bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose escalation and pharmacodynamic study of intravenous adminstration of Reolysin, a live replication competent RNA virus in patients with advanced solid tumors
Authors: Ghalib M. H. , Desai K. K. , Gollamudi R. , Chaudhary I. , Einstein M. , Coffey M. , Mettinger K. , Mani S. , Goel S.
Published: August 2020

3583

Background: Reolysin is reovirus serotype 3 - Dearing strain, a double-stranded replication- competent RNA non-enveloped icosahedral virus. It induces cytopathic and anti-cancer effects in cells with an activating mutation in the ras proto-oncogene. Methods: This was a single center dose escalation trial of Reolysin administered intravenously every four weeks in doses ranging from 1X108 to 3X1010 tissue culture infective dose (TCID)50. Serum for neutralizing antibody, and serum, stool, saliva, and urine for viral shedding were collected. Tumor samples were analyzed for activating mutations in the ras and braf oncogenes. Results: Eighteen patients received 27 doses of Reolysin in 6 dose cohorts accomplishing a 300 fold dose escalation without a protocol-defined dose limiting toxicity. Drug related grade 2 toxicities included fatigue and fever (1 patient each). All patients developed neutralizing antibody during the course of the study. Viral shedding was observed in 6 patients [urine (5), serum (4), saliva (3), and stool (2)]. One patient with anthracycline and taxane refractory breast cancer experienced a partial response (PR) and her tumor had a mutation in the ras oncogene. Biopsy from a chest wall mass showed evidence of necrosis and viral replication by electron microscopy. The overall clinical benefit rate was 45% and appeared higher in patients with viral shedding (67%) than those without (33%). Conclusions: Reolysin administered as a one hour infusion on a monthly schedule is safe and well-tolerated even in multiple doses. Reolysin has anti-tumor activity as a single agent warranting further evaluation, including in combination with chemotherapy. Viral shedding may suggest intrapatient replication yielding a benefit and should be studied carefully in future studies.

[Table: see text]
Results of a completed phase I clinical trial of CYT-6091: A pegylated colloidal gold-TNF nanomedicine
Authors: Libutti S. K. , Paciotti G. F. , Myer L. , Haynes R. , Gannon W. , Walker M. , Seidel G. , Byrnes A. , Yuldasheva N. , Tamarkin L.
Published: August 2020

3586

Background: CYT-6091 is the first tumor-targeted nanomedicine formulation designed to safely deliver an API that itself is not approved for systemic administration due to unacceptable toxicity. CYT-6091, consisting of tumor necrosis factor-α (TNF) covalently linked to pegylated colloidal gold nanoparticles, has been safely administered in preclinical models, demonstrating an increased T1/2 compared to native TNF, a documented trafficking of nanoparticles to tumor, and no hypotension, the known DLT for TNF. Methods: CYT-6091 was tested in a phase I open label trial in solid tumor, advanced stage patients. Patients (n = 3/dose), admitted to the NIH Clinical Center ICU, received two IV injections of CYT-6091 on day 0 and 14. Dosing started at 50 μg/m2 of TNF, up to 600 μg/m2. Vital signs were monitored and blood samples were drawn over 48 h. The primary endpoint of the study was to determine the MTD for CYT-6091. Secondary endpoints included PK, disease response (staged 45 days post treatment by RECIST), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue. Results: Twenty-nine patients were treated. Even at the lowest dose (50 μg/m2), patients exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the 29 patients treated with doses of 50–600 μg/m2 showed a DLT hypotensive response, and in fact, no DLT was seen. T1/2 estimates for TNF, administered as CYT-6091, are 120, 131, 127, 146, 112, 113, 266, 371, and 160 minutes for 50, 100, 150, 200, 250, 300, 400, 500, 600 μg/m2, respectively (published T1/2 for native TNF is ∼27 minutes). In the 28 patients eligible for response assessment, there was 1 PR (100 μg/m2 dose, 7 months duration) and 3 SD (2, 2, and 3 months duration). Electron micrographs show gold nanoparticles in tumor biopsies. Conclusions: CYT-6091 is well tolerated at doses up to 600 μg/m2 of TNF, levels 3-times greater than the published MTD for native TNF. CYT-6091 targets tumors in humans. Efficacy studies in combination with chemotherapy are planned.

[Table: see text]
A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study
Authors: Kerr D. , Gray R. , Quirke P. , Watson D. , Yothers G. , Lavery I. C. , Lee M. , O’Connell M. J. , Shak S. , Wolmark N. ,   Genomic Health and QUASAR Colon Teams
Published: August 2020

4000

Background: New clinical tools are needed to improve risk assessment and treatment decisions in stage II colon cancer. Four development studies [Surgery (Sx) alone: NSABP C-01/C-02 (n=270) and CCF study (n=765); Sx+5FU/LV: NSABP C-04 (n=308) and C-06 (n=508)] were performed to select the genes for prediction of recurrence and 5FU/LV benefit. To determine clinical utility of the prespecified assay, we performed a large, independent, prospectively designed, clinical validation study in stage II colon cancer pts from the QUASAR trial. Methods: Gene expression was quantitated by RT-PCR from 30 μm manually microdissected fixed paraffin-embedded primary colon cancer tissue. Recurrence-free interval (RFI), disease-free survival (DFS), and overall survival (OS) were analyzed using Cox regression. Results: Combined analysis of the four development studies (total n=1,851; 761 candidate genes) identified 48 genes significantly associated with recurrence risk and 66 genes predictive of 5FU/LV benefit. Multivariate analysis, in the context of stage, grade, nodes examined, and MSI status, yielded 18 genes (7 prognostic genes, 6 predictive genes, 5 reference genes) and separate prognostic recurrence score (RS) and predictive treatment score (TS) algorithms. In the QUASAR validation study, tumor blocks were collected for 68% of pts; 1,490 pts with blocks had stage II colon cancer and RT-PCR was successful in 1,436 eligible pts (711 Sx, 725 Sx+5FU/LV). Median FU=6.6 yrs. In the primary analysis of RFI in pts following Sx, the RS predicted recurrence risk (HR/25 units=1.58, 95% CI 1.15–2.15; p=0.004). The RS also predicted DFS (p=0.01) and OS (p=0.04). Recurrence risk increased monotonically with increasing RS. In multivariate analyses, RS retained prognostic significance (p=0.008) independent of mismatch repair (MMR), T stage, nodes examined, grade, and lymphovascular invasion. MMR deficiency (HR=0.31, 95% CI 0.15–0.63; p<0.001) and T4 stage (HR=1.94, 95% CI 1.35–2.79; p=0.005), together ∼25% of pts, also were independently prognostic. 5FU/LV benefit was significant (p<0.001). However, TS was not validated as a predictor of 5FU/LV benefit (interaction p=0.19). Conclusions: The colon cancer recurrence score is a validated, independent predictor of individualized recurrence risk for stage II colon cancer patients following surgery.

[Table: see text]
Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial)
Authors: Tejpar S. , Bosman F. , Delorenzi M. , Fiocca R. , Yan P. , Klingbiel D. , Dietrich D. , Van Cutsem E. , Labianca R. , Roth A.
Published: August 2020

4001

Background: Patients with high MSI (MSI H) tumors are increasingly being recognized as a prognostic and predictive subgroup in colon cancer (COC). We investigated the incidence of MSI-H in stage II (n=395) and stage III (n=859) COC, its association with histopathological variables and its prognostic and predictive impact. Methods: The study accrued 3278 patients with Stage II and Stage III COC to receive post-operative 5-FU -LV with or without irinotecan (IRI). Paraffin tissue blocks of 1327/1405 available patients were successfully analyzed for MSI status using the NCI extended panel of 10 markers. MSI-H was defined as instability in ≥3 markers. Relapse Free Survival (RFS) and Overall Survival (OS, median follow up 68 months) were assessed. Results: MSI H was present in 22% (85) of Stage II and 12% (103)of Stage III colon cancer . MSI H status was significantly associated with age <60, higher T stage, higher grade, lower N stage and right sided tumor location. The table presents univariate RFS and OS hazard rates (with 95% confidence intervals) for prognostic and predictive impact per stage and arm, estimated by a survival regression analysis using Cox proportional hazards model and of selected P values by Wald tests. Conclusions: Microsatellite instability is a strong prognostic factor for RFS and OS when considering Stage II and Stage III COC. Subgroup analysis suggests a stronger effect in Stage II than in Stage III, but is limited by sample size and multiple testing. Taken together with differences in incidence between the stages, this may suggest stage specific biological effects of MSI. In contrast to previous reports (a) in Stage II the prognostic effect of MSI remained significant even in pts treated with 5FU (w/o IRI),(b) There is no evidence for an effect of the addition of IRI.

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Stage-specific prognostic value of molecular markers in colon cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60–00 trial
Authors: Roth A. D. , Tejpar S. , Yan P. , Fiocca R. , Dietrich D. , Delorenzi M. , Labianca R. , Cunningham D. , Van Cutsem E. , Bosman F.
Published: August 2020

4002

Background: We compared the incidence of molecular markers in stage II (SII) and III (SIII) colon cancer and tested their prognostic value per stage, using PETACC 3, an adjuvant trial with 3,278 patients. We included expression of P53, SMAD4, thymidylate synthetase (TS) and hTERT, mutations of KRAS and BRAF, microsatellite instability (MSI) and 18qLOH. Methods: 1,564 formalin fixed paraffin embedded tissue blocks were prospectively collected and DNA from normal and tumor tissue was extracted after macrodissection. High P53, TS and hTERT expression and SMAD4 loss were assessed by immunohistochemistry. MSI was studied with 10 markers. KRAS exon 2 and BRAF exon 15 mutations were analyzed by allele specific real time PCR. 18qLOH was studied by pyrosequencing 7 SNPs. Prognostic value of the markers was analysed per stage by Cox regression for Relapse Free Survival (RFS). Results: marker frequencies and stage specific p-values in prognostic models in 420 SII and 984 SIII patients are listed in the table . Significant differences in frequency per stage were found for all markers except KRAS and BRAF. An interaction test for differences between marker prognostic value for SII and SIII was significant for MSI (p=0.04) and 18qLOH (p=0.04) in SII. Multivariate analysis including markers, T stage, N stage (for SIII), Tu grade, age <60, sex, treatment arm, and Tu site found T stage (p=0.0001) and MSI (p=0.02) as independently significant clinical predictors in SII; N stage (p<0.0001), T stage (p<0.0001), SMAD4 (p<0.0001) and P53 (p=0.01) in SIII. Conclusions: Molecular markers in colon cancer have a stage specific prognostic value. The possibility that the stages represent different diseases, rather than sequential steps in the evolution of a single disease, needs to be considered.

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The German quality assurance system for the molecular-pathological detection of KRAS-mutations in colorectal cancer
Authors: Jung A. , Baretton G. , Dietel M. , Gabbert H. , Kreipe H. , Schlake W. , Tannapfel A. , von Knebel Döberitz M. , Kirchner T.
Published: August 2020

4018

Background: In the beginning of 2008 the EMEA (European Medicines Agency) approved with panitumumab for the first time an EGFR (epidermal growth factor receptor) targeting therapy for patients with metastatic colorectal cancer overexpressing the EGFR and showing wildtypic sequences in the KRAS gene as a predictive biomarker. Thus, the need for assuring the quality of laboratories emerged. The German Society for Pathology in cooperation with the Federation of the German Pathologist supported by an unrestricted financial grant of Amgen Germany arranged a quality assurance system (QAS). In this context two round- robin tests were carried out which results are presented here. Methods: Collection of results from two round -robin tests and their statistical analysis applying binary classification tests. Results: Test sets of 4 histological sections from ten different cases of colorectal tumors with known mutational status of the KRAS gene were prepared for the round-robin tests. The method for the mutation detection was unrestricted. A total of 74 participants from universities (44 - 59.5 %) or other institutions (30 - 40.5 %) attended the tests. 11 participants (14.8 %) failed the test (6 universities: 13.6 %, 5 institutions: 16.6 %). For the analysis didesoxy-sequencing (DDS: 55 - 66.2 %), ARMS®-PCR (8 - 10.4 %), melting-point analysis (MPA: 7 - 9.1 %), pyrosequencing (PS: 6 - 7.8 %), hybridization (HYB: 4 - 5.2 %), or SSCP (1 - 1.3 %) were used, in which some participants (3) used more than one method. It turned out that all methods employed for the testing gave similar results when comparing the rate of correct or wrong hits or the rate of false positive detection: DDS (0.92, 0.07, 0.02), ARMS®-PCR (0.91, 0.08, 0.05), MPA (0.94, 0.06, 0.04), PS (0.95, 0.05, 0.03) or HYB (0.90, 0.10, 0.08). Conclusions: The quality of the molecular-pathological detection of KRAS mutations as precondition for an EGFR targeted therapy should be tested since about 15 % of laboratories did not meet a sufficient grade. For the mutation detection no method seemed superior.

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Evaluation of the effect of intravenous calcium and magnesium (CaMg) on chronic and acute neurotoxicity associated with oxaliplatin: Results from a placebo-controlled phase III trial
Authors: Grothey A. , Nikcevich D. A. , Sloan J. A. , Kugler J. W. , Silberstein P. T. , Dentchev T. , Wender D. B. , Windschilt H. E. , Zhao X. , Loprinzi C. L.
Published: August 2020

4025

Background: Cumulative sNT is the dose-limiting toxicity of oxaliplatin which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant setting. We recently demonstrated the protective effect of CaMg against oxaliplatin-induced sNT as assessed by NCI-CTC (Nikcevich ASCO 2008). It is unclear, though, if CaMg reduced acute and/or chronic, cumulative sNT. Methods: 104 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to IV CaMg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo (PL) in a double-blinded manner. NCI-CTC, an oxaliplatin-specific sNT scale and patient-reported outcome (PRO) questionnaires were used to differentially assess the effect of CaMg on acute (effect on sNT on days 1–4 after oxaliplatin) and chronic sNT (area between curves over whole course of therapy). Results: A total of 102 pts (50 CaMg, 52 PL; 96 mFOLFOX6, 6 FOLFOX4) were available for analysis. Apart from a strong reduction in muscle cramps with CaMg (p=0.002), no difference was found between CaMg and PL in PRO with regard to items reflecting acute sNT (e.g. sensitivity to cold, swallowing of cold liquids, throat discomfort) on days 1–4 after oxaliplatin of any treatment cycle. In contrast, CaMg was able to significantly reduce cumulative sNT in form of numbness in fingers (p=0.02), impaired ability to button shirts (p=0.05), tingling in fingers (p=0.06), and muscle cramps over the course of therapy (p=0.01). Conclusions: In our phase III, placebo-controlled trial, CaMg was able to significantly reduce chronic, cumulative sNT related to oxaliplatin as evaluated by specific PRO questionnaires. No effect was noted on phenomena associated with acute sNT. CaMg can be recommended as neuroprotectant against oxaliplatin-related chronic sNT, oxaliplatin's dose-limiting toxicity.

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Treatment intensification by induction chemotherapy (ICT) and radiation dose escalation in locally advanced squamous cell anal canal carcinoma (LAAC): Definitive analysis of the intergroup ACCORD 03 trial
Authors: Conroy T. , Ducreux M. , Lemanski C. , Francois E. , Giovannini M. , Cvitkovic F. , Mirabel X. , Bouché O. , Montoto-Grillot C. , Peiffert D.
Published: August 2020

4033

Background: Concomitant radiochemotherapy (CRT) is the standard treatment of LAAC. The addition of an ICT (2 cycles of 5 FU-Cisplatin) and of a higher dose of irradiation boost (HDRT) to CRT were evaluated in a factorial 2X2 arms trial (A= ICT; B=ICT+HDRT; C= Reference arm = Pelvic RT 45 Gy/25 fractions with 2 cycles of 5FU-Cisplatin and a boost of 15 Gy; D= HDRT). The aim of the study was to detect a increase from 70 to 85% of colostomy-free survival (CFS) at 3 years. Methods: 307 pts with T2 > 4 cm or T3-T4 Nx or any T, N1–3 M0 LAAC were included. Mean age was 59 y and sex-ratio was 1/6. The 4 arms were well balanced concerning the sex-ratio, age, stage, T size and differentiation. Results: 306/307 pts were eligible. Toxicities were similar in the 4 arms (toxic deaths: A=4, B=2, C=2, D=1). The compliance was: 99% for ICT, 100% for pelvic RT-CT, and 96% for the boost. The tumour complete response (+ partial response) at 2 months were: A=78% (+18%), B=86% (+13%), C=74% (+21%), D=74 % (+22%) (NS). The median follow-up was 43 months. Overall failure rates were 28% (A=28%, B=21%, C=30%, D= 30%). The actuarial results at 3 years were: CFS was 83%: A= 83%, B= 85%, C= 86%, D= 80% with no significant difference of ICT nor HDRT (A+B=84% vs C+D=83% for ICT; A+C= 84% vs B+D=83% for HDRT). Local control was 88%: A= 80%, B= 96%, C= 90 %, D= 87%: (NS). Event-free survival was 71% : A= 70%, B= 78%, C= 67%, D= 68%: (NS). Overall survival was 78% at 3 y (73% at 5 y) with no difference between arms. Specific survival was 84 % : A= 79%, B= 88,5%, C= 89%, D= 79%: (NS) Conclusions: Neither ICT nor HDRT improved the CFS at 3 years, nor the secondary end points.

No significant financial relationships to disclose.
Generation and validation of a primary-tumor-derived four-gene prognostic signature for recurrence (R) of stages I/II colorectal cancer (CRC) following potentially curative resection
Authors: Lenehan P. F. , Fry D. W. , Heyman E. R. , Eliason J. F. , Worzel W. P.
Published: August 2020

4035

Background: Current guidance for postoperative clinical management of stages I/II CRC patients (pts) is suboptimal. We hypothesized that a molecular prognostic test using primary CRC tissue would better predict the chances of tumor R within 3 years (y) than NCCN Clinical Practice Guidelines. Methods: Archival formalin-fixed paraffin-embedded (FFPE) primary adenocarcinoma tissues obtained at initial resection with curative intent were retrieved for 145 stage I/II (pT1–4 pN0 M0) CRC pts from multiple international sites; none had neoadjuvant or adjuvant therapy. Pts had tumor R by 36 months (mo) or confirmed non-recurrence (NR) for ≥36 mo after surgery. Pts were stratified by R/NR status and then randomized to a Training Set (TSet) (n=73; 34R, 39NR) or Validation Set (VSet) (n=72; 33R, 39NR). Tumor gene expression was quantified by DASL assay (Illumina, San Diego) using a custom 512-gene panel. Genetic programming (GP), a machine-learning technique, defined 15 TSet genes as key for differentiating pts with R versus NR. Results: Successive GP analyses of TSet data evolved a prognostic signature that mathematically combined 4 of the 15 key genes identified. This selected dichotomous rule correctly classified 28/33 R and 35/39 NR VSet pts (85% sensitivity, 90% specificity). ‘High risk’ pts had a significantly higher probability of R by 36 mo than ‘low risk’ pts: 88% PPV, 88% NPV; relative risk (RR) 7.0 (95% CI: 3.1, 16.1; p<0.0001). RR by stage (I/II) = 7.00/7.28 and tumor site (colon/rectum) = 8.75/4.50. Kaplan-Meier recurrence-free survival: hazard ratio 11.8 (95% CI: 4.5, 31.1; p<0.0001). NCCN Guidelines (V.2.2008) correctly classified 24/33 R and 15/39 NR VSet pts: 73% sensitivity, 38% specificity, 50% PPV, 63% NPV; RR 1.33 (95% CI: 0.74, 2.40; p=0.32). Conclusions: A GP derived 4-gene prognostic test using FFPE tumor tissue can differentiate early stage CRC pts at high versus low risk for R within 3y better than current NCCN Guidelines.

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Identification of subtypes in colorectal cancer and their prognostic values
Authors: Kennedy R. D. , Proutski V. , Tanney A. , Winter A. , Black J. M. , Kerr P. , Johnston P. G. , Harkin D. P.
Published: August 2020

4041

Background: The discovery and widespread acceptance of molecular subtypes in breast cancer has changed the way that this disease is viewed. Similarly, we have focussed on stage II colorectal cancer where 20–25% of patients are at risk of recurrent disease following surgery. There are currently several types of colorectal cancer recognised by histopathological methods, however, little has been published regarding disease classification at a molecular level. Methods: We have taken an unbiased approach to the molecular classification of colorectal cancer. Using a colorectal cancer disease specific microarray platform we have performed expression profiling and bioinformatic analysis of 500 formalin fixed and paraffin embedded (FFPE) stage II colorectal cancer samples, in order to identify and characterise molecular subtypes. Results: We have identified molecular subtypes for colorectal cancer. One of these subtypes is enriched with tumours with microsatellite instability (MSI) that are predominantly proximal, mucinous and poorly differentiated. It is notable that while MSI is generally accepted to be associated with a good prognosis, we have found both good and poor prognosis patients within this subtype. A second subtype contains tumors with a low CpG island methylator phenotype. Another subtype is defined by an expression pattern consistent with activation of tumor suppressors. The remaining subtypes are newly identified. Conclusions: We have identified molecular subtypes in colorectal cancer. We will present how knowledge about these subtypes may affect patient management and may be used to guide the development of novel therapeutic strategies.

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CHFR methylation as an epigenetic marker for recurrence of colon cancer
Authors: Tanaka M. , Sethi S. , Li D. , Bland G. , Hamilton S. R. , Abbruzzese J. L. , Eng C.
Published: August 2020

4043

Background: Currently, no definitive epigenetic markers exist to predict recurrence and overall survival (OS) of colorectal cancer patients after surgical resection. Promoter hypermethylation of the ID4 (inhibitor of DNA binding), RECK (reversion-inducing cysteine rich protein with Kazal motifs), and CHFR (checkpoint with forkhead-associated and RING finger domains) genes have been associated with reduced mRNA and protein expression in colorectal cancer. The purpose of this study was to determine the association of methylation of these genes and also MINT1 (methylated in tumor loci) with recurrence-free survival (RFS) and OS in colon cancer patients. Methods: DNA methylation was quantitatively evaluated using pyrosequencing in tissue samples from 64 patients with AJCC stage II and III colon cancer without HNPCC seen at M.D. Anderson during 1999–2007. Survival outcomes were determined by retrospective chart review and evaluated by Kaplan-Meier plot and log-rank test for univariate analysis and Cox's proportional hazard model for multivariate analysis. Mean methylation rate of multiple CpG sites in the promoter region was used. For this analysis, we defined <15%, 15%-30%, and >30% as methylation-negative, -low, and -high, respectively. Results: There were 19 stage II (30%) and 45 stage III (70%) patients. The median age was 62.1 years (range: 31–86). Adjuvant chemotherapy was completed in 49 patients (77%). After a median follow-up of 54.9 months, 12 (19%) patients developed recurrence and 7 (11%) have died. Methylation of MINT1, ID4, and RECK did not correlate with RFS and OS. The CHFR methylation-high (42%) group had low RFS (P=.04) and OS (P=.03) when compared with the CHFR methylation- negative (38%) and -low (20%) group. CHFR methylation-high was associated with N2 disease (P=.04) and right-sided tumors (P=.002). Multivariate analysis indicated T4 disease [P=.004, HR=8.42 (95% CI: 1.98–35.8)] and CHFR methylation-high [P=.04, HR = 3.79 (95% CI: 1.04–13.8)], were poor prognostic factors for recurrence. Conclusions: The presence of high CHFR promoter methylation correlates with advanced lymph node metastasis and shortened RFS and OS. Methylation of the CHFR promoter is a potential epigenetic marker for colon cancer recurrence and overall survival.

No significant financial relationships to disclose.
Adjuvant therapy report card: Patients with stage II/III colon cancer grade their oncologists
Authors: Love N. , Ault Ziel K. , Bylund C. , Elder M. , Ellis L. M. , Grothey A. , Meropol N. J. , Paley D. , Ravdin P. M. , Saltz L. B.
Published: August 2020

4045

Background: Our group previously reported on patient (Pt) recollections of adjuvant therapy (AT) for colon cancer and their grading of medical oncologists (MO) regarding various aspects of care. Overall, MO were highly rated, but grades for presenting information were lower, and patient expectations about side effects often did not match experiences. To further examine the Pt experience with AT, a prospective study was launched in Feb 2008. Methods: Pts with Stage II/III colon cancer about to begin or within 4 months of starting AT were recruited for a 4-part survey regarding sources and quality of treatment information and their experiences with AT. The survey also asked Pts to provide a grade (A-F) for their MO in 8 areas. Results: 85 Pts (71% female, 79% Stage III, median age 52 years) completed Part 1 of the survey. 93% stated that their MO explained the risks and benefits of AT. Of those, 92% stated they understood this information completely or almost completely (3 or 4 on a 0–4 scale) and 79% received numerical estimates of recurrence risk with and without treatment. When questioned about the potential absolute benefit of AT, 26% of Pts who received numerical estimates “had no idea” and other answers ranged from 3% to 100% for recurrence risk. Pt grade point averages for their MO ranged from 3.0 to 3.6 ( Table 1 ). As in the prior survey, expectations about side effects frequently did not accurately reflect experiences. For example, 54% of Pts expected alopecia but only 5% experienced it to a significant degree. 84% of Pts also sought information from websites, and 87% rated this as helpful and valuable (3 or 4 on a 0–4 scale). Conclusions: Pts are generally satisfied with their MO but less so with the presentation of treatment-related information and thus frequently consult additional resources, such as cancer information websites. This suggests an opportunity for improved information delivery within oncology offices and via the Internet.

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Does delay of adjuvant chemotherapy affect the clinical outcome in patients with colon cancer?
Authors: Bayraktar U. D. , Bayraktar S. , Herna S. , Ku N. , Jones C. , Merchan J. , Sands L. R. , Marchetti F. , Montero A. , Rocha-Lima C. M.
Published: August 2020

4046

Background: Adjuvant chemotherapy (AC) in patients with stage III colon adenocarcinoma prevents recurrences and improves survival. Although most trials mandate initiation of AC within 8 weeks of resection, the impact of timing of AC is still not clear with few studies reporting conflicting results. We hypothesized that AC commenced within 60 days of resection would increase survival in patients with stage II and III colon cancer. Methods: Patients with newly diagnosed stage II or III colon adenocarcinoma who received fluoropyrimidine based AC in two centers (a private cancer center and a large community hospital) between 2000 and 2007 were included into analysis. Time to adjuvant chemotherapy (TTC), overall survival (OS), and relapse-free survival (RFS) were calculated from the surgery date. Patients were dichotomized into early- (group 1) and late-treatment (group 2) groups using the TTC of 60 days. The demographic, clinical, and laboratory characteristics of patients in two groups were compared using chi-square and t-test. Kaplan-Meier survival curves were constructed employing univariate log-rank test to assess the effects of demographic and clinical characteristics on OS. Then the impact of TTC on OS and RFS was analyzed using a Cox proportional hazard model incorporating the significant factors found in the univariate analysis. Results: 190 patients were eligible for the study (median age: 57 yrs [range 14–84]). 116 patients (61%) were female and 35 patients (18%) had stage II disease. Median TTC was 49 days (range 24–196) and median follow-up was 143 weeks (range 9–451). 134 patients (70%) received AC within 60 days of surgery (group 1) and 56 (30%) received after (group 2). The only difference between the two groups was the higher N stage in group 1. The treating hospital and the N stage were found to be the factors affecting the OS in univariate analysis. Five-year OS for group I was 75.2% as compared to 61.3% for group II (HR 2.11, CI: 1.00–4.45, p=0.049). Five-year RFS for group I was 65.7% as compared to 59.0% for group II (HR: 1.19, CI: 0.65–2.20, p=0.570). Conclusions: Delay of AC more than 60 days after resection is associated with inferior survival in stage II/III colon cancer.

No significant financial relationships to disclose.
Progression-free survival in intention to treat populations versus total KRAS populations in patients treated for metastatic colorectal cancer: A pooled review
Authors: Costello B. A. , Hecht J. R. , Grothey A.
Published: August 2020

4054

Background: In treatment trials of patients with metastatic colorectal cancer (mCRC), KRAS mutation status of tumor samples has been retrospectively demonstrated to be predictive of treatment benefit. Historically, clinical trials have not required tissue samples to be tested for KRAS mutation status as a condition of enrollment. Therefore, KRAS analyses have been based on available tissue samples representing only a portion of patients retrospectively analyzed for KRAS status and correlated with treatment end- points. Methods: A weighted analysis of pooled data was performed using six recently presented or published clinical trials of targeted therapy in mCRC which tested for the association of KRAS status with Progression Free Survival (PFS). The goal of the analysis was to determine whether there is a significant difference in PFS between the intention to treat (ITT) population and KRAS population in both the treatment and control arms. Results: The total ITT population of the pooled studies is 3864, and for the total KRAS population, 2295; a 59.4% retrieval rate (range 28–92%) for tissue samples available for KRAS analysis. The weighted Δ PFS across all arms between the ITT population and the KRAS population was 0.2 months with a range of 0–0.7 months. Of the 12 subgroups (6 control and 6 treatment arms), five had no difference in PFS between ITT and KRAS evaluable populations at all, and two additional subgroups demonstrated a difference PFS of only 0.1 months. The two studies with the lowest tissue retrieval rates (28% and 45%) had the largest Δ PFS. Conclusions: There is no meaningful difference in the PFS between the ITT and KRAS populations based on our analysis of pooled data. The difference in PFS was greatest in the two studies with the lowest rate of retrieval of tissue samples for KRAS testing. As such, subgroup analysis is better able to estimate and reflect the ITT population if a higher percentage of samples is able to be obtained. Further, our results suggest that there is not an inherent systemic bias influencing any potentially observed differences in PFS. Tissue samples should be required for all patients entering a clinical trial to avoid this issue and to make retrospective analysis more valid.

[Table: see text]
Correlation of KRAS status with clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated first-line with FOLFOX6 + cetuximab (FX+C) or FOLFIRI + cetuximab (FF+C): The CECOG/CORE1.2.001 trial
Authors: Koza I. , Wrba F. , Vrbanec D. , Ocvirk J. , Ciuleanu T. E. , Beslija S. , Papamichael D. , Messinger D. , Zielinski C. C. , Brodowicz T.
Published: August 2020

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Background: Previous retrospective analyses of KRAS mutation status from the randomized CECOG/CORE 1.2.001 phase II trial has shown that treatment with cetuximab plus standard chemotherapy (CT) in pts with KRAS wild-type (wt) tumors leads to significantly better progression-free survival (PFS) and overall survival (OS) compared with KRAS mutant (mt) tumors. Methods: CECOG investigators performed a post-study survival update, re-assessing the impact of KRAS status and other possible predictive factors for OS using multivariable Cox proportional hazard methods. Results: KRAS-evaluable tissue was available from 117 (77%) of 151 pts in the ITT population. KRAS wt status was detected in 53% (n=62) of tumors (34/57 and 28/60 in the FX+C and FF+C arm, respectively). After a median follow up of 29 months (mo), OS in pts with KRAS wt tumors was significantly improved compared to pts with KRAS mt tumors (median 20.8 vs 15.9 mo; hazard ratio (HR)=1.62; p=0.0296). OS analysis by treatment arm revealed a statistically significant difference in favor of pts with KRAS wt tumors in the FX+C arm (median 22.5 vs 15.2; HR=2.06; p=0.0201) and no significant differences in the FF+C arm. Exploratory multivariable Cox proportional hazard analysis showed that as well as KRAS wt status (vs KRAS mt), an acne-like rash of grade 2/3 (vs grade 0/1) in the first 6 weeks and no prior treatment (vs prior neo-/adjuvant treatment) were the strongest independent predictors for prolonged survival (each p<0.005). Conclusions: This analysis confirmed the results of previous studies: treatment with cetuximab plus standard CT in pts with KRAS wt tumors leads to significantly better OS compared to pts with KRAS mt tumors. The early occurrence of a cetuximab-related grade 2/3 acne-like rash seems to be an independent predictor for prolonged survival in addition to KRAS status. The relevance of the lower predictive value of KRAS status noted for OS in the FF+C arm pts vs the significant effect in the FX+C arm is undetermined due to the low sample size of the subgroup analyses.

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Association of BRAF mutations and EGFR Intron-1 L/L genotype with resistance to cetuximab plus irinotecan treatment in KRAS wild-type metastatic colorectal cancer patients
Authors: Ruzzo A. , Cremolini C. , Loupakis F. , Fornaro L. , Santini D. , Vincenzi B. , Canestrari E. , Magnani M. , Falcone A. , Graziano F.
Published: August 2020

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Background: KRAS and BRAF mutations are associated with resistance to anti-EGFR monoclonal antibodies. EGFR Intron-1 (CA)n genotype has been suggested to influence the activity of cetuximab. Methods: We retrospectively assessed KRAS and BRAF mutational status and EGFR Intron-1 (CA)n genotypes in 117 irinotecan-refractory EGFR-positive mCRC patients treated with cetuximab plus irinotecan. We defined short (S) and long (L) allelic variants those presenting < and ≥17 CA repeats respectively. Among KRAS wild-type patients, we investigated the association between BRAF mutational status and EGFR Intron-1 genotype and treatment outcome in terms of RR and PFS. Results: Among 66 (56%) KRAS wild-type patients, BRAF V600E mutation was detected in 9 (14%) patients. BRAF wild-type patients reported improved RR (0/9, 0% vs 19/57, 33%, p = 0.04) and PFS (3.3 vs 5.1 months, p = 0.076; HR = 0.54 [95%CI: 0.18–1.09]) in comparison with BRAF-mutated. EGFR Intron-1 L/L genotype was detected in 13 (20%) KRAS wild-type patients. Objective responses were reported in 1/13 (8%) EGFR Intron-1 L/L patients and in 18/53 (34%) S/L or S/S patients (p = 0.061). Significantly longer PFS was observed among EGFR Intron-1 S/L or S/S patients (5.3 vs 3.3 months, p = 0.0062; HR = 0.45 [95%CI: 0.14–0.72]). Among 57 KRAS and BRAF wild-type patients, 1/11 (9%) EGFR Intron-1 L/L patients and 18/46 (39%) S/L - S/S patients responded to treatment (p = 0.058), achieving median PFS of 3.7 and 5.4 months, respectively (p = 0.022; HR = 0.48 [95%CI: 0.15–0.87]). Conclusions: In KRAS wild-type patients, BRAF mutations are confirmed to predict resistance to cetuximab treatment. EGFR Intron-1 allelic variants are promising markers of benefit in patients with both KRAS and BRAF wild-type and may help to better select mCRC patients candidate to receive cetuximab-containing treatment.

No significant financial relationships to disclose.
Duration of disease control (DDC) or time to failure of strategy (TFS) to evaluate a chemotherapy strategy in advanced colorectal cancer (ACC)
Authors: Chibaudel B. , Tournigand C. , Perez-Staub N. , Bourges O. , Maindrault-Goebel F. , André T. , Lledo G. , Louvet C. , Bonnetain F. , de Gramont A.
Published: August 2020

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Background: Progression-free survival (PFS) is not an optimal endpoint in therapeutic strategies evaluating either stop and go or alternated therapies, or a fixed sequence of two therapies. DDC (Tournigand, JCO 2006) and TFS (Allegra, JCO 2007) composite endpoints have been proposed to evaluate efficacy of these strategies in ACC. This study compared these two alternative endpoints. Methods: DDC is defined as the sum of the PFS of each sequence, except when progressive disease is observed at either reintroduction or second-therapy (DDC=PFS1+PFS2 if treatment 2 achieved stabilization or response). TFS is defined as the total PFS from the initiation of the strategy to disease progression while on all the planned agents, or disease progression during a treatment-free interval and no further therapy received within 1 month, or death (TFS=PFS 1+2). Both DDC and TFS have been calculated in three trials: OPTIMOX1 (oxaliplatin stop and go vs continuous administration, updated database, Tournigand, JCO 2006), OPTIMOX2 (oxaliplatin stop and go vs complete stop and go, updated database, Maindrault-Goebel, ASCO 2007) and C97–3 (FOLFIRI1- FOLFOX6 or reverse sequence, Tournigand 2004). Results: The median potential follow-up time was 39.8 months. There was a moderately shorter DDC than TFS in the two stop and go studies, but a much shorter DDC than TFS in the sequential therapy study. There was a significant correlation between DDC and OS (r=0.96, p=.002) but not between TFS and OS (r=0.71, p=.11) Conclusions: Two bias impacted TFS 1) the results of resuming the planned therapeutic strategy for progression after a chemotherapy-free interval of more than one month was not considered, 2) patients who were not progressive at the end of planned strategy could not be censored at that time. The shorter duration of DDC over TFS may have an advantage in terms of sample size for evaluation of therapeutic strategies. In case of drug registration, DDC does not increase in case of inactive second sequence.

[Table: see text]

No significant financial relationships to disclose.
Efficacy of intraoperative radiofrequency ablation (IRFA) combined or not with resection to treat unresectable colorectal metastases, with or without preoperative chemotherapy: The ARF2003 Study (NTC 00210106): Preliminary results
Authors: Becouarn Y. , Mathoulin-Pélissier S. , Rivoire M. , Ayav A. , Arnaud J. , Sa Cunha A. , Brunet R. , Fonck M. , Bellera C. , Evrard S.
Published: August 2020

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Background: Only few patients suffering from colorectal metastases (CRM) can have surgery and thus hope for a 40% 5-year survival rate. Adding IRFA to resection may improve the efficacy of surgery. Methods: The primary objective was to evaluate the efficacy of IRFA combined or not with resection in terms of 3-month complete hepatic response (CHR) in patients with unresectable CRM. Secondary endpoints were overall survival (OS), disease-free survival (DFS), morbidity and quality of life. A phase II study based on a Simon's two-stage design was conducted in 6 university French hospitals. Number of subjects estimated was 53, with 19 for the 1st stage. At the end of the 1st stage, 12 CHR were required to continue recruiting. At the end of 2nd stage, 37 CHR would be required to claim efficacy. Results: Fifteen of the first 19 patients exhibited CHR allowing the study to pursue accrual which ended in Nov 08; some patients are still followed up. As of Nov 08, data had been collected on 47 patients (mean age 61 years): 6 had RFA alone (13%), 37 had RFA and resections (82%), 2 could not be treated (4%). Median number of CRM was 5 (1–12). All had chemotherapy pre-op and 12 post-op (29%). Three-month data were available for 36 patients: 1 patient died on the 3rd week following intervention. Scans were available for 35 patients (independently reviewed). Of these, 29 had CHR (83%); 13 had 3-month morbidity (37%). The median follow-up was 15 months. One-year OS and DFS rates were 92.3% and 26% respectively. Analysis on all 53 patients will be communicated in June 09. Conclusions: These preliminary results suggest that IRFA combined or not to resection may be efficient in treating unresectable diseases despite their more aggressive pattern. This corroborates the EORTCC CLOCC Trial findings which demonstrated IRFA superiority upon chemotherapy alone. IRFA could thus be valuably associated to resection in treating patients with colorectal metastases that resection alone could not handle.

No significant financial relationships to disclose.
Addition of bevacizumab to induction plus concomitant capecitabine-oxaliplatin (XELOX) chemoradiotherapy (CRT) in MRI poor prognosis locally advanced rectal cancer: Avacross study
Authors: Nogue M. , Salud A. , Vicente P. , Pericay C. , Arriví A. , Roca J. M. , Losa F. , Ponce J. , Safont M. J. , Guasch I.
Published: August 2020

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Background: Concomitant CRT with 5-FU followed 6–8 weeks later by TME surgery is well accepted standard treatment for locally advancer rectal cancer. This approach focuses only into local control. Trimodal induction approaches with chemo, radiation and anti VEGFR therapy may induce additional tumor growth delay. Methods: Eligible patients (pts) had high-risk rectal adenocarcinoma defined by MRI: distal T3 at/below levators, T3 at any other level within 2 mm of mesorectal fascia, resectable T4 and any T3 with nodal metastases. We excluded pts with any antecedent of heart disease. Treatment consisted in four 21 day cycles of oxaliplatin 130 mg/m2 d 1, bevacizumab 7.5 mg/kg d 1 and capecitabine 1000 mg/m2/12 h d 1–14. After 3–4 weeks they received concomitant RT (50.4 Gy in 28 fractions) with capecitabine 825 mg/m2/12 h plus bevacizumab 5 mg/kg, three biweekly doses. TME was planned 6–8 weeks after CRT. Primary end point was pathologic complete response rate with standarized pathology examination. Results: From July 2007 to July 2008, 47 pts were enrolled. Median age was 58 (30–78). Median KPS was 90%. Clinical stage was T3N1: 51.1%, T3N2: 25.5%, T4N0–2: 10.6%, T3N0: 8.5% of pts. 40 pts completed the induction phase: G 3–4 toxicity were diarrhea 12.7%, neutropenia 8.5%, peripheral neuropathy 6.3% and thrombocytopenia 4.2%.. 39 pts completed the CRT phase. Grade 3–4 toxicity were rectitis, linfopenia and hipertrigliceridemia in 2.5% of pts. Until now we have data on 35 resections, 2 with only one induction cycle. R0 resections were achieved in 34 pts (R1 resection in a patient with only one induction cycle). There were 7 wound complications and 10 pts required surgical reintervention. pCR were obtained in 13 pts (37,1 %, 95% CI:21.1–53.2) with 18 (51.4%) additional pts with only residual microscopic foci. There were two treatment related-deaths: one sudden death and one grade 4 diarrhea and diabetic ketoacidosis. Conclusions: Preliminary results show that our preoperative schedule appears feasible, with impressive activity level (pCR + Tmic of 88.5%), achieving downstaging in nearly all pts. Toxicity was manageable, nevertheless we stress caution with cardiac and GI events and surgical complications.

No significant financial relationships to disclose.
Screening candidate targets by SAGE evaluation of rectal cancer transcriptome after chemoradiotherapy: Association of trefoil factor-family 3 (TFF3) expression with patients prognosis
Authors: Casado E. , Cejas P. , Sanchez J. , Blanco M. , Maurel J. , Castelo B. , Feliu J. , Miquel R. , De Castro J. , Sereno M. , Gonzalez Baron M.
Published: August 2020

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Background: Treatment resistance and the lack of reliable prognostic factors are major obstacles in rectal cancer (RC) management. A blind screening of RC transcriptome changes after chemoradiotherapy (CRT) could pinpoint proteins potentially involved in CRT resistance. Evaluation of their relation with disease outcome could help to identify novel therapeutic and prognostic candidates. Methods and Results: In a first stage we screened dynamic changes of RC transcriptome after CRT using blind and directed strategies. On one side, we selected fresh RC samples, before and after CRT, from three uT3N0 patients with poor response, as assessed by Dworak´s TRG2 and minimal downstaging (ypT2–3N0). Serial Analysis of Gene Expression (microSAGE) was conducted, six libraries were generated, sequencing around 30.000 tags. MonteCarlo analysis of dynamic “intra-patient” changes, and “inter-patient” comparisons revealed a set of 25 genes with shared significant changes. On another side, a collection of 29 genes was selected from the literature, In a second stage we evaluated dynamic changes in the mixed set of 54 genes in a cohort of 125 stage II-III RC patients treated with preopCRT. Samples from 74 patients assured sufficient tumor quality and quantity before and after CRT. mRNA dynamic changes of gene expression were evaluated by TaqMan Low Density Arrays (TLDAs), and statistical analysis done by Wilcoxon test with bootstrap and regulated genes selected for discriminant and Cox proportional-hazards regression analysis. Induction of mRNA TFF3, screened in the blind phase SAGE and exhibiting important tumor promotion and progression functions, was associated with tumor relapse and shorter survival. Also, analysis of TFF3 immunohistochemical expression in surgical samples revealed that an on/off pattern of intraluminal gland expression (PAS independent) strongly predicted tumor relapse. Conclusions: Upregulation of TFF3 after CRT, and an easily determined IHC pattern, predicted RC relapse in preoperatively treated patients. Confirmatory prognostic studies in independent series should be conducted, and its potential therapeutic merits as a candidate target evaluated.

No significant financial relationships to disclose.