bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of vascular endothelial growth factor (VEGF) signaling inhibition on human erythropoiesis
Authors: Maitland M. L. , Kasza K. E. , Snider K. L. , Sit L. , Cohen E. E. , Seiwert T. Y. , Karrison T. , Ratain M. J. , Vokes E. E.
Published: August 2020

3575

Background: In rodents, inhibition of VEGF signaling increases production of red blood cells. Major clinical trials of VEGF signaling inhibitors have not reported on these effects in human patients (pts). Methods: To determine whether disruption of VEGF signaling in humans is associated with increased erythropoiesis, we analyzed red blood cell (RBC) and hemoglobin (Hgb) measurements in pts at a single institution enrolled in a phase II trial of axitinib in advanced thyroid cancers (16 pts), a study of sorafenib in advanced solid tumors (57 pts), and a randomized phase II trial of concomitant fluorouracil, hydroxyurea, and radiation with (14 pts) or without bevacizumab (8 pts) for locally advanced cancers of the head and neck. In the axitinib and sorafenib trials, no pt received red cell transfusions (Tf) or erythropoiesis stimulating agents (ESAs). Three pts in the chemoradiotherapy study received Tf or ESAs and were excluded from further analysis. Erythropoietin (EPO) plasma concentrations were measured only on pts in the sorafenib study at baseline, and days 8 and 35. Mixed models with random intercept were used to determine the effect of VEGF signaling inhibitors on RBC and Hgb. Repeated measures analysis of variance was used to examine whether EPO levels changed over time. Results: Over the first 84 day interval of treatment RBC increased for each day on axitinib (4 K/mcl [95% CI 2, 7], p < 0.001) or sorafenib (3K/mcl [2, 4], p < 0.001). Similar results were detected for Hgb. For the first 68 day interval of chemoradiotherapy alone, the RBC declined over time (-13K/mcl/day [-16, -10]) but less so (-7K/mcl [-10, -5]) with added bevacizumab (interaction p = 0.003). EPO levels changed with sorafenib exposure, most notably, increasing by 38% between days 8 and 35 (p < 0.001 by Wilcoxon signed rank test). Conclusions: VEGF signaling inhibition is associated with increased RBC and EPO production. This effect might contribute to positive and negative clinical consequences of exposure to VEGF signaling inhibitors.

[Table: see text]
A safety and schedule seeking trial of Bcl-2 inhibitor obatoclax in previously untreated older patients with acute myeloid leukemia (AML)
Authors: Raza A. , Galili N. , Borthakur G. , Carter T. H. , Claxton D. F. , Erba H. P. , DeAngelo D. J. , Berger M. S. , Schimmer A.
Published: August 2020

3579

Background: Obatoclax (Ob) is a small-molecule inhibitor of all Bcl-2 prosurvival proteins. In a previous study a 70 year old patient with untreated AML had a cytogenetic CR 8 days after receiving 20 mg/m2 of Ob over 24 hrs. This study evaluated the single-agent response rate in older patients with previously untreated AML. Methods: A Safety phase to evaluate escalating doses of Ob given by 3-hr infusion was performed. Based on previous results, the dose of 60 mg over 24 hrs was used for the 24-hr infusion arm of the Schedule Seeking phase, in which Ob was administered as either a 3-hr or 24-hr infusion for 3 consecutive days every 2 wks. The endpoint of the Schedule Seeking phase was CR after C2 in 16 randomized patients. Eligibility criteria included age ≥ 70, untreated AML (1 prior Rx allowed in Safety phase), ECOG PS ≤2, adequate renal and hepatic function. PK samples were collected during C1. Results: 18 patients (8 male; median age 82) were enrolled. 2/3 patients enrolled into the 1st cohort (30 mg x 3 days) of the Safety phase had DLT events (ataxia and somnolence). 3 patients enrolled into a 20 mg x 3 days cohort had no DLTs; this dose was used for Schedule Seeking patients receiving 3-hr infusions. In the Schedule Seeking phase, 7 patients were randomized to receive 20 mg by 3-hr infusion and 5 were randomized to receive 60 mg by 24-hr infusion. The most common (>25%) AEs were euphoric mood (50%), ataxia (38%), & somnolence (38%). Efficacy data after C2 show that 3 patients in the 20 mg 3-hr infusion cohort in the Safety phase and 1 at the same dose & schedule in the Schedule Seeking phase had ≥50% decrease in BM blasts after C2, which was not seen in the 60 mg 24-hr infusion cohort. There were no CRs. There was a single death by D28 (24-hr infusion). There were significant differences in PK by infusion schedule. Conclusions: MTD for Ob as a 3-hr infusion administered in older patients with AML on 3 consecutive days is 20 mg/day, and both this regimen and 60 mg as a 24-hr infusion x 3 days were well tolerated. Evidence of biological activity was seen with the 3-hr infusion schedule but not with the 24-hr infusion schedule, suggesting that efficacy may be improved with the 3-hr infusion schedule and may be related to PK differences.

[Table: see text]
A phase I trial of GMX1777, an inhibitor of nicotinamide phosphoribosyl transferase (NAMPRT), given as a 24-hour infusion
Authors: Pishvaian M. J. , Marshall J. L. , Hwang J. J. , Malik S. , He A. R. , Deeken J. F. , Kelso C. B. , Cotarla I. , Berger M. S.
Published: August 2020

3581

Background: GMX1777 is a pro-drug which converts to GMX1778, a potent and specific small molecule inhibitor of NAMPRT, the rate-limiting enzyme in NAD+ synthesis. NAMPRT activity is increased in tumor cells dependent on the glycolytic pathway. The aims of this first-in-man study were to define a dose of GMX1777 administered by 24-hr infusion with acceptable safety for phase II studies, and to determine the pharmacokinetic (PK) parameters of both GMX1777 and GMX1778. Methods: GMX1777 was administered at ascending doses as a 24 hour IV infusion q21 days to successive cohorts of patients with advanced malignancies. Single patient cohorts were utilized until a toxicity >Grade (Gr) 1 was observed during cycle (C) 1; then a standard 3+3 dose escalation schema was used. PK samples were drawn during C1. Results: 19 patients (11 males; median age 57) received doses of 60, 120, 160, 200 or 140 mg/m2 over 24 hours. 49 doses were administered. There were no toxicities >Gr 1 during C1 at 60 mg/m2; however Gr 2 toxicities were observed at 120 mg/m2 and the cohort was expanded to 3 patients. Gr 4 GI hemorrhage and Gr 4 thrombocytopenia occurred at 200 mg/m2, leading to expansion of the 160 mg/m2 cohort. 3/6 patients at 160 mg/m2 had erythematous symmetrical Gr 3 rash occur during C2–5. Six patients enrolled at 140 mg/m2 had no Gr 3 rash and 140 mg/m2 was determined to be the MTD. Preliminary data indicate that the most common (>30%) adverse events of all grades were nausea (89%), diarrhea (79%), fatigue (68%), vomiting (58%), anorexia (42%), pruritis (42%), thrombocytopenia (42%), rash (37%), anemia (32%), constipation (32%), dyspnea (32%), and insomnia (32%). Lab findings include lymphopenia. Two patients had stable disease for > 4 cycles (6 & 4 mos), and 3 additional patients had SD for ≥ 3 mos. Preliminary PK data document rapid conversion of GMX1777 to GMX1778 at all dose levels. Conclusions: The MTD for GMX1777 administered as a 24 hour infusion q21 days is 140 mg/m2. Thrombocytopenia, GI hemorrhage, and skin rash (the last occurring after multiple cycles) were encountered at higher doses. Single-agent GMX1777 exhibited moderate clinical activity, suggesting that inhibition of NAMPRT should be explored in other schedules or in combination with other agents.

[Table: see text]
Pharmacogenetic analysis in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line irinotecan (IR)+/− cetuximab (CB): The EPIC experience
Authors: Yang D. , Pohl A. , Zhang W. , Lurje G. , Ning Y. , El-Khoueiry A. , Khambata-Ford S. , Langer C. , Iqbal S. , Lenz H.
Published: August 2020

4022

Background: EPIC, a multinational phase III clinical trial with IR + CB vs IR alone in mCRC pts in the second-line setting after failure of FOLFOX demonstrated a benefit for IR+CB in progression-free survival (PFS) and response rate (RR). We evaluated functional germline polymorphisms involved in the EGFR- (EGF, EGFR), angiogenesis- (VEGF, IL-8, CXCR-2) - and drug- metabolism related genes (UGT1A1, MTHFR) for their potential role as molecular predictors for clinical outcome in pts treated with CB/IR vs. IR alone. Methods: DNA was extracted from all available formalin-fixed paraffin-embedded tumor samples from the phase III EPIC trial (US sites only). Genotyping was performed using PCR-RFLP assays and 5’ -end [g-33P] ATP’ labeled PCR-protocols. Results: 186 pts were treated either with IR/CB (arm A, 84 pts) or IR (arm B, 102 pts) only. In arm A, 11/84 pts (13%) showed CR or PR, whereas 73/84 (87%) pts had SD or PD. For arm B, 6/102 pts (6%) showed CR or PR, whereas 96/102 pts (94%) had SD or PD. Median PFS in arm A was 3.0 months (95%CI: 2.4- 4.1 months) vs 2.7 months (95%CI: 2.2–2.9 months) in arm B; median overall survival (OS) was 9.3 months (95%CI: 7.1–12.1 months) in arm A vs. 12.3 months (95%CI: 10.4- 17.9 months) in arm B. K-ras mutation status was not significantly associated with PFS or response to CB/IR in the subgroup of 186 patients. We found an EGFR-CA- repeat in intron 1 in arm A to be associated with PFS (p=0.031, log-rank test). In arm B, we found a significant association with RR (p=0.0103, Fisher's exact test) for MTHFR1298. Furthermore, MTHFR 677 (p =0.0048, log-rank test) and MTHFR 1298 (p=0.038, log-rank test) were also found to be associated with OS in arm B. In multivariate analysis, EGFR-CA-repeat was significantly associated with PFS (adjusted p= 0.023). Furthermore, MTHFR 677 and MTHFR 1298 was associated with OS (adjusted p=0.028 and 0.026, respectively, Cox-proportional hazards models), independent from K-ras mutation status, race and number of disease sites. Conclusions: Our study demonstrates the potential predictive value of polymorphisms in the EGFR- and MTHFR- gene in mCRC pts treated with IR+ CB. Further validation in additional clinical trials is necessary.

[Table: see text]
TYMS genotype-directed neoadjuvant chemoradiation for rectal cancer
Authors: McLeod H. L. , Myerson R. J. , Zehnbauer B. , Trinkaus K. , Malyapa R. S. , Mutch M. G. , Abbey E. E. , Alyasiry A. , Fleshman J. W. , Tan B. R.
Published: August 2020

4028

Background: Downstaging (DS) of rectal cancers is achieved in 45% of pts with neoadjuvant 5FU and radiation (XRT). A 28bp repeats in the thymidine synthase gene (TYMS) appears to define disparate DS rates (60% vs 22%). We conducted a prospective single-institution Phase II study using TYMS genotyping to direct neoadjuvant chemoRT for pts with rectal cancer. Methods: Pts with T3/ T4, N0–2, M0–1 rectal adenocarcinoma staged with transrectal ultrasound (TRUS) or CT/MRI are eligible. After informed consent is obtained, pts with TYMS *2/*2, *2/*3, or *2/*4 (Good-risk) are treated with 50.4 Gy 3-D XRT and 5FU continuous infusion at 225 mg/m2/d throughout XRT. Patients with TYMS *3/*3 or *3/*4 (Bad-risk) are treated with 5FU and XRT plus irinotecan at 50 mg/m2 IV weekly x 5. Pts underwent restaging and resection 6–10 weeks after therapy. The 1o endpoints are DS and pathologic complete response (pCR) rates. 2o endpoints include toxicity, recurrence rates and OS. Adjuvant therapy was directed by the pt's physician. The study was powered to ascertain whether DS was significantly >45% in ‘good risk‘ patients and >22% in ‘bad risk‘ patients. Results: Overall, 135 pts (median age 56, range 26–85; M:F 2:1; black-18, white-119) are enrolled, of which 27.4% (37/135) are ‘bad risk‘. DS, pCR and toxicity rates were evaluable in 121 patients and are shown below. The rate of DS met the a priori criteria for significance for both the ‘good risk‘ and ‘bad risk‘ groups. 1 death/1 perforation was observed in each group. Conclusions: This is the first study to prospectively use TYMS genotyping to direct neoadjuvant chemoXRT in pts with rectal cancer. The high efficacy of 5FU/XRT in ‘good risk‘ pts was prospectively confirmed. High rates of DS and pCR were also achieved among ‘bad risk‘ pts with the addition of irinotecan to neoadjuvant 5FU/XRT. These results are encouraging for the conduct of a randomized study of genotype-guided neoadjuvant therapy for locally advanced rectal cancer.

[Table: see text]

[Table: see text]
Outcome of colon cancer patients with synchronous metastases
Authors: Sobhani I. , Roudot-Thoraval F. , Mesli F. , Landi B. , Aparicio T. , Louvet C. , DesGuetz G. , Mitry E.
Published: August 2020

4029

Background: Metastatic colon cancer patients may undergo chemotherapy without colon surgery. However, the outcome of patients has not been evaluated and antiagiogenic agents can not be given. The aim of the present cohort study was to analyse factors influencing patients’ survival. Methods: Consecutive patients [N=228, mean age (sd) 64 (12) yrs, median follow-up 20 mths;84 females] treated in 6 teaching hospitals received chemotherapy for metastatic colonic cancer, either as the first step, or after surgery. Progressive free survival (PFS) was estimated using Kaplan-Meïer method. Factors associated with PFS were tested by means of Log rank test and results are presented in terms of medians of survival (95% CI). Factors independently related to PFS were tested using a Cox model and results are presented as hazard ratio. Results: 105 patients with colon cancer and synchronous metastatsis underwent colon surgery prior to chemotherapy (68 males, mean age 64 yrs) when 123 patients were treated first by chemotherapy ± biotherapy (76 males, mean age 63 yrs). By univariate analysis, following factors were significantly associated with PFS: surgery first 25.5 (18.6 - 32.5) vs chemotherapy first 18.3 (14.7 - 21.9) mths p = 0.006; curative surgery: yes 35.7 (29.6 - 41.8) vs no 18.4 (15.6 - 21.2) mths p < 0.001; tumour histological differentiation : no : 13.4 (6.2 - 20.6) vs well : 24.7 (20.4 - 29.1) mths p<0.001; synchronous metastases: liver only 25.5 (20.5 - 30.6) vs peritonea&nodes : 18.4 (10.6 - 26.1) vs pulmonary & other sites : 16.5 (14.7 - 18.3) mths p < 0.0001; need for colonic stent: yes 16.4 (9.3 - 23.5) vs no 23.9 (21.1 - 26.7) months p < 0.0001; antiangiogenic drug: yes 36.6 (28.7 - 44.5) vs no : 20.7 (18.3 - 23.1) p = 0.033. After Cox multivariate analysis five independent factors were found to be associated with PFS. Conclusions: Colon surgery before chemotherapy plus bevacizumab appears to be the more appropriate choice, and associated with longer PFS, especially for those patients with well differentiated tumours and synchronous liver metastases.

[Table: see text]

No significant financial relationships to disclose.
Polypectomy or surgery for malignant colonic polyps: Do we need to change the NCCN guidelines?
Authors: Wasif N. , Tomlinson J. S. , Maggard M. A. , Giuliano A. E. , Ko C. Y.
Published: August 2020

4031

Background: Colonoscopic screening and appreciation of the adenoma-carcinoma sequence have led to increased detection and removal of colonic polyps. The National Comprehensive Cancer Network (NCCN) considers polypectomy alone to be adequate therapy for low-grade invasive T1 polyps that are limited to the head/stalk region and can be excised with negative margins. We examined the implications of this guideline for the general population. Methods: The National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database (1988–2003) was queried to identify patients with invasive T1 colonic polyps. Patients treated with a polypectomy (PP) were compared with those who received a surgical resection (SR). Results: Of 9,162 patients with invasive T1 colonic polyps, 61.6% (11,812) underwent SR and 38.4% (7,350) underwent PP. The percentage of polyps removed increased from 4.2% (812) in 1988 to 9% (1739) in 2003. Patients undergoing SR vs. PP had larger polyps (median size 1.3 vs. 1.0 cm, p <0.001) and higher grade tumors (8.6% vs. 4.7%, p <0.001). The percentage of node positivity was 7% after SR, or 8.9% if at least 12 nodes were resected. The percentage of node positivity reached a surprising 6% in 1,478 patients who underwent SR for low-grade polyps limited to the head/stalk, and nodal status significantly affected the 3-year disease-specific survival of this subgroup: 83% with nodal metastases vs. 96% without nodal metastases (p < 0.003). Conclusions: Malignant colonic polyps with favorable histological features have a 6% risk of lymph node metastases even when removed with negative margins, bringing into question the NCCN recommendation that PP alone is adequate therapy.

No significant financial relationships to disclose.
Overall survival using local excision techniques with and without radiation compared with APR for stage I rectal cancer: A SEER based analysis
Authors: Wortham A. H. , Schreiber D. , Rineer J. , Katsoulakis E. , Sroufe R. , Marienberg E. , Nwokedi E. , Han P. , Choi K. , Rotman M.
Published: August 2020

4032

Background: The standard of care for Stage I rectal cancer is radical resection. Increasingly, local therapies have been used to decrease morbidity and preserve sphincter control. Due to increased risk of local recurrence with less radical surgery, patients often receive adjuvant radiation. This analysis compares the outcomes of sphincter sparing treatment with radical surgery in Stage I rectal cancer. Methods: Using the Surveillance, Epidemiology and End-Results (SEER) registry, we performed a query of patients with Stage T1–2N0 (T=4 cm or less) rectal adenocarcinoma between 1988 and 2003 who were treated with either local excision alone (LE), local excision followed by radiotherapy (LE+RT) or abdominoperineal resection (APR). APR was selected as comparison group to select for a similar cohort of patients with distal tumors that would be eligible for LE. Kaplan-Meier analysis was performed to compare overall survival for patients receiving radical surgery versus local therapy. Subgroup survival analysis was performed by T-stage (T1 vs T2). Results: 2,144 patients were identified: 744 were treated with LE alone, 197 underwent LE+RT, and 1203 underwent APR. Patients undergoing LE ± RT had a median survival (MS) of 131 vs 121 months in the APR group (p=0.574). When comparing LE vs LE+RT, there was no difference in MS for the whole cohort (134 vs 108 months, p=0.39). However, on subgroup analysis there was a significant survival benefit in favor of LE+RT for T2N0 only (104 vs 74 months, p=0.048). For T1N0, the MS for LE+RT was 161 vs 147 months for LE (p=0.621). Comparing with APR, patients undergoing LE+RT had a MS of 108 vs 121 months in the APR group (p=0.684). For T1N0, the MS for LE+RT was 161 vs 153 months for APR (p=0.62). For T2N0 patients, the MS for LE+RT was 104 vs 114 months for APR (p=0.726). Conclusions: According to this analysis, there was no statistical difference in survival for patients with Stage I rectal carcinoma undergoing APR versus LE+RT. Selected patients with T1N0 may undergo local excision alone. However, patients with T2N0 disease should undergo adjuvant radiation after local excision. The risks and benefits of these treatment strategies should be weighed and treatment should be individualized.

No significant financial relationships to disclose.
ACRIN 6664: Patient acceptance and preferance of CT colonography compared to optical colonoscopy for colon cancer screening
Authors: Siewert B. , Gareen I. , Vanness D. , Herman B. , Johnson C. D. , Gatsonis C.
Published: August 2020

4034

Background: Colorectal cancer screening must be repeated on a regular basis. Understanding patient perceptions and willingness to be rescreened will help to determine future compliance rates. The purpose of this study was to compare National CT Colonography Trial (NCTCT) screening participant experiences with CT colonography (CTC) and optical colonoscopy (OC), willingness to return for each procedure, and procedure preference. Methods: NCTCT participants underwent a single bowel preparation (BP). Participants were scheduled to receive CTC, followed by sedation and OC. Participants were asked to complete a questionnaire two weeks post-exam on physical discomfort and embarrassment during BP, CTC and OC and willingness to repeat CTC and OC (with or without BP) at different time intervals. McNemar's Test and logistic regression were used for statistical analysis. Results: 2310 of 2600 patients (89%) responded (1224 women, 1086 men). Mean age was 58.39 years (range 50–86). The participant population was 85% Caucasian, 11% African American and 4% other. Severe discomfort was reported by 7.1% participants with BP, 6.3% with CTC, and 2.2% with OC. Severe embarrassment was reported by 1.6% participants with BP, 1.3% with CTC, and 0.7% with OC. Forty-six percent of participants preferred CTC, 27.4% reported no preference, and 24.9% preferred OC (p<0.001). Repeat screening with CTC is currently recommended every 5 years and with OC every 10 years. 80.5% of the participants were willing to be screened again with CTC in 5 years and 97.5 % were willing to be screened again with OC in 10 years (p<0.001). If the screening interval for CTC were extended to ten years, 93.7% of participants were willing to return for screening (p<0.001). If BP were unnecessary, 91.0% were willing to be rescreened with CTC in 5 years and 97.5% were willing to be rescreened with OC in 10 years (p<0.001). Conclusions: NCTCT participants preferred CTC to OC, but their willingness to undergo repeat CTC was limited by the shorter interval between screenings currently recommended for CTC as opposed to OC. Improvements in technology that would eliminate the need for bowel preparation or extend the recommended screening interval would likely improve adherence to recommended repeat screening.

[Table: see text]
Development and validation of a robust prognostic and predictive signature for colorectal cancer (CRC) patients
Authors: Glas A. M. , Roepman P. , Salazar R. , Capella G. , Moreno V. , Westerga J. , Kuppen P. J. , Simon I. , Van ’t Veer L. J. , Tollenaar R.
Published: August 2020

4036

Background: Between 25 and 35% of stage II CRC patients will experience a recurrence of their disease and may benefit from adjuvant chemotherapy. Official guidelines give suggestions but no clear recommendation for best risk stratification. Here we describe the development a robust signature that predicts disease relapse and can assist in treatment decisions. Methods: Fresh frozen tumor tissues from 180 patients with stage I, II and III colorectal cancer undergoing surgery were analyzed using high density Agilent 44K oligonucleotide arrays. Median FU was 70.2 months; 85% of patients did not receive adjuvant chemotherapy. Unsupervised hierarchical clustering based on full-genome gene expression measurement indicated the existence of 3 main colon molecular subclasses. Survival analysis of the 3 classes showed that subtype C (n= 27) had a poor outcome and subtype A (n= 48) good outcome. Only the intermediate group B (n=104) was used to develop a signature by using a cross validation procedure to score all genes for their association with 5-yr distant metastasis free survival (DMFS) and subsequently applied to all samples (n=180). The obtained gene signature was further validated on an independent cohort of 178 stage II + III colon samples. Results: A set of 38 prognosis related gene probes showed robust DMFS association in over 50% of all iterations in the Training Set of 180 samples. The gene signature was validated on an independent cohort of 178 samples from stage II + III colon cancer patients. The profile classified 61% of the validation samples as low-risk and 39% as high-risk. The low- and high-risk samples showed a significant difference in DMFS with a HR of 3.19 (P= 8.5e-4). Five-year DMFS rates were 89% (95%CI 83–95) for low-risk and 62% (95%CI 50–77) for high-risk samples. Moreover, the profile showed a significant performance within stage II (P=0.0058) and III (P=0.036) only samples. The performance of the profile was significant for both untreated (P=0.0082) and treated patients (P=0.016) suggesting that its power is independent of treatment benefits. Conclusions: ColoPrint is able to predict the prognosis of stage II and III colon cancer patients and facilitates the identification of patients who would benefit from adjuvant chemotherapy.

[Table: see text]
Concordance of K-Ras status between colorectal cancer (CRC) primaries and related metastatic samples considering clinicopathological features
Authors: Cejas P. , López-Gómez M. , Madero R. , De Castro J. , Casado E. , Belda C. , Larrauri J. , Barriuso J. , González-Barón M. , Feliú J.
Published: August 2020

4053

Background: K-Ras mutations in CRC primaries may predict resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, but we don´t know its behaviour in metastatic tissue. The aims of this study were: 1) Evaluate the grade of concordance of K-Ras status between primary and related metastatic samples 2) Establish a correlation between k-ras status and individual clinicopathological features Methods: K-ras mutations were retrospectively analysed in primary tumours of 124 patients and 138 related metastatic sites. The primary tumour site was colon in 87 patients and rectum in 37. Sites of metastases were liver (115 samples,83.3%) and lung (23 samples,16.7%). Some patients underwent surgery several times. We analyzed K-Ras point mutations in codons 12 and 13 by direct DNA sequencing from paraffin-embedded tumour and studied its relation with 13 clinicopathological features Results: K-Ras mutation was observed in 42(33.6%) primary tumours and in 52(39.1%) related metastatic sites, being the grade of concordance between primary and metastatic sites of 93% (95% CI: 97.5–88.3%). Discordance was observed in 9 (7%) patients: in 2, K-Ras status was wild type in metastatic site and expressed a mutational pattern in the primary tumour; vice versa, in 7, the mutation status was detected in the metastases meanwhile primary tumour was wild type. We also found statistically significative differences in mutation patterns regarding the site of the metastasic tissue: K-ras mutations were detected in 13 lung samples (61.9%) and in 39 liver samples (34.8%) (p=0.028). Of all the clinicopathological features analyzed we confirmed an increase of mutated K-ras status in tumours which had presented as perforation (p=0.044). No other relation with clinicopathological data was detected Conclusions: With this observational analysis, we confirm the high concordance (superior to 90%) between primary and related metastatic sites in terms of K-Ras status; for the first time, we have reported a higher mutational pattern in lung metastases than in liver disease, founds that may have important relevance regarding clinical/treatment decisions. For the realization of this study we received a grant from Amgen.

No significant financial relationships to disclose.
Phase II trial of chemotherapy with high-dose FOLFIRI plus bevacizumab in the front-line treatment of patients with metastatic colorectal cancer (mCRC) and genotype UGT1A1*1/ UGT1A1*1 or UGT1A1*1/ UGT1A1*28 (FFCD 0504 trial). Results of a planned interim analysis
Authors: Mitry E. , Bouché O. , Dahan L. , Bonnetain F. , Laurent-Puig P. , Aparicio T. , Etienne P. L. , Lecaille C. , Lafargue J. P. , Jouve J. L. ,   Fédération Francophone de Cancérologie Digestive (FFCD)
Published: August 2020

4065

Background: The antitumor efficacy of irinotecan may be dose dependent. In a recent phase II trial, the combination of high-dose irinotecan (260 mg/m2) with LV5FU2 regimen was feasible with an acceptable safety profile and promising efficacy data (Ducreux et al. Oncology 2008;74:17–24). The aim of this study was to evaluate the association of the high-dose FOLFIRI plus bevacizumab in patients (pts) selected on the UGT1A1 polymorphism, which could be predictive of the irinotecan toxicity. Methods: Pts with UGT1A1 *1/*1 (group 1) or *1/*28 (group 2) genotypes and previously untreated mCRC were treated with bevacizumab 5 mg/kg D1, irinotecan 260 mg/m2 D1, LV 400 mg/m2 D1, 5FU 400 mg/m2 IV bolus D1 and 5FU 2400 mg/m2 46h infusion D1–2 every 2 weeks. Using Bryant & Day design with OR (independent review, H0 ≤ 40%; H1 : ≥ 60%) and toxicity (gr 4 neutropenia or febrile neutropenia or gr3–4 diarrhea; H0 ≥ 20%; H1≤ 5% ) as primary endpoints; a total of 108 pts, 54 in each group, was required (alpha 5% and power 80%) with a planned interim analysis after the inclusion of 17 pts by group. The trial will be stopped at interim analysis if ≤ 7 pts had an OR and/or ≥ 3 pts had a severe toxicity. All analyses were performed in ITT. Results: At the time of interim analysis, done for group 1 when the 17th pt had a 6-months follow-up, 96 pts have been included (group 1: 40 pts, group 2: 46 pts). An objective response rate was observed in 9/17 pts but 7/17 pts had a severe toxicity (gr 4 neutropenia: 2 pts, febrile neutropenia: 2 pts, gr 3 diarrhea: 4 pts). Overall, 14/17 pts had a gr3–4 toxicity. There was no toxic death. According to interim analysis rules, the trial was closed to inclusion (for both groups) on December 16th 2008 for toxicity. The interim analysis for pts of group 2 is planned for February 2009 when the 17th patient will have a 6-months follow- up. Conclusions: High-dose FOLFIRI plus bevacizumab, although effective, was associated with a high toxicity rate among pts with UGT1A1 *1/*1 genotype. Complete tolerance, efficacy and survival results for all included patients will be presented at the meeting.

[Table: see text]
Pharmacogenetic analysis of TS and UGT1A polymorphisms predictive for response and toxicity in Spanish patients with advanced colorectal cancer treated with first-line irinotecan and 5-fluorouracil
Authors: Martinez-Balibrea E. , Abad A. , Valladares M. , Martinez-Villacampa M. , Aranda E. , Marcuello E. , Benavides M. , Martinez-Cardús A. , Ginés A. , Manzano J. L. ,   Spanish Group for the Treatment of Digestive Tumors
Published: August 2020

4066

Background: The possible role of uridine diphosphate-glucuronosyltransferase 1A (UGT1A) and Thymidylate Synthase (TS) gene polymorphisms in predicting toxicity and outcomes in irinotecan/ 5-Fluorouracil (5FU)-treated patients is still controversial. The aim of this work was to determine whether UGT1A1, UGT1A7, and UGT1A9 as well as TS polymorphisms affect toxicities and/or outcomes of Spanish patients with advanced colorectal cancer (mCRC) Methods: A total of 149 patients with mCRC were treated either with weekly irinotecan plus high-dose 5FU (FUIRI) or biweekly irinotecan plus 5FU/Leucovorin (FOLFIRI) as first-line chemotherapy (Aranda E; Ann Oncol. 2008 Aug 20). Genomic DNA was extracted from peripheral blood and genotyped using allelic discrimination and direct sequencing. Chi-square test, Fisher's exact test and logistic regression were used to study the association of genotypes with toxicity and response. Log rank and cox regression were used in survival analysis. All statistical tests were two-sided. Results: According to TS 5’TRP genotypes, 79.3% of the 2R/2R patients responded to therapy while only 52.5% of 2R/3R or 3R/3R patients do so (HR=3.5; 95% CI=1.3- 9.1; p=0.009). TS genotypes were not associated with toxicity. UGT1A1*28 TA7/TA7 genotype was clearly associated with severe toxicity (HR=12.7; 95% CI=3.1–51.3; p=0.001) and diarrhea (HR=4; 95% CI=1.3–12; p=0.016) when compared to TA6/TA7 and TA6/TA6 genotypes. These patients also experienced more severe neutropenia (40% vs. 18.8%, p=0.087) and more frequent dose reductions (53.3% vs. 38.1%, p=ns). UGT1A7*3/*3 and UGT1A9–118(dT)9/9 were associated with severe diarrhea (50% vs. 27% p=0.032 and 43% vs. 23% p=0.012). When all non-favourable genotypes (TA7/TA7, *3/*3 and 9/9) were taken into account, there was a statistically significant association with severe diarrhea (HR=4.5; 95% CI 1.3–16.3; p=0.021), neutropenia (HR=3.5; 95% CI=1–12.7; p=0.047) and both (HR=12.4; 95% CI=2.8–54.2; p=0.001). Conclusions: Our data clearly link UGT1A genotypes with irinotecan-related severe toxicity. TS 5’TRP genotypes are predictive of response to irinotecan/5FU first-line chemotherapy.

No significant financial relationships to disclose.
Predictive biomarkers to improve treatment of metastatic colorectal cancer (mCRC): Outcomes with cetuximab plus FOLFIRI in the CRYSTAL trial
Authors: Kohne C. , Stroiakovski D. , Chang-chien C. , Lim R. , Pintér T. , Bodoky G. , Stroh C. , Celik I. , Rougier P. , Van Cutsem E.
Published: August 2020

4068

Background: KRAS oncogene mutation status is predictive of efficacy of cetuximab alone or combined with chemotherapy (CT) in mCRC. Previous data from the phase III CRYSTAL trial showed that adding cetuximab to FOLFIRI in first-line mCRC significantly improved the overall response rate (ORR) and progression-free survival (PFS) in pts with KRAS wild-type (wt) tumors. The serine-threonine kinase BRAF is a direct downstream effector of KRAS. Here, we report the influence of KRAS and BRAF status on mature overall survival (OS) data. Methods: DNA was extracted from archived tumor material where available from randomized pts. KRAS and BRAF mutation status (wt or mutant [mt]) was determined by quantitative PCR. Treatment arms were compared using two-sided log-rank tests (5% significance level) for PFS and OS, and the CMH test for best ORR. Results: The KRAS-evaluable cohort (n=540; 64.4% KRAS wt) was similar to the overall ITT group. In KRAS wt pts, adding cetuximab to FOLFIRI significantly increased the odds for tumor response nearly 2-fold, reduced the risk of progression by 32% and extended median OS from 21.0 months (mo) to 24.9 mo (details in Table ). KRAS mt pts did not benefit from cetuximab. Data on the impact of BRAF mutations on cetuximab activity will be presented at the meeting. In the FOLFIRI and cetuximab + FOLFIRI arms, 31.2% and 36.1% of pts, respectively, received no further line of therapy, while 25.4% and 6.2%, respectively, received EGFR antibody therapy. Conclusions: The benefits of adding cetuximab to CT were greater in KRAS wt pts than ITT pts for all clinically relevant endpoints. KRAS is a key biomarker for selecting a targeted therapy combined with standard CT in first-line mCRC.

[Table: see text]

[Table: see text]
Pegfilgrastim in colorectal cancer (CRC) patients (pts) receiving every-two-week (Q2W) chemotherapy (CT): Long-term results from a phase II, randomized, controlled study
Authors: Hecht J. R. , Pillai M. , Gollard R. , Dreiling L. , Mo M. , Malik I.
Published: August 2020

4072

Background: Survival in advanced CRC is prolonged by adding oxaliplatin (Ox) and/or irinotecan (Iri) to Q2W 5-fluorouracil/leucovorin (5FU/LV). Combination therapy, however, has a higher incidence of febrile neutropenia (FN) and related toxicities. This study evaluated pegfilgrastim dosing on day 4 of Q2W regimens in CRC. Here we present long-term follow-up of these pts. Methods: Advanced CRC pts were randomized (1:1) to pegfilgrastim 6mg or placebo, which was stratified by CT regimen received: FOIL, FOLFOX, or FOLFIRI. We previously reported grade 3/4 neutropenia (primary endpoint) in 43% placebo and 13% pegfilgrastim pts in the 4-cycle treatment phase (odds ratio = 0.19, 95% CI: 0.10–0.37; p < 0.0001). After end of treatment, pts were followed long term for ≤ 2 years (inclusive of ≤ 8 additional cycles) for serious adverse events (SAEs), overall survival (OS), and progression-free survival (PFS). Median follow-up time was 519 days. Kaplan-Meier methods estimated OS and PFS from study day 1. The study was not powered to detect PFS or OS differences between treatment groups. Results: Of 241 pts analyzed (123 pegfilgrastim, 118 placebo), 49% received FOLFOX, 26% FOLFIRI, and 25% FOIL. In the treatment period, 8% placebo and 2% pegfilgrastim pts had grade 3/4 FN ( Table ). Pegfilgrastim was well tolerated with no dose delays attributed to leukocytosis. Pegfilgrastim and placebo had similar PFS and OS ( Table ). No SAEs related to study drug were reported in the follow-up period. Conclusions: In this randomized, placebo-controlled study, pegfilgrastim significantly lowered neutropenic risk. Bone pain incidence in this CRC population was lower than in breast cancer pts treated with a taxane (Vogel J Clin Oncol 2005); the incidence in pegfilgrastim pts was modestly increased over placebo. Leukocytosis was not a concern despite the 11-day dosing interval. Long-term results suggest similar PFS and OS in the pegfilgrastim and placebo pts in this CRC study.

[Table: see text]

[Table: see text]
Efficacy and safety of bevacizumab (BEV)-based combination regimens in patients with metastatic colorectal cancer (mCRC): Randomized phase II study of BEV + FOLFIRI versus BEV + XELIRI (FNCLCC ACCORD 13/0503 study)
Authors: Ducreux M. , Adenis A. , Mendiboure J. , François E. , Boucher E. , Chauffert B. , Ychou M. , Pierga J. , Montoto-Grillot C. , Conroy T.
Published: August 2020

4086

Background: The combination of BEV and chemotherapy is highly effective in patients with mCRC and improves response rate, progression-free survival and overall survival compared with chemotherapy alone. This randomized non-comparative phase II trial evaluated the efficacy and safety of BEV in combination with either XELIRI or FOLFIRI as first-line therapy for mCRC. Methods: Patients were eligible for inclusion in this study if they had histologically proven measurable mCRC, were aged 18–75 years, and had an ECOG performance status (PS) of 0–2. Patients were treated with 8 cycles of XELIRI (irinotecan 200 mg/m2 on Day 1 and capecitabine 1000 mg/m2 bid on Days 1–14) + BEV 7.5 mg/kg on Day 1, every 3 weeks or 12 cycles of FOLFIRI (irinotecan 200 mg/m2 on Day 1 + 5-fluorouracil (5-FU) 400 mg/m2 + folinic acid 400 mg/m2 on day 1 followed by 5-FU 2400 mg/m2 via 46-h infusion) + BEV 5 mg/kg on day 1, every 2 weeks. BEV was continued to disease progression. Patients aged ≥65 years received a lower daily dose of capecitabine (800 mg/m2 bid). The primary endpoint was crude progression-free survival (PFS) at 6 months. Results: In total, 145 patients were entered in the study between March 2006 and January 2008; 72 patients received BEV + XELIRI and 73 patients received BEV + FOLFIRI (male 64%/48%; median age 61/61 years; 35/36% aged >65 years). Preliminary results from the first 6 months of follow-up are reported here. A total of 491/783 cycles was administered, 63%/67% receiving at least the initially planned number of cycles (8 cycles for BEV + XELIRI and 12 for BEV + FOLFIRI). Main results are given in the table . Conclusions: This randomized non-comparative study has shown that BEV + XELIRI and BEV + FOLFIRI are similarly effective treatments for patients with mCRC, with manageable toxicity profiles. Results with updated follow-up will be presented at the Meeting.

[Table: see text]

[Table: see text]
Phase II study of bevacizumab in combination with cetuximab plus irinotecan in irinotecan-refractory colorectal cancer (CRC) patients who have progressed on a bevacizumab-containing regimen (The BOND 2.5 Study)
Authors: Segal N. H. , Reidy-Lagunes D. , Capanu M. , Kemeny N. , Chung K. , Kelsen D. , Hollywood E. , Goodman-Davis N. , Saltz L. B.
Published: August 2020

4087

Background: We previously showed that adding bevacizumab (bev) to cetuximab (cetux) plus irinotecan (IRI) in bev-naïve, IRI-refractory CRC patients is feasible, and yielded a favorable response rate and time to tumor progression (TTP) compared with historical controls (Saltz: JCO, 2007). Since most CRC patients now receive a bev-containing regimen prior to cetux, we evaluated the addition of bev to cetux plus IRI (CBI) in patients with metastatic CRC who had previously progressed on chemo + bev. Methods: All patients were naïve to cetux. The importance of KRAS mutation was not appreciated when the trial was designed and this has not yet been evaluated. Patients received IRI at the same dose and schedule as last received prior to study, Cetux 400 mg/m2 loading dose, then weekly at 250 mg/m2, plus Bev 5 mg/kg given every two weeks or 7.5 mg/kg given every three weeks. Results: 33 received treatment. Median age was 58 (range 29–85). Median number of prior regimens was 2 (range 1–2). Median performance status was ECOG 1 (range 0–1). Patients received a median of 2 cycles (range 1–15). Grade 3/4 Toxicities: Acneiform Rash 18%, hypomagnesemia 6%, hypophosphatemia 6%, Neutropenia 15%, Diarrhea 6%. One patient developed neutropenic fever and one patient had a hypersensitivity reaction to cetux. At a median follow up of 32 months (range 21–32 months) in 33 evaluable patients, we observed 3 (9%) partial responses and 11 (33%) patients with stable disease for > 4 months. Median TTP was 3.9 months (95% CI: 1.3 - 6.8). Median survival was 10.6 months (95% CI: 6.6 - 13.8). Conclusions: The toxicity profile was similar to what would have been expected from the individual agents alone. Recognizing the limitations of cross-study comparisons, the response rates and TTP seen with CBI in patients who have previously progressed on bev do not appear to be as encouraging as the 37% response rate and 7.3 months TTP seen in the BOND 2 trial of bev-naïve CRC patients. Ongoing randomized trials, including SWOG 0600, will be needed to definitively determine the contribution of continued use of bev after progression on a bev-containing regimen. Supported by Genentech.

[Table: see text]
Phase II study of NGR-hTNF, a selective vascular targeting agent (VTA), administered as single agent in patients (pts) with colorectal cancer (CRC) refractory to standard regimens
Authors: Rimassa L. , Sobrero A. F. , Santoro A. , Andretta V. , Gregorc V. , Sclafani F. , Caprioni F. , Caligaris-Cappio F. , Lambiase A. , Bordignon C.
Published: August 2020

4088

Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to an aminopeptidase N/CD13 overexpressed by tumor blood vessels. In preclinical models, NGR-hTNF showed antitumor activity both at low and at high doses. Methods: Pts with CRC resistant/refractory to standard treatments, including biological agents, were treated with low-dose NGR-hTNF given intravenously at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and 27 pts to be enrolled after first and second stage, respectively. Progression-free survival (PFS) was the primary end-point with reassessment performed q6w. Results: From January to May 2007, 33 pts with radiologically- documented progressive disease after last therapy were evaluated over 111 cycles (range, 1–10). Pts characteristics were: median age: 65 years (range, 53 to 79); M/F 16/17; PS 0/1 26/7. Median number of prior regimens was 3 (range, 2 to 5). Eight pts (25%) were pre-treated with ≥4 lines and 22 (67%) with biological agents. Neither grade 3–4 treatment-related adverse events nor toxicity-related deaths were observed. Main grade 1–2 toxicities per patient were infusion-related chills (47%) and transient blood pressure increase (9%). One partial response (3%) lasting 5 months and 12 stable diseases (36%) were reported. Median PFS was 2.5 months (95% CI, 2.2–2.8). In a post-hoc analysis, no differences in PFS were detected according to baseline characteristics. With a median follow-up time of 18.4 months (95% CI, 18.3–18.5), 11 pts (33%) were still alive. Median overall survival (OS) was 13.1 months and the 2-year OS rate was 22%. In the subset of stable or responder pts, the median PFS and OS were 3.8 months and 15.4 months, respectively. The 6-month PFS rate in the prior-biological and biological-naïve cohorts was 5% and 20%, respectively, whereas 1-year OS rate was 41% and 72%, respectively. Conclusions: Based on the favorable toxicity profile and disease control in heavily pre-treated CRC patients, NGR-hTNF will be further developed in combination with standard chemotherapy.

[Table: see text]
Prospective randomized study comparing hepatic intra-arterial injection of Yttrium-90 resin-microspheres (HAI-Y90) with protracted IV 5FU (5FU CI) versus 5FU CI alone for patients with liver-limited metastatic colorectal cancer (LMCRC) refractory to standard chemotherapy (CT)
Authors: Van Den Eynde M. , Hendlisz A. , Peeters M. , Defreyne L. , Maleux G. , Vannoote J. , Delatte P. , Paesmans M. , Van Laethem J. , Flamen P.
Published: August 2020

4096

Background: Chemorefractory LMCRC has a poor prognosis. We hypothesized a significant improvement of the patient's outcome after internal radiotherapy of the hepatic metastases with HAI-Y90 given along with 5FU CI over 5FU CI alone. Methods: This prospective, multicentric, randomized trial compared arm A: 5FU CI (300 mg/m2 D1–14 q3weeks) with arm B: HAI-Y90 and 5FU CI (225 mg/m2 D1–14 followed by 300 mg/m2 D1–14 q3weeks) until disease progression. Eligibility criteria were: chemo-refractory (5FU, oxaliplatin, irinotecan) LMCRC, PS max 2, normal direct bilirubin, and no lung shunting. Primary endpoint was time to liver progression (TTLP). Secondary endpoints were time to progression (TTP), overall survival (OS) and safety. Cross-over (HAI-Y90 monotherapy) was permitted in arm A after disease progression. Analysis was by intention to treat. To detect an increase in median TTLP from 6 to 18 weeks, 35 local progressions were needed (alpha 5%, power 90%). Distribution of time to events variables was modelled through Cox regression (likelihood ratio tests). Results: Trial randomized 46 patients (pts) of whom 44 were eligible for analysis (23 in arm A and 21 in arm B). Pts’ characteristics in the 2 arms were well balanced. Local progression was documented in 41 pts. Median length of follow-up was 108 weeks. Results are summarized in the table . Treatment was well tolerated with few side effects reported, essentially grade 3 asthenia (5 pts; 22%) in arm A. Most pts (25/44) received further treatment after local progression, including 10 pts with cross-over to HAI-Y90 in arm A, which may explain to some degree the lack of difference in OS. Conclusions: HAI-Y90 with 5FU CI significantly improves TTLP and TTP over 5FU CI alone and is a valid salvage therapeutic option for chemo-refractory LMCRC.

[Table: see text]

No significant financial relationships to disclose.
Multicenter randomized phase II study of chemoradiation (CRT) followed by surgery (S) and chemotherapy (CT) versus induction CT followed by CRT and S in high-risk rectal cancer: GCR-3 final efficacy and safety results
Authors: Fernandez-Martos C. , Aparicio J. , Salud A. , Alonso V. , Massuti B. , Safont M. , Vera R. , Escudero P. , Maurel J. , Pericay C.
Published: August 2020

4103

Background: In locally advanced RC the optimal therapeutic sequence remains an important clinical question. Induction CT prior to CRT and S may be associated with better efficacy and compliance. Methods: Eligible pts had medium or distal high risk RC defined by MRI and/or US: Tumors within 2mm of mesorectal fascia, distal T3 at/below levators, resectable T4 and T3N+. Pts, stratified by center, were randomized assigned to receive either Arm A : capecitabine (Cap) 825 mg/m2 BID 5 d/w, oxaliplatin (Ox) 50 mg/m2 IV weekly x 5 and concomitant RT: 50.4 Gy in 28 fractions. S was planned 5–6 w after CRT. Post-op four cycles of Cap 1,000 mg/m2 bid days 1 to 14; Ox 130 mg/m2 day 1 or Arm B: Induction CapOx followed by CRT and S. Two parallel, Simon 2-stage designs: α=0.05 β=0.1; 24 evaluable pts/arm 1st stage and 54 pts/arm for 2nd stage. Primary endpoint: pathological complete response (pCR). Secondary endpoints included toxicity and treatment compliance. Results: 108 Pts were randomly assigned (arm A/B, 52/56), and 103 were assessable (49/54) from 14 sites. Median age 62/60 years, Male 65/70%. During treatment period 6 pts died A/B: 2 vascular, 1 suicide/ 3 post-op. Pts with any grade ¾ toxicity during CRT were arm A/B: 29% (14/49) and 23% (12/53). Any grade ¾ toxicity during adjuvant/induction CT were 51% (19/37) and 17% (9/54); χ2,p= 0.0004. On an intent-to-treat basis the pCR for Arm A/B was achieved in seven (13.5%; 95% CI, 5.6%-25.8%) and eight (14.3%; 95% CI, 6.4%-26.2%). R0 resections were achieved in 92% (45/49) and 88% (48/54). 51% (25/49) and 93% (50/54) received all four cycles of adjuvant/induction CT (χ2;p<0.0001). Relative Median Dose intensity of adjuvant /induction CT was 0.74/0.96 (Wilcoxon; p<0.0001) for Cap and 0.75/1.0 (Wilcoxon; p<0.0001) for Ox. Conclusions: Induction CT prior to CRT has more favorable compliance and toxicity profiles. Furthermore, there is no compromise in pCR and R0 resection rates. Larger trials evaluating this strategy are justified.

[Table: see text]