bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of autophagy: Phase I safety, tolerability, and pharmacokinetics (PK) of hydroxychloroquine (H) in combination with vorinostat (V) in patients with advanced solid tumors.
Authors: Mahalingam Devalingam , Mita Monica M. , Sarantopoulos John , Wood Leslie , Mita Alain C. , Curiel Tyler J. , Argiris Athanassios , Nawrocki Steffan T , Carew Jennifer S. , Giles Francis J.
Published: March 2020

3073

Background: The histone deacetylase (HDAC) inhibitor V has pleiotropic effects, and induces both apoptosis and autophagy. As autophagy can promote cancer cell survival, we hypothesized that inhibiting autophagy would enhance the anti-cancer activity of V. Our pre-clinical studies showed that inhibition of autophagy using H significantly increased the pro-apoptotic effects of V. The primary objective of this NCI-funded study was to determine the maximum tolerated dose (MTD) of H in combination with V in patients (pts) with advanced solid tumors. Methods: Pts with ECOG PS 0-2 and adequate organ function received PO V 300-400 mg QD and H 400-1000 mg QD in 21d cycles. 3+3 dose escalation. Dose limiting toxicities (DLTs) = non-hem toxicity ≥ grade (Gr) 3 or hem toxicity ≥ Gr 4 in the first 2 cycles. PBMCs were analyzed for autophagic changes at baseline, week 1 + 6. PKs done on cycle 1.Tumor biopsies were performed at baseline and post-cycle 2 on 3 pts at MTD. Results: 31 pts enrolled, 27 evaluable for DLT. No DLT was observed in cohort 1 (300 mg V/400 mg H) or cohort 2 (400 mg V/400 mg H). In cohort 3 (400 mg V/600 mg H) 1/6 pts experienced a DLT of Gr 3 fatigue. Cohort 4 (400 mg V/800 mg H) 3/6 pts had DLT of Gr 3 fatigue, and 1 had a Gr 2 seizure. Expansion of cohort 3 resulted in no further DLTs. 10 pts got the MTD. Treatment-related toxicities were mostly Gr 1- 2: nausea/vomiting (10 pts), diarrhea (7), fatigue (5), anorexia (4), weight loss (3), anemia (4), elevated creatinine (4) and thrombocytopenia (2). Gr 3 toxicities were fatigue (4), anemia, thrombocytopenia and neutropenia (1 each). No drug-related deaths or Gr 4 toxicities were noted. One pt (RCC) had a confirmed PR (cohort 2 active on cycle 32) and 2 pts with CRC had prolonged SD (>4 cycles). PK analysis indicated dose-proportional exposure for H. Changes from baseline in biomarkers of autophagy and HDAC inhibition were observed in PBMC and primary tumors with therapy. Conclusions: Recommended dose is V 400 and H 600 mg QD. Dose-dependent fatigue was observed with the combination, but well tolerated at the MTD without any further increase in toxicities compared to V alone. Analyses of PK-PD interactions are underway.
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]
Meta-analysis of anti-VEGF class adverse events from three double-blind (db), placebo (pbo)-controlled phase III trials with IV aflibercept (Afl).
Authors: Tabernero Josep , Allegra Carmen Joseph , Rougier Philippe R , Scagliotti Giorgio , Philip Philip Agop , Lakomy Radek , Ramlau Rodryg , Assadourian Sylvie , Chevalier Soazig , Van Cutsem Eric
Published: March 2020

3579

Background: Three db, pbo-controlled studies were conducted with IV Afl in metastatic cancer patients (pts) (colorectal [CRC], Afl + FOLFIRI [WCGC 2011, abstract O-0024]; lung [LC], Afl + docetaxel [WCLC 2011, abstract 511]; and pancreatic [PC], Afl + gemcitabine [WCGC 2009 abstract O-0006]). Each study used the same weekly Afl dose intensity (4 mg/kg q2w for CRC and PC; 6 mg/kg q3w for LC). A safety meta-analysis of anti-VEGF class adverse events (AEs) was performed on data from these studies. Methods: A fixed-effect logistic regression model was used, including study, treatment, and study-by-treatment interaction factors as covariates to test the consistency of treatment effect across studies for each of the considered AE. When no evidence of heterogeneity of treatment effects was found across studies, relative risks (RRs) and 95% confidence intervals (CIs) were estimated. Summary incidences (% of pts) and RR are presented for NCI grade 3-4 events. Results: Safety data from a total of 2662 pts (Afl, 1333; pbo, 1329) were included for analysis. Among pts treated with Afl, 0.4 and 0.5% experienced grade 4 hypertension and nephrotic syndrome, respectively. Conclusions: The addition of Afl to concurrent chemotherapies did not increase the risk of VTE. The risk of grade 3-4 anti-VEGF class AEs was increased when adding Afl to concurrent chemotherapies. This increased risk was statistically significant only for hypertension, proteinuria, and hemorrhage. Further analyses, when more data are available, should improve the precision of these results. [Table: see text]
Mechanisms mediating the negative interaction between oxaliplatin (Ox) and epidermal growth factor receptor (EGFR) inhibitors in patients (pts) with KRAS mutant (MT) colorectal cancer (CRC).
Authors: Freeman Daniel J. , Ogbagabriel Selam , Xie Jiansong , Juan Gloria , Potter Nicholas , Dekeyser Josh , Radinsky Robert
Published: March 2020

3580

Background: Phase 3 trials have shown that pts with MT KRAS tumors have shorter progression-free survival and overall survival when an EGFR inhibitor is added to Ox-containing chemotherapy (CT) (Bokemeyer et al 2011, Douillard et al 2010). However, KRAS status alone is not predictive of pt outcomes in this setting. The negative interaction has not been observed in pts with wild-type (WT) KRAS tumors receiving an EGFR inhibitor and platinum-CT or with MT KRAS tumors receiving an EGFR inhibitor with irinotecan (Peeters et al 2010, Van Cutsem et al 2009). Our goal was to understand the pharmacodynamic interaction between EGFR inhibitors and Ox in KRAS MT CRC cells. Methods: Isogenic MT and WT KRAS-expressing HCT116 CRC cells were treated with Ox, SN-38 (the active metabolite of irinotecan), panitumumab, gefitinib, or inhibitors of MEK, PI3K or Src as single agents or in combination. Viability was measured using an ATPlite assay. Cellular distribution of EGFR was visualized by a confocal microscopy. Downstream activation of MAPK and PI3K was detected by Western blotting. Results: Treatment (tx) with gefitinib, but not panitumumab, reversed the anti-proliferative effects of Ox in the MT KRAS-expressing CRC cells vs Ox alone (p<0.0005) despite no differences in the number of platinum-DNA adducts. Neither tx reversed the anti-proliferative effects of Ox observed in the WT KRAS-expressing cells or SN-38 in either the MT or WT KRAS-expressing cells. EGFR was predominantly expressed in the cytoplasm of KRAS MT cells vs on the cell surface in the KRAS WT cells, which may explain the inability of panitumumab to reverse the anti-proliferative effects of Ox in the CRC cells. Combination tx of MT KRAS CRC cells with Ox and gefitinib increased pAKT which was not observed with Ox alone. Tx of the MT KRAS-expressing cells with a MEK, PI3K or Src inhibitor reversed the negative interaction between Ox and gefitinib (p<0.0005). Conclusions: Feedback though AKT may contribute to the increased resistance to Ox in KRAS MT cells. Inhibitors of MEK, PI3K, or Src reversed the negative interaction between the EGFR inhibitors and Ox in a MT-KRAS genetic background.
Mutant (MT) KRAS codon 12 and 13 alleles in patients (pts) with metastatic colorectal cancer (mCRC): Assessment as prognostic and predictive biomarkers of response to panitumumab (pmab).
Authors: Peeters Marc , Douillard Jean-Yves , Van Cutsem Eric , Siena Salvatore , Zhang Kathy , Williams Richard Thomas , Wiezorek Jeffrey S.
Published: March 2020

3581

Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR). Significant improvement in progression-free survival (PFS) was demonstrated in pts with wild-type (WT) KRAS mCRC treated with pmab+FOLFOX4 (1st-line; study 20050203), pmab+FOLFIRI (2nd-line; study 20050181), and pmab monotherapy (study 20020408). In mCRC, mutations in KRAS codons 12 and 13 are established biomarkers for lack of clinical benefit to anti-EGFR therapies. We retrospectively examined individual MT KRAS codon 12 and 13 alleles as prognostic and predictive biomarkers of response in three phase 3 studies. Methods: Pts were randomized to receive FOLFOX4, FOLFIRI, or best supportive care +/- pmab 6.0 mg/kg Q2W in trials 20050203, 20050181, and 20020408, respectively. The MT KRAS codon 12 and 13 alleles (G12A, G12C, G12D, G12R, G12S, G12V, G13D) were detected using the Therascreen K-RAS Mutation Kit (Qiagen). Results: MT KRAS codon 12 and 13 alleles were detected in 40% (440/1096), 45% (486/1083), and 43% (184/427) of pts in trials 20050203, 20050181, and 20020408, respectively. MT KRAS allele distribution was conserved across studies and balanced between treatment arms. Baseline demographic and clinical features were comparable between all MT KRAS allele subgroups. There was no consistent evidence that any individual MT KRAS allele, compared to the remaining MT KRAS alleles or the entire MT KRAS group, differentially impacted PFS or overall survival (OS) in control arm-treated or pmab-treated pts. Only in the pmab+FOLFOX4 arm of study 20050203 were G13D (unfavorably) and G12V (favorably) significantly associated with OS. Response rates were similar between MT KRAS allele groups in the 1st- and 2nd-line mCRC treatment setting. Finally, in analyses of pts pooled from all 3 trials, only the G12A KRAS allele emerged as a significant negative predictive factor for OS. Conclusions: The lack of consistent results across three lines of therapy indicates pts whose tumors harbor MT KRAS codon 12 or 13 alleles are unlikely to respond to pmab therapy. Currently, only pts with WT KRAS mCRC should be treated with EGFR antibodies.
Examining the effects of metformin on survival outcome in stage II/III colorectal cancer patients with diabetes mellitus.
Authors: Lee Guek Eng , Aung Thinzar , Lim Kiat Hon , Tan Wah Siew , Tai Wai Meng David , Suhaimi Nur-Afidah Binte , Tan Min-Han , Tan Iain B.
Published: March 2020

3589

Background: Insulin resistance and deregulation of the insulin-like growth factor (IGF) axis is implicated in colonic carcinogenesis. Metformin inhibits hepatic gluconeogenesis and increases insulin sensitivity. It induces AMPK activation, thus inhibiting mTOR and downstream survival and proliferation pathways. We evaluated the effects of metformin on survival outcomes of patients with stage 2 and 3 colorectal cancer (CRC). Methods: Among 1455 patients with stage II or III colorectal cancer, we identified 344 patients with both CRC and diabetes mellitus. 219 diabetic patients received metformin and 125 diabetic patients were not receiving metformin. Patient’s demographics, clinical and histopathologic characteristics, overall survival, time to recurrence and relapse-free survival were evaluated. Molecular analysis for AMPK, and mTOR pathway on archival tissue is ongoing. Results: After a median follow-up of 78 months (6.5 years), there was no difference in survival outcomes between diabetic and non-diabetic patients. Among diabetic patients, there were 99 relapses and 90 deaths. Metformin use was associated with improved overall survival (HR 0.23; 95%CI: 0.15-0.35 p<0.01), time to recurrence (HR 0.63; 95%CI: 0.41-0.96) and relapse-free survival (HR 0.47; 95%CI:0.33-0.67,p<0.01). In multivariate analysis, after adjustment for T stage, N stage and patients' age, metformin use remained associated with improved overall survival (HR 0.18, p<0.01); time to recurrence (HR 0.55; p<0.04) and relapse-free survival (HR 0.44, p<0.01). Results of molecular correlative studies performed on archival tissue will be presented at the meeting. Conclusions: Among patients with diabetes and colorectal cancer, use of metformin is associated with improved survival outcomes in both univariate and multivariate analysis lending support to the hypothesis that it may have anti-cancer activity.
U.S. patients receiving resin 90Y microspheres for unresectable colorectal liver metastases: A multicenter study of 506 patients.
Authors: Kennedy Andrew S. , Ball David , Cohen Steven J. , Cohn Michael , Coldwell Douglas M. , Drooz Alain , Ehrenwald Edward , Kanani Samir , Rose Steven C. , Nutting Charles W. , Moeslein Fred M , Savin Michael , Schirm Sabine , Sharma Navesh K , Wang Eric
Published: March 2020

3590

Background: Implantation of radioactive microspheres via the hepatic artery with Yttrium-90 (90Y) is termed “radioembolization, (RE)”. Resin microspheres were FDA cleared for use in colorectal liver metastases (mCRC) in 2002. Rapid worldwide acceptance of this therapy has resulted in greater than 30,000 procedures conducted in the past 10 years. This investigator-initiated study focuses on RE treatment outcomes in US-only patients since 2002. Methods: A retrospective multi-institutional study was designed to analyze the outcome of consecutively treated mCRC patients undergoing RE by experienced treatment centers in the USA using resin 90Y microspheres. IRB approval was obtained by each center with independent data collection and analyses. Primary endpoints: CTC 3.0ae toxicity, RECIST response and survival; baseline treatment parameters, prior chemotherapy, and liver directed therapies. Results: 506 patients at 10 institutions (193 M, 313 F) received 770 RE treatments; median age = 60.4 years (20.8 – 91.9 years); median number of RE treatments per patient = 1.0 (1-5 treatments). Active extrahepatic disease was present at first RE in 34.8% of patients. The majority (90%) of patients received prior chemotherapy, with 30.6% also having undergone prior hepatic surgery/ablative procedures. Median follow up after RE = 8.4 mo. (0.4 – 67.6 mo.) with median survival = 10.1 mo. (95% CI 9.1 – 12.0). For first RE treatment, median tumor volume was 146.0 mL (2.8 – 3228.0 mL). Median radiation activity delivered = 1.18 GBq (0.12 – 2.29 GBq), lung shunt median = 4.8 % (.02 – 45%). Total grade 1-3 events were 32% GI, 44% fatigue and 1% liver failure. Only 2.4% of all treatments required an overnight stay post-procedure. Conclusions: The modern USA experience of 90Y therapy for unresectable, heavily pretreated mCRC liver metastases is encouraging with a median survival of 10.1 months after first RE procedure. Toxicity was mild and of short duration in most patients. RECIST response is being analyzed currently as are data of additional patients.
First-line chemotherapy plus cetuximab in patients grouped according to prognostic risk factors: Analysis of the CRYSTAL and OPUS studies.
Authors: Folprecht Gunnar , Van Cutsem Eric , Bokemeyer Carsten , Schlichting Michael , Heeger Steffen , Kohne Claus-Henning
Published: March 2020

3591

Background: Analysis of randomized trials has shown that mCRC patients (pts) can be divided into prognostic risk groups according to baseline clinical parameters including ECOG performance status, white blood cell count (WBC), alkaline phosphatase (ALP) and number of metastatic (met) sites (Köhne C, et al. Ann Oncol 2002;13:308-17). The effect of adding cetuximab to first-line chemotherapy (CT) on overall survival (OS) in these groups of KRAS wild-type mCRC pts was investigated in the CRYSTAL and OPUS studies. Methods: Pt risk groups were: low-risk (LRG= ECOG 0/1, 1 met site) intermediate-risk (IRG= ECOG <1, >1 met site, ALP <300 U/L or, ECOG>1, low WBC, 1 met site) and high-risk (HRG= ECOG<1, >1 met site, ALP>300 U/L or ECOG>1, high WBC, or ECOG>1, low WBC and >2 met sites). Exploratory analyses comprised estimates of effects using Cox‘s proportional hazards model for OS on individual pt data and comparison of treatment arms by log-rank test. Results: Data are shown in the table. In the pooled analyses, in both treatment arms OS was longest in LRG pts and shortest in HRG pts. Adding cetuximab to CT led to marked improvements in OS in the HRG (Hazard ratio [HR] 0.765, 95% CI 0.506–1.157, p=0.203) and IRG (HR 0.781, 95% CI 0.622–0.981, p=0.033), while improvements in LRG pts (HR 0.869, 95% CI 0.672–1.124, p=0.287) were observed only after prolonged follow up. Data were similar in the separate CRYSTAL and OPUS studies. Conclusions: The analysis confirms the concept of prognostic risk groups for OS according to baseline clinical parameters in pts with KRAS wt mCRC. Benefit from the addition of cetuximab to first-line CT in terms of OS appears to be more pronounced in the IRG and HRG. [Table: see text]
Integrin genetic variants and stage-specific tumor recurrence in patients with stage II and III colon cancer.
Authors: Bohanes Pierre Oliver , Yang Dongyun , Loupakis Fotios , Labonte Melissa Janae , Gerger Armin , Ning Yan , Wakatsuki Takeru , Zhang Wu , Benhaim Leonor , Páez David , El-Khoueiry Anthony B. , El-Khoueiry Rita , Lenz Heinz-Josef
Published: March 2020

3604

Background: Integrins are key elements in cancer biology regulating tumor growth, angiogenesis and lymphangiogenesis through interactions of the tumor cells with the microenvironment. Recent evidence showing that integrins are critical in cancer dormancy suggests that their differential expression or activity may be responsible for tumor recurrence. Moving from the hypothesis that integrins could have different effects in stage II and III colon cancer, we tested as a primary endpoint whether a comprehensive panel of germline single nucleotide polymorphisms (SNPs) in integrin genes could predict stage-specific time to tumor recurrence (TTR) in stage II and III colon cancer patients. Methods: A total of 234 patients, 105 high-risk stage II and 129 stage III, treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. The median follow-up time was 4.4 years. Whole blood samples were analyzed for 22 germline SNPs in integrin genes using PCR-RFLP or direct DNA-sequencing. Results: In the multivariate analysis,stage II colon cancer patients with at least one G allele for ITGB3 rs4642 had higher risk of recurrence (HR=4.027, 95%CI 1.556-10.421, p=0.004). This association was also significant in the combined stage II-III cohort (HR=1.975, HR 95%CI 1.194-3.269, p=0.008). The predominant role of ITGB3 rs4642 in stage II diseases was confirmed using recursive partitioning, showing that ITGB3 rs4642 was the most important factor in stage II diseases. In contrast, in stage III diseases, both ITGB1 rs2298141 (HR=1.909, 95%CI 1.054-3.459, p=0.033) and ITGA4 rs7562325 (HR=0.227, 95%CI 0.064-0.804, p=0.022) were associated with TTR. The latter showed a significant interaction between stages (p=0.048). Conclusions: This study identifies germline polymorphisms in integrin genes as independent stage-specific prognostic markers for stage II and III colon cancer. These data strengthen the role of tumor dormancy in early colon cancer and may help to select subgroups of patients who may benefit from integrin-targeted treatments.
Effect of postoperative complications on adjuvant chemotherapy use in stage III colon cancer.
Authors: Merkow Ryan P , Bentrem David J , Mulcahy Mary Frances , Ko Clifford Y. , Bilimoria Karl Y.
Published: March 2020

3608

Background: The National Quality Forum has endorsed the use of adjuvant chemotherapy in stage III colon cancer, yet a substantial treatment gap exists in the United States. Our objective was to evaluate the contribution of postoperative complications on the use of adjuvant therapy after colectomy for cancer. Methods: Patients from the National Surgical Quality Improvement Program and the National Cancer Data Base who underwent colon resection for cancer were linked (2006-2008). The association of complications on adjuvant chemotherapy use was assessed using multivariable regression models. Results: From 140 hospitals, 2368 patients underwent resection for stage III colon adenocarcinoma. Overall, 36.8% (871/2,368) patients were not treated with adjuvant therapy, of which 47.8% (416/871) had documented severe comorbidities or advanced age (≥80) as the reason for no adjuvant therapy receipt. Of the remaining 455 patients, 21.3% (97/455) had ≥1 serious complication that could account for adjuvant therapy omission. The remaining 41.1% (358/871) patients did not have a documented reason for not recieving adjuvant therapy. Complications associated with adjuvant therapy omission were abscess/anastomotic leak (OR 1.91, 95% CI 1.02-3.59), renal failure (OR 7.16, 95% CI 1.92-26.79), prolonged ventilation (OR 7.92, 95% CI 2.97-21.13), re-intubation (OR 5.69, 95% CI 2.13-15.18), and pneumonia (OR 4.05, 95% CI 2.07-7.90). Abscess/anastomotic leak was associated with a 28-day delay in time to adjuvant chemotherapy (73 vs. 45 days, p<0.05). Superficial surgical site infection did not decrease adjuvant therapy receipt but delayed the time to its use (57 vs. 44 days, p<0.05). The occurrence of postoperative sepsis was associated with a 15-day delay to adjuvant chemotherapy (60 vs. 45 days, p<0.05). Conclusions: Serious postoperative complications explained nearly one quarter of the adjuvant chemotherapy treatment gap among stage III colon cancer patients. Postoperative complications affect treatment utilization and should be considered when calculating adherence with the Stage III adjuvant therapy for colon cancer measure. Judging provider performance using quality metrics is challenging without clinical data.
Incidence and prognostic impact of KRAS and BRAF mutations in patients undergoing liver surgery for colorectal metastases.
Authors: Karagkounis Georgios , Torbenson Michael S. , Daniel Hubert D , Azad Nilofer Saba , Diaz Luis A. , Donehower Ross C. , Hirose Kenzo , Pawlik Timothy M. , Choti Michael A.
Published: March 2020

3616

Background: Molecular biomarkers offer the potential for refining prognostic determinants in patients undergoing cancer surgery. Among patients with colorectal cancer metastases, KRAS and BRAF are important biomarkers, but their role in patients undergoing surgical therapy for liver metastases is unknown. In this study, the prevalence and prognostic significance of KRAS and BRAF mutations were determined in patients undergoing surgical therapy of colorectal liver metastases (CRLM). Methods: KRAS and BRAF analysis was performed on 202 patients undergoing curative intent surgical therapy of CRLM between 2003 and 2008. Tumor samples were analyzed for somatic mutations using sequencing analysis (KRAS: codon 12/13, BRAF: V600E). The frequency of mutations was ascertained and their impact on outcome determined relative to other clinicopathologic factors. Results: KRAS gene mutations were detected in 58/202 patients (29%) undergoing surgery for CRLM, comparable to that reported in non-surgical patient series. In contrast, mutation in the BRAF gene was identified in very low frequency in this surgical cohort, found in only 4/202 (2%) patients. KRAS mutations were associated with worse long-term survival (HR=2.13, CI=1.25-3.65), as well as risk of recurrence (HR=1.89, CI=1.12-3.19). ). In addition, KRAS mutation was also associated with risk of recurrence following surgical therapy (HR=1.89, CI=1.12-3.19).While other clinicopathologic features, including tumor number, CEA and primary stage were also associated with survival, KRAS status remained independently predictive of outcome. The low incidence of BRAF mutation limited the ability to determine its prognostic impact. Conclusions: While KRAS mutations were found in approximately one third of patients, BRAF mutations were found in only 2% of patients undergoing surgery for CRLM. KRAS status was an independent predictor of overall and disease-free survival. Molecular biomarkers such as KRAS may help to refine our prognostic assessment of patients undergoing surgical therapy for CRLM.