bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial
Authors: Van Cutsem E. , Nowacki M. , Lang I. , Cascinu S. , Shchepotin I. , Maurel J. , Rougier P. , Cunningham D. , Nippgen J. , Köhne C. 
Published: March 2020

4000 Background: Cetuximab in combination with irinotecan-based regimens has proven activity in previously-treated patients (pts) with mCRC. The present trial investigated the effectiveness of cetuximab in combination with standard FOLFIRI compared with FOLFIRI alone in the first-line treatment of pts with epidermal growth factor receptor (EGFR)-expressing mCRC. Methods: Pts were randomized 1:1 to receive either cetuximab (400 mg/m2 initial dose then 250 mg/m2/week [w]) plus FOLFIRI q 2 w (irinotecan 180 mg/m2, FA 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours) (Group A) or FOLFIRI alone (Group B). The primary endpoint was progression-free survival (PFS), with secondary endpoints of overall survival (OS), response rate (RR), disease control rate and safety. 633 events were required to statistically differentiate PFS between groups with 80% power. Results: Between August 2004 and October 2005, 1,217 pts were randomized, 608 to Group A and 609 to Group B (60% male, median age 61 [19–84], ECOG performance status: 0=54%; 1=43.5%; 2=3.5%). Median PFS was significantly longer for Group A compared to Group B (8,9 months [8 - 9,5] for Group A vs. 8 months [7.6 - 9] for Group B, p=0.036). Response Rate was also significantly increased by cetuximab (46.9% vs. 38.7%, p=0.005). Treatment was generally well tolerated with neutropenia (26.7% Group A, 23.3% Group B), diarrhea (15.2% and 10.5% respectively) and skin reactions (18.7% and 0.2% respectively) being the most common grade 3/4 adverse events. Conclusions: Cetuximab in combination with FOLFIRI significantly increases response rate and significantly prolongs PFS in the first-line treatment of pts with mCRC, reducing the relative risk of progression by approximately 15%. Treatment-related side effects of cetuximab in combination with FOLFIRI were as expected, with diarrhea being moderately and skin reactions significantly more frequent as compared to FOLFIRI alone. [Table: see text]
Circulating tumor cells (CTC) predict progression free (PFS) and overall survival (OS) in patients with metastatic colorectal cancer
Authors: Meropol N. J. , Cohen S. J. , Iannotti N. , Saidman B. H. , Sabbath K. D. , Miller M. C. , Doyle G. V. , Tissing H. , Terstappen L.W.M.M. , Punt C.J.A. 
Published: March 2020

4010 Background: Treatment options for patients with metastatic colorectal cancer (mCRC) have recently expanded. However, the introduction of new regimens has highlighted the need for biomarkers to guide and monitor therapy. This study investigates the hypothesis that CTC levels can predict clinical outcomes in patients with mCRC. Methods: In a prospective multi-center study, 7.5 mL of blood from 456 patients with mCRC were tested for CTC using immunomagnetic separation before starting 1st, 2nd or 3rd line therapy and at subsequent radiographic follow-up timepoints. Response on imaging was determined by participating centers. Results: Patients were stratified into unfavorable and favorable prognostic groups based on levels of =3 or <3 CTC per 7.5mL, respectively. Median PFS, OS and significance between the two groups (log rank test) at different timepoints after the initiation of therapy is indicated in the table . The OS of patients converting to or maintaining unfavorable CTC at follow up timepoints was worse than for patients maintaining favorable CTC (12.6, 7.0 vs. 21.1 months, respectively, p<0.0001). In multivariate analyses, which included age, ECOG performance status, and the line and type of therapy, CTC remained the most significant independent predictor of outcome. Conclusions: CTC levels before treatment and at subsequent timepoints are an independent predictor of PFS and OS in patients with mCRC. CTC levels of =3 per 7.5mL of blood after initiation of therapy are highly predictive of shorter PFS and OS. A large randomized phase III study to confirm these findings in mCRC patients receiving first line therapy recently completed accrual (DCCG CAIRO- 2). [Table: see text] No significant financial relationships to disclose.
Analysis of potential predictive factors of clinical benefit in patients (pts) with metastatic colorectal cancer (MCRC) treated with single-agent cetuximab as first-line treatment
Authors: Gravalos C. , Sastre J. , Aranda E. , Massutí B. , Vega-Villegas M. E. , Gómez A. , Varella-Garcia M. , Jimeno A. , Díaz- Rubio E. , Hidalgo M. 
Published: March 2020

4120 Background: Our group has recently shown that single-agent cetuximab in first-line treatment of elderly MCRC pts has a favorable safety profile and similar activity to that observed in pretreated pts: 15% RR and 54% disease control (DC) (ESMO 2006: A324O). In this study, we aimed to identify predictive factors of clinical benefit from cetuximab without chemotherapy. Methods: This was a optional prospective ancillary study conducted in 36 of 41 pts included in the TTD 04–01 trial to explore potential predictive factors of response or resistance to single-agent cetuximab (400 mg/m2 as initial dose and 250 mg/m2 weekly thereafter). To this end we conducted a comprehensive analysis of potential predictive assays including polymorphisms of intron 1 of the EGFR gene, EGFR gene copy number by FISH (Varella-García Diagn Pathol 2006), IHC expression of signaling pathway proteins (EGFR, MAPK, AKT, PTEN), K-RAS, B-RAF, PI3KCA and PTEN mutations, as well as basal serum levels and dynamic changes of circulating EGFR after 4 weeks of treatment. Results: 9 of 41 pts (22%; 95%CI: 11–38) achieved DC at 12 weeks (2 CR, 4 PR, and 3 SD) with a median time to progression (TTP) of 8,3 months (range 4–11.3), similar to that observed with FOLFOX or FOLFIRI in first line treatment. Increased EGFR copy number (FISH+: scores 5–6) was observed in a total of 11 pts (11/36: 30,5%). Five of these 11 FISH+ pts had DC at 12w (45%) vs. 3 of 25 FISH- pts (12%) (p=0.04). No correlation was found between DC at 12w and polymorphisms of intron 1 of the EGFR gene, basal serum levels and dynamic changes of EGFR, IHC expression of pEGFR and pMAPK, or PI3KCA mutations. Analyses of PTEN and AKT by IHC, as well as K-RAS and PTEN mutations are ongoing. Conclusions: Although cetuximab provides higher efficacy in combination with chemotherapy, 22% of MCRC pts treated with monotherapy in first-line treatment present a remarkable median TTP of 8,3 months. This subgroup of pts can be selected in advance based on FISH+ combined or not with other possible predictive factors still under analysis. The full detailed analysis of data will be presented at the meeting. [Table: see text]
Pharmacogenomic analysis of a randomized phase II trial (BOND 2) of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer
Authors: Zhang W. , Yang D. , Capanu M. , Hollywood E. , Lue-Yat M. , Borucka E. , Azuma M. , Gordon M. , Saltz L. , Lenz H. 
Published: March 2020

4128 Background: Phase II CBI VS CB trial has shown that bevacizumab added the efficacy of cetuximab and cetuximab/irinotecan in irinotecan-refractory bevacizumab-naïve CRC patients. We tested the germline polymorphisms involved in angiogenesis pathway(VEGF, IL-8, TGF-β), EGFR pathway (EGFR, COX-2, CyclinD1,E-cadherin,FCGR2A,3A), DNA repair pathway(ERCC1, XRCC1, XPD) and drug metabolism pathway (GSTP1, UGT1A1) to evaluate their association with clinical outcome. Here we expand our gene polymorphisms data involving EGFR pathway (EGF, FCGR2B, Survivin, ADAMS10/17), Angiogenesis pathway (Neuropilin-1, HIF-1, Tissue factor) and irinotecan metabolism pathway(ABCB1,OATPC). Methods: Genomic DNA was extracted from blood samples. 65 out of 81 patients enrolled in the BOND 2 trial were available for molecular correlates study. these 65 patients include 44 men, 21 women, median age 58 years (range 24–86). Patients received either with CBI (n=31) (Arm A) or with CB (n=34) (Arm B). In Arm A, 12 pts (43%) had PR, the median TTP was 7.1 months, and the median survival was 18.0 months. In Arm B, 9 pts (27%) had PR, the median TTP was 4.6 months, and the median survival was 10.3 months. PCR-RFLP based technique was used to determine polymorphisms. Univariate analysis (Fisher’s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: For Arm B, we found significant associations between HIF-1 polymorphism and tumor response (P=0.017), between HIF-1, FCGR2B polymorphisms and TTP, and between OATPC polymorphism and OS (P values < 0.05). For Arm A, we found a trend in association between EGF polymorphism and tumor response (P=0.08). Conclusions: These data suggest that germline polymorphisms may be potential molecular markers for clinical outcome for patients with mCRC treated with CBI or CB. Prospective studies are needed to confirm these preliminary findings. [Table: see text]
Predictive value of skin toxicity severity for response to panitumumab in patients with metastatic colorectal cancer (mCRC): A pooled analysis of five clinical trials
Authors: Berlin J. , Van Cutsem E. , Peeters M. , Hecht J. R. , Ruiz R. , Wolf M. , Amado R. G. , Meropol N. J. 
Published: March 2020

4134 Background: Panitumumab, a fully human monoclonal antibody against the epidermal growth factor receptor (EGFr), is approved for EGFr-expressing mCRC patients (pts) with disease progression (PD) on or following fluoropyrimidine (5FU)-, oxaliplatin (Ox)-, and irinotecan (Ir)-containing chemotherapy. Skin toxicities are common with panitumumab; we examined the association between severity of skin toxicity and panitumumab efficacy. Methods: Data from 5 clinical trials were pooled (4 phase II studies and 1 phase III study). Pts with mCRC had documented PD on or after 5FU, Ox, and/or Ir. Pts received panitumumab 6 mg/kg every two weeks (Q2W) or 2.5 mg/kg weekly (QW) until PD or intolerability. Tumors were assessed using modified WHO or RECIST criteria (blinded central review in 4/5 studies). Endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). PFS and OS were measured from enrollment. Only pts with =2 infusions (exposure over 2 wks for QW dosing or over 4 weeks for Q2W dosing) were analyzed to help correct for lead-time bias. Results: 612 of 640 pts were included in the analysis set (62% were male, 92% were white, and median age [range] was 61 [21, 88] years). The median (95% CI) duration of PFS was 8.4 weeks (8.0 to 11.3), the median (95% CI) survival was 6.9 months (6.2 to 7.9), and the ORR (95% CI) was 9.0% (6.8 to 11.5). The most common skin toxicities (any grade, grade 3/4) were erythema (54%, 4%) pruritus (53%, 2%), dermatitis acneiform (52%, 5%), and rash (39%, 2%). ORR, PFS, and OS appeared to favor pts with grade 2–4 skin toxicity vs pts with grade 0- 1 skin toxicity ( table ). Conclusion: In this large combined analysis, severity of skin rash was correlated with increased efficacy of panitumumab in terms of ORR, PFS, and OS. [Table: see text] No significant financial relationships to disclose.
A phase II study of sunitinib in patients with advanced hepatocellular carcinoma
Authors: Zhu A. X. , Sahani D. V. , di Tomaso E. , Duda D. , Sindhwani V. , Yoon S. S. , Blaszkowsky L. S. , Clark J. W. , Ryan D. P. , Jain R. K. 
Published: March 2020

4637 Background: Patients (pts) with advanced hepatocellular carcinoma (HCC) have a poor prognosis. HCC is a highly vascular tumor with increased levels of angiogenic factors including VEGF and VEGFR. Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with activity against VEGFR, PDGFR, and c-KIT. We performed a phase II study to evaluate the efficacy and toxicity of sunitinib in advanced HCC. Methods: Eligibility criteria included unresectable or metastatic measurable HCC, 0–1 prior chemotherapy regimens, performance status = 1, CLIP score = 3, and adequate organ functions. Pts were treated with sunitinib at 37.5 mg po qd on a standard 4 weeks on, 2 weeks off regimen (6 weeks/cycle). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed to assess changes in tumor permeability. Plasma angiogenic markers were assayed by multiplex array. The primary endpoint of the study is progression-free survival (PFS). Results: 19 pts have been enrolled since May 2, 2006: median age = 59 (30–77), M/F = 16/3, ECOG 0/1 = 7/12, CLIP 1/2/3=7/7/5. The treatment was generally well tolerated. Grade 3/4 toxicities included neutropenia (n=4, 21%), lymphopenia (n=3, 16%), SGOT/SGPT (n=3, 16%), fatigue (n=2, 11%), rash (n=2, 11%), and thrombocytopenia (n=2, 11%). One pt had a partial response and 8 pts had stable disease of at least 12 weeks; 8 pts currently remain on study. The median number of treatment cycles received per patient was 2 (range 1–6). The mean tumor permeability (Ktrans) following 2 weeks of sunitinib administration in 13 pts decreased from mean baseline value of 3.77 to 1.06 (an average of 52% decrease). Of the 15 pts analyzed, changes in plasma angiogenic markers from baseline to day 15 following sunitinib treatment were observed as follows: sVEGFR1 remained constant in 15 pts; 8/15 had decreased sVEGFR2 levels; 13/15 and 11/15 pts had increased PlGF and VEGF levels respectively; bFGF levels decreased in 9 and increased in 5 patients. Conclusions: Sunitinib administered in the current dose schedule can be safely given with close monitoring in HCC patients. Preliminary evidence of antitumor activity was observed. Changes in angiogenic parameters on DCE-MRI and in blood markers were seen following sunitinib administration. [Table: see text]
Could treatment with tamoxifen be superior to aromatase inhibitors in early-stage breast cancer after pharmacogenomic testing? A modeling analysis
Authors: Punglia R. S. , Winer E. P. , Weeks J. C. , Burstein H. J. 
Published: March 2020

502 Background: Adjuvant endocrine treatment with upfront aromatase inhibitors yields improved disease-free survival compared to tamoxifen in unselected women with estrogen receptor-positive breast cancer. However, levels of endoxifen, the active tamoxifen metabolite, are known to vary with the number of mutant alleles of the cytochrome P450 CYP2D6 enzyme. We created a Markov model to examine whether the optimal treatment strategy for patients with wild type genetics (wt/wt) might differ from that for patients with homozygous (*4/*4) or heterozygous (wt/*4) mutations. Methods: Annual recurrence risks with aromatase inhibitors and tamoxifen in unselected women were taken from the BIG 1–98 trial. Based on data from Goetz et al., we assumed that the percent of patients who are homozygous and heterozygous for mutations are 6.8% and 21.1%, respectively, and that the hazard ratio (HR) for increased cancer recurrence on tamoxifen among *4/*4 carriers is 1.86 relative to patients with wt/wt or wt/*4 genotypes. Because the efficacy of tamoxifen among wt/*4 patients is not known, we tested the full possible range, from efficacy same as wt/wt patients (Ehet=0) to that of *4/*4 mutation carriers (Ehet=1). Results: In the unselected group, 5-year disease-free survival (5-DFS) with aromatase inhibitors and tamoxifen was 0.840 and 0.813, respectively. Under baseline assumptions, tamoxifen is more effective than aromatase inhibitors among wt/wt patients as long as the effect in heterozygotes is at least 54% (Ehet=0.54) of that in *4/*4 patients. With increasing HR for *4/*4 patients, tamoxifen estimates exceed those of aromatase inhibitors in the wt/wt cohort even at lower assumed Ehet ratios (see table ). Conclusion: In patients without CYP2D6 mutations, modeling suggests that initial treatment with tamoxifen could be superior to treatment with aromatase inhibitors, supporting the use of genetic testing to determine the optimal treatment strategy. [Table: see text] No significant financial relationships to disclose.
WBC changes as a pharmacodynamic marker of outcome in metastatic renal cell carcinoma (mRCC) patients (Pts) receiving sunitinib
Authors: George S. , Richmond A. , Elson P. , Jin T. , Wood L. , Garcia J. A. , Rini B. I. , Finke J. , Bukowski R. M. 
Published: March 2020

5043 Background: Sunitinib is a VEGF, PDGF, c-Kit and FLT-3 inhibitor with significant anti-tumor activity in mRCC. Myelosuppression is a common side effect observed in mRCC pts treated with sunitinib. Thus, the association of myelosuppression with clinical outcome was investigated. Methods: All mRCC pts receiving sunitinib at The Cleveland Clinic Taussig Cancer Center with available data were investigated. White blood cell (WBC) and differential counts at baseline and day 28 of cycle 1 were collected. Peripheral blood mononuclear cell (PBMC) T helper 1 (Th1), T helper 2 (Th2) and T regulatory cell (Treg) numbers at baseline and day 28 of C1 were determined using flow cytometry. Hematologic parameters were analyzed as continuous variables and also dichotomized using a recursive partitioning algorithm. Fisher’s exact test was used to analyze categorical data, the log rank test was used to assess time to progression (TTP) and Spearman’s rank correlation was used to summarize associations between hematologic and immune parameters. Results: Sixty-seven pts were studied (75% male, median age 59 yrs). Objective responses (OR) included 2 complete and 35 partial responses (overall response rate 55%), with a median (m) TTP of 12.4 months. There was a significant reduction (end of C1 vs. baseline) in the absolute neutrophil count (ANC) (m decrease of 46.4%; p <0.001) and absolute monocyte count (m decrease of 41.3%; p<0.001), but not absolute lymphocyte count (m 6.6% decrease; p=0.5). A decrease in the ANC of =2.5K/uL compared to <2.5 K/uL was associated with improved OR (64% vs. 36%; p= .07) and TTP (m 20.6 months vs. 8 months; p=.003). Patients demonstrating a maximum lymphocyte count =1.2 K/uL at anytime during treatment compared to patients with a maximum lymphocyte count <1.2 K/uL also had a greater OR (64% vs. 25%, p=.02) and TTP (m 17.6 months vs. 4.2 months, p=.03). Changes in Treg number and Th1 and Th2 response bias of PBMC did not correlate with ANC/ lymphocyte changes or clinical outcome. Conclusions: Treatment with sunitinib produces significant neutropenia with minimal effects on total lymphocyte numbers. Changes in ANC and maximum lymphocyte count could represent a pharmacodynamic marker of clinical outcome for mRCC patients treated with sunitinib. No significant financial relationships to disclose.
Randomized trial of active cellular immunotherapy with sipuleucel-T in androgen dependent prostate cancer (ADPC)
Authors: Beer T. M. , Bernstein G. T. , Corman J. M. , Glode M. L. , Hall S. , Poll W. L. , Schellhammer P. F. , Xu Y. , Yu L. , Frohlich M. W. 
Published: March 2020

5059 Background: Sipuleucel-T is an investigational, active cellular immunotherapy product for prostate cancer. To explore the potential benefit in ADPC, sipuleucel-T was studied in a randomized, double blind, multicenter, placebo controlled study, P-11. Methods: ADPC patients with a rise in serum prostate specific antigen (PSA) as the only sign of disease recurrence after prostatectomy were randomized (2:1) to sipuleucel-T or placebo, administered in weeks 0, 2, and 4, following 3-months of hormonal therapy. PSA kinetics were evaluated by time to biochemical failure (BF), defined as any PSA = 3 ng/mL (primary endpoint), as well as PSA doubling time (PSADT). Clinical endpoints included time to distant metastases (DF) and survival. The effect of a single booster infusion of sipuleucel-T on the immune system was also evaluated. Results: 176 patients were randomized (117 sipuleucel-T:59 placebo) and analyzed by intent to treat. Median time to BF was 18.0 months for sipuleucel-T and 15.4 months for placebo (hazard ratio (HR)=0.94 [95% confidence interval (CI): 0.64, 1.38]; p>0.05, log rank). The hazard ratio for BF was 0.80 in favor of sipuleucal-T ([95%CI: 0.53, 1.20], p>0.05) when the analysis was restricted to patients with a confirmed BF. An analysis of PSADT calculated from 90 days following randomization to BF or the initiation of systemic therapy demonstrated that patients randomized to sipuleucel-T had a 35% increase in PSADT (125 vs 91 days; p=0.046, F-test). PSADT calculated after testosterone recovery to baseline levels demonstrated a 48% increase in PSADT for the sipuleucel-T arm (155 vs 105 days; p=0.038). Only 16% of patients developed distant metastases. The hazard ratio for time to DF was 0.78 (95%CI: 0.34, 1.58, p>0.05, log rank). Patients are still being followed for DF and survival. The most common treatment-associated adverse events were chills, fatigue, headache, and pyrexia, which were primarily Grade 1–2. Conclusions: Time to BF was not different between the two study arms. The effect on PSADT, an important prognostic indicator in ADPC, may suggest the biologic activity of sipuleucel-T in this population. Additional follow-up for clinical endpoints of DF and survival is of interest. No significant financial relationships to disclose.
Phase III results of adjuvant radiotherapy (RT) versus wait-and-see (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP)(ARO 96–02/AUO AP 09/95)
Authors: Wiegel T. , Bottke D. , Willich N. , Piechota H. , Siegmann A. , Stoeckle M. , Ruebe C. , Hinke A. , Hinkelbein W. , Miller K. 
Published: March 2020

5060 Background: Adjuvant RT for pT3 R1 or R0 patients (pts.) after RP remains controversial. Results of an EORTC-phase-III- study (with unknown PSA-status after RP) suggested a 20% better biochemical control (bNED) after 5 years for RT. Methods: 385 men with prostate cancer were randomized to either 60 Gy RT (arm A; n=193) or WS (arm B; n=192) before achieving an undetectable PSA. Pts. were stratified for Gleason-score, margin status, neoadjuvant hormonal treatment and stage (pT3A+B vs. C). When the undetectable PSA-level after RP was not achieved, the pts. were stated as progressive disease and left arm A/B and were irradiated. PSA-progression for pts. with undetectable PSA was stated after two consecutive increasing PSA out of the undetectable range. Primary endpoint was bNED. Study was powered to demonstrate a 15% increase in bNED for RT. Results: 78 pts. (20%) did not achieve an undetectable PSA and were stated as progressive disease (arm A: 45 pts., arm B: 33 pts.). Additionally, 34 pts. (23%) from the RT-arm did not receive RT. Therefore, 114 pts. had RT (arm A) and 159 pts. WS (arm B). Median follow up was 53.6 months for arm A and 53.7 months for arm B. BNED at 5 years increased to 72% for arm A (RT) compared with 54% for arm B (WS) (p=0.0015, hazard ratio 0.53). Pts. with a preop. PSA > 10 ng/ml, tumor stage =pT3b, Gleason score =8 as well as positive margins profited significantly from adjuvant RT. The rate of late grade II side effects for the rectum was 1%. Conclusions: Adjuvant radiotherapy for pT3 prostate cancer significantly reduces the risk of biochemical progression after radical prostatectomy. The rate of side effects is very low. No significant financial relationships to disclose.