bluuebunny/crossref_metadata_2025 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.

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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).

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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.

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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.

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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)

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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.

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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.

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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.

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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.

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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.

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First-line single-agent cetuximab in patients with advanced colorectal cancer
Authors: Pessino A. , Artale S. , Guglielmi A. , Sciallero S. , Fornarini G. , Andreotti I. C. , Mammoliti S. , Marrapese G. , Siena S. , Sobrero A.
Published: March 2020

3553

Background: The most relevant recent advance in the treatment of metastatic colorectal cancer is the fact that cure is still possible under very selected conditions. However the goal of chemotherapy remains palliative in the great majority of patients, justifying less toxic innovative approaches in so- called “window of opportunity trials”. We have pursued this idea in a phase II study of cetuximab monotherapy in chemo-naive patients with advanced colorectal cancer beyond any possibility of curative resection. Methods: Patients with non-resectable metastatic colorectal cancer (at least two metastatic sites and/or otherwise inoperable metastatic disease) were treated with cetuximab (400 mg/m2 week 1 and 250 mg/m2 weekly thereafter) until progressive disease (PD) or unacceptable toxicity. The primary end-point was objective response; secondary end-points were: stable disease, time to treatment failure and time to progression. According to Simon’s two-stage design, the number of responses/patients to stop the trial was 0/10 for stage 1 and 3/29 for stage 2. Results: Of the 44 patients screened, 42 (97%) had EGFR-expressing tumors. Thirty-nine patients (median age: 69) initiated the treatment. Two had grade 3 allergic reactions to cetuximab at the first administration leading to treatment discontinuation. The most common adverse event was skin toxicity, which occurred in 90% of the patients ( 31% grade 2, 10 % grade 3). We observed 1 complete response, 3 partial responses, 13 stable diseases (5 of which were minor responses), and 22 PD. The duration of the 4 responses were 12, 9, 9 and 6 months. Median time to progression was 2.0 months. Conclusions: The study is negative because the response rate is low. However, the duration of benefit in the few responding patients is such that it is imperative to find the molecular determinants of cetuximab activity in these cases.

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Cetuximab in combination with irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFIRI) in second and third-line treatment of metastatic colorectal cancer (mCRC): Safety and efficacy analysis
Authors: Smith D. M. , Legoux J. , Brunet R. , Adhoute X. , Blanc J. , Fonck M. , Vendrely V. , Becouarn Y.
Published: March 2020

3558

Background: The Folfiri regimen demonstrated high efficacy and favorable safety profile compared to irinotecan plus bolus 5-FU/FA (IFL regimen) or irinotecan alone. Folfiri is a standard option in first line treatment of mCRC. Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR), which is commonly expressed in mCRC, is approved in France in combination with irinotecan after failure of an irinotecan-based therapy. We have prospectively evaluated the combination cetuximab-FOLFIRI in patients with mCRC refractory to FOLFIRI administered in first line treatment. Methods: Patients with EGFR-expressing mCRC, who progressed following first line treatment with FOLFIRI regimen were eligible for this study. Treatment consisted of cetuximab (initial dose 400 mg/m2 followed by 250mg/m2/week) combined with FOLFIRI (given every 2 weeks: irinotecan 180 mg/m2, FA 400 mg/m2 and 5-FU 400 mg/m2 bolus plus 2400 mg/m2/46-h infusion) until either disease progression or unacceptable toxicity. Tumor reponse was assessed by CT scan every 2 months (OMS criteria), and adverses events were registered. Results: 41 patients where included from 09/2004 to 11/2005. 78% Male/ 22% Female, mean age 63 years, median KPS 80, 68% colon primary tumour. 5 patients were treated in second line, 24 patients in third line and 12 in fourth line or more. 40 patients are evaluable for response. They were 8 objective responses (20%) and 11 patients with stable disease (27.5%). The median progression free survival was 4,3 months and the median overall survival was 5 months. 61 % of the 41 patients experienced grade 3–4 adverses events, the most frequent of which were leucopenia (16%), asthenia (9%), vomiting and diarrhoea (5%), and acneiform skin rash in 11 patients (24%), severe xerosis (7%). 6/11 patients who experienced acneiform eruption grade 3 were alive at 12 months. Conclusions: The combination of cetuximab with FOLFIRI demonstrated promising efficacy and acceptable safety profile without increasing chemotherapy adverse reactions. A prospective randomised trial would confirm the advantage of FOLFIRI over irinotecan alone in combination with cetuximab.

No significant financial relationships to disclose.
Phase I trial of preoperative cetuximab with concurrent continuous infusion 5-fluorouracil and pelvic radiation in patients with local-regionally advanced rectal cancer
Authors: Chung K. Y. , Minsky B. , Schrag D. , O’Reilly E. , D’Adamo D. , Hollywood E. , Quinones M. , Saltz L.
Published: March 2020

3560

Background: Cetuximab, a chimeric anti-EGFR monoclonal antibody, has clinical activity in colorectal cancer with demonstrated safety, efficacy and additive synergy with radiation in solid tumors (head & neck, lung). A pilot trial was therefore designed to investigate the safety of cetuximab in combination with standard neoadjuvant protracted infusion 5-FU and radiation therapy in ultrasound T3–4 (uT3–4) or clinical T4 (cT4) or locally recurrent rectal adenocarcinoma. Secondary objectives of clinical activity were assessed by R0 resection and pathologic complete response (CR) rates. Methods: uT3–4 or cT4 or locally recurrent rectal adenocarcinoma patients received cetuximab 400mg/m2 day 1 (250mg/m2 weekly thereafter) and 5-FU IVCI (225mg/m2) over 5.5 weeks with concurrent pelvic radiation (5040cGy), and cetuximab (250mg/m2 Qweek) for 4 additional weeks, followed by surgical resection 1–3 weeks later. Results: Total Treated: 20 patients (ages 27 - 72), 19 uT3 patients, 1 Local Recurrence patient. Cetuximab Therapy (10 planned treatments): Too early 2 pts, ≥ 8 doses 12 pts, 5 - 8 doses 2 pts, < 5 total doses 4pts* (*cetuximab not given due to: 1 pt - acute cholecystitis from cholelithiasis; 1 pt - Grade 3 radiation perineal toxicity; 2 pts - treatment non-compliance). Radiation Therapy - 18 pts completed, 2 pts too early. Grade 3/4 Toxicities: Diarrhea 10%, Acneiform Rash (outside RT field) 15%, Stomatitis 5%, Radiation Field Dermatitis 5%, Transaminitis 5%. Surgical Outcomes: (17 pts completed surgery): R0 Resection 100%, Pathologic CR 12%. Conclusions: Cetuximab in combination with protracted infusion 5-FU and concurrent radiation is feasible without synergistic or unexpected toxicities. Further randomized investigation of this regimen in the neoadjuvant setting for rectal cancer is warranted.

No significant financial relationships to disclose.
Irinotecan in first line therapy of elderly and non-elderly patients with metastatic colorectal cancer: Meta-analysis of four trials investigating 5-FU and irinotecan
Authors: Folprecht G. , Rougier P. , Saltz L. , Van Cutsem E. , Douillard J. Y. , Sastre J. , Mitry E. , Hecker H. , Schubert U. , Köhne C. H.
Published: March 2020

3578

Background: Irinotecan has been shown to improve response rate and progression free survival in three randomized studies. In a recent metaanalysis showed that elderly patients have a similar benefit from 5-FU containing palliative treatment as younger patients (Folprecht 2004). Methods: We performed a metaanalysis of three randomized trials investigating 5-FU/FA/irinotecan vs. 5-FU/FA (Saltz 2000, Douillard 2000, Köhne 2005 [EORTC 40986]), and one phase II trial with 5-FU/irinotecan (Sastre 2005) to explore the efficacy and toxicity in elderly (≥70 years) and non-elderly (< 70 years) patients. Only data from randomized trials were used to compare the treatment arms 5-FU/FA plus irinotecan (IFL, FOLFIRI or Irinotecan/AIO) vs. 5-FU/FA (Mayo clinic regimen, LV5FU2 or AIO). Results: In total, 303 patients ≥70 y. and 1181 patients < 70 y were analyzed. Overall response rate was 39.5% in elderly and 33.1% in non-elderly patients (p=.055). Progression free survival was 6.7 (5.6–7.8) and 5.7 (5.2–6.1) months in elderly and younger patients (p=.12), respectively, overall survival 15.9 (13.6–18.3) vs. 15.4 (14.3–16.5) months (p=.9). Neutropenia gr. 3/4 and stomatitis gr. 3/4 was found to be more frequent in elderly patients. No differences were found in the other toxicities. Conclusion: The analysis confirms that neutropenia and stomatitis is moderately increased in elderly patients. However elderly patients benefit from treatment with irinotecan/5-FU in a similar way as younger patients do, and (fit) elderly should be offered the irinotecan-containing therapy in the same way as younger patients.

[Table: see text]

No significant financial relationships to disclose.
A randomised phase II study comparing irinotecan (IRI) plus leucovorin (LV) and 5-fluorouracil (5FU) versus IRI-LV-5FU followed be oxaliplatin (OXA) plus LV-5FU in patients with previously untreated metastatic colorectal cancer (CRC)
Authors: Kalofonos H. P. , Papakostas P. , Aravantinos G. , Papadimitriou C. , Pentheroudakis G. , Varthalitis I. , Tsavdaridis D. , Syrigos K. , Kosmidis P. , Fountzilas G.
Published: March 2020

3583

Background: IRI and OXA are both effective in the treatment of CRC. A theoretical framework supports the hypothesis that sequential administration of cytotoxic drugs at adequate doses can maximize the cell kill and overcome drug resistance. The aim of the study was to compare the response rate (RR), the time to tumor progression (TTP), the overall survival (OS) and to assess the toxicity profile of previously untreated patients with advanced CRC randomly assigned between IRI-LV-5FU (arm A) versus IRI-LV-5FU followed by OXA-LV-5FU (arm B). Methods: Intent to treat analysis was performed on 429 patients (219 in arm A and 210 in arm B) who were randomized from 31/10/2001 to 21/10/2004. The treatment schedules consisted of weekly IRI, 80 mg/m2 or OXA, 45 mg/m2 plus LV 200 mg/m2 followed immediately by intravenous bolus 5FU, 450 mg/m2 for 6 weeks followed by a 2-week rest period. Treatment was continued for 4 cycles, patients in arm B were treated initially with IRI-LV-5FU for 2 cycles followed by sequential administration of 2 cycles of OXA-LV-5FU. Results: The study failed to show any superiority of the sequential regimen. There were no significant differences between the two arms in the overall RR (26% versus 28%, p=0.631), TTP (Median, 7.8 versus 8.4 months, p=0.149). Toxicity profiles (grade III and IV) were equally frequent in both arms (diarrhea 13% versus 13.5%, febrile neutropenia 2% versus 1.5%, neurotoxicity 0% versus 0.5%). Conclusions: IRI-LV-5FU or IRI-LV-5FU followed by QXA-LV-5FU show equally substantial activities with manageable toxicity profile in advanced CRC.

No significant financial relationships to disclose.
Allogeneic hematopoietic cell transplantation after reduced intense conditioning as adoptive cell therapy in resistant metastatic colorectal carcinoma. The European experience
Authors: Aglietta M. , Barkholt L. , Caravelli D. , Minotto C. , Capaldi A. , Omazig B. , Ciccone G. , Niederwieser D. , Ringden O. , Demirer T.
Published: March 2020

3596

Background: Allogeneic reduced intense conditioning regimens decreased morbidity and mortality related to hematopoietic stem cell transplantation (HCT), retaining a powerful graft versus tumor effect (GVT). On this basis, it became possible to explore the existence of alloreactivity in solid tumors. A GVT effect was described in metastatic colorectal cancer (CRC). Methods: We report the data on 35 patients with CRC treated with non-myeloablative allogeneic HCT in Europe. Median time from the diagnosis of metastatic disease to transplant was 16 (4–47) months; 25 patients (67%) received at least 2 lines of therapy before transplant. Disease status at transplant was progressive disease (PD) in 31 patients (80%), stable disease (SD) in 6 (14%) and partial response (PR) in 2 (6%). Patients were treated according to different nonmyeloablative regimens. All but one patient received allogeneic peripheral hematopoietic cells [median CD 34+ cells/kg was 6.7 × 106 (2,5–55), median CD3 + cells/kg was 4.9 × 108 (0,11–33)] from HLA identical familiar donors. GVHD prophylaxis consisted of cyclosporine A (CyA) + Mycophenolate Mofetil in 24 (68%), of CyA + methotrexate in 6 (25%) and other CyA regimens in the others (18%). Results: Myelosuppression was mild and all patients engrafted with a median donor chimerism of 90% (45–99) on CD 3 cells on day +60. Transplant-related toxicities were limited. Grades II-IV acute GVHD occurred in 18 patients (51%) and chronic GVHD in 6 patients (25%). Transplant-related mortality was the cause of death in 4 patients (11%). As best tumor response we observed: 1 complete response (3%), 8 PRs (20%) and 9 SDs (29). Overall median survival from the date of transplant was 198 days (6–1020); median overall survival for the responding patients was 353 days (113–1020). Conclusions: Allogeneic HCT after RIC is safe and feasible in metastatic CRC. The results obtained compared favorably with those observed in patients with hematologic malignancies or metastatic CRC beyond second line in terms of transplant-related complications and tumor response respectively. Thus a study of allogeneic cell therapy in a less advanced patient cohort is warranted.

No significant financial relationships to disclose.
Effect of oxaliplatin-capecitabine first-line chemotherapy and tumor response on serum proteomic profiles in advanced colorectal cancer and identification of diagnostic biomarkers
Authors: Helgason H. H. , Engwegen J. Y. , Cats A. , Boot H. , Bonfrer H. G. , Beijnen J. H. , Schellens J. H.
Published: March 2020

3603

Background: Colorectal cancer (CRC) is the third most common cause of cancer related death. Prognosis is highly dependent on stage at diagnosis making early diagnosis mandatory. Previously we identified serum biomarkers for CRC, by comparing serum from CRC patients and healthy controls, using SELDI-TOF mass spectrometry. Methods: We validated our identified biomarkers and assessed the effect of first-line oxaliplatin (130 mg/m2 day 1, q21)-capecitabine (1000 mg/m2 d1–14, q21) therapy by prospective standardized serum sampling at < 2 weeks prior to start of chemotherapy and serially before each chemotherapy cycle in patients with advanced CRC. Samples were drawn according to standardized protocol, centrifuged within 1 hour and stored at -30°C. After thawing they were analyzed with SELDI-TOF MS on CM10 chips at pH 5. Healthy control subjects were matched according to age, gender and time of serum collection. For serial analysis the time points T: 0, 6, 12 and 18 - 24 weeks were used. All patients had given written consent, had WHO PS ≤ 2 and measurable disease, according to RECIST criteria, and/or were evaluable by CEA. Results: In total 42 patients (mean age: 57 years; range: 37 - 73; male 62%), were treated between 06/2003 and 09/2005. All patients were previously untreated except 8 patients who had received radiation or chemo-radiation for rectal carcinoma (all > 6 months). Median follow up was 45 weeks and median number of courses was 5.5 (range: 1 -10). Response rate was 46%; PR in 19, SD in 12 and PD in 10 patients, respectively (1 not evaluable) and median overall survival was 10.5 months. We identified 6 peptides/proteins (m/z: 31948, 8078, 28101 (apolipoprotein A-I), 7970, 5912 and 12861 Da, respectively (in order of significance) discriminating between CRC and healthy controls (p < 0.001). In a serial analysis of the patients a peptide, with m/z: 5.9-kDa (most likely fibrinogen split product) declined, during chemotherapy in some responsive patients, but apolipoprotein A-I appeared not to change. Conclusions: We confirmed our previous identification of apolipoprotein A-I (m/z: 28-kDa) as a potential biomarker for CRC and suggest a peptide with m/z: 5.9-kDa as a potential biomarker of response.

No significant financial relationships to disclose.
Molecular signatures generated with RNA isolated from formalin-fixed paraffin-embedded tumor specimens differentiate metastatic and non-metastatic primary colorectal cancer
Authors: Shimizu D. , Kuramochi H. , Tanaka K. , Cooc J. , Xiong Y. , William M. , Li R. , Danenberg K. D. , Danenberg P. V. , Lenz H. J.
Published: March 2020

3615

Background: Colorectal cancer (CRC) can be either non-metastatic (locally-advanced) or metastatic, with the latter having a considerably worse prognosis. Because tissue from patients is generally available only as FFPE specimens, we investigated whether distinct molecular signatures could be obtained for these CRC types using RNA isolated from archival FFPE specimen blocks in gene expression arrays. Methods: FFPE specimens were available from 12 non-metastatic tumors and 9 primary tumors along with their matching metastases. Up to 5 10-micron sections of each were microdissected to isolate areas of tumor tissue. RNA was extracted using a proprietary procedure of Response Genetics, Inc. and was then amplified and labeled. The resulting cRNA was hybridized to the U133 plus 2.0 GeneChip. Unsupervised PCA analysis of the samples resulted in the first principal component separating 2 distinct groups, which consisted of the non-metastatic and metastatic tumors. A differentially expressed gene list between metastatic and non-metastatic CRC was determined. These data were also analyzed for differential canonical pathways using Ingenuity Pathway Analysis. Results: Hierarchical clustering analysis segregated locally advanced primary tumors and metastatic primary tumors into two clusters with distinct gene signatures. A T-test with unequal variance assumption identified 609 differentially expressed probe sets with FDR (false discovery rate) = 0.05. Comparison of primary tumors with their liver metastases using a paired T-test showed only 2 differentially expressed genes at FDR = 0.05 but 526 genes with significance p value < 0.005. Pathway analysis showed significant deregulation of VEGF, hypoxia, B Cell receptor, PI3K/AKT, ERK/MAPK and G-protein coupled receptor signaling between locally advanced and metastatic tumors. Pathway analysis of primary tumors and metastases showed deregulated TGF-b, integrin and chemokine signaling pathways. Conclusion: We have demonstrated the feasibility of identifying metastatic and non-metastatic tumors by microarray analysis using FFPE CRC tissue. This result is currently being validated in a separate larger cohort of patients.

[Table: see text]
Fecal mutational load and distribution analysis in the non-invasive diagnois of colorectal cancer
Authors: Tarafa G. , Blanco I. , Casadomé L. , Mora F. , Vilardell F. , Moreno V. , Lizardi P. , Costa J. , Capellá G.
Published: March 2020

3618

Background: Specific molecular profiles of exfoliated tumour cells may lead to non invasive diagnosis of cancer. We have developed a DNA chip-based methodology that allows for the simultaneous and quantitative detection of multiple allelic substitutions in bodily fluids. Total Mutational Load Distribution Analysis (MLDA) of DNA found in bodily fluids yields biometrics that may enable early tumor diagnosis. We wanted to ascertain whether the MLDA of selected K-ras and p53 mutations in fecal DNA distinguishes between absence of tumor and the presence of neoplastic disease and whether patients with adenomas can be distinguished from those bearing carcinomas. Method: DNA was obtained from solid stools or colonic lavage in 67 patients undergoing colonoscopy: non-neoplastic condition (n=24); adenomas (n=16); carcinomas in situ (n=6) and carcinomas (n=21). Quantitative and simultaneous detection of 8 substitutions at codons 12 and 13 of K-ras gene and 15 hotspots substitutions at exons 5 and 7 of p53 gene was performed using an oligonucleotide zip-code microarray with rolling circle amplification signal enhancement. Total Mutational Load (TML) and relative prevalence values of independent alleles were measured. Results: MLDA separated the three groups: Total Mutational Load (TML) of non-neoplastic conditions ranged from 5.3 to 7.15. TML of adenomas ranged from 16.50 to 22.24 and of carcinomas in situ from 22.30 to 36.29. TML of invasive carcinomas ranged from 25.06 to 67.9. In a training set of the first 40 samples analyzed a halfway cut-off value of 11.87 was established to discriminate between non-neoplastic and neoplastic disease. Sensitivity was 100% (95% CI 91.7–100) and specificity was 100% (95% CI 86.2- 100) in both sets. We have reproduced similar results with classic techniques like sequences and cloning. Conclusion: Stool MLDA appears to be a useful non-invasive marker of distal and proximal colonic neoplasms that deserves widespread validation.

No significant financial relationships to disclose.
Assessment of the role of Fanconi Anemia (FA) genes in colorectal cancer: A new pathogenetic pathway?
Authors: Palmieri G. , Colombino M. , Camboni M. G. , Manca A. , Baldinu P. , Izzo F. , Tatangelo F. , Calemma R. , Cossu A. , Galimi F.
Published: March 2020

3629

Background: Fanconi Anemia (FA) is an autosomal recessive disease marked by congenital defects, bone marrow failure, and high incidence of leukemia and solid tumors. Eight FA associated genes have been cloned, and their products are thought to function in an integrated pathway which includes BRCA genes and maintains genomic stability. A molecular mechanism involved in the development and progression of some human malignancies, including colorectal cancer, is represented by a defective replication fidelity. Here we tested the role of the main FA genes in colorectal cancer (CRC). Methods: One hundred consecutively-collected patients with histologically-proven diagnosis of CRC and no mutation in the main mismatch repair genes (MLH1 and MSH2) were included into the study. Genomics DNA was screened using DHPLC for FANC-C/G/E/F genes and using MPLA for FANC-A/D2 genes. All PCR products with abnormal DHPLC profiles were sequenced on an automated sequencer. For 28 cases, tumor tissue samples were also analyzed. To date, total RNA was isolated from paired normal and tumor samples of 12 CRC patients. Gene expression was quantified by real-time RT-PCR using the Taqman approach. Results: At germline level, 2 cases presented FANC-C sequence variations (Asp267Ser, Val449Ser) and 5 cases showed a exon 26 deletion in FANC-A as detected by MLPA analysis. Among the 28 tumor samples available from patients negative for mutations in germline DNA, 2 (7%) cases presented a FANC-E mutation (Ala552Thr). Moreover, one of such somatic samples presented a BRCA2–8765delAG mutation (BRCA2 is also recognized as FANC-D1 gene). Assuming as significant difference in gene expression the presence of a variation of more than 50% in mRNA levels between normal and corresponding tumor samples, all tested FA genes (FANC-C/G/E/F) were found overexpressed in 5/12 (42%) tumor samples. Conclusions: Although preliminary, our findings seem to identify a subset of CRC patients with alterations in the FA/BRCA pathway which is required for the activation of DNA repair. Ongoing molecular analyses will better clarify the real frequency of each alteration in FA genes and their relationship with the histological and/or clinical features in colorectal cancer.

No significant financial relationships to disclose.