Mazier M. , Lutiger B. , Cunningham D. 
Published: March 2020

4072 Background: In a phase III pivotal trial in patients (pts) with metastatic colorectal cancer (mCRC), BEV (BEV, Avastin®) increased overall survival (OS) by 30% when added to first-line IFL chemotherapy (CT). Recently, a second trial reported a significant improvement in progression free survival (PFS) when BEV was added to FOLFOX/XELOX in a similar patient population. Although, First BEAT was opened to evaluate the safety profile of BEV in a broader pt population using a variety of CT regimens, efficacy endpoints were investigated. Methods: First BEAT enrolled 1,927 mCRC patients in 41 countries between June 2004 and February 2006. Eligible pts were treated with first-line CT (physician’s choice) in combination with BEV (5mg/kg q2w [5-FU-based CT] or 7.5mg/kg q3w [capecitabine [cap, Xeloda®]-based CT]) until disease progression. Secondary endpoints included OS, time to progression (TTP) and PFS. Disease progression was assessed by investigators. Results: By Nov 15th, 2006, 1,914/1,927 pts had data available for analysis (male 58%; median age 59 years, 33% =65 years; ECOG PS 0/1 65%/34%). Median follow-up was 15 months; 60-day mortality was 2.5%. Patients receiving 5-FU/cap CT appeared to have poorer prognosis with respect to age =65 years (41%), ECOG PS 0/1 (58%/42%) and 60-day mortality rate (6.6%), compared with those receiving doublet CT regimens. The most common first-line CT regimens used with BEV were FOLFOX (28%), FOLFIRI (26%), XELOX (18%) and 5-FU or cap CT (16%). Median PFS was 10.4 (95% CI: 10.1–10.9 months, based on 882 events), 10.5 (9.7 - 11.6) in FOLFOX, 10.3 (9.7 - 10.7) in XELOX, 11.1 (10.2–12.0) in FOLFIRI and 9.1 (8.1–10.3) in pts receiving 5-FU or cap CT, respectively. TTP was 10.8 (95% CI: 10.4–11.3 months, based on 805 events). Updated analyses will be presented. Conclusions: In this ongoing, large community-based study, the preliminary efficacy of first line BEV in mCRC pts receiving a variety of CT regimens appears consistent with that observed in large phase III randomised trials. [Table: see text]