bluuebunny/crossref_metadata_2025_split huggingface dataset:
EGFR, HER2 and Kras as predictive factors for cetuximab sensitivity in colorectal cancer
Authors: Finocchiaro G. , Cappuzzo F. , Jänne P. A. , Bencardino K. , Carnaghi C. , Franklin W. A. , Roncalli M. , Crinò L. , Santoro A. , Varella-Garcia M. 
Published: March 2020

4021 Background: In colorectal cancer, biological mechanisms underlying response or resistance to cetuximab, a monoclonal antibody against the extracellular domain of the EGFR are not defined. Small retrospective studies suggested that EGFR increased gene copy number measured by fluorescence in situ hybridization (FISH) or presence of KRAS mutations were associated with cetuximab response or resistance, respectively. This study aimed to identify biological predictors for sensitivity/resistance to cetuximab treatment in colorectal cancer. We also compared biomarker results in primary tumors and corresponding metastases. Methods: We analyzed EGFR (IHC, FISH), HER2 (FISH), and KRAS (mutation) in paraffin embedded tumor blocks from 85 colorectal cancer patients treated with cetuximab. For FISH analyses, a positive result was defined according to criteria described in breast (Wolff et al. J Clin Oncol 2007), lung (Cappuzzo et al. JNCI 2005) and colorectal cancer (Moroni et al. Lancet Oncology 2005). EGFR, HER2 and PIK3CA mutation analyses are ongoing. Results: EGFR FISH positive patients (N=41), defined as ratio EGFR/nucleus =3, had a significantly higher RR (29.3% versus 6.8%, p=0.007) and TTP (6.6 versus 3.7 months, p=0.053) than EGFR FISH negative (N=44). No difference for clinical endpoints was observed using other scoring systems. EGFR expression assessed by IHC was not associated with any clinical end-point. Increased HER2 gene copy number was associated with shorter TTP (p=0.09) and survival (p=0.03). Compared to patients with wild type KRAS (N=49), KRAS mutation carriers (N=32) had a significantly lower RR (6.3% versus 26.5%, p= 0.02), shorter TTP (3.7 versus 6.3 months, p=0.07) and shorter survival (8.3 versus 10.8 months, p=0.2). In 22 patients with available primary and metastatic tumor tissue, there was no difference between these sites for EGFR FISH, HER2 FISH and KRAS results. Conclusions: This study, the largest biomarker analysis in colorectal cancer patients treated with cetuximab, shows a significant benefit in response and TTP for EGFR FISH positive patients. KRAS mutation analysis identifies a group of patients with the lowest chance to benefit from the therapy. Increased HER2 gene copy number predicts early escape from cetuximab therapy. No significant financial relationships to disclose.
Is more aggressive lymph node assessment associated with improved survival in stage II-III colorectal cancer? Evidence from the Surveillance, Epidemiology and End Results (SEER) cancer registry
Authors: Yeh Y. , Cai Q. , Chao J. , Russell M. 
Published: March 2020

4048 Background: NCCN guidelines recommend assessment of =12 lymph nodes (LN) to improve accuracy in colorectal cancer (CRC) staging. Previous studies have used various cut-points to assess the relationship between the number of LN sampled and survival. The association between NCCN guideline-compliant nodal sampling and survival is assessed, while controlling for other risk factors. Methods: We selected 145,485 adult patients newly diagnosed with stage II or III from SEER during 1990–2003. Kaplan-Meier curves were compared using the log-rank test. Cox proportional hazards models were constructed to determine the effect of sampling ≥ 12 LN on survival. Results: Median patient follow-up was 5.7 years. The table shows overall survival rates in CRC patients with < 12 versus =12 LN assessed: After adjusting for age, sex, tumor size and grade, sampling ≥ 12 LN was independently associated with improved survival. For patients with =12 versus <12 LN assessed, survival increased by 13% for stage IIa [HR=0.75; 95%CI 0.72–0.78; p< .001], 16% for stage IIb [HR=0.69; 95%CI 0.67- 0.71; p< .001], 12% for stage IIIb [HR=0.75; 95%CI 0.72–0.77], and 10% for stage IIIc [HR=0.85, 95%CI 0.81–0.89]. The association was not statistically significant for stage IIIa patients. Conclusion: Consistent with previous reports, this analysis found that optimal nodal sampling increased survival across stage II and III, specifically when ≥ 12 LN are sampled and when controlling for other risk factors. Furthermore, the results underscore the need for adhering to the NCCN guidelines. The lack of a statistically significant association in stage IIIa patients may be due to small cohort size. [Table: see text] [Table: see text]
Phase II trial of FOLFOX6, bevacizumab and cetuximab in patients with Colorectal Cancer
Authors: Ocean A. J. , O’Brien K. , Lee J. , Matthews N. , Holloway S. , Christos P. , Kung T. S. , Kaubisch A. , Chen H. , Wadler S. 
Published: March 2020

4075 Background: Bevacizumab (B) + FOLFOX is widely accepted as a standard first-line therapy for metastatic colorectal cancer (mCRC). Recent treatment strategies have included the use of targeted therapies combined with chemotherapy to improve efficacy and to reduce chemotherapy-related toxicities. This Phase II study assesses first-line mFOLFOX6 + B + cetuximab (C), a monoclonal antibody approved for use in irinotecan-refractory mCRC. Methods: All pts had ECOG PS = 1, normal bone marrow, hepatic and renal function. Pts received mFOLFOX6 + B (5mg/kg) biweekly and C weekly (initially at 400 mg/m2, then subsequent doses at 250 mg/m2). Tumor assessment by imaging was done every 8 weeks. Primary endpoints are response rate, progression free-survival (PFS), overall survival (OS), and safety. The regimen would be considered promising if there were = 32 responses, or if = 60% of pts were progression-free for at least 8 months. Results: 67 pts (37 males, 30 females) were enrolled from 12/04–11/06. Median age was 57. Toxicities included Grade 4: neutropenia (6%), thrombosis/embolism (5%). Grade 3: neutropenia (13%), rash (13%), fatigue (11%), diarrhea (11%), abdominal pain (6%), neuropathy (5%), infection with ≤ Grade 2 ANC (4.5%). There were 2 deaths, 1 due to neutropenia and diarrhea and 1 to pulmonary fibrosis. As of 12/06, 9 pts were too early to evaluate. Of the remaining 58 pts, there were 32 responses (55%; 95% CI: 42%, 68%), including 3 CRs and 29 PRs; Median PFS was 9.6 months (95% CI: 8.8, 13.9 months), 71% were progression-free for at least 8 months, and median OS was not reached after a median follow-up of 11.4 months (range 1.5–25.2 months). Conclusions: Treatment with mFOLFOX6+ B + C met the pre-specified criteria for objective response and PFS to be considered promising. This regimen is associated with an acceptable toxicity profile and merits further evaluation. Supported by N01-CA-62204. No significant financial relationships to disclose.
Panitumumab activity in metastatic colorectal cancer (mCRC) patients (pts) with low or negative tumor epidermal growth factor receptor (EGFr) levels: An updated analysis
Authors: Mitchell E. P. , Hecht J. R. , Baranda J. , Malik I. , Richards D. , Reiner M. , Stout S. , Amado R. G. 
Published: March 2020

4082 Background: Panitumumab, a fully human monoclonal antibody against EGFr, is approved for EGFr-expressing mCRC pts with disease progression (PD) on or after fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. However, the predictive value of EGFr tumor-membrane staining as measured by immunohistochemistry (IHC) is undetermined. Methods: This multicenter, single arm, phase 2 study enrolled pts with documented PD during or after fluoropyrimidine and adequate doses of irinotecan and oxaliplatin, and within 6 months after the most recent chemotherapy regimen (determined by an independent eligibility review committee [IERC]), 2–3 prior regimens, and low (1%-9%) or negative (<1%) EGFr tumor membrane staining (by IHC). Pts received panitumumab 6mg/kg Q2W until PD or intolerability. Tumor assessments (modified WHO, blinded central review) were performed every 8 weeks until PD or discontinuation. Endpoints were objective response rate (ORR) through wk 16 (+ =4 wk confirmation; primary), overall ORR, response duration, progression-free survival (PFS), and safety (secondary). Results: In this interim analysis, 91 pts had =20 wks of potential follow-up and comprised the IERC efficacy set; 118 pts comprised the evaluable safety set (=20 wks potential follow-up). In the IERC efficacy set, 57% were male, 86% were white, and median age (range) was 61 (26–85) years. ORR through week 16 is shown; overall ORR was the same ( Table ). The most common adverse events (all, grade 3/4) were dermatitis acneiform (72%, 6%), erythema (69%, 6%), pruritus (65%, 4%), and hypomagnesaemia by lab values (53%, 10%). Four pts (3%) had an infusion reaction per investigator (1 was grade 3). Conclusions: This analysis confirms earlier findings that panitumumab has anti-tumor activity in pts with low or undetectable EGFr tumor membrane levels as measured by IHC. This study has completed enrollment, and updated data will be presented. [Table: see text] No significant financial relationships to disclose.
Phase I/II study of oral fluoropyrimidine S-1 plus oral Leucovorin as first-line treatment for metastatic colorectal cancer
Authors: Yoshino T. , Koizumi W. , Yamaguchi K. , Miyata Y. , Kato T. , Toh Y. , Sawaki A. , Hyodo I. , Nishina T. , Boku N. 
Published: March 2020

4093 Background: The results of phase I portion of the treatment with the oral S-1 (a new oral fluoropyrimidine) plus oral leucovorin (LV) in patients (pts) with untreated metastatic colorectal cancer (mCRC) was reported at ESMO 2006. Dose limiting toxicities (DLTs) were grade 3 stomatitis/pharyngitis, nausea, diarrhea, ileus and exanthema. The recommended doses (RDs) for this phase II portion were determined to be S-1 40 mg/m2 and LV 25 mg/body orally given twice daily on days 1 to 14 of a 28-day cycle. The PK profiles of S-1 plus LV were similar to those of S-1 monotherapy and UFT plus LV, respectively. The main purpose of this phase II portion is to evaluate the efficacy and safety of S-1 plus LV at RD level in pts with untreated mCRC. Methods: Pts were eligible as follows; unresectable mCRC with no prior chemotherapy or receiving adjuvant chemotherapy completed at least 6 months before, histologically proven adenocarcinoma, PS(ECOG) 0–2, age 20 to 75, measurable lesions, adequate organ function and written informed consent. The pts received 40 mg/m2 of S-1 plus 25 mg/body of LV twice daily as RD in this phase II portion. The primary endpoint was the objective response rates (RRs), and secondary endpoints were time to progression (TTP) and toxicities. Results: Between Sep 2004 and Jun 2006, 56 pts of 65 enrolled pts received the treatment at RD level. The objective RRs were 55% (36 of 65) for all pts and 55% (31 of 56) for pts at RD. Disease control rates (DCRs) were 86% (56 of 65) for all pts and 86% (48 of 56) for pts at RD. Median TTP was 5.5 months for pts at RD, with a median follow-up of 5.5 months. The median survival time is under observation. During the 6 months from starting the treatment, the most common grade 3/4 toxicities at RD were as follows: diarrhea, 23%; stomatitis, 20%; anorexia, 18%; and neutropenia 13%. Conclusions: A combination of S-1 plus oral LV is an effective, well tolerated, and convenient regimen in pts with untreated mCRC, without the addition of either oxaliplatin or irinotecan. The updated results of the objective RRs, DCRs, TTP reviewed extramurally, and detailed safety profile will be presented at the meeting. This trial was supported by Taiho pharmaceutical co., Ltd., Tokyo, Japan. No significant financial relationships to disclose.
Modified (m)Folfox7/bevacizumab (B) or modified (m)Xelox/bevacizumab with or without erlotinib (E) in first-line metastatic colorectal cancer (MCRC): Results of the feasibility phase of the DREAM-OPTIMOX3 study (GERCOR)
Authors: Tournigand C. , Lledo G. , Delord J. , André T. , Maindrault-Goebel F. , Louvet C. , Scheithauer W. , de Gramont A. 
Published: March 2020

4097 Background: Targeted therapy against VEGF and EGFR both demonstrated clinical activity in combination with chemo in MCRC. In 1st line, B with Folfox or Xelox increase progression-free survival (Cassidy ESMO 2006). In 2nd L, B with Folfox increases overall survival (Giantonio 2005). In this preliminary study, a double inhibition is tested combining mFolfox+B or mXelox+B with or without E, an oral EGFR tyrosine kinase inhibitor. Methods: 38 pts with untreated MCRC were randomly assigned to: mFolfox+B (1A), mFolfox+B+E (1B), mXelox+B (2A) or mXelox+B+E (2B). mFolfox-B=LV 400 mg/m2, Oxaliplatin (ox) 100 mg/m2, B 5 mg/kg day 1, 5FUc 2.4- 3g/m2 46h q2w, mXelox-B=Ox 100 mg/m2 d1 q2w, capecitabine 3–3.5 g/m2 d1 to 7 q2w, B 5mg/kg q2w. Erlotinib=100 mg/day. 6 cy planned. The primary end-points were toxicity and RR. Results : 9pts/41cy in 1A, 10/60 (1B), 9/39 (2A), 10/44 (2B). Median age 62yrs (43–78). 24/38 pts had poor prognosis factors (>1 met. site and/or PS2, LDH>3N, elevated alk Ph): 5, 6, 7, 6 in each arm respectively. 17 pts had a gr3- 4 toxicity: 4/9 arm 1A, 4/10 arm 1B, 2/9 arm 2A, 7/10 arm 2B. Diarrhea (dia) was the main gr3–4 tox: 2/10pts in 1B, 1/9 in 2A & 6/10 in 2B. 3 pts had gr4 dia in arm 2B. Other gr3 tox were nausea-vomiting 4pts (2/0/0/2), cutaneous rash 2 pts (0/1/0/1), hypertension 1 pt (1B), mucositis 1pt (1A), neutropenia 1 pt (1A), thrombocytopenia 1 pt (1A). 1pt had a gr4 venous thrombosis (2A) and 1pt had pulmonary embolism. 1pt died with perforation in arm 1A, and 1pt died with gr4 dia in arm 2B. Amongst the 17pts with gr3–4 toxicity, 11 pts had poor prognosis criteria and 6 had good prognosis. PR, SD, PD and NE are respectively: arm 1A: 5/2/0/2, 1B: 4/6/0/0, 2A:5/3/1/0, 2B:4/3/0/3. Conclusion: The results of this feasibility phase indicate that adding E with mXelox and bevacizumab increases toxicity (70% gr3–4) and is not feasible. Based on these results, the DREAM study was redesigned to evaluate erlotinib in maintenance with B after 6 cycles of mXelox-B or mFolfox-B. No significant financial relationships to disclose.
A comparison of medical resource use for 4 chemotherapy regimens as first-line treatment for metastatic colorectal cancer (MCRC): XELOX vs. FOLFOX4 ± bevacizumab (A)
Authors: Scheithauer W. , Cassidy J. , Figer A. , Wong R. , Koski S. , Lichinitser M. , Yang T. , Clarke S. , Diaz-Rubio E. , Garrison L. 
Published: March 2020

4098 Background: A recent randomized phase III trial with a 2x2 factorial design compared 4 chemotherapy regimens as first-line treatment for MCRC: oral capecitabine + i.v. oxaliplatin q3w (XELOX); 5-FU/LV + i.v. oxaliplatin (FOLFOX4); XELOX+A; and FOLFOX4+A. The XELOX regimens were found to be non-inferior to FOLFOX4 in terms of progression-free survival (the primary endpoint), and the A regimens were superior to the placebo arms. The attractiveness of these regimens to providers, patients, and payers will also depend on the medical resources involved. The purpose of this analysis was to compare the expected resource use across the 4 groups. Methods: A resource use model was constructed based on trial data and projections from trial protocols. Both medical resources and patient time were considered. The medical resources included visits for chemotherapy administration, central venous access (CVA), treatment of adverse events (AEs), and hospital use for common treatment-related AEs. Patient time for chemotherapy administration, ambulatory visits, and hospital stays was estimated. Results: FOLFOX and FOLFOX4+A required more administration visits due to the q2w cycle (22–27 visits in total for the FOLFOX arms vs. 7–9 visits for the XELOX arms). With FOLFOX regimens, patients spend 60–200 additional hours receiving i.v. drug administration, and 22–27 additional hours traveling and waiting to receive chemotherapy. The rate of hospital admissions for common AEs did not differ among the arms, but mean hospital days for common AEs were slightly higher in the XELOX arms. Ambulatory encounters to treat AEs added only about 1 hour of encounter time per patient on average in all 4 arms. The 2 FOLFOX4 arms had twice as many placements for CVA. Conclusion: In the first-line setting, the 2 FOLFOX4 chemotherapy regimens involve substantially more i.v. drug administration visits and time - the equivalent of more than two 40-hour workweeks. The 4 regimens were similar in terms of the amount of resource use needed to treat AEs. No significant financial relationships to disclose.
Serious arterial thromboembolic events (sATE) in patients (pts) with metastatic colorectal cancer (mCRC) treated with bevacizumab (BV): Results from the BRiTE registry
Authors: Sugrue M. M. , Yi J. , Purdie D. , Dong W. , Grothey A. , Kozloff M. 
Published: March 2020

4136 Introduction: BV prolongs overall survival (OS) and progression-free survival (PFS) when added to 1st- or 2nd -line chemotherapy (CT) in mCRC. Though serious toxicities specific to BV are uncommon, a retrospective pooled analysis of 5 randomized trials showed an association of arterial thromboembolic events (ATEs) with BV use (3.8% vs 1.7% with CT alone), with age ≥65 and prior history (Hx) of ATE identified as associated risk factors (Skillings, JCO 2005). The BRiTE mCRC registry evaluated BV-associated serious adverse events (SAEs), including ATEs presenting as SAEs (sATE), in a general practice setting. Methods: Pts and methods have been described (Hedrick ASCO 2006). Hx of sATE, timing of prior sATE relative to starting BV, and anti-platelet agent (anti-plt) use were summarized. Definition of sATE included myocardial infarction (MI), cerebral vascular accident (CVA), transient ischemic attack (TIA), and peripheral arterial disease. Incidence rate of sATE was expressed as events per pt-yr of follow-up. Fisher’s exact test and multiple logistic regression was used to assess the univariate and multivariate associations. Results: Median follow- up was 17.5 mo. Of 1953 evaluable pts, 45.9% (n=896) were ≥65, 18.0% (n=352) had Hx of sATE, and 11.2% (n=219) received anti-plt. A total of 38 sATE [CVA (n=14), MI (n=11), sudden cardiac death (n=1), TIA (n=7), and other (n=5)] were reported in 34 (1.7%) pts. Median time to sATE was 3.6 mo. The calculated sATE rate was 2.2/100 pt-yr overall and 4.7/100 pt-yr in pts with prior sATE. Table 1 summarizes the results of univariate and multivariate analyses. Conclusions: In this series of BV-treated pts, the incidence of sATE associated with BV use was comparable with the rate of analogous events reported in previous controlled trials of BV in mCRC. In this series, prior history of sATE and ECOG PS were found to be associated with sATE risk in multivariate analyses. [Table: see text] [Table: see text]
Final results of a randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial
Authors: Boige V. , Pignon J. , Saint-Aubert B. , Lasser P. , Conroy T. , Bouché O. , Segol P. , Bedenne L. , Rougier P. , Ychou M. 
Published: March 2020

4510 Background: The combination of 5FU in continuous infusion and cisplatin (FP) is one of the most active regimen in advanced ASLE. The trial was designed to evaluate the impact on survival of 2–3 cycles of preoperative FP in resectable ASLE. Methods: Patients (pts) with resectable adenocarcinoma of the stomach (S) without cardia involvement, cardia (C) or lower esophagus (LE), age ≤ 75 yrs, WHO performance status (PS) < 2 were eligible. Pts were centrally randomized between surgery alone (arm 1) and preoperative FP (arm 2). Chemotherapy (CT) included 2–3 cycles of P (100 mg/m2) and F (800 mg/m2 d1-d5 continuous infusion) every 28 days. Post- operative FP was recommended in arm 2 in case of response to FP preoperative or stable disease with pN+. The main endpoint was overall survival. Comparison of disease-free survival (DFS) used 6-month landmark method and two-sided logrank test. Results: Between 1995 and 2003, 224 pts (arm 1 = 111 pts, arm 2 = 113 pts) were randomized from 28 centers. Initial pts characteristics were equally balanced for age (mean, 61 yrs), gender (83 % male), PS (75 % WHO 0), tumor site (S = 25 %,C = 64 %, LE = 11 %). Median follow-up was 5.7 years. In arm 2, FP was given before surgery in 109 pts (98 pts > 2 cycles) and after surgery in 54 pts. R0 resection rate was 73 % in arm 1 versus 84 % in arm 2 (p=0.04). Preoperative CT improved DFS (p=0.003): hazard ratio (HR) 0.65 (95%CI 0.48–0.89), with 3 and 5-year DFS of 25% (18–34%) and 21% (14–30%) in arm 1 vs. 40% (31–49%) and 34% (26–44%) in arm 2, respectively. HR of death was 0.69 (0.50–0.95, p=0.02) with 3 and 5- year overall survival (OS) of 35% (27–44%) and 24% (17–33%) vs. 48% (39–57%) and 38% (29–47%), respectively. Similar results on OS were observed using Cox model stratified on center and adjusted on gender, age, performance status, and tumor localization. No significant variation of chemotherapy effect with tumor localization was observed. Conclusions: Preoperative chemotherapy using 5- fluorouracil/cisplatin improves disease-free and overall survival in patients with resectable adenocarcinoma of stomach and lower esophagus. No significant financial relationships to disclose.
Gemcitabine-based combinations (gem+x) vs gemcitabine (gem) alone in the treatment of advanced pancreatic cancer: a meta- analysis of sixteen randomized trials
Authors: Heinemann V. , Hinke A. , Böck S. , Labianca R. , Louvet C. 
Published: March 2020

4515 Background: Sixteen randomised trials have compared Gem-based combination chemotherapy to Gem alone in advanced and metastatic pancreatic cancer. This analysis was performed to better define the role of combination chemotherapy in pancreatic cancer. Methods: The meta-analysis included 16 studies comparing Gem vs. Gem+X. Fifteen trials were evaluable for survival, the primary end-point of the investigation. Overall, 4465 patients (pts) were included, 2222 pts in the Gem+X arm, and 2243 pts in the Gem arm). The analysis was predominantly based on published summary data. Results: Three groups were formed: combinations with platinum analogs, fluoropyrimidines, or other cytotoxic agents. Five trials evaluated platinum-based combinations (3 cisplatin, 2 oxaliplatin). The combined analysis indicated a hazard ratio (HR) of 0.85 (95% CI: 0.76–0.96) demonstrating a significant (p=0.010) superiority of the combination. Further 6 trials investigated the combination of Gem with fluoropyrimidines (3 5-FU, 3 capecitabine). Again, a significant superiority of the combination therapy was observed with a HR of 0.90 (95% CI: 0.81–0.99; p=0.030). Among the fluoropyrimidine combinations greatest homogeneity of results was observed in trials combining gemcitabine with capecitabine. In four randomised trials no improvement of survival was observed when Gem was combined with other cytotoxic agents such as pemetrexed, exatecan or irinotecan (HR=0.99; 95% CI: 0.88–1.10; p=0.80). When all 15 evaluable trials are taken together, an overall hazard ratio of HR=0.91 (95% CI: 0.85–0.97; p=0.004) was achieved. Five trials including 1682 pts provided adequate information on baseline performance status (PS). Combination chemotherapy had a marked benefit on survival in pts with a good PS (HR=0.76; 95%CI: 0.67 - 0.87; p<0.0001), while it was not more effective than Gem alone in pts with an initially poor PS (HR=1.08; 95% CI: 0.90 - 1.29). Conclusions: A meta-analysis of fifteen randomised trials indicated a significant survival benefit for Gem+X as compared to Gem alone when Gem was combined with either a platinum analog or capecitabine. This benefit was greatest in pts with a good PS, while no benefit was evident in poor PS pts. No significant financial relationships to disclose.