bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I/II study of cetuximab dose-escalation in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic (PK), Pharmacodynamic (PD) and efficacy data
Authors: Tejpar S. , Peeters M. , Humblet Y. , Gelderblom H. , Vermorken J. , Viret F. , Glimelius B. , Ciardiello F. , Kisker O. , Van Cutsem E.
Published: March 2020

4037

Background: Response to epidermal growth factor receptor (EGFR) inhibitor, cetuximab appears to correlate with the intensity of the associated skin reaction. This randomized study investigated cetuximab dose-escalation in patients (pts) with EGFR-expressing mCRC failing irinotecan-including therapy (I). Methods: Pts were randomized 22 days after starting cetuximab (400 mg/m2 initial dose then 250 mg/m2/week [w]) with I (180 mg/m2 q 2 w) if they had not experienced >grade (G) 1 skin reaction, any other >G 2 cetuximab-related adverse event and were tolerant to I. Randomization was to standard cetuximab dose (Arm A; 250 mg/m2/w) or dose-escalation (Arm B; cetuximab dose increased by 50 mg/m2 q 2 w, until >G 2 toxicity, tumor response or dose = 500 mg/m2). Pts not randomized (Arm C) continued on standard cetuximab dose. Primary endpoint was to compare in skin and tumor biopsies, taken before and during treatment, the effects of dose-escalation on EGFR and downstream signalling markers with those of the standard cetuximab regimen. Secondary endpoints were PK, efficacy, safety, tolerability, biomarker analyses on tumor biopsies and plasma samples. Results: 284 pts screened, 221 pts EGFR-expressing, 166 pts enrolled and randomized: 45 to Arm A; 44 to Arm B. 77 non-randomized pts were included in Arm C. M/F 106/60, median age 60 years [25–79], median KPS 90 [70–100]. 24 pts in Arm B reached 500 mg/m2/w. By the cut-off date of July 31st 2006 the preliminary response rate (RR) in Arm B was 30% vs. 13% in Arm A. RR in arm C was 22%. Preliminary progression-free survival in Arm A was 3,9 mo vs. 4,8 mo in Arm B and 3,9 mo in Arm C. In Arm B, 9% pts had G 3/4 skin reactions, 0% in Arm A (14% in Arm C). Dose related increases in Cmax and AUC were observed. T1/2 values were dose independent. Conclusions: Cetuximab dose- escalation up to 500 mg/m2/w improves RR in pts with no or slight skin reactions on standard dose treatment. Overall cetuximab PK behavior is in good agreement with previous experience. Treatment was generally well tolerated. PD and biomarker results will be presented at the meeting.

No significant financial relationships to disclose.
Validation of sentinel lymph node (SLN) mapping (M) in colon cancer (Cca) over three continents: An international experience
Authors: Saha S. , Patel M. , Bilchik A. , Beutler T. , Zuber M. , Bembenek A. , Kitagawa Y. , Duben J. , Codignola C. , Cserni G.
Published: March 2020

4047

Background: Lymph node (LN) status is the most important prognostic factor in colon cancer (Cca). In various trials, the average nodal positivity of conventional surgery in Cca is about 33%. Ultrastaging of SLNs results in higher and more accurate nodal staging of patients (pts) with Cca. However, some recent publications of SLNM in Cca have shown variable results with differing conclusions. Hence, prospective data from 3 continents were analyzed to study the international experience of SLNM in Cca. Methods: Only centers with experience of 40 or more cases of SLNM in Cca were included in the study. SLNM was performed by peri-tumoral injections of 1–3 ml of 1% lymphazurin. First 1–4 blue nodes marked as SLNs were ultrastaged by multilevel microsections for H&E and IHC. Data for calculating the success rate, accuracy, skip metastases (mets), sensitivity, negative predictive value; nodal positivity and upstaging were collected from each center. Results: Our study included a total of 1,216 Cca pts from 9 centers over 3 continents. SLNM was successful in 92.9% pts ( Table 1 ). The average number of LN/pt was 18.5 and the average number of SLN/pt was 2.7. The overall sensitivity, accuracy rate and negative predictive value were 78.3%, 89.4% and 82.8% respectively. Nodal mets were found in 52.9% pts. Of these, SLNs were the exclusive site for mets in 30.1% pts while 18.3% pts were upstaged by SLNM. Skip mets were seen in 21.7% pts (range 9.5% - 44.1%). Conclusions: SLNM is highly successful in Cca when performed by experienced surgeons worldwide. Nodal positivity was found to be much higher in pts undergoing SLNM compared to conventional surgery. Upstaged pts may benefit from adjuvant chemotherapy. Though the variation of skip mets was wide, the clinical impact of skip mets in Cca is negligible compared to that in melanoma and breast cancer, since all pts undergo standard lymphadenectomy and all node positive pts (true +ve & skip mets) are usually treated with adjuvant chemotherapy.

[Table: see text]

No significant financial relationships to disclose.
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
Authors: Alberts S. , Mahoney M. R. , Donohue J. H. , Roh M. S. , Green E. M. , Sargent D. J. , Wagman L. D. , Bolton J. S.
Published: March 2020

4057

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. Dual therapy OXAL+CAPE has demonstrated activity in advanced CRC. We report final results of an analysis of SYS OXAL+CAPE, alternating with HAI FUDR. The primary endpoint is 2-yr survival (2YS), with 36 of 45 patients surviving 2 yrs as evidence of promising efficacy. Methods: Patients with M-CRC liver lesions amenable to resection ± ablation were eligible. Prior adjuvant chemotherapy for completely resected primary was allowed. HAI+SYS therapy was initiated 21–56 days post-metastasectomy. Four alternating courses of HAI consisted of 0.2 mg/m2/d FUDR and dexamethasone, d1–14 wks 1&2. SYS included 130 mg/m2 OXAL d1, with CAPE at 1,000 mg/m2 po BID, d1–14, wks 4&5. Two additional 3-wk courses of SYS were given. CAPE was reduced to 850 mg/m2/BID after interim review of toxicity. Results: 54 of 73 eligible patients initiated HAI FUDR + SYS. 52% had a solitary met and 24% presented with bilobar mets. 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 HAI+SYS related deaths occurred. Median follow-up on the 42 survivors is 28 months (range 7–51). 6 deaths occurred within 2 yrs. 48% (26/54) have recurred; 42% (11/26) with liver involvement. Median time-to-progression is 30 months. The estimated 2YS rate is 88% (95% CI 80–98%) and median overall survival is 46 months (95% CI 41.3-NA). Conclusions: The combination of HAI FUDR and SYS therapy appears to improve outcome following resection of hepatic CRC-M. A 2YS of 88% exceeds our preplanned level of success, supporting the use of this combination in the ongoing NSABP trial C-09. Supported by NIH Grant CA25224–18, Sanofi-Synthelabo, and Roche Laboratories, Inc.

No significant financial relationships to disclose.
Liver metastases of colorectal carcinoma: Prospective study on the use of transarterial chemoembolization (TACE)
Authors: Vogl T. J. , Gruber T. , Zangos S. , Balzer J. O.
Published: March 2020

4062

Background: To evaluate the efficacy of chemoembolization (TACE) in the treatment of liver metastases in colorectal cancer patients concerning local control and survival. Methods: 207 patients with liver metastases of colorectal cancer were treated with repeated TACE in 4-week intervals. In total, 1,307 chemoembolizations were performed with a mean of 6.3 sessions per patient. At the time of first chemoembolization the average age of the patients was 68.8 years (range, 39.4–83.5 years). 158 patients were treated palliatively, 35 symptomatically and 14 patients neoadjuvantly. The chemotherapy consisted of Mitomycin C with/without Gemcitabin; embolization was performed with Lipiodol and starch microspheres for vessel occlusion. Tumor response was evaluated by magnetic resonance imaging (MRI). The change in size was calculated and the response was evaluated according to the RECIST criteria. Survival rates from the first diagnosis and from the first TACE session were both calculated according to the Kaplan-Meier method to obtain the median survival. Results: While 70% of the patients showed multiple metastases, 6% had 1 metastasis, 5.8% had 2 metastases and 18.2% had 3 to 4 metastases. Lesion size and number before, during and after treatment were assessed to deduce the morphological response. Local control results according to the RECIST criteria were as follows: partial response 12% of patients, stable disease in 51% and progressive disease in 37%. The 1-year survival rate after TACE was 62%, but the 2-year survival rate had been reduced to 38%. The median survival time from the date of diagnosis of metastases was 3.4 years (according to Kaplan-Meier), the median survival time from the start of TACE treatment was 1.34 years. The median survival time of the palliative group was 1.4 years, of the symptomatic group 0.8 years and of the neoadjuvant group 1.5 years. Conclusions: TACE is an effective minimal-invasive therapy for neoadjuvant, symptomatic or palliative treatment of liver metastases in colorectal cancer patients.

No significant financial relationships to disclose.
Complete pathological response of colorectal liver metastases after neoadjuvant chemotherapy: myth or reality?
Authors: Wicherts D. A. , Haas de R. J. , Levi F. , Aloia T. , Paule B. , Bralet M. , Kunstlinger F. , Azoulay D. , Castaing D. , Adam R.
Published: March 2020

4063

Background: A complete clinical response (CCR) of colorectal liver metastases (CLM) following chemotherapy has been shown unrelated to the real disappearance of active tumor. By contrast, a complete pathological response (PCR) could be more clinically relevant, but has not been explored. The aim of this study was to evaluate the incidence and outcome as well as predictive factors of PCR, in patients resected from CLM after neoadjuvant chemotherapy. Methods: In our institution 791 consecutive patients with CLM underwent liver resection after neoadjuvant chemotherapy. CCR was defined as the disappearance of all lesions after chemotherapy, and PCR was defined as the total necrosis of all metastases on the resection specimen. Both were selected from a prospective database. Patients with and without PCR were compared, survivals were determined and predictive factors for PCR were analyzed using a multivariate risk model. Results: There were 0.4% CCR (3/791) and 4% PCR (31/791). Among the 31 patients with PCR, the median number of CLM was 2.0 (range 1–13) with a maximum diameter = 3 cm for most cases (73%) at diagnosis. Ten patients (32%) had extrahepatic metastases. Compared to patients without PCR, patients with PCR were younger (p< 0.05) and had a smaller maximum tumor size (p=0.007). Rate of objective response was higher (81% vs. 52%; p=0.002) and last chemotherapy regimen contained more frequently oxaliplatin than irinotecan (p=0.05). Number of chemotherapy cycles and treatment lines were not different. At multivariate analysis, 4 predictive factors of PCR were identified: age = 60 yrs, maximum size at diagnosis = 3 cm, CEA = 40 ng/ml at diagnosis and achievement of an objective response. The probability of PCR ranged from 0.2% when all were absent to 33.8% when all were present. PCR strongly impacted overall survival (OS) that was 69% and 62% at 5 and 10 years with a disease-free survival (DFS) of 42% for both. Conclusions: PCR concerns overall 4% of patients receiving neoadjuvant chemotherapy allowing for surgery, but as much as one third of those aged less than 60 years, developing response on liver metastases smaller than 3 cm, with low CEA values. Uncommon high survival rates are observed in this setting. PCR more than CCR is a reality and strongly impacts patient outcome.

No significant financial relationships to disclose.
Encouraging results from a phase I study of capecitabine (X), irinotecan (I) and oxaliplatin (O) as first-line therapy in patients (pts) with metastatic colorectal cancer (MCRC)
Authors: Maroun J. , Jonker D. , Cripps C. , Goel R. , Lister D. , Chiritescu G.
Published: March 2020

4086

Background: First-line treatment with I, O and infusional 5-FU/Leucovorin (LV) triplets is associated with high response rates and long survival in MCRC. The oral fluoropyrimidine X is better tolerated and shows improved response rates vs. 5- FU/LV in MCRC. This dose-escalation study aims to establish dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase II doses (RPIID) of I, O and X and to evaluate efficacy and safety in first-line. Methods: Starting doses were: I (180mg/m2 i.v. d1), O (85mg/m2 i.v. d1), × (850mg/m2 bid orally d2–15). Dose escalations are based on toxicity observed at previous dose level (DL), until DLT, MTD and RPIID are reached. Results: We have enrolled 27 pts (21 men, 6 women), median age 59 years (range 25–74), at 6 DLs. ECOG PS was 0 or 1 in 25 pts, and 2 in 2 pts. Pts received a median of 10 cycles (range 1–23). All pts are evaluable for toxicity (24 for efficacy). Most common grade 3/4 hematological adverse events (AEs) during dose escalation: granulocytopenia (41%), anemia (7%), and thrombocytopenia (15%). Most common grade 3 non-hematological AEs: late-onset diarrhea (11%), fever (14%), and fatigue (4%). DLTs at each dose level: DL1 (1 febrile neutropenia with bowel perforation); DL2 (1 grade 3 diarrhea); DL3 (1 febrile neutropenia with grade 2 edema); DL4 (1 severe febrile neutropenia in cycles 2&3, pt deceased due to sepsis); no DLTs were reported at DL5 & 6. MTD has not yet been reached. Overall response rate is 79% (95% CI, 62–97%), including 2 CRs and 17 PRs (3 still unconfirmed). Disease control rate is 92%. Two pts had subsequent curative liver resection and 4 pts are under consideration for curative procedures. Median progression-free survival is 15 months (95% CI, 8–22). Conclusions: XIO is well tolerated and highly effective as first-line treatment for MCRC. Severe neutropenia was significant but of short duration and manageable; it is likely to be the main DLT. MTD has not yet been identified but is expected shortly. A phase II study to confirm the efficacy and safety of XIO, possibly in combination with targeted agents, will follow. Supported by Roche, Sanofi-Aventis, and Pfizer Canada.

No significant financial relationships to disclose.
CETUFTIRI, a new combination of UFT with leucovorin (LV), irinotecan, and cetuximab as first-line treatment for patients (pts) with unresectable metastatic colorectal cancer (mCRC): Preliminary results from a multicenter phase II trial
Authors: Bennouna J. , Faroux R. , François E. , Ligeza C. , El Hannani C. , Perrier H. , Jacob J. , Desseigne F. , Perrocheau G. , Douillard J. Y.
Published: March 2020

4087

Background: A phase II study (ASCO 2004) established that the combination of UFT (tegafur-uracil) with LV and irinotecan (TEGAFIRI) could be safely administered to pts with unresectable mCRC, with an objective response rate (ORR) of 34% and a median time to progression (TTP) of 5.7 months. We initiated CETUFTIRI, a phase II study, to evaluate the efficacy and tolerability of cetuximab added to TEGAFIRI in chemonaïve pts with unresectable mCRC. Methods: Patients in this single-stage study were aged =18 years, with histologically or cytologically confirmed, bidimensionally measurable mCRC, ECOG performance status 0 or 1, and adequate bone marrow, renal, and hepatic function. EGFR expression was not an inclusion criterion. Treatment consisted of UFT 250 mg/m2/day d1–14, LV 90 mg/day d1–14, and irinotecan 250 mg/m2 d1 every 3 weeks, plus cetuximab 400 mg/m2 week 1 then 250 mg/m2 weekly thereafter. The primary endpoint was ORR and the planned sample size was 61 pts. The study is now closed to accrual. Results: To date, 48 patients are evaluable for safety and 31 are evaluable for efficacy. Patient characteristics (n=48): median age 65 years (range 45–84 years); ECOG PS 0/1: 73/27%; male 65%; tumor sites: colon 69%; rectum 17%; junction 14%; liver metastasis 83%; lung metastasis 46%; other 27%. Adverse events per patient (n=48) after a total of 230 cycles were: grade G3 mucositis 10%; G3/4 neutropenia 10%; G3 nausea/vomiting 8%; G3 asthenia 6%; febrile neutropenia 6%; G3 hypokalemia 6%; G3/4 anemia 4%; G3 diarrhea 2%; acne-like rash G1/2 50% (G3 4%); infusion- related reaction to cetuximab 6%. Two of 31 evaluable pts had a complete response and 11 had a partial response, for an ORR of 42%; 5 pts had stable disease (16%) and 11 pts had progressive disease (35.5%). An independent radiologist review is planned for all 61 pts included up to December 2006. Conclusions: The CETUFTIRI combination seems to have an acceptable toxicity profile with an attractive objective response rate in the first-line treatment of pts with mCRC.

No significant financial relationships to disclose.
Results of a phase II trial of cetuximab + XELIRI as first-line therapy of patients with advanced and/or metastatic colorectal cancer
Authors: Cartwright T. H. , Kuefler P. , Cohn A. , Hyman W. , Yoffe M. , Boehm K. A. , Ilegbodu D. , Asmar L.
Published: March 2020

4094

Background: We have previously shown that capecitabine/irinotecan (XELIRI) is effective and well-tolerated in metastatic colorectal cancer (mCRC). Cetuximab, a monoclonal IgG1 antibody that binds to the extracellular domain of EGFR, is active in mCRC alone or in combination with chemotherapy. This study was designed to evaluate if cetuximab (Erbitux®) added to XELIRI improves outcome in first-line treatment of mCRC. Methods: Subjects had histologically confirmed colorectal adenocarcinoma with T4 lesions that were unresectable after preoperative chemoradiation therapy and/or metastases. The study regimen was capecitabine 1700 mg/m2 (850 mg/m2 PO BID Days 1–14), irinotecan 200 mg/m2 IV Day 1 every 3 weeks, and weekly cetuximab (initial dose 400 mg/m2 IV over 120 minutes, subsequent doses 250 mg/m2 over 30 minutes). Results: Between February and October 2005, 70 subjects enrolled. Baseline characteristics: 43 males (61%), median age 61.5 years, and ECOG PS 0/1= 66%/34%; 94% of subjects had adenocarcinoma. Prior therapy; surgery (91%), chemotherapy (20%), or radiotherapy (7%). Responses (pts >2 cycles) were; CR (4%), PR (36%), SD (40%) and PD (20%); 15 patients failed treatment; (n=4 allergic reaction, n=2 MD request, n=2 withdrew consent, n=2 Grade 4 neutropenia, and n=5 other AEs). The overall response rate was 40% and the disease control rate was 80%. Median duration of response was 8.8 months (range, 2.6–15.1) and median time to response was 2.0 months (range, 1.2–8.3). 64% of patients remain alive; of the 25 deaths, 84% were due to PD. No death was drug related. The most frequent Grade 3 and 4 treatment-related adverse events (AEs) included: diarrhea (25%), neutropenia (18%), nausea/vomiting (12%), rash and dehydration (9%, each), HFS and fatigue (7%), and allergic reaction (6%). 54% of patients required dose reductions. To date, 64 patients (91%) have gone off study, primarily due to PD (39%) or AE (33%); 3 patients remain on treatment. Conclusions: The combination of cetuximab and XELIRI is feasible and tolerable in first line mCRC. Toxicities are expected and manageable with dose reductions/delay. Funded in part by Bristol-Myers Squibb, Plainsboro, NJ.

No significant financial relationships to disclose.
Predictors of colon cancer screening among low-income urban minority residents: The Cancer Risk Assessment in Baltimore (CRAB) Study
Authors: Mentor-Marcel R. A. , Visvanathan K. , Garza M. A. , Xie Y. , McCaffrey L. , Ford J. G.
Published: March 2020

4101

Background: Colorectal cancer mortality can be reduced through early detection, using recommended screening tests (fecal occult blood test (FOBT), sigmoidoscopy, or colonoscopy). However, screening is underutilized, especially among low-income and racial/ethnic minority groups. Few studies have examined determinants of screening in these groups. Methods: We analyzed data on predictors of colon cancer screening from a cross-sectional study of Baltimore City Residents (N = 534). Participants responded to a questionnaire administered by an interviewer, on screening practices, behavioral, social and demographic factors, including income level. Eligible respondents for this analysis were age = 50, aware of colorectal screening tests, but not diagnosed with colon polyps or cancer. Multivariate techniques were used to examine predictors of having undergone any recommended colon cancer screening test. Results: The eligible population for this analysis (N=202) was 49.0 % male and 51.0 % female. The median income fell within the $12,000-$24,999 bracket. The proportion of participants that had received colon cancer screening was 34.5 % among those in the highest income bracket (i.e. =$25,000) compared to 30.0 % in the lowest income bracket (i.e. =$11,999). This difference was statistically significant after adjusting for other sociodemographic factors (odds ratio (OR)=3.12, p=0.023). Multivariate analysis indicated that screening was associated with having one (OR: 3.56, p=0.016) or more than one (OR: 7.31, p=0.006) primary health care provider. Having health care coverage, a doctor who recommended exercise, and having at least some college education, were also associated with screening. Conclusions: Negative predictors of colorectal cancer screening include: extremely low income levels (= $11,999), lack of health care coverage, primary care providers, and college education level. Provider recommendations for healthy behaviors (e.g. exercise) are associated with patient adherence to recommended cancer screenings. The design of interventions to promote use of screening tests by low-income populations should be informed by the substantial heterogeneity in patient and provider characteristics within these populations.

No significant financial relationships to disclose.
Randomized multicenter phase III trial of oxaliplatin plus raltitrexed compared to oxaliplatin plus fluorouracil and leucovorin treatment in recurrent and metastatic colorectal cancer
Authors: Wang J. , Li J. , Qin S. , Liu T. , Ye Z. , Zheng L. , Tao M. , Zhuang Z. , Zhang Q. , Xu N. , Zhang Y.
Published: March 2020

4102

Purpose: To compare oxaliplatin (L-OHP) plus raltitrexed (RTX) with L-OHP plus fluorouracil and leucovorin (LV/5FU) for patients (pts) with recurrent and metastatic colorectal cancer(CRC). Methods: Eligible pts had to have histologically proven recurrent or metastatic CRC,not having previously received oxaliplatin as palliative chemotherapy,ECOG PS = 2,age:18∼70,and adequate hematological,renal and hepatic function.After written informed consent,pts were randomized to L-OHP:130 mg/m2 d1 + RTX: 3 mg/m2 d1 (Arm A) or + LV: 200 mg/m2 + 5FU:375 mg/m2 d1–5 (Arm B). Results: Between Jan 2005 and July 2006, 216 pts were enrolled at 15 centers in China.112 pts (mean age: 55.0 (19∼70), M/F: 57/46, PS 0/1/2: 46/53/13) were randomly assigned to A and 102 (mean age: 54.2(22∼70), M/F: 54/46, PS 0/1/2: 44/59/9) to B. 203 pts were eligible for response evaluation (A:103, B:100).The median number of cycles was 4 (1∼6) in A and 3 (1∼6) in B (P=0.1431).The RR was 29.1% (CR:2, PR:28, SD:50 , PD:23) in A and 17.0% (CR:2, PR:15, SD:46 , PD:37) in B (P=0.0437).The disease-control rate was 77.7% in A and 63.0% in B (P=0.0237). After a median follow-up of 10 months (4–16.5),92 pts had had progression of disease (40 in A and 52 in B); 73 deaths had occurred (35 in A and 38 in B), median time to progression was not reached. Following-up is ongoing.The median QoL scores for the two arms were comparable. 214 were included in the safety analyses (A:112, B:102). There was a higher incidence of neutropenia (48.2% verse 29.4%, P=0.005) and transaminase increase (49.1% verse 35.3%, P=0.041) among A. Grade 3 or 4 neutropenia was much common in pts in A than those in B (20.5% verse 4.9% , P=0.001), but was complicated by fever in only 3.6% of cases (4 pts) in A and in 2.9% of cases (3 pts) in B. No pts were dead or infectious due to neutropenia. There were similar rates of grade 3 or 4 transaminase elevation in the two groups. Vomitting and anorexia were much commoner with B. Conclusions: The L-OHP+RTX seems beneficial in recurrent and metastatic CRC, demonstrating better response rate and higher disease control rate with acceptable tolerability, maintenance of QoL and convenient administration schedule.

No significant financial relationships to disclose.
Application of the RTOG recursive partitioning analysis classification to brain metastases from colorectal cancer
Authors: Yasui H. , Yoshino T. , Boku N. , Onozawa Y. , Hironaka S. , Fukutomi A. , Yamazaki K. , Machida N. , Tochikubo J. , Mitsuya K.
Published: March 2020

4104

Background: Colorectal cancer infrequently causes brain metastases (BMs). Recently, the incidence of BMs from colorectal cancer (CRC) has been reported to be increasing as 3 % of all metastatic CRCs, especially in patients (pts) with lung metastases (LMs). The RTOG previously developed three prognostic classes for BMs using a recursive partitioning analysis (RPA) classification, including Karnofsky performance status, controlled primary tumor, extracranial metastases, and an age. However, the relevance of this classification for CRC remains unclear, because only a few CRC pts were included in the RTOG database. The present studies retrospectively evaluate the usefulness of RPA classification for BMs from CRC. Methods: The subjects were consecutive 290 metastatic CRCs without symptomatic BMs who treated with any chemotherapy initiated in our institution between 2002 and 2005. The treatment of BMs, including whole brain radiation therapy (WBRT), surgery, and stereotactic radiosurgery (SRS), were indicated for pts whose life expectancy was considered to exceed 3 months (M). Results: BMs were detected in 20 pts out of 133 (15%) with LMs at base line, with a median follow-up time of 17.7 M. In the remaining 157 pts, BMs were found in 3 pts out of 41(7%) who had developed LMs during follow-up and 2 pts out of 116 (2%) without LMs. In total, overall incidence of BMs was 9% (25/ 290). Median duration from the diagnosis of LMs to BMs was 12 M (range: 4.4–33.6). According to RPA, the 25 pts with BMs were classified into Class I 0 (0%), Class II 12 (48%) and Class III 13 (52%). Treatments for BMs were performed to all pts of Class II, and to 6 pts (46%) of Class III. Median overall survivals from detecting BMs were Class II 9.7 M and Class III 3.0 M (logrank test; p=0.02). In the 18 pts treated for BMs, median BMs progression-free survival of Class II and Class III were 3.0 M and 3.1 M. Conclusions: It is suggested that the incidence of BMs from CRC is more common than previously reported. Overall survivals for BMs reproduce the results from RPA classification.

No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) mRNA expression levels are strongly correlated between primary colorectal cancer and corresponding liver metastases
Authors: Kuramochi H. , Hayashi K. , Uchida K. , Yamamoto M. , Danenberg K. D. , Danenberg P. V.
Published: March 2020

4106

Background: As it has been well known that epidermal growth factor receptor (EGFR) is strongly related to a tumor proliferation and a metastasis, new EGFR-inhibitory small molecules, such as gefitinib and erlotinib, and EGFR antibodies have been developed recently. It is reported that the high expression levels of EGFR mRNA are associated with high response probability and longer progression-free survival in gefitinib-treated lung cancer patients. Thus, since liver metastases are the main cause of death for most of colorectal cancer (CRC) patients, it is reasonable to expect that measurement of EGFR gene expression levels in liver metastases would provide the best prediction of therapy benefit, but in most cases, only biopsies of the patient’s primary tumor are readily available for analysis. Our aim was to determine how EGFR gene expression levels in primary CRC were related to those in liver metastases. Methods: Thirty-one pairs of primary CRC and corresponding liver metastases were analyzed. (18 males and 13 females: Median age 66 (range 45–85)). Formalin-fixed, paraffin-embedded tumor specimens were dissected by using laser-captured microdissection. RNA was extracted and cDNA was prepared by reverse-transcription. Quantitation of target gene and internal reference gene was performed using real-time PCR (Taqman PCR). Results: No significant difference was seen between median mRNA expression levels of EGFR in primary cancer and those in corresponding liver metastases (Median value: 1.35 vs 1.24, p=0.99 , Wilcoxon signed rank test), although the median value of EGFR mRNA from normal liver tissue is significantly higher than those from normal colon mucosa (Median value: 5.06 vs 1.39, p<0.0001). When matched tissue sets were compared on an individual basis, there was a significant correlation for EGFR mRNA expression between primary cancer and corresponding liver metastases (rs=0.78, p<0.0001, Spearman rank correlation coefficient). Conclusions: A good prediction of EGFR mRNA levels in liver metastases can be obtained by measuring those of primary CRC.

No significant financial relationships to disclose.
Molecular markers associated with response and clinical outcome to cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer (BOND2)
Authors: Azuma M. , Yang D. , Carpanu M. , Hollywood E. , Lue-Yat M. , Zhang W. , Danenberg K. D. , Danenberg P. V. , Saltz L. , Lenz H.
Published: March 2020

4113

Background: Phase II (BOND2) trial of Cetuximab/Bevacizumab/Irinotecan (CBI) vs Cetuximab/Bevacizumab (CB) has shown that bevacizumab added to the efficacy of cetuximab and cetuximab/irinotecan in irinotecan-refractory bevacizumab-naïve CRC patients. We tested whether expression levels of genes involved in angiogenesis (VEGF, IL-8), the EGFR pathway (EGFR, COX2) and DNA repair (ERCC1) are associated with clinical outcome. Patients and Methods: This randomized phase II trial enrolled 81 patients. Treatment plan as: Arm A received IRI at the same dose and schedule as last received prior to study, plus Cetuximab 400 mg/m2 loading dose, then weekly at 250 mg/m2, plus Bevacizumab 5 mg/kg given every other week. Arm B received the same as arm A, but without IRI. FFPE samples for 35 out of 81 patients (M:W 24:11, median age 56 (29–80) enrolled in the BOND2 study were tested. Patients received either with CBI (n=18, Arm A) or with CB (n=17, Arm B). FFPE tissues were dissected using laser-captured microdissection and analyzed EGFR, ERCC1, VEGFA, VEGFR2, COX2, Cyclin D1, IL-8, and NRP1 mRNA expression using a quantitative real-time RT-PCR. Gene expression values are expressed as ratios between the target gene and internal reference gene. Results: All eight genes and treatment arm were considered in the CART analysis. The classification tree for response, progression-free survival, and overall survival are evaluated. The expression levels of VEGFR2 and NRP1 classified patients in 3 response groups with response rate range from 61% to 0%. Patients who were classified as responders (Group I; VEGFR2=0.65 and NRP1<2.285) were at a lower risk for progression, compared with patients who were classified as non- responders (Group II; VEGFR2=0.65 and NRP1=2.285 and Group III; VEGFR2<0.65). The expression levels of NRP1 and ERCC1, and EGFR and VEGFR2 were chosen to classify patients into 3 groups with distinct risk of progression-free survival and overall survival, respectively. Conclusion: These data suggest that gene expression levels may be molecular markers of response for patients with mCRC treated with CBI or CB. Prospective studies are needed to validate these preliminary findings.

No significant financial relationships to disclose.
Relationship of insulin-like growth factor-1 receptor and epidermal growth factor receptor expression to clinical outcomes in patients with colorectal cancer
Authors: Takahari D. , Yamada Y. , Okita N. , Hirashima Y. , Matsubara J. , Takashima A. , Kato K. , Hamaguchi T. , Shirao K. , Shimada Y. , Shimoda T.
Published: March 2020

4117

Background: Insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), and HER2 have been reported to regulate tumor growth by interfering with apoptosis, cell proliferation, angiogenesis, and metastasis. However, the clinical significance of these molecules in colorectal cancer (CRC) remains undetermined. To gain further insight, we evaluated the prognostic implications of these biomarkers in patients with CRC treated with fluoropyrimidines or irinotecan. Methods: The study group comprised 91 patients who underwent surgery at National Cancer Center Hospital and subsequently received fluoropyrimidines as 1st-line chemotherapy for recurrent or residual tumors. The expressions of IGF-1R, EGFR, and HER2 in surgically removed specimens of primary lesions were analyzed immunohistochemically to determine the prognostic significance of these biomarkers. Results: IGF-1R expression (defined as >10% membranous staining) was found in 81 tumors (89%), EGFR in 77 (85%), and HER2 in 3 (3%). IGF-1R expression significantly correlated with EGFR expression (P=0.038). Overexpression (defined as >50% membranous staining) of IGF-1R was found in 48 tumors (53%), EGFR in 57 (63%), and HER2 in 2 (2%). Overexpression of IGF-1R significantly correlated with shorter survival from the start of 1st-line chemotherapy (P=0.032). Overexpression of EGFR was a significant predictive factor for a clinical response to fluoropyrimidines (P=0.037) and tended to correlate with TTP in patients given irinotecan as 2nd-line therapy (P=0.087). A multivariate analysis of potential prognostic factors showed that IGF-1R expression and worse performance status were independent predictors of poor outcomes ( Table ). Conclusions: IGF-1R and EGFR were highly positive in patients with CRC. Overexpression of IGF-1R predicts a poor outcome, and overexpression of EGFR predicts a good clinical response to fluoropyrimidines.

[Table: see text]

No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) serum level may predict response in patients with advanced colorectal cancer (ACC) treated with gefitinib
Authors: Zampino M. G. , Magni E. , Zorzino L. , Santoro L. , Massacesi C. , Zaniboni A. , Di Clemente F. , Martignetti A. , Boselli S. , de Braud F.
Published: March 2020

4119

Background: EGFR-overexpression reported in colorectal cancer, justifies use of EGFR inhibitors. We conducted a phase II study (ESMO 2005) in ACC with the aim to assess efficacy of gefitinib plus oxaliplatin containing regimen. Main biological objective was to assess serum EGFR extra-cellular binding domain as surrogate marker of tyrosine-kinase inhibition and as predictor of outcome. Methods: 57 patients with EGFR-positive ACC,received gefitinib 250 mg/day combined with simplified FOLFOX-6 for at least 4 cycles,for a maximum of 10 courses.In not progressive disease, gefitinib was continued as maintenance treatment. Tumour assessment by RECIST criteria was performed at baseline and every 4 cycles.Serum EGFR extracellular binding-domain was evaluated by quantitative enzyme-linked immunoadsorbent.Serum EGFR as predictive factor was evaluated both taking into account the basal value only,and the whole EGFR pattern over time.The analyses were performed by logistic and Cox’s regression model with time-dependent covariate respectively;both models included centre, gender,age and site of primary tumours as adjusting factors. Results: Serum samples for EGFR were obtained at baseline and at every assessment.During mono-therapy phase the patients with serum samples decreased. Over treatment,34 patients reported a CR or PR as best objective response (BOR),while 9 patients showed SD or PD. Higher serum EGFR was associated to BOR both at baseline and over time.This result was confirmed by a similar analysis,which considered the whole EGFR profile,instead of the basal value only. Conclusions: Serum EGFR at baseline can be considered a significant predictor for the BOR.This observation is in line with data reported on lung cancer (Gregorc V, 2004).Although the EGFR trend over time seems to confirm the basal difference,this result should be taken with caution,due to the little number of cases reporting EGFR values besides the basal one.

[Table: see text]

No significant financial relationships to disclose.
A phase II study of preoperative chemotherapy with irinotecan(CPT) and cisplatin(CIS) for gastric cancer(NCI 5917): FDG-PET/CT predicts patient outcome
Authors: Shah M. A. , Yeung H. , Coit D. , Trocola R. , Ilson D. , Randazzo J. , Tang L. , Brennan M. , Divgi C. , Kelsen D. P.
Published: March 2020

4502

Introduction: Preoperative chemotherapy is a standard option for the treatment of locally advanced gastric cancer(GC). FDG-PET scans have been examined to identify early treatment response in esophagus and GEJ adenocarcinoma. We evaluated the utility of an early change in FDG-PET/CT at several time points in predicting response to preoperative chemotherapy in gastric cancer. Methods: 42 pts with locally advanced GC(preoperative stage T2N+M0 or T3–4NanyM0) were treated with CPT 65 mg/m2 and CIS 30mg/m2 on day(d)1 and d8, every 21 days for 4 cycles. FDG-PET/CT scans were performed at baseline, and in FDG avid patients, again on d15 and d35. The primary objective was to demonstrate that a decrease in FDG-SUV discriminates treatment response. Response was defined pathologically based on microscopic inspection for residual cancer cells and fibrosis(Mandard, Cancer 1994). Disease free survival(DFS) and overall survival(OS) were secondary endpoints. Results: Pt characteristics are as follows: median age 59(35–77), KPS 90%(70–100%), 27 male, gastric:GEJ 31:11. Median follow up is 23.3 months, with median DFS 23.8 months(95%CI 14-infinity) and median OS 39.1 months(95%CI 31–39months). Surgical resection occurred at a median of 101 days from study initiation. Pathologic response correlates significantly with DFS(p=0.005) and with OS(p=0.01). Amongst 31 FDG avid pts, a drop in SUV from baseline to d35 significantly predicts pathologic response(p=0.007) and DFS(p=0.01), whereas the change at d15 does not. 45% decrease in SUV at d35 best distinguishes good from poor pathologic response. With this cutoff, median DFS has not been reached(eg.>23.3 months) for patients with good PET response, and is 14.4 months(95%CI 8.3-infinity) for poor PET responders, p=0.03. Conclusions: Following preoperative chemotherapy, pathologic response at the time of resection significantly correlates with DFS and OS. We confirm that FDG-PET/CT response predicts both pathologic response and DFS following preoperative chemotherapy for locally advanced GC, although at d35. An early PET response assessment provides an opportunity to change therapy in non responding patients, and is currently under investigation(supported by ASCO CDA).

No significant financial relationships to disclose.
A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB
Authors: Kindler H. L. , Niedzwiecki D. , Hollis D. , Oraefo E. , Schrag D. , Hurwitz H. , McLeod H. L. , Mulcahy M. F. , Schilsky R. L. , Goldberg R. M.
Published: March 2020

4508

Background: In a phase II trial in 52 PC pts, GB yielded a 21% response rate and a median survival of 8.8 months (mo) (Kindler, JCO 2005). These data led CALGB to conduct a phase III trial of GB vs. GP in advanced PC pts. Methods: This randomized trial was double-blind, placebo-controlled. Eligible pts had no prior therapy for advanced disease, PS 0–2, no tumor invasion of adjacent organs, no increased bleeding risk. Primary endpoint: overall survival (OS). Stratification: PS (0/1 or 2), disease extent (locally advanced or metastatic), prior radiation (RT) (yes/no). Statistics: 90% power to detect a difference in median OS of 6 vs. 8.1 mo. Treatment: Pts received G 1,000 mg/m2 over 30 minutes days (D) 1, 8, 15 Q28D; B 10 mg/kg or P D 1, 15 Q28D. CT scans: Q2 cycles. Results: 602 pts enrolled 6/30/04–4/14/06. Based on a protocol-specified interim analysis with 64% of information on OS, the CALGB Data Safety Monitoring Board released study data in 6/06 because a futility boundary was crossed. Pts on treatment were notified and unblinded. Pt characteristics (302GB/300GP): male 58%/51%; median age 63.8/65.0; PS 2 9%/9%; stage IV 85%/84%; prior RT 11%/11%. Median follow-up: 11.3/11.7 mo. As of 12/22/06, 436 pts (224/212) have died (93% of total expected deaths at planned final analysis). Median OS 5.7/6.0 mo (95% CI: 4.9, 6.5/5.0, 6.9). Median failure-free survival 4.8/4.3 mo (95% CI: 4.3, 5.7/3.8, 5.6). Response (includes unconfirmed responses): complete (CR) 1.9%/3.0%; partial (PR) 11.2%/8.3%, stable disease (SD) 40.7%/35.7%. Disease control rate (CR/PR/SD) 54%/47%. 525 pts (268/257) are currently evaluable for toxicity. Median cycles 3.5/3.1 (p=0.09). Total mg/m2 G received 9095/8334 (p=0.22). Grade ¾ toxicity (%pts GB/GP): neutropenia 33%/30%; anemia 5%/8%; thrombocytopenia 12%/12%; hypertension 8%/2%; perforation 0.4%/0%; GI bleed 3%/2%; CVA 2%/2%; proteinuria 4%/1%; venous thrombosis 9%/9%. Conclusion: The addition of B to G does not improve survival in advanced PC.

[Table: see text]
Combination of endoscopic mucosal resection and chemoradiotherapy as a nonsurgical treatments for patients with clinical stage I esophageal squamous cell carcinoma
Authors: Minashi K. , Ohtsu A. , Mera K. , Muto M. , Yano T. , Tahara M. , Doi T. , Nishimura M. , Nihei K.
Published: March 2020

4529

Background: Endoscopic mucosal resection (EMR) has become the standard treatment for mucosal cancer. For the other clinical stage I esophageal squamous cell carcinoma (ESCC), radical surgery is standard and chemoradiotherapy (CRT) is optional but has high locoreginoal failure. If EMR and CRT are combined efficiently, these may improve outcomes with less invasion. A retrospective analysis was conducted to evaluate the efficacy of these combined nonsurgical modalities. Methods: Recruitment criteria were histologically proven SCC, clinically estimated as stage I except for the candidates of the standard EMR, age ≤ 75, PS ≤ 2, no prior therapy, no serious complication and no other active malignancy. Primary EMR was indicated if a tumor was within the focal submucosal (SM) invasion and a width of less than two-thirds of its circumference. EMR was followed by prophylactic CRT (5-FU + cisplatin + RT; 40Gy) for latent node metastasis when SM invasion was present pathologically. The remaining patients (pts) underwent primary CRT (5-FU + cisplatin + RT; 60Gy); salvage EMR was indicated for local residual, recurrent, or metachronous tumors. Results: Between Jan. 1996 and Apr. 2004, 86 pts fulfilled the criteria; median age 60 years (46–75), male/female; 74/12. Forty-one received primary EMR and 45 received primary CRT. Pathological diagnoses of primary EMR revealed eight mucosal cancers of the epithelium and lamina propria, 19 of the musclaris mucosae (MM), and 14 SM cancers. Eleven pts with SM cancers subsequently underwent prophylactic CRT, one with SM cancer underwent surgery, and the remaining 29 pts with mucosal and MM cancers received no additional treatment. Of the 45 CRT pts, 11 (24%) received salvage EMR. Three (3%) (one primary EMR pt and two primary CRT pts) underwent salvage surgery. With a median follow-up of 4.2 years, the 4-year overall survival of all, primary EMR, and primary CRT pts was 76%, 78%, and 72%, respectively; the disease-specific survival was 86%, 91%, and 81%, respectively. Conclusion: The survival of combination treatment with EMR and CRT for clinical stage I ESCC was comparable with that of surgery in Japan. EMR and/or CRT may be highly effective, minimally invasive treatments for stage I ESCC.

No significant financial relationships to disclose.
Multi-centre prospective assessment of accuracy and impact on management of positron emission tomography (PET) in esophageal and gastroesophageal junction cancers (EC). Australian PET Data Collection Project
Authors: Chatterton B. E. , Ho-Shon I. , Lenzo N. , Patrikeos A. , Kelley B. , Baldey A. , Ramshaw J. , Scott A.
Published: March 2020

4534

Background: In localized EC, radical surgery may be curative. This study evaluated PET and conventional imaging techniques (CI) for staging, and the potential impact of PET on management and prognosis of EC. Methods: Subjects had confirmed EC (SCC or adenocarcinoma), were fit for investigation and surgery and/or chemoradiotherapy and had no unequivocal distant metastatic disease clinically or by CT and endoscopy at presentation. Sensitivity, including N and M staging of pre-operative CT, PET and endoscopic ultrasound (EUS) and clinical impact of confirmation or detection of metastases on intent (curative or palliative) were recorded. Management changes, including radiotherapy field determined by new information from PET, were recorded. Variables, including standardized uptake value (SUV) were compared with progression-free survival (PFS.) Results: 129 patients (104 male), mean age 66 (range 36- 87) were evaluated. 127 of 129 primary lesions were detected. In 41% of patients, PET detected a total of 148 additional lesions, 75 regional lymph nodes, 72 distant metastases and 1 second EC primary. 22% of patients were upstaged from M0 to M1. CT detected regional and distant metastases in 57% and 0% (entry criterion), PET in 70% and 44%. Of 20 patients who had EUS, it detected regional metastases in 67%, PET in 33%.The number of patients intended to be treated palliatively increased from 10 pre- to 32 post-PET. Of patients with curative management intent based on PET 34% progressed in 12 months, with palliative intent 59%. Significant changes in management (high or medium impact) occurred in 38%. The PFS of 54 patients below and 54 above the median SUV(8) was no different (p=0.79) Conclusions: PET influenced management in 38% of patients with EC already studied by CI.

No significant financial relationships to disclose.