bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) ± cetuximab for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results
Authors: Venook A. , Niedzwiecki D. , Hollis D. , Sutherland S. , Goldberg R. , Alberts S. , Benson A. , Wade J. , Schilsky R. , Mayer R. 
Published: March 2020

3509 Background: FOLFIRI or FOLFOX are 1st-line treatments (Rx) for MCRC. Cetuximab is an IgG1 Mab that targets the epidermal growth factor receptor (EGFR) and is approved as monotherapy or in combination with irinotecan in irinotecan-refractory, EGFR + pts with MCRC. CALGB 80203 randomized untreated MCRC pts to FOLFOX or FOLFIRI ± cetuximab (independent of EGFR status.) Methods: Pts with performance status 0–1 with tumor blocks available for EGFR analysis received either irinotecan 180 mg/m2 over 1.5 hours (h) or oxaliplatin 85 mg/m2 over 2h combined with LV 400 mg/m2 over 2h and 5FU 400 mg/m2 bolus, then 46–48h CI 5FU 2400 mg/m2 q o w. Cetuximab dose: 400 mg/m2 loading dose, then 250 mg/m2 qw. Rx continued until progression or toxicity; subsequent Rx was not mandated although information was collected on such rx. Accrual goal was 2200 pts with intended 1° endpt of overall survival (OS). 80203 closed administratively in 1/05 (due to slow accrual) with 238 pts accrued. 2° endpts of response rate (RR), progression free survival (PFS), duration of R and toxicity are now able to be analyzed. Results: Accrual: FOLFIRI (A) - 61; FOLFIRI + cetuximab (B) - 59: FOLFOX (C) - 60; FOLFOX + cetuximab (D) - 58; approx median follow-up (f/u) is 12 months. RR (CR + PR, not all yet confirmed): A - 34%; B - 42%; C - 32%; D - 55%. RR was similar in the FOLFIRI or FOLFOX arms (A+B v. C+D; 38% v. 43%, p=0.44; chi-square) while C225 containing arms (B+D) v. non-C225 arms (A+C) had a superior RR (49% v. 33%; p=0.014, chi-square) It is too early to tell if there are differences in PFS, duration of response or OS. No significant differences in gr III diarrhea or any gr IV toxicities were seen. Conclusions: These results suggest that FOLFIRI and FOLFOX are similar in efficacy for pts with untreated MCRC and that adding cetuximab to either in1st-line Rx appears to increase response rates. PFS and duration of response do not appear different at this analysis. Further f/u and an analysis of prospective companion correlative studies may help to further clarify these results. [Table: see text]
The triplet combination of irinotecan, oxaliplatin and 5FU/LV (FOLFOXIRI) vs the doublet of irinotecan and 5FU/LV (FOLFIRI) as first-line treatment of metastatic colorectal cancer (MCRC): Results of a randomized phase III trial by the Gruppo Oncologico Nord Ovest (G.O.N.O.)
Authors: Falcone A. , Masi G. , Brunetti I. , Benedetti G. , Bertetto O. , Picone V. , Chiara S. , Merlano M. , Vitello S. , Ricci S. 
Published: March 2020

3513 Background: We demonstrated interesting activity and manageable toxicities for the FOLFOXIRI regimen in phase I-II studies. Methods: The G.O.N.O. conduced a phase III study comparing FOLFIRI (CPT11 180 mg/sqm d1, l-LV 100 mg/sqm d1+d2, 5FU 400 mg/sqm bolus d1+d2, 5FU 600 mg/sqm 22-h inf. on d1+d2, arm A), to FOLFOXIRI (CPT11 165 mg/sqm d1, LOHP 85 mg/sqm d1, l-LV 200 mg/sqm d1, 5FU 3200 mg/sqm 48-h inf. starting on d1, arm B). Both treatments were repeated every 2 weeks and at progression to FOLFIRI a FOLFOX combination was recommended. Selection criteria included measurable and not resectable MCRC, age 18–75 years, no prior chemotherapy for advanced disease. Primary endpoint was response rate (RR) and planned accrual was 240 pts. Secondary endpoints were PFS, OS, post-CT R0 surgical resections, safety and QoL. Results: A total of 244 pts were randomized. Main toxicities were (arm A/arm B): grade 3–4 diarrhea 12%/20%, grade 3–4 vomiting 2%/7%, grade 3–4 stomatitis 3%/5%, grade 2–3 peripheral neurotoxicity 0%/20%, grade 4 neutropenia 11%/17%, febrile neutropenia 3%/5%. Two pts in each arm died within 60 days, but no toxic deaths occurred. Responses, assessed by investigators, were (arm A/arm B): complete 6%/8%, partial 35%/58%, stable 33%/21%, progression 24%/11%, for an overall RR of 41% vs 66%, p=0.0002. RR confirmed by an external panel was 34%/60%, p<0.0001. This increased activity allowed a radical secondary resection of mts in a greater percentage of patients in the FOLFOXIRI arm (6% vs 14%, p=0.05, among all 244 pts and 12% vs 36%, p=0.02, among 81 patients with liver mts only). At a median follow-up of 15.2 months 112 vs 104 pts have progressed and 81 vs 65 have died with a significant improvement in progression-free and overall survival in favor of the triplet (median PFS 6.9 vs 9.8 mos, HR: 0.63, p=0.0006; median S 16.7 vs 22.6, HR:0.70, p=0.032). Conclusions: The FOLFOXIRI regimen is feasible with manageable toxicities and significantly increases RR, R0 resection of mts, PFS and overall S compared to FOLFIRI. (Partially supported by Fondazione ARCO). [Table: see text]
UGT1A1*28, toxicity and outcome in advanced colorectal cancer: Results from Trial N9741
Authors: McLeod H. L. , Parodi L. , Sargent D. J. , Marsh S. , Green E. , Abreu P. , Cisar L. A. , Goldberg R. M. 
Published: March 2020

3520 Background: This report examines UGT1A1*28, toxicity, and outcome in trial NCCTG N9741 patients (pts) receiving combination chemotherapy for advanced colorectal cancer. Methods: Blood samples were collected from 520 pts randomized between 2/18/00 and 7/18/02. Pts were treated with irinotecan/5-fluorouracil (5FU)/leucovorin (LV) (IFL, n=114), oxaliplatin/5FU/LV (FOLFOX, n=299), irinotecan/oxaliplatin (IROX, n=107). 19% of IFL pts received full-dose (125 mg/m2) irinotecan; the rest received a reduced dose (100 mg/m2). Toxicity was evaluated every cycle. Correlation of dichotomous outcomes and genotype status used Fisher’s exact tests. Univariate logistic regression was used to test the association between continuous variables and binary outcomes, including a test of trend, and multivariate logistic regression to adjust for known risk factors: performance status, age, gender. Time to progression (TTP) and overall survival (OS) were tested for association with UGT1A1 using the log-rank test. Statistical significance was prospectively set at .01 to control for multiple comparisons. Results: Frequency of UGT1A1 genotype was 44% 6/6, 42% 6/7, and 9% 7/7. In all arms, the rate of grade (G) 4 neutropenia (neut) ( Table ) and G3+ febrile neut (FN) was higher in pts with the 7/7 than in pts with 6/7 and 6/6. No association was seen between UGT1A1 and diarrhea, tumor response, TTP, or OS overall or for any treatment arm. The odds ratios for pts with 7/7 developing G4 neut and G3+ FN compared with pts with 6/6 are shown ( Table ). Statistically significant associations between the 7/7 polymorphism and G4 neut were seen in pts treated with IROX (P=.004) and in all pts (P=.007). The association between 7/7 and G3+ FN was also significant for IROX (P=.006). Conclusions: There is a higher risk of neut in 7/7 pts. Due to low frequency of the 7/7, exclusion of all pts with 7/7 reduces the overall G4 neut rate from 18% to 17%. UGT1A1 was not a predictor of response, TTP, or OS for any arm. [Table: see text] [Table: see text]
Surgery of colorectal metastasis in the Optimox 1 study. A GERCOR Study
Authors: Perez-Staub N. , Lledo G. , Paye F. , Gayet B. , Flesch M. , Cervantes A. , Figer A. , Bourges O. , André T. , De Gramont A. 
Published: March 2020

3522 Background: Surgery of metastasis can cure arround 20% of metastatic colorectal cancer (MCRC) patients. The Optimox 1 study achieved a response rate over 50% with FOLFOX therapy in patients (pts) with initially unresectable metastasis which allowed to perform surgery in a significant number of pts (JCO 2006). We report here the results in pts who underwent surgery of metastasis (met). Methods: From jan 2000 to june 2002, 620 previously untreated patients with unresectable metastasis were randomized between FOLFOX4 every two weeks until progression (arm A), or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 (arm B). 101 pts were resected with a curative intent, 57 in arm A and 45 in arm B. Results: Patients characteristics were (arm A/B %): metachronous metastasis 77/51, liver met 82/91, lung met 16/11, other met 7/4, PAL < 3 ULN: 98/97, normal LDH: 52/51. 8% of pts achieved a complete response, 72% a partial response, 16% a stable disease. 89 pts had a single resection, 12 had a two-stage surgery. One patient died in arm B. Eleven pts who relapsed had a second surgery. Resection was radical (R0) for 71 pts (43 in arm A and 28 in arm B), 15 were R1 (margin invasion) and 15 were R2. R0/R1 patients had a median overall survival (OS) of 51 mo in arm A and 38 mo in arm B. Median disease-free survival (DFS) since surgery was 12 mo in arm A and 9 mo in arm B, with no statistical difference. 32% of R0/R1 pts were alive with no progression at 3 years in arm A and 20% in arm B. Median time from randomization to surgery was 8 mo. No difference was found between patients resected before 8 mo (n = 50) and after (n = 37) in OS (39 vs 45 mo, p = .67) nor in DFS (11.6 vs 9.5 mo, p = .24). Neither in pts resected before and after 6 mo in OS (p = .77) and DFS (p = .44). Conclusions: FOLFOX treatment allowed 14 % of unresectable patients to be rescued by surgery. There was no additional benefit to perform surgery after 6 months of therapy compared to early surgery. [Table: see text]
Systemic capecitabine and oxaliplatin administered with hepatic arterial infusion (HAI) of floxuridine (FUDR) following complete resection of colorectal metastases (M-CRC) confined to the liver: A North Central Cancer Treatment Group (NCCTG) phase II intergroup trial
Authors: Alberts S. R. , Mahoney M. R. , Donohue J. , Roh M. S. , Green E. M. , Sargent D. J. , Wagman L. D. , Bolton J. S. 
Published: March 2020

3525 Background: The prognosis for patients with hepatic metastases from M-CRC can be poor. However, surgery followed by HAI FUDR plus systemic (SYS) 5-FU improves 5-yr survival rates. Oxaliplatin (OXAL) combined with capecitabine (CAPE) has demonstrated activity in advanced CRC. We report early results of an analysis of SYS OXAL plus CAPE, alternating with HAI FUDR. The primary endpoint is 2-yr survival (2YS). Methods: Patients with M-CRC liver lesions amenable to resection ± ablation were eligible. HAI + SYS therapy was initiated following metastasectomy. Alternating courses of HAI consisted of 0.2 mg/m2/d FUDR and dexamethasone, d1–14 weeks 1 & 2. SYS therapy included 130 mg/m2 OXAL d1, with CAPE at 1000 mg/m2 p.o. BID, d1–14, weeks 4 & 5. Two additional 3-wk courses of SYS therapy were given. CAPE was reduced to 850 mg/m2/BID after interim review of toxicity (GI Cancer Symposium 2004). Patient Characteristics: 54 of 70 patients were able to initiate HAI FUDR + SYS. 52% had a solitary met and 24% presented with bilobar mets. Results: Patients completed median of 6 cycles (range 1 - 6). Reasons for discontinuation included: refusal/toxicity (10), completed per protocol (32), recurrence (4), and medical/other (3). No post-operative or treatment related deaths were reported. 69% (31/45) of evaluable patients are alive with a minimum 18 mos of follow-up. 6 deaths occurred in less than 2 yrs. 44% (20/45) have recurred, with 40% (8/20) having liver involvement. Median time-to-progression is 32 mos with an estimated 2YS rate of 86% (95% CI 76–97%). Conclusions: The combination of HAI FUDR and SYS therapy appears to improve outcome following resection of hepatic CRC-M. Updated follow-up is necessary to solidify the primary endpoint of 2YS. Supported by NIH Grant CA25224–18, Sanofi-Synthelabo, and Roche Laboratories, Inc. Maximum Severity, Grade 3+ (N=54) [Table: see text] [Table: see text]
ECOG E3201: Intergroup randomized phase III study of postoperative irinotecan, 5- fluorouracil (FU), leucovorin (LV) (FOLFIRI) vs oxaliplatin, FU/LV (FOLFOX) vs FU/LV for patients (pts) with stage II/ III rectal cancer receiving either pre or postoperative radiation (RT)/ FU
Authors: Benson A. B. , Catalan P. , Meropol N. J. , Giantonio B. J. , Sigurdson E. R. , Martenson J. A. , Whitehead R. P. , Sinicrope F. , Mayer R. J. , O’Dwyer P. J. 
Published: March 2020

3526 Background: In the US pts with stage II/III rectal cancer routinely receive pre or postoperative RT/FU. To date, in addition to chemoradiation, standard adjuvant chemotherapy has been limited to single agent FU. Improved survival with irinotecan and oxaliplatin in pts with metastatic colorectal cancer led to exploration of combination chemotherapy in the adjuvant setting in pts with rectal cancer. Methods: Pts on E3201 (T3–4 Nany M0, T1- 2 N + M0) had the option to receive FU with either pre- or postoperative RT (50.4 Gy). Pts were randomized to postoperative chemotherapy: FU (500mg/m2) + LV (500mg/m2) weekly x 6/8 wks x 3 cycles or irinotecan (FOLFIRI) (180mg/m2) vs oxaliplatin (FOLFOX) (85mg/m2) both administered with LV (400 mg/m2) FU (400mg/m2 bolus) + continuous FU (2.4 gm/m2/46 hours) q 2 wks x 8 cycles. Results: 225 pts of 3150 planned were recruited. 178 pts were randomized and 126 pts submitted treatment completion forms (accrual period 10/03–4/05). The Data Monitoring Committee closed E3201 when the GI Intergroup developed an alternative trial with bevacizumab (E5204). Toxicity information is reported for 93% of pts (165/178) ( Table ). There were no significant differences in toxicity between those pts treated with pre- vs postoperative RT/FU, although, for the subset of pts who received adjuvant FOLFIRI after postoperative RT/FU, there was a trend towards more diarrhea. Conclusion: FOLFOX as rectal adjuvant therapy is a common platform for new clinical trials, although there have been limited toxicity data reported. E3201 provides important comparative toxicity information demonstrating that FOLFOX can be safely administered to rectal cancer pts following chemoradiation. [Table: see text] [Table: see text]
Tumor VEGFA gene expression is associated with serum lactate dehydrogenase (LDH) levels and intratumoral mRNA expression of genes involved in glycolysis in patients with metastatic colorectal cancer (mCRC)
Authors: Azuma M. , Shi M. M. , Jacques C. J. , Barrett C. , Danenberg K. D. , Iqbal S. , El-Khoueiry A. , Yang D. , Zhang W. , Lenz H. 
Published: March 2020

3530 Background: It is well known that angiogenesis and glycolysis are regulated by hypoxic conditions. Recent clinical trials (CONFIRM1 and CONFIRM2) have shown that patients with mCRC with high serum LDH benefited from PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor. We tested the hypothesis that patients with high serum LDH have increased intratumoral expression of genes involved with hypoxia (hypoxia inducible factor (HIF1a and 2a) and lactate dehydrogenase A (LDHA) and glycolysis (glucose transporter 1 (Glut-1) and genes involved in angiogenesis such as vascular endothelial growth factor A (VEGFA) and neuropilin 1 (NRP1) in patients with mCRC. Methods: 78 formalin fixed paraffin embedded (FFPE) tumor samples from 36 patients (20 males, 16 females: Median age 59 years (range 29–84) with mCRC who underwent first line therapy (not from CONFIRM trials) were analyzed. In addition, tumor gene expression was correlated with serum LDH levels from the same group of patients. FFPE tissues were dissected using laser-captured microdissection and analyzed LDHA, VEGFA, HIF1a, HIF2a, Glut-1 and NRP1 mRNA expression using a quantitative real-time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference gene (beta-actin). Results: Spearman Rank Correlation Analysis of Associations Between serum LDH levels and Gene Expression values. Conclusions: Our results demonstrate that intratumoral gene expression of LDHA, HIF1a and HIF2a, Glut-1 and VEGFA are significantly correlated. Patients with high serum LDH have increased intratumoral gene expression of VEGFA. These results support the hypothesis that serum LDH levels may serve as a surrogate marker for activation of the HIF related genes in the tumor. These observations may explain the efficacy of PTK787 in metastatic colorectal cancer patients with high serum LDH levels. [Table: see text] [Table: see text]
Efficacy of bevacizumab plus chemotherapy as first-line treatment of patients with metastatic colorectal cancer: Updated results from a large observational registry in the US (BRiTE)
Authors: Kozloff M. , Hainsworth J. , Badarinath S. , Cohn A. , Flynn P. , Steis R. , Dong W. , Suzuki S. , Sugrue M. , Grothey A. 
Published: March 2020

3537 Background: Bevacizumab (BV) prolongs overall survival and progression-free survival (PFS) when added to standard chemotherapy (CT) in patients with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of patients with mCRC receiving BV plus first-line CT. Safety and efficacy information in unselected patients with mCRC are collected. Chemotherapy regimen choice is at the physician’s discretion. Methods: 1968 patients receiving BV plus first-line CT were enrolled at 248 sites in 49 states between Feb 2004 and Jun 2005. Patients are followed for up to 3 years, with data reporting every 3 months (mo) including disease status as assessed by investigator using his/her method of choice. Patients were grouped twice by CT. Cox regression models, adjusted and unadjusted for treatment assignment, were used to identify baseline characteristics (BC) and differential chemotherapy effects on PFS. Results: Cohort demographics were consistent with the NCI Surveillance, Epidemiology, and End Results (SEER) database for mCRC. Median study follow-up was 10 months by Nov 4, 2005. CT regimens included FOLFOX (55.8%), FOLFIRI (14.1%), and IFL (9.7%). Based on observed progression events (n=800) or deaths (n=123), projected median PFS is 11.3 mo (95% CI: 10.4–11.7). Median PFS was comparable in patients treated with CT regimen based on irinotecan (11.3 mo), oxaliplatin (11.4 mo), or neither (10.2 mo) (CT Grouping 1); or 5FU infusion (11.5 mo), 5-FU bolus (9.7 mo), or capecitabine (11.6 mo) (CT Grouping 2). Significant BC in adjusted and unadjusted models are ECOG performance status (PS), primary disease site, and albumin, with no significant difference among CT regimens. Conclusions: This large, community-based registry included a patient population with demographics consistent with the SEER database for mCRC. Preliminary median PFS of 11.3 mo compares favorably to that reported in the pivotal trial. Median PFS appears to be comparable for all CTs when combined with BV. Higher baseline albumin, PS of 0, and primary disease site of rectum were associated with improved outcome. [Table: see text]
Simplification of bevacizumab (bev) administration: Do we need 90, 60, or even 30 minute infusion times?
Authors: Saltz L. B. , Chung K. Y. , Timoney J. , Park V. , Hollywood E. 
Published: March 2020

3542 Background: Bev is a humanized monoclonal antibody that targets VEGF. Due to concerns of infusion related hypersensitivity reactions, phase I trials of bev used an initial 90 minute infusion of bev, a 60 minutes for on the next dose, and 30 minutes for all doses thereafter. This has remained the administration schedule throughout development and registration. No significant infusion-related toxicities were reported in the pivotal phase III registration trial. We postulated therefore that bev could be safely given without initially prolonged infusion times. Methods: We obtained an IRB waiver of authorization to review the records of patients at Memorial Sloan Kettering Cancer Center (MSKCC) who were treated with bev in the first 3 months of commercial availability (cut-off date 5/15/05). Our institutional adverse drug reaction reporting program was utilized to identify any infusion reactions related to bev. Additionally, patient medical records were reviewed for further confirmation. Results: Following initial commercial availability of bev in February 2004, 202 consecutive colorectal cancer (CRC) patients were treated with bev (5 mg/kg) at MSKCC starting as a 90 minute, then 60 minute, then 30 minute infusion. No hypersensitivity reactions were seen. A decision was then made to establish an institutional practice of using 30 minute infusion times for all doses, including initial doses, of bev. Subsequently, 212 consecutive CRC patients were treated with bev 5 mg/kg, initially as a 30 minute infusion. No infusion reactions were observed. Conclusions: Administration of the initial dose of bev over 30 minutes appears to be safe and well-tolerated. This has been the standard initial infusion time at MSKCC for 5 mg/kg, 10 mg/kg and 15 mg/kg doses of bev. Based on our favorable experience with 30 minute infusions of 15 mg/kg (0.5 mg/kg/minute), as of Nov ’05 we have changed our institutional guidelines such that all non-protocol patients receiving bev are initiated at the infusion rate of 0.5 mg/kg/minute. Thus, our standard 5 mg/kg doses of bev are given over 10 minutes, 10 mg/kg doses are given over 20 minutes, and 15 mg/kg doses are given over 30 minutes. Active quality assurance and safety monitoring are maintained throughout. Data will be updated for the meeting. [Table: see text]
Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing ≥ 10% epidermal growth factor receptor (EGFr)
Authors: Berlin J. , Neubauer M. , Swanson P. , Harker W. G. , Burris H. , Hecht J. R. , Navale L. 
Published: March 2020

3548 Background: Panitumumab is a fully human monoclonal antibody directed against EGFr. We investigated panitumumab antitumor activity in pts who failed prior therapy and had EGFr tumor expression levels ≥ 10%. Methods: In this multicenter, phase 2 study of 300 planned pts, pts had documentation of disease progression (PD) during or following adequate doses of fluoropyrimidine, irinotecan, and oxaliplatin (centrally confirmed refractory disease [CCRD]), 2–3 prior regimens, ECOG score 0–2, and EGFr staining (by IHC) in ≥ 10% of evaluable tumor cells. Pts received panitumumab at 6 mg/kg Q2W until PD. Tumor assessments (modified WHO, blinded central review) were taken periodically from wk 8–48 until PD. Study endpoints were objective response rate (ORR) at wk 16 (+ ≥ 4 wk confirmation; primary) and ORR throughout study, response duration, progression-free survival (PFS) time, survival time, and safety (secondary). Results: In this interim analysis (5/05), 91 enrolled pts received ≥ 1 dose of panitumumab (safety set); 39 had ≥ 20 wks before the cutoff and CCRD (efficacy set). The efficacy set consisted of 23M/16W, mean (SD) age of 58.6 (10.1) years, 82% white, 95% ECOG ≤ 1, 74% colon cancer and 26% rectal cancer; all had ≥ 2 prior regimens (equivalent characteristics for safety set). At wk 16, 3 (8%) had a partial response, 8 (21%) had stable disease, and 19 (49%) had PD as best OR (9 not done/unevaluable). At the time of this interim analysis, response durations were 12.4, 13.2, and 14.0 wks. In the safety set, 96% had at least 1 treatment-related adverse event (24% grade [gr] 3, 1% gr 4, 1% gr 5). Integument and eye toxicities were: 96% skin, 30% nail, 8% eye, 5% hair, and 7% chelitis. 25 (27%) had diarrhea (3 gr 3); 11 (12%) had hypomagnesemia (3 gr 3/4). One pt had a gr 3 hypersensitivity reaction considered related to panitumumab, received medication, and the event resolved; this pt continued treatment with premedication; no further reactions occurred. In 66 pts with both a baseline and postdose sample, no human anti-human antibodies to panitumumab were detected.Additional data will be presented. Conclusions: Panitumumab has antitumor activity and is well tolerated in pts with EGFr tumor expression levels ≥ 10% who failed standard chemotherapy. [Table: see text]