bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I trial of the mTOR inhibitor temsirolimus (TEM) in combination with capecitabine (CAP) in patients with advanced malignancies.
Authors: Pishvaian Michael J. , Wang Hongkun , Hardesty Rosemarie A. , Deeken John F. , He Aiwu Ruth , Subramaniam Deepa Suresh , Zhuang Tingting , McCarthy Damian L. , Melville Heather , Albanese Christopher , Marshall John , Hwang Jimmy J. 
Published: March 2020

3095 Background: The mammalian target of rapamycin (mTOR) signaling pathway is critical for cell growth and proliferation. mTOR antagonists, such as TEM, have proven anti-cancer efficacy. Pre-clinical models and early phase clinical trials have demonstrated increased efficacy when an mTOR antagonist is combined with cytotoxic chemotherapy. Methods: Patients (pts) with advanced malignancies and adequate hepatic and renal function were eligible for enrollment. An alternating dose escalation of TEM and CAP was employed in separate q2week and q3week arms. Planned dose levels were: TEM 15 and 25mg IV weekly; and CAP 500, 750, 1000, and 1250 mg/m2 orally twice daily (BID). Restaging occurred every 4 cycles for the q2week arm, and every 3 cycles for the q3week arm. PK samples assessed serum levels of sirolimus at Day 0, 8, and 15 of the q2week arm. Archived tumor specimens were assayed by immunohistochemistry (IHC) for expression of phospho-AKT, phospo-4EBP1, phoshpo-p70S6, and PTEN. Results: Thirty-two pts were enrolled, 30 of whom were evaluable for toxicity, of which 18 were male, age range 30-72 years, 25 with colorectal cancer. Pts had received an average of 4 prior lines of therapy. The most common adverse events (AEs) were mucositis and fatigue. The most common grade 3/4 AEs were fatigue (n=4), diarrhea (n=2), and hypophosphatemia (n=2). In 16/30 pts, the dose of CAP was reduced. There were two DLTs, both hypophosphatemia in the q3week arm (TEM=25mg and CAP=1000mg/m2). For the q2week arm, the recommended phase II dose (RP2D) was TEM 25 mg + CAP 1000mg/m2. For the q3week arm, the RP2D was TEM 25mg + CAP 750mg/m2. Twenty-five pts were evaluable for response (18 for OS). There were no PRs or CRs, but 14/25 pts (56%) had SD, with 4/24 (16%) having prolonged SD of >6 months. Median TTP and OS were 3 and 7 months, respectively. Five pts are still on study. PK assessment of serum sirolimus levels, and the results of the IHC on archived tumor samples will be presented. Conclusions: The combination of TEM and CAP is safe on both a q2week and a q3week schedule. The combination demonstrated promising evidence of disease control in this highly refractory population and should be tested in disease-specific phase II trials.
A phase I study of S-222611 an oral reversible dual inhibitor of EGFR and HER2, in patients with solid tumors.
Authors: Baird Richard D , Papa Sophie , Cresti Nicola , Hatcher Helen , Hogarth Linda , Jamal-Hanjani Mariam , Frenkel Eugene P. , Donaldson Kirsteen , Posner John , Kawabata Izumi , Jodrell Duncan Ian , Plummer Ruth , Spicer James F. 
Published: March 2020

3100 Background: S-222611 is a novel oral, potent, reversible tyrosine kinase inhibitor with antiproliferative activity in human tumor cell lines expressing EGFR and/or HER2 in vitro and in mouse xenograft models. We conducted the first study in patients (pts) with solid tumors expressing EGFR or HER2. Methods: Daily oral doses of S-222611 were escalated in successive cohorts from 100 mg to a maximum 1600 mg, using a 3 + 3 design. Full plasma pharmacokinetic (PK) profiles were obtained in all pts for 7 days after a single dose on Day 1 and for 24 h following 21 days of once daily dosing (Cycle 1). Trough PK samples were drawn weekly during the first 3 weeks of daily dosing. A CT scan was performed at baseline and every 8 weeks post-dose to assess response (RECIST). Results: Of 23 treated pts (16 male) aged 24-77y, 19 completed Cycle 1. One dose-limiting toxicity (DLT) has been seen to date, a rash at 1200 mg, which resolved on interruption and dose reduction. Other adverse events related to drug, diarrhea, rash, and nausea, were mild (grade 1 or 2) but more frequent at higher doses. Tumor responses have been seen over a wide range of doses. One complete clinical response was observed at 1200 mg in a pt with HER2 positive breast carcinoma previously treated with lapatinib and trastuzumab. Two pts showed confirmed partial responses (one with EGFR positive renal cell carcinoma at 200 mg daily and one with EGFR and HER2 positive esophageal carcinoma at 400 mg daily); 2 pts showed unconfirmed partial responses and 3 pts (with vaginal, gastric and pancreatic adenoCa) showed stable disease for >6 months (mo); 2 pts have been treated for >12 mo. Plasma Cmax, AUC and steady state concentrations increased with dose up to 1200 mg, exceeding those eliciting maximal responses in mice. The plasma t½ is >24 h. Conclusions: S-222611 was generally tolerated well in doses up to 1200 mg, with only one DLT; rash, diarrhea and nausea have been readily manageable. PK data support once daily dosing to achieve highly effective concentrations. A substantial proportion of patients with HER2 or EGFR expressing tumors have shown partial responses or stable disease (>6 mo) and one patient has shown a complete clinical response.
Effects of prior bevacizumab (B) use on outcomes from the VELOUR study: A phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin regimen.
Authors: Allegra Carmen Joseph , Lakomy Radek , Tabernero Josep , Prausová Jana , Ruff Paul , Van Hazel Guy , Moiseyenko Vladimir Mikhailovich , Ferry David R , McKendrick Joseph J , Van Cutsem Eric 
Published: March 2020

3505 Background: Aflibercept (Afl; also known as VEGF Trap) is a recombinant human fusion protein that acts as a decoy receptor and prevents the interaction of vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF) with their receptors. In the phase III VELOUR study, Afl + FOLFIRI improved overall survival (OS) compared with FOLFIRI + placebo (pbo) in mCRC (ECCO 2011, abstract 6LBA). We report outcomes from a pre-specified subgroup analysis by prior B use. Methods: Pts with mCRC and progression during or after oxaliplatin were randomized 1:1 to receive either FOLFIRI + pbo or FOLFIRI + Afl 4 mg/kg IV Q2W with stratification by ECOG performance score (PS, 0 v 1 v 2) and prior B. OS and progression-free survival (PFS) in the prior B-treated pts are reported as median estimate and hazard ratios (HRs); 95.34% CI for OS and 95% CI for PFS. Results: Of the 1226 pts in the overall study, 187 in the pbo and 186 in the Afl group were stratified to prior B. The 2 arms were well balanced: median age 60 yrs; male 58%; PS 0-1 97%; and 55% >1 metastatic organ. Although not powered for survival, Afl produced a consistent trend towards prolonged OS and PFS, regardless of prior B use, with no evidence of interaction (OS, P=0.7231; PFS, P=0.6954). The incidence of treatment-emergent adverse events in the Afl arm was similar in pts with prior B (100%) to those without (98.9%), with a similar incidence of grade 3/4 events (82.5% and 83.9%, respectively). Conclusions: Results of this pre-specified subgroup analysis indicate that adding Afl to FOLFIRI resulted in a consistent trend of increased OS and PFS, regardless of prior B use. Prior treatment with B did not appear to impact the safety profile of Afl. [Table: see text]
Impact of age and medical comorbidity (MC) on adjuvant treatment outcomes for stage III colon cancer (CC): A pooled analysis of individual patient data from four randomized controlled trials.
Authors: Haller Daniel G. , O'Connell Michael , Cartwright Thomas H. , Twelves Christopher , McKenna Edward , Sun Weijing , Saif Wasif M. , Lee Luen F. , Yothers Greg , Schmoll Hans-Joachim 
Published: March 2020

3522 Background: Studies show significantly improved disease-free and overall survival (DFS, OS) for oxaliplatin (Ox)-based vs. leucovorin/5-fluorouracil (LV/5-FU) adjuvant therapy in CC, with conflicting reports of Ox benefit in patients > 70 years old. The impact of MC on Ox benefit has not been assessed. We assessed the impact of age and MC on adjuvant treatment outcomes for stage III CC. Methods: N = 4,819 patients from NSABP C-08, XELOXA, X-ACT, and AVANT were analyzed by Ox therapy (XELOX/FOLFOX) vs. LV/5-FU, MC, and age; patients treated with bevacizumab were excluded. Endpoints were DFS (primary), OS, and safety. MC was assessed (except NSABP C-08) by adapted Charlson Comorbidity and NCI Combined Indices (CCI, NCI): Low (≤ 1) vs. high (> 1). Hazardratios (HR) were estimated by Cox regression analyses. Multivariate Cox regression analyses (MVA) tested for independent effects of age and MC on Ox benefit, controlling for gender, T, and N stage. Results: Patient demographics, MC, and disease characteristics (except lymph nodes examined) were well balanced across groups. Median follow-up was shorter in NSABP C-08 and AVANT (36 and 50 months) vs. XELOXA and X-ACT (83 and 74 months). MVA-confirmed DFS/OS benefit was consistently shown for XELOX/FOLFOX vs. LV/5-FU, regardless of age or MC. Grade 3/4 serious adverse event (AE) rates were comparable across cohorts and CCI scores, and higher in patients aged ≥ 70. Grade 3/4 AEs of interest, including peripheral sensory neuropathy, were comparable across ages and CCI scores, and higher with XELOX/FOLFOX. Conclusions: Ox benefit is modestly attenuated in patients aged ≥ 70; however, significant benefit is observed regardless of age or MC in this analysis. Our results further support XELOX or FOLFOX as standard options for the adjuvant management of stage III CC in all age groups. [Table: see text]
Capecitabine (cape)-associated hand-foot skin reaction (HFS) as a clinical predictor of improved survival in patients (pts) with colorectal cancer.
Authors: Hofheinz Ralf , Heinemann Volker , Fischer von Weikersthal Ludwig , Laubender Ruediger Paul , Gencer Deniz , Burkholder Iris , Hochhaus Andreas , Stintzing Sebastian 
Published: March 2020

3541 Background: HFS is frequently observed during treatment with cape. Post hoc analyses of the X-ACT trial suggested that HFS may be associated with improved prognosis in cape recipients in stage III colon cancer. In the present analysis we evaluated the potential association of HFS and survival in pts with metastatic colorectal cancer and locally advanced rectal cancer. Methods: Pts receiving cape within AIO KRK-0104 and Mannheim rectal cancer trials were analyzed. HFS was graded according to NCI-CTC. Time to first occurrence of HFS was described per cycle and HFS developing during cycles 1 and 2 was defined as “early HFS”. Baseline characteristics in the groups of pts with or without HFS were compared using standard tests. Toxicities observed in both groups were compared with Fisher’s exact test. Progression-free (PFS) or disease-free (DFS) and overall survival (OS) data from both trials were pooled and the HFS group was compared to the non-HFS using Kaplan-Meier analysis. Results: A total of 374 pts are included, of whom 29.3% developed HFS. Of these, 70.9% had “early HFS”. Baseline characteristics were comparable between the HFS and the non-HFS groups concerning age, gender, ECOG status and UICC stage. On multivariate analysis none of these factors had influence on the occurrence of HFS. The percentage of all-grade hematological toxicities did not differ between both groups. Contrarily, patients in the HFS group had a significantly higher rate of all grade (but not grade 3-4) diarrhea, stomatitis/mucositis and fatigue (p<0.01 resp.). Moreover, pts in the HFS group had improved PFS/DFS (29.0 vs. 11.4 months; p=0.015, HR 0.69) and OS (75.8 vs. 41.0 months; p=0.001, HR=0.56). Within the HFS group the PFS/DFS and OS were comparable between pts in the “early” and the “late HFS” groups. Conclusions: This analysis provides further evidence for the association of HFS and survival in patients with colorectal cancer. Baseline characteristics and the time of occurrence of HFS had no impact on survival. Patients developing HFS had a higher probability of developing any-grade gastrointestinal toxicity and fatigue while no correlation with hematological toxicity was noticed.
Adjuvant chemotherapy (ACT) in stage II colon cancer (CC) in patients with Lynch syndrome.
Authors: Schulmann Karsten , Koepnick Sven , Engel Christoph , Bernhardt Christiane , Steinke Verena , Royer-Pokora Brigitte , Schackert Hans K. , von Knebel Doeberitz Magnus , Holinski-Feder Elke , Büttner Reinhard , Schmiegel Wolff H. ,   German HNPCC Consortium
Published: March 2020

3550 Background: Previous studies showed conflicting results regarding the value of ACT in MSI-H CC. A recent study reported differential benefits from 5-FU-based ACT comparing suspected sporadic vs suspected hereditary MSI-H CC. We sought to evaluate the prognostic impact of ACT in a large cohort of Lynch syndrome (LS) patients (pts) with stage II CC. Methods: To minimize selection bias diagnoses >2 years prior to registration in the database of the German HNPCC consortium were excluded. 278 patients (61% male, mean age 42.9y, 13% stage IIB, 51% with MMR gene mutation) were eligible. Overall Survival (OS), CC-specific Survival (CSS), and Disease Free Survival (DFS) were analyzed using Kaplan-Meier and Cox Regression analyses. Results: 5y OS, CSS and DFS were 95%, 95% and 93% respectively. Right-sided CC was independently associated with lower DFS in stage II and IIA. Increasing age was associated with lower OS, CSS and DFS in stage IIA, however we observed only trends in the multivariate analysis. Surgery alone (without ACT) was associated with a slightly lower OS in stage IIA (univariate HR 3,659; 95% CI 0,81-16,5; P=0.092); but not with lower DFS and CSS. Prognosis was not different comparing FOLFOX vs. 5-FU-based ACT. Conclusions: Our data suggest that LS pts with stage II CC do not benefit from ACT. FOLFOX was not superior to 5-FU-based ACT. If our results are confirmed, LS pts with stage IIA CC should not receive ACT. The group of stage IIB CC was too small to make definite conclusions. [Table: see text]
Association study of the let-7 microRNA-binding site polymorphism in 3'-untranslated region (UTR) of the KRAS gene in stage III colon cancers from adjuvant trial NCCTG N0147.
Authors: Sha Dan , Lee Adam , Shi Qian , Alberts Steven R. , Sargent Daniel J. , Sinicrope Frank A. , Diasio Robert B. 
Published: March 2020

3564 Background: Lethal-7 (let-7) microRNA has been shown to inhibit colon cancer cell proliferation by inducing KRAS downregulation after binding to specific sites in the 3’- UTR. Recent studies identified a KRAS 3’-UTR polymorphism in the let-7 complimentary site (LCS6) that has been shown to weaken let-7 binding and alter KRAS expression. Carriers of the LCS6 G-allele showed worse survival in metastatic colorectal cancer from prior studies of limited sample size. In the current study, we evaluated the LCS6 variant in 2,834 Stage III colon cancer patients and its association with disease-free survival (DFS), KRAS mutation status, and other clinicopathological features. Methods: In the NCCTG phase III trial (N0147), the LCS6 variant was assayed in germline DNA extracted from whole blood using RT-PCR. Extracted tumor DNA was analyzed for KRAS exon 2 mutations. Chi-squared and two-sample t test were used to compare baseline factors and KRAS mutation status between patients defined by LCS6 variant status. Log-rank tests and multivariate Cox models assessed the unadjusted and adjusted associations between LCS6 status and DFS, respectively. Results: We identified 432 (15.2%) patients heterozygous or homozygous for the LCS6 G-allele and 2402 (84.8%) patients homozygous for the LCS6 T-allele. G-allele carriers were significantly more frequent in Caucasians than other races (Chi-Squared Test, p<0.0001). No associations were found between the LCS6 genotype and T stage, positive lymph node number, tumor differentiation, or primary tumor location (all p>0.2). Moreover, the LCS6 genotype was not associated with DFS (hazard ratio = 0.93, p=0.49) even after combining LCS6 genotype with KRAS mutation status. Conclusions: We report the largest association study investigating the LCS6 polymorphism and colon cancer outcome. There is no significant evidence that the germline LCS6 genotype was associated with DFS in stage III colon cancer patients. Additional studies are needed to determine if LCS6 genotype differs between tumor and germline DNA which may further clarify its prognostic value.
Association of microsatellite instability with prognosis in the pathologic N2 colon cancer patients treated with adjuvant FOLFOX chemotherapy.
Authors: Kim Jeong Eun , Kim Hwa Jung , Hong Yong Sang , Lee Jae-Lyun , Kim Kyu-Pyo , Jang Se Jin , Hong Seung-Mo , Yu Chang Sik , Kim Jin Cheon , Kim Tae Won 
Published: March 2020

3568 Background: The impact of microsatellite instability (MSI) on survival has been rarely explored, with controversy, in stage III colon cancer treated with adjuvant 5-flurouracil-oxaliplatin combination (FOLFOX) chemotherapy. We evaluated association between MSI and survival in this population. Methods: We analyzed 312 patients (pts) with curatively resected stage III colon cancer treated with adjuvant FOLFOX chemotherapy. We determined MSI status using polymerase chain reaction amplification as high levels of MSI (MSI-H, ≥ 2 unstable markers), low levels of MSI (MSI-L, 1 unstable marker), and microsatellite stable (MSS, no unstable marker). Results: Of 312 pts, 8.3% showed MSI-H and they were younger (median age, 51.5 vs. 58 years, p=0.018). MSI-H tumors were more commonly located ascending colon (46.2% vs. 23.1%, p=0.002) and had poorly differentiated features (30.8% vs. 5.2%, p<0.0001). After the median follow-up of 30.9 months, 3-year relapse-free (RFS) and overall survival (OS) rates were 76.1% and 91.7%, respectively. In univariate analysis, pathologic N2 (pN2) was associated with reduced RFS (p<0.0001) and OS (p=0.002), while MSI status did not affect either RFS (p=0.254) or OS (p=0.961). In patients with pN2 tumors, however, MSI-H was associated with better survival compared with MSS/MSI-L; the RFS and OS in pts with pN2/MSI-H were comparable to those in pts with pN1 tumors (table). Conclusions: MSI status alone did not affect survival in our population. However, pts with pN2/MSI-H showed favorable survival outcomes comparable to those with pN1, and MSS/MSI-L/pN2 was associated with worst survival, implicating that MSI-H modifies the inherent worse prognosis of pN2 tumors. [Table: see text]
Short-term clinical outcomes from a randomized controlled trial to evaluate laparoscopic versus open complete mesocolic excision for stage II,III colorectal cancer (CRC): Japan Clinical Oncology Group study JCOG0404 (NCT00147134).
Authors: Nishizawa Yusuke , Saito Norio , Inomata Masafumi , Etoh Tsuyoshi , Kitano Seigo , Katayama Hiroshi , Mizusawa Junki , Yamamoto Seiichiro , Kinugasa Yusuke , Fujii Shoichi , Konishi Fumio , Saida Yoshihisa , Shimada Yasuhiro , Moriya Yoshihiro 
Published: March 2020

3569 Background: The benefits of laparoscopic surgery (LAP) in comparison with open surgery (OP) have been suggested; however, the long-term survival of LAP for advanced CRC requiring complete mesocolic excision is still unclear. We conducted a study to confirm the non-inferiority of LAP to OP in terms of overall survival (OS)with less frequent post-operative morbidity. Short-term outcomes including post-operative complications are presented here. Methods: Only accredited surgeons from 30 Japanese institutions participated. Eligibility criteria included histologically proven CRC; tumor located in the cecum, ascending, sigmoid or rectosigmoid colon; T3 or deeper lesion without involvement of other organs; N0–2 and M0; tumor size =<8 cm; patient age 20-75 years. Patients were randomized preoperatively.Patients with pathological stage III received adjuvant chemotherapy with fluorouracil plus leucovorin. The primary endpoint is OS. and the planned sample size was 1050. Results: A total of 1057 patients were randomized (OP: 528, LAP: 529) between October 2004 and March 2009. Conversion to OP was needed for 29 (5.4%) patients in LAP arm (technical conversion; 2.3%, indicated conversion; 2.8%, complicated conversion; 0.4%). Patients assigned to LAP had less blood loss compared with those assigned to OP (median 30 ml vs 85 ml, p<0.001), although LAP lasted 52 minutes longer than did OP (p<0.001). Radicality of resection as assessed by number of resected lymph nodes did not differ between two groups. LAP was associated with earlier recovery of bowel function (p<0.001), and with a shorter hospital stay (p<0.001) compared with OP. Morbidity and mortality untill discharge did not differ between two groups, except for less wound-related complications in LAP (p=0.007). Conclusions: Laparoscopic complete mesocolic excision for stage II,III colorectal cancer can be performed safely and short-term clinical benefits was demonstrated. If the non-inferiority of LAP in OS is demonstrated in the primary analysis planned in 2014 , LAP will be the new standard procedure for CRC.
A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer.
Authors: Martinez Villacampa Mercedes , Capdevila Jaume , Manzano Jose Luis , Pericay Carles , Salazar Ramon , López-López Carlos , Losa Ferran , Safont M. José , Gomez Auxiliadora , Alonso Vicente , Escudero M. Pilar , Gallego Plazas Javier , Sastre Javier , Gravalos Castro Cristina , Biondo Sebastiano , Palacios Amalia , Aranda Enrique ,   Spanish Cooperative Group for Digestive Tumour Therapy
Published: March 2020

3571 Background: The addition of bevacizumab (BEV) to capecitabine (CAP)-based chemoradiation (CRT) has shown encouraging efficacy in locally advanced rectal cancer (LARC), in nonrandomized studies. This randomized phase II study investigated the effect of adding BEV to preoperative CAP-based CRT in patients (pts), with LARC. Methods: The primary end point was pathologic complete response (pCR). A two-stage design was used. Assuming a minimum pCR rate of at least 15% in one of the arms, a difference between the two arms of 10%, and accepting a probability of correct selection of 87%, 41 pts per arm were needed. Patients with LARC (Stages II-III assessed by MRI) and ECOG PS <2 were randomized to concurrent radiotherapy 45Gy/25f/5 weeks + CAP (825mg/m²/bid) + BEV every 2 weeks (5 mg/kg for 3 doses) (arm A) or the same schedule without BEV (arm B). Surgery was scheduled 6-8 weeks after completing CRT. Results: 90 pts were randomized (arm A/B: 44/46). Patient’s characteristics were well balanced between both arms: male 61%, median age 62 years, median distance from anal verge 7 cm, T3 79%, N+ 87%. 40 (91%)/43 (93%) of pts (arm A/B) finalized the planned CRT + surgery treatment. Overall grade 3-4 toxicity rates were 18 % and 13% (arm A/B, p=0.50); no grade 3-4 hematological toxicity was reported. Postoperative complications were 19(43%)/17(37%)(arm A/B). Efficacy data on patients who actually underwent surgery are reported in the table. Conclusions: The addition of BEV to CAP-based preoperative CRT has shown to be feasible and safe in the local control of LARC. No differences in pCR were observed and longer follow-up is needed to assess the impact on survival endpoints. [Table: see text]