bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of bevacizumab in combination with irinotecan and infusional 5-FU as first-line treatment for patients with metastatic colorectal cancer
Authors: Sobrero A. , Ackland S. , Carrion R. P. , Chiara S. , Clarke S. , Giron C. G. , Langer B. , Zurlo A. , Young S. 
Published: March 2020

3544 Background: Bevacizumab is a monoclonal antibody that, by inhibiting VEGF, inhibits tumour angiogenesis. It has been proven to improve overall (OS) and progression-free survival (PFS) when administered first-line in combination with the bolus 5-FU-based IFL regimen to patients with metastatic colorectal cancer [Hurwitz et al. NEJM 2004;350:2335–42]. We have conducted a multicentre, open-label trial to further evaluate the efficacy and safety of first-line bevacizumab in combination with regimens combining irinotecan with infusional 5-FU (FOLFIRI). Methods: Eligible patients had: metastatic colorectal cancer; no surgery within 28 days; no prior chemotherapy for metastatic disease; ECOG PS 0/1; adequate organ function; no CNS metastases. Chemotherapy consisted of 6 cycles of irinotecan plus infusional 5-FU and leucovorin, according to the classical FOLFIRI regimen; however, such variations as the simplified FOLFIRI or the weekly regimen were allowed. Bevacizumab 5mg/kg was given on day 1 of chemotherapy, every 2 weeks until disease progression. Safety assessments were made at the time of chemotherapy administration during the first 12 weeks and every 4 weeks thereafter. Tumour assessments were performed every 3 months for the first year and 4-monthly thereafter. The primary objective was PFS; secondary objectives were to evaluate the safety profile of this combination as well as to determine the overall response rate, time to response, duration of response and OS. Results: A total of 209 patients were enrolled at 31 centres in Australia, Canada, Italy, Spain and China between April 2005 and November 2005. 60% of patients were male and median age was 61.9 (range 31–82) years. All patients will be eligible for interim analysis, that will be performed after the last patient enrolled has been followed for a minimum of 12 weeks (6 cycles of chemotherapy), in February 2006. Data on safety and efficacy from this analysis will be presented. Conclusions: This is the largest clinical trial that will report efficacy and safety data for bevacizumab in combination with an irinotecan and infusional 5-FU regimen. [Table: see text]
MABEL—A large multinational study of cetuximab plus irinotecan in irinotecan resistant metastatic colorectal cancer
Authors: Wilke H. , Glynne-Jones R. , Thaler J. , Adenis A. , Preusser P. , Aranda Aguilar E. , Aapro M. , Van Den Berg N. , Eggleton S. , Siena S. 
Published: March 2020

3549 Background: Cetuximab is an IgG1 anti-EGFR monoclonal antibody, active alone and in combination with irinotecan in metastatic colorectal cancer (mCRC) patients (pts) who failed irinotecan (Cunningham et al, NEJM 2004). MABEL investigated cetuximab plus irinotecan in an uncontrolled, multicenter study in pts with EGFR-detectable mCRC whose last treatment regimen contained irinotecan. MABEL is to date the largest cetuximab study published in this setting. Methods: Primary endpoint was the progression-free survival (PFS) rate at 12 weeks (wks), (expected rate 50% ± 3%). Study treatment was cetuximab, initial dose 400 mg/m2, weekly 250 mg/m2, plus irinotecan with dose and schedule as pre-study: Regimen A: 125 mg/m2 weekly for 4/6 wks, B: 180 mg/m2 q 2 wks, or C: 350 mg/m2 q 3 wks. Results: 197 centers from 7 countries screened tumors of 1681 pts for EGFR expression: 1461 (87%) pts had EGFR-detectable tumors. 1123 pts are currently evaluable: median age is 62 years (25–84), Karnofsky status ≥70% in all pts, and 64% pts were male. 64% pts had ≥ 2 prior therapy lines. 76% pts were also pretreated with oxaliplatin. On-study distribution of pts to irinotecan regimens was A: 92, B: 674, C: 357. 12-week PFS rates were: A: 60% (50–71%); B: 60% (56–64%); C: 63% (58–68%); overall: 61% (58–64%), and at 24 wks: A: 29% (19–39%); B: 32% (28–36%); C: 39% (34–45%); overall 34% (31–37%). The current estimate of median survival, based on 717 deaths, is 9.2 (8.7–9.9) months. Treatment was generally well tolerated with grade 3/4 adverse events >5%: diarrhea 20%, skin and subcutaneous tissue disorders incl. acne-like rash 19%, neutropenia 9%, asthenia 8%. Grade 3/4 immune system disorders incl. hypersensitivity reactions occurred in 1.5%, hypomagnesemia in 0.4% pts. Conclusions: The PFS rates observed in this heavily pretreated population fully met the primary endpoint of this study. Similar PFS rates were seen at 12 weeks (overall 61%) and 24 weeks (overall 34%) for all irinotecan regimens. Estimated survival time is in line with previously published results. MABEL clearly confirmed in a wider setting the efficacy and safety of cetuximab plus irinotecan seen in previous studies. [Table: see text]
Phase I study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer
Authors: Machiels J. P. , Sempoux C. , Scalliet P. , Coche J. C. , Coster B. , Canon J. L. , Kerger J. , Van Cutsem E. , Peeters M. , Haustermans K. 
Published: March 2020

3552 Background: Capecitabine has the potential to replace 5-FU as standard agent in combination with radiotherapy in rectal cancer. Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor. Both agents are active in the treatment of colorectal cancer and have demonstrated radiosensitising properties. The aim of this study was to assess the feasibility of combining cetuximab and capecitabine with concurrent radiation in the preoperative treatment of patients with rectal cancer. Methods: Twenty patients with rectal cancer (T3-T4 and/or N+, endorectal ultrasound) received radiotherapy (1.8 Gy, 5 days a week over 5 weeks, total dose 45 Gy, 3D conformal technique) in combination with cetuximab (initial dose 400 mg/m2 given one week before the beginning of radiation followed by 250 mg/m2/week for 5 weeks) and 2 different doses of capecitabine for the duration of radiotherapy (650 mg/m2 twice-daily, first dose level; 825 mg/m2 twice-daily, second dose level, including weekends). During treatment all patients were scored weekly using the NCI-CTC v.2.0. Dose-limiting toxicity (DLT) was defined acccording to Dunst (JCO 2002). Six to 8 weeks after the end of chemoradiation surgery was performed. Results: Four and six patients were treated at the first and second dose level of capecitabine, respectively. No DLT occurred at either capecitabine dose. Ten additional patients were treated at the higher dose level. Out of these 20 patients, Grade 3 toxicity included diarrhea (n=2), rectal pain (n=5), ileitis (n=2), radiation dermatitis (n=1) and neutropenia (n=1). The most frequent grade 1/2 side effects were acneiform rash (n=16, 80%), fatigue (n=12, 60%), and diarrhea (n=12, 60%). Until now, 2 pathological complete responses were observed in 19 evaluable patients. Conclusions: Preoperative radiotherapy in combination with capecitabine and cetuximab is feasible and well-tolerated with promising efficacy results. The recommended doses for phase II evaluation are capecitabine 825 mg/m2 twice-daily without interruption during the duration of radiotherapy and cetuximab at an initial dose of 400 mg/m2 followed by 250 mg/m2/week. No significant financial relationships to disclose.
Cetuximab with irinotecan in first-line treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC): Preliminary safety results (CRYSTAL)
Authors: Lang I. , Zaluski J. , Changchien C. R. , Makhson A. , Pinter T. , D’Haens G. , Lim R. , Nippgen J. , Van Cutsem E. 
Published: March 2020

3555 Background: Cetuximab is an IgG1 monoclonal antibody targeting the EGFR with proven activity in previously treated mCRC patients (pts). The modified two-weekly de Gramont regimen of irinotecan with infusional 5-fluorouracil (5-FU)/folinic acid (FA) (FOLFIRI) is a standard for metastatic disease. This randomized trial investigates the effectiveness of cetuximab with this chemotherapy combination versus chemotherapy alone in (pts) with EGFR-expressing mCRC previously untreated for metastatic disease. Methods: This phase III trial compares cetuximab (400 mg/m2 week 1 then 250 mg/m2 weekly) added to FOLFIRI (irinotecan 180 mg/m2, FA 400 mg/m2, 5-FU bolus 400 mg/m2, 2400 mg/m2 infusional 5-FU) (group A) vs. FOLFIRI alone (group B) in pts with EGFR-detectable tumors. 1080 pts are planned to detect a difference of ≥ 2 months in PFS with 80% power. The Data Safety Monitoring Board (DSMB) has performed an independent preplanned safety evaluation of 401 treated pts. Results: Pts (M/F 252/149, median age 62 years [range, 19–84], ECOG performance status [PS]: PS0, 57.1%: PS1, 38.4%: PS2, 4.5%) received at least 3 treatment cycles to date. Of the 401 pts, 83 (20.7%) pts completed/discontinued the trial. There were 11 deaths (2.7%) within 30 days of the last study treatment: 5 related to disease, 3 to chemotherapy, and 3 other (2 unknown, 1 intercurrent illness). Most common adverse events of the pooled safety data were skin reactions, diarrhea and nausea. Conclusions: After review of all relevant safety information by the DSMB, the trial continues. Recruitment was completed with 1220 patients in December 2005. [Table: see text] [Table: see text]
FOLFOX-4 + cetuximab in untreated patients with advanced colorectal cancer. A phase II study of the Gruppo Oncologico dell’Italia Meridionale (prot. GOIM 2402)
Authors: Colucci G. , Giuliani F. , Mattioli R. , Garufi C. , Mallamaci R. , Pezzella G. , Lopez M. , Maiello E. 
Published: March 2020

3559 Background: Cetuximab is an IgG monoclonal antibody targeting the EGFR showing to be effective both as single agent or in combination with Irinotecan (CPT-11) or Irinotecan/FU/FA in patients (pts) with EGFR-expressing metastatic colorectal cancer (CRC) in the first and second/subsequent-line setting. The current trial was designed to evaluate the efficacy and the safety of Cetuximab plus Folfox-4 as first -line treatment. The main objective was the percentage of confirmed objective response rate. Methods: Chemonaivepts with non-resectable metastatic CRC and expressing EGFR were treated with Cetuximab (400 mg/m2 week 1 and 250 mg/m2 weekly thereafter) plus Folfox-4 (every 2 weeks: Oxaliplatin 85 mg/m2, day 1; FA 100 mg/m2 2h, simultaneously with OH-P, and FU 400 mg/m2 iv bolus followed by 600 mg/m2 iv for 22h on days 1 and 2). The first evaluation of disease status (Recist criteria) was performed after the first 4 cycles and confirmed after one month. The treatment was continued until a maximum of 12 cycles of chemotherapy; the maintenaice with Cetuximab was permitted. Preliminary results: On the 65 screened pts, 47 (72%) had EGFR-expressing metastatic disease and were enrolled. Their main characteristics were: median Ecog PS 0; median age 66 yrs (range 43–74); main sites of disease: liver 31, lung 12, lymph-nodes 3, others 8. To date twenty-two pts are evaluable for activity and 27 for toxicity; 2 pts are not evaluable and 25 are too early. We observed 16 PR (72.7%), 5 NC (22.7%) and 1 PD (4.6%) for an ORR of 72.7% and a TGCR of 95.4%; the confirmed PR were 15 (68%). To date 2 pts undergone surgery of their metastases both for lung. The main adverse events grade 3/4 (NCI criteria) were: acne-like rush 18.5%, diarrea 7%, nausea/vomiting 4% and anemia 4%. Conclusions: Our preliminary results confirm that the combination of Cetuximab plus Folfox-4 has an high activity and a good safety profile in advanced CRC pts. The study is ongoing. No significant financial relationships to disclose.
Epidermal growth factor gene amplification is not frequent and cannot account for antitumor activity of cetuximab plus chemotherapy in advanced colorectal cancer patients
Authors: Garufi C. , Mottolese M. , Cianciulli A. , Zeuli M. , Buglioni S. , Torsello A. , Vanni B. , Campanella C. , Merola R. , Terzoli E. 
Published: March 2020

3561 Cetuximab has been shown to be active in the metastatic colorectal cancer, but EGFR detection by immunohistochemistry is not predictive for tumor response. Moroni et al (Lancet Oncology 2005) showed that, in patients responsive to Cetuximab, EGFR gene copy number, assessed by FISH, was increased. On this basis, copy number and protein status of EGFR were investigated in 70 primary and/or metastatic colorectal carcinomas. Protein expression was assessed by immunohistochemistry (IHC) using DAKO EGFRPharmDX kit. Gene and chromosome 7 copy numbers were identified by fluorescent in situ hybridization (FISH). Dual-target, dual-color FISH assays were performed using the LSI EGFR SpectrumOrange/CEP 7 Spectrum Green probe. EGFR gene copy number, chromosome 7 copy number and the average EGFR gene to chromosome 7 signal ratio were reported as FISH genetic variables. Chromosome 7 was polysomic when cancer cells showed multiple centromere signals: low polysomy (2 to 5 signals), high polysomy (>5 signals). Samples with a ratio value ≥ 2.0 were considered to be amplified. EGFR protein was overexpressed in 57 out of 70 patients (81%). In the group of 58 patients evaluated as polysomic, 48 (82,7%) had a low polysomy level, whereas 20 (12.7%) had a high polysomy level. Gene amplification was seen only in 3/70 patients. High polysomy was evidenced only in the group of patients displaying an EGFR IHC score 2+/3+. Forty-six pretreated patients received a cetuximab-based treatment. Response to treatment has been already evaluated in 26 FISH-negative patients while for the other 20 it is still too early. We observed 7 PR (27%), 9 SD (35%) and 10 PD (38%). This study shows that in this series of advanced colorectal cancer patients, EGFR amplification, measured by FISH, is a rare event (4%) and could be considered together with chromosome 7 polysomy for the antitumor activity. No significant financial relationships to disclose.
Angiogenesis modifications are predictive of response and outcome in heavily pretreated advanced colorectal cancer patients during therapy with cetuximab plus irinotecan
Authors: Vincenzi B. , Santini D. , Russo A. , Dicuonzo G. , Michele G. , Battistoni F. , Avvisati G. , Rocci L. , Gebbia N. , Tonini G. 
Published: March 2020

3562 Background: Angiogenesis has been correlated with increased invasion and metastases in a variety of human neoplasms. Inadequate inhibition of the growth of tumor microvessels by anticancer agents may result in treatment failure, rated clinically as progressive or stable disease. We designed this trial to investigate if Vascular Endothelial Growth Factor (VEGF) circulating levels modifications may be related with clinical response and outcome in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. Methods: 45 heavily pretreated metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF during the treatment with cetuximab (initial dose of 400 mg per square meter, followed by weekly infusions of 250 mg per square meter) plus weekly irinotecan (90 mg per square meter). VEGF circulating levels were assessed at the following time-points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. Results: Basal serum VEGF median levels were significantly decreased just at the first day (after the first treatment infusion (P=0.016). The VEGF persisted at the following time points reaching the highest statistical significance 92 days after the first infusion (P<0.0001). Twenty-two patients showed a reduction in median VEGF circulating levels of at least 50% 92 days after the first infusion respect to the basal time point. In the group of patients with at least 50% reduction of VEGF levels the response rate was 59.1% vs 21.7% in the non reduced VEGF group (P=0.024). Moreover, the median time to progression was 6.12 months (95% C.I.: 3.9 - 7.1) in the reduced VEGF group vs 2.3 months (95% C.I.: 1.6 - 3.5) in the other patients (P=0.001). Finally, also overall survival was longer in patients who developed VEGF reduction (12.3 months; 95% C.I.: 8.65 - 15.9) than this recorded in patients without the reduction (6.4 months; 95% C.I.: 5.6 - 8.4) (P=0.05). Conclusions: The present data represent the first evidence that suggest a role of VEGF reduction in the prediction of efficacy of treatment with cetuximab plus weekly irinotecan in heavily pretreated advanced colorectal cancer patients. No significant financial relationships to disclose.
Folinic acid modulated bolus 5-FU or infusional 5-FU for adjuvant treatment of patients of UICC stage III colon cancer: Preliminary analysis of the PETACC-2-study
Authors: Carrato A. , Köhne C. , Bedenne L. , Popov I. , Bouche O. , Gaspar E. , Rougier P. , Schubert U. , Biertz F. , Becker H. 
Published: March 2020

3563 Background: Patients with stage III colon cancer have a high risk for recurrence. Infusional 5-FU may be more active than bolus application. Methods: From 01/1997 to 03/2004 a total of 1601 patients with UICC stage III colon cancer were randomized to receive the Mayo-Clinic regimen or infusional 5-FU either the weekly high dose AIO regimen, the bi-weekly LV5FU2 regimen or the Spanish weekly high dose TTD-regime. The major aim of this study was to demonstrate a difference of 7 % in the 5 year survival rate in favour of the infusional arm for which a total of 424 events were required. Results: After a median follow-up of 31 months 478 events have occurred. 804 patients received the standard arm and 797 the experimental arm (AIO N=331, EORTC N=92, FFCD N=211, TTD N=163). The median age was 64 years; patients were well distributed according to TNM-category (T3 73 vs. 75%, T4 17 vs. 16%, N2 31 vs. 34%), vascular and lymphatic invasion and grading. The bolus regimen induced a higher rate of grade 3 or 4 leukopenia (7.1% versus 2.0%), stomatitis grade 3 or 4 (9.8% versus 3.3%) or diarrhea grade 3 or 4 (16% vs. 15%). Hand-Foot-Syndrome was more frequent in the experimental arm (4.4% versus 0.4%). There was no difference in the recurrence free survival at 5 years (57% versus 56%; hazard ratio 1.00, 95% CI, 0.84 to 1.21; P=0.9) or overall survival at 5 years 71% versus 72%; hazard ratio 0.91, 95% CI, 0.71 to 1.16; P=0.44). Conclusions: Infusional 5-FU does not improve RFS or overall survival of stage III colon cancer compared to the Mayo regimen but is less toxic. Supported by Deutsche Krebshilfe No significant financial relationships to disclose.
Prognostic significance of mesenteric tumor nodules in patients with stage III colorectal cancer
Authors: Lo D. S. , Pollett A. , Gallinger S. , Siu L. L. , Burkes R. L. 
Published: March 2020

3566 Background: Tumor nodules are occasionally found in adjacent mesentery of colorectal cancer specimens, but their prognostic significance is unclear. According to the TNM staging system, mesenteric nodules are classified as part of T or N categories, but clinically they are regarded to reflect a worse prognosis, more like M1. We investigated the clinical significance of mesenteric tumor nodules. Methods: We reviewed 786 patients with stage III colorectal cancer referred between 1995 and 1999. We standardized TNM staging by assigning N status based on number of definite lymph nodes. Mesenteric nodules were considered separately and not assigned to T or N categories. Survival analyses were performed. Results: Mesenteric tumor nodules were found in 116 patients (14.8%); 48 with colon cancer (41.4%) and 68 rectal cancer (58.6%). Mean age at surgery was 62.8±1.0 yrs (SE), and the male: female ratio was 1.2. All tumors were adenocarcinomas with an average size of 4.3±0.1 cm, and the majority were moderately differentiated. Resection margins were clear except in 7 cases. With respect to high risk features, 6 cases (5.2%) had bowel perforation, 12 (10.3%) obstructive symptoms, 41 (35.3%) lymphovascular invasion, and 11 (9.5%) were T4 lesions. Adjuvant chemotherapy was given to 84.8% of colon cancer patients. Two (2.9%) rectal cancer patients received neoadjuvant chemo-radiation, and 63 (92.6%) received adjuvant therapy; chemotherapy, radiation or both. In the cohort with mesenteric nodules, the median time to progression was 23.1 months; the median 5-yr disease free survival was 35%; and the median overall survival (OS) was 47.9 months, with 44% OS at 5 yrs. After TNM standardization, 19 (16.4%) patients were down-staged to either stage I or II, and their 5-yr OS was 60% (SEER Stage II 5 yr survival 82.5%). In the remaining cohort-patients with stage III disease after standardization, the 5-yr OS was 40% (SEER 5yr survival Stage IIIc 44.3%; Stage IV 8.1%). Conclusions: In comparison to SEER survival data, the presence of mesenteric nodules appears to worsen prognosis of any T/N0 disease to that of overall stage III disease. Patients with mesenteric nodules in the setting of any T/N1+ disease had prognosis similar to that of stage IIIC disease, but their prognosis was better than M1 disease. No significant financial relationships to disclose.
Preoperative uracil/tegafur and concomitant radiotherapy in locally advanced rectal (LAR) cancer: Updated results with a median follow-up of 5 years and analysis of prognostic factors (PF)
Authors: Fernandez-Martos C. , Romero I. , Aparicio J. , Bosch C. , Girones R. , Campos J. M. , Garcera S. , Safont M. J. , Maeztu I. , Climent M. A. 
Published: March 2020

3573 Background: Preop chemoradiotherapy (CRT) with CI 5-FU is a standard of care for LAR cancer. Oral fluoropyrimidines, an attractive alternative to intravenous 5-FU, are perceived by patients as more convenient. Methods: We performed a phase II study in patients with potentially resectable tumors, localized in middle or distal rectum, ultrasonographically staged as T3 or T4 or N+ who were treated with UFT (400 mg/m2/d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Pts underwent surgery 5 to 6 weeks later followed by four cycles of 5-FU/LV (Mayo Clinic Scheme). Early end points of efficacy (pCR, downstaging, sphincter preserving surgery) and toxicity have already been reported (JCO 2004;22:3016). We now present data on secondary objectives (RFS, DFS and OS) and univariate and multivariate analysis of clinical and pathological PF. Results: 94 patients were included and complete information on 88 (94%) is availablewith a median follow-up of 5 years (60.4 months). Actuarial Kaplan-Meier DFS, RFS and OS are 61%, 66%, and 70 %. Patterns of failure are 7% pelvic and 25% distant. Univariate analysis results are shown in the table . Survival rate was also higher among patients with no or few residual disease after CRT but did not reach statistical significance. In Cox multivariate analysis both ypT and ypN are independent PF for DFS and RFS but only ypT is an independent PF for OS. Conclusions: This approach with preop UFT/RT reproduces the results that have been accomplished with 5-FU. ypT and ypN could be helpful to identify different risk groups and to select adjuvant treatments. [Table: see text] No significant financial relationships to disclose.