bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcome for patients with metastatic colorectal cancer (mCRC) enrolled in phase I clinical trials: Single institution experience.
Authors: Shah Umang , Pendurti Gopichand , Swami Umang , Hou Yijuan , Ghalib Mohammad Haroon , Chaudhary Imran , Mani Sridhar , Goel Sanjay , Aparo Santiago
Published: March 2020

e13550

Background: Phase I studies are a fundamental step in anti-cancer drug development. Prior meta-analysis looking at phase I studies showed an overall response rate (ORR) of 10.6 % and grade 4 toxicity rate of 14.3 %, and specifically, patients (pts) with mCRC enrolled in phase I trials had an ORR of 1.3 %. Herein, we report the results of a 12-year experience from our institution. Methods: Records from pts with metastatic colorectal adenocarcinoma enrolled in phase I studies at our institution from January 1999 to December 2010 were reviewed. Recorded data included treatment related responses, survival times and adverse events (AE). Kaplan-Meier analysis, t-test and X2 tests were used to analyze data. A Cox proportional-hazard model using clinical parameters at enrolment was used to predict survival. Results: Our cohort included 141 pts with mCRC (83% colon and 17% rectum) enrolled in 25 unique phase I trials. Median patient age at enrolment was 59 years, 66% were female and 81% had an ECOG PS of 0-1. Pts received a median of 3 lines of chemotherapy prior to enrolment. The median overall survival (OS) was 8.9 months. The ORR was 4.2%. The clinical benefit rate (ORR or stable disease for ≥ 4 months) was 22%. Univariate analysis showed that being female (P=0.02), Hb <12 g/dL (P=0.01), Alb < 4 g/dL (P=<0.001), Alkaline phosphatase > 150 U/L (P=<0.001) and LDH ≥ 300 U/L (P=<0.001) were independently associated with shorter survival. Multivariate analysis showed that females (HR of 2.81 95% CI 1.71-4.59, p= <0.001), Hb ≥ 12 g/dL (1.67, 95%CI 1.03-1.71, p=0.04), Alb < 4 g/dL (HR 2.51, 95% CI 1.59-3.98, p= <0.001) and LDH ≥300 U/L (HR 2.59, 95% CI 1.65-4.03, p= <0.001) were associated with shorter survival. Grade 3/4 non-hematological and hematological AE were seen in 25% and 45% of patients, respectively. Conclusions: This cohort of pts that received a median of 3 prior lines of therapy had a median OS and ORR of 8.9 months and 4.2%, respectively. These findings are similar to the ones reported in the recent phase III trial using regorafenib. Interestingly, multivariate analysis showed that a Hb of ≥ 12g/dL was associated with worse survival, in agreement with prior reports in which red cell growth factors were used.
Effective treatment of aggressive B-cell lymphomas by downregulated NIK-induced noncanonical NF-κB pathway activation through inhibition of BAFF.
Authors: Kuo Sung Hsin , Chen Li-Tzong , Yeh Kun-Huei , Tsai Hui-Jen , Lee Hsiao-Wei , Cheng Ann-Lii
Published: March 2020

e13554

Background: We recently reported that autocrine BAFF (B cell–activating factor belonging to the TNF family) signal transduction pathway contributes to H. pylori-independent growth of gastric diffuse large B-cell lymphoma (DLBCL) (Blood 2008;112:2927-34; Ann Hematol 2010;89:431-6). In this study, we sought to investigate whether activation of BAFF signaling pathway can promote the survival and proliferation of aggressive B-cell lymphoma. Methods: Seven aggressive NHL cell lines (EBV-negative Burkitt’s lymphoma (Ramos), EBV-positive Burkitt’s lymphoma (Raji), EBV-negative undifferentiated lymphoma (MC116), activated B cell (ABC)-like DLBCL (OCI-Ly3, OCI-Ly10), and germinal center B cell (GCB)-like DLBCL (OCI-Ly7, and Pfeiffer) were used in this study. Cell cycle was analyzed by flow cytometry. The DNA-binding activity of NF-kB was determined by the luciferase assay. Expression of non-canonical NF-κB signatures-related proteins (BAFF, BAFF-R, NIK, cIAP1, TRAF2, cIAP1/2, TRAF3, IKKa, p100, p52 and RelB, BCL10, BCL3, and STAT3) was assessed by immunoblotting. Results: Our results showed that in GCB-DLBCL cell lines, activation of BAFF induced recruitment and degradation of TRAF3, which resulted in NIK kinase accumulation, BCL10 Ser138 phosphorylation, IKKa phosphorylation, and NF-kB p100 processing, thereby resulting in continuous activation of non-canonical NF-kB pathway. This phenomenon also resulted in BCL3 nuclear translocation and STAT3 activation, and subsequently activated STAT3 downstream-regulated genes (BCL2, survivin, and cyclin D1). Furthermore, we found that inhibition of BAFF by short hairpin RNA (shRNA) suppressed the growth of ABC-DLBCL cells and Burkitt lymphoma cells through the down-regulation of BAFF/BAFF-R/TRAF3/NIK/BCL3/NF-kB signaling pathway. Conclusions: Our results indicate that constitutive BAFF signaling activates NIK-induced non-canonical NF-kB signaling pathway in aggressive B-cell lymphoma, and inhibition of BAFF is particularly effective in the treatment of this subgroup of tumors.
Focal adhesion kinase inhibition as a therapeutic strategy in differentiated thyroid cancer.
Authors: O'Brien Shalana , Golubovskaya Vita , Zajac-Kaye Maria , Hochwald Steven N. , Cance William G.
Published: March 2020

e13556

Background: Thyroid cancer, themost common endocrine malignancy, can be curable with resection of low stage tumors, but new treatments are needed for advanced differentiated cancers with radioiodine resistance. Focal Adhesion Kinase (FAK), a tyrosine kinase involved in protein-protein interactions regulating crucial cellular functions, is upregulated in thyroid cancer, and is a drug target along with its autophosphorylation site Y397. Clinical trials are ongoing for FAK inhibitors PF04554878 and GSK2256098. 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15), a small molecule FAK scaffolding inhibitor targeting the Y397 autophosphorylation site, and TAE226, a FAK/Insulin-like Growth Factor-1 Receptor inhibitor are in preclinical studies . In this report, we compared the effects of these FAK inhibitors on thyroid cancer cell lines. Methods: Four human thyroid cancer cell lines were cultured in vitro: K1, BCPAP, TPC1 derived from papillary thyroid carcinoma, and TT derived from medullary thyroid carcinoma. Western blots detected expression of FAK and pY397 FAK. Clonogenicity and MTS assays measured effects of the inhibitors on cell viability and colony formation. Results: The most significant dose-dependent decrease of FAK Y397 autophosphorylation and p125FAK expression was seen with Y15, with significant decrease at 10μM and near complete inhibition at 50μM. PF04554878, GSK2256098 and TAE226 at 50μM showed lowered pY397 expression, but less effect than Y15 at 10μM concentrations. TAE226 had the most effect on clonogenicity, with complete colony inhibition at doses 1μM and higher. Least effect was with GSK2256098. Y15 and PF04554878 had moderate inhibition of clonogenicity. Y15 had greatest inhibition of cell viability, with IC50s less than 15μM, two to over five-fold more potent than TAE226, GSK2256098, and PF04554878. Conclusions: All FAK inhibitors caused dose-dependent effects on thyroid cancer cell viability, clonogenicity and expression of pY397 FAK. Y15 had the most potent effects on cell viability and expression of FAK and p397 FAK. Our data suggests targeting the FAK scaffold, as Y15 does, is more effective than targeting the kinase function as a potential therapeutic agent for thyroid cancer.
Cytotoxic activity of semi-synthetic ingenol derived from Euphorbia tirucalli on a large panel of human cancer cell lines.
Authors: Silva Viviane Aline Oliveira , Rosa Marcela Nunes , Tansini Aline , Lima Joao Paulo Da S.N. , Jones Chris , Pianowski Luiz Francisco , Reis Rui Manuel
Published: March 2020

e13559

Background: The latex from Euphorbia tirucalli is used in Brazil as anticancer and other disease as folk treatment; however, little is known about its anticancer proprieties. We report in vitro activity of 3 semi-synthetic ingenol compounds derived from E. tirucalli, ingenol A (ingenol-3-trans-cinnamate), ingenol B (3-caproyl-ingenol) and ingenol C (ingenol-3-dodecanoate), against a large panel of human cancer cell lines. Methods: Anti-tumor effects of the 3 semi-synthetic compounds were assessed using MTS assays on 77 cancer lines from 13 tumor models, such as breast, colon, bladder, prostate, lung, pancreas, esophagus, glioblastoma, melanoma, head and neck and cervical cancer. Additionally, we evaluate the its potential combinatorial value with temozolomide (TMZ) in gliomas. Ongoing experiments will identify potential drug target(s) by assessing changes in global protein expression. Results: Ingenol A, B and C exhibited dose-dependent and time-dependent cytotoxic effects. Amongst the derived tested, ingenol C displayed the best activity across the tumor cell lines. In comparison with TMZ, ingenol C showed a median of 136 fold higher efficacy, range 15-511 fold, in the glioma cell lines analyzed. Conclusions: The semi-synthetic ingenol compounds, in particular the ingenol C, demonstrated a potent anti-tumor activity on all cancer cell lines evaluated. Our findings may provide insight into designing ingenol-based therapies for cancer patients. [Table: see text]
Everolimus (E) and octreotid (O) in metastatic high-risk MEN IIb disease: A case report.
Authors: Dresemann Antje , Dresemann Gregor Paul
Published: March 2020

e13565

Background: Multiple endocrine neoplasia (MEN) type IIB is characterized by missense mutation in exon 16 of the RET-proto-onkogen. Malignant c-cell-(medullar)-carcinoma of the thyroid gland (MTC) is part of the disease. Prognostic factors for metastatic MTC (m-MTC) are tumor grading, vessel- and peri-neural infiltration, age and performance status (PS). Irradiation and chemotherapy have limited activity in m-MTC. Thyrosine-kinase inhibitors like vandetanib, sorafenib or sunitinib were not admitted in Germany in 2011, August. As mTor-pathway seems to play a role in m-MTC E was suggested to be a treatment alternative. In somatostatin receptor (SR) positive tumors O might be beneficial. Methods: In 2011, August, a 23 years old man presented with metastatic MEN IIB disease after palliative irradiation therapy. ECOG-PS was 2 to 3, Calcitonin was 3.615 pg/ml, CEA was 467 ng/ml. The patient (pt) had a non-resectable m-MTC, SR positive, with esophageal, pleural, tracheal and lymph node infiltration still with metabolic activity in PET-CT. Grading was G3 with strong vessel and peri-neural infiltration. Right adrenal tumor and tongue tumor were present. After written informed consent the pt started treatment with E 10 mg/day orally in 2011, November. A loperamide resistant diarrhea was treated with O 20 mg/4 weeks i. m. additionally since 2012, July. Results: During treatment with E Calcitonin and CEA levels continuously decreased and CT scans every 3 months demonstrated a continuous shrinkage of all tumor sites, especially after additional treatment with O, which also was associated with an improved PS. Since 2012, October, ECOG PS was 0 enabling the patient to go to work again. Since 2012, October no relevant treatment related side effects were present. Conclusions: E showed efficacy as single agent treatment in a young man with metastatic high risk MEN IIB disease, the addition of O seems to reduce side effects and to improve efficacy of single agent E in this case. Further investigation is needed to verify these results
Effect of salmonella typhimurium A1-R on quiescent cancer cells that do not respond to standard chemotherapy.
Authors: Yano Shuya , Zhang Yong , Uehara Fuminari , Hiroshima Yukihiko , Miwa Shinji , Hoffman Robert M. , Zhao Ming
Published: March 2020

e13576

Background: Quiescent cancer cells are a major impediment to treating solid cancer with chemotherapy, since in most tumors the majority of the cells are quiescent. Methods: The cell-cycle phase of each human MKN45 gastric cancer cell was imaged using a fluorescence ubiquitination cell cycle indicator (FUCCI). With FUCCI, quiescent cancer cells express mKusabira-Orange fluorescent protein (red) and proliferating cells express mAzami-Green fluorescent protein (green). FUCCI-labeled cancer cells in tumor spheres and subcutaneous tumor in nude mice were treated with Salmonella typhimurium A1-R. Results: Time-lapse confocal imaging showed that cancer cells in tumor spheres in serum-free culture become and remained quiescent. S. typhimurium A1-R infected and killed quiescent cancer cells in tumor spheres. In contrast, cytotoxic agents did not kill the quiescent cancer cells in the tumor spheres. S. typhimurium A1-R targeting of FUCCI-expressing subcutaneous tumors growing in nude mice resulted in the killing of quiescent cancer cells resistant to cytotoxic agents. Conclusions: S. typhimurium A1-R can kill quiescent cancer cells which suggests a new therapeutic paradigm potentially more effective than current therapeutics which are ineffective against quiescent cancer cells.
Effect of dormant cancer cells on angiogenesis after resisting chemotherapy.
Authors: Mii Sumiyuki , Tome Yasunori , Hiroshima Yukihiko , Uehara Fuminari , Miwa Shinji , Fujiwara Toshiyoshi , Hoffman Robert M. , Yano Shuya
Published: March 2020

e13577

Background: Dormant cancer cells are a significant problem in clinical cancer as they are usually chemoresistant and can give rise to recurrence years after treatment. Methods: Dormant cancer cells were identified with a fluorescence ubiquitination cell cycle indicator (FUCCI) and confocal microscopy. FUCCI-expressing xenografts were established from MKN45 gastric cancer cells. Results: Within 7 days after implantation in nude mice, FUCCI-expressing tumors contained a mixture of cancer cells in G0/G1 and S/G2/M phases. Cancer cells in G0/G1 phase survived and become dormant after treatment with cytotoxic agents. As the tumors grew, proliferating cells were only found at the surface. Chemotherapy killed only the proliferating cancer cells at the surface and had little effect on the majority of dormant cancer cells in the tumor center. Furthermore, we investigated tumor chemoresistance using nestin-driven green fluorescent protein (GFP) transgenic mice that have GFP-expressing nascent tumor vessels. Chemotherapy-treated tumors had much more and deeper tumor vessels than control tumors. Conclusions: These results suggest that dormant cancer cells may protect themselves by inducing angiogenesis.
Downregulation of Let-7i to promote stem-like properties of head and neck cancer cells through activating ARID3B-Oct4 axis.
Authors: Liao Tsai-Tsen , Yang Muh-Hwa
Published: March 2020

e13584

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the major male cancers worldwide, and the main therapeutic strategies include surgery, radiotherapy and chemotherapy. Cancer stem cells are a small population of tumor cells that are responsible for tumorigenesis, tumor recurrence and treatment resistance. let-7 family microRNAs have been shown to function as a tumor suppressor. Here we aim to investigate the role of let-7i in regulating stem cell properties in HNSCC. Methods: Luciferase reporter assay were used to identify the targets of let-7i; Western blot to analysis the correlation between ARID3B and Oct4; ChIP assay confirm the binding of ARID3B to Oct4 proximal promoter; Quantitative RT-PCR to analyzed the level of ARID3B, Oct4, and let-7i in the 52 pairs of samples containing primary tumor tissues and adjacent normal epithelium from head and neck cancer patients with different stage receiving surgery. Results: ARID3B, a member of the AT-rich interaction domain family proteins which plays an essential role during embryogenesis, is a bona fide target of let-7i. ARID3B promotes stem-like properties of HNSCC cells and upregulates a panel of stemness genes, and Oct4 is one of the most prominent ones to be upregulated. ARID3B direct binds to the AT-rich region of Oct4 promoter to activate its transcription. Downregulation of let-7i in HNSCC samples correlates with a corresponding upregulation of Oct4 and ARID3B. Conclusions: We propose a mechanism of let-7i repression-mediated stem-like properties through releasing the suppression of a novel let-7i target ARID3B, which leads to transcriptional activation of stemness genes. The results provide useful information in elucidating the mechanism of HNSCC progression and also provide potential targets in developing HNSCC-specific treatment.
Arterial stiffness to predict hypertensive response to antiangiogenic drugs.
Authors: Giroux Julie , Alivon Maureen , Briet Marie , Boudou-Rouquette Pascaline , Ropert Stanislas , Cessot Anatole , Durand Jean-Philippe , Boutouyrie Pierre , Laurent Stephane , Goldwasser Francois
Published: March 2020

e13589

Background: Targeting angiogenesis with anti-VEGF receptors is a new approach for cancer treatment. The most common side effect is arterial hypertension. We hypothesize that pre-existing large artery remodeling with increased arterial stiffness is a determinant of blood pressure (BP) increase under antiangiogenic (AAD) and that AAD may alter mechanical properties of large arteries independently of BP increase. Methods: 49 patients (mean age=57[15] years, mean bSBP=128[22] mmHg and mean DBP=75[11] mmHg; treated for a cancer with an indication to start AAD (Sorafenib, Sunitinib or Bevacizumab) were included in this longitudinal study. Arterial evaluation was assessed at baseline (BL) before the introduction of AAD and every two weeks for 2 months (V1 to V4) with aortic stiffness (PWV) and central BP measurements by aplanation tonometry (SphygmoCor), carotid distensibility with high resolution echotracking system (ArtLab). Results: 43% of the patients developed hypertension between BL and V1. Using linear mixed model analysis with random effects, PWV significantly increased between BL and V1 (BL-V1, adjusted slope 0.89 m/s, F value=6.8, p=0.04) after adjustment to age and mean BP, carotid distensibility decreased significantly during follow-up (BL-V1, adjusted slope= -4.4, p=0.04; BL-V2, adjusted slope= -5.23, p=0.001) after adjustment to age and mean BP. The determinants of BP increase were studied between BL and V1 since anti-hypertensive drugs were introduced after V1. Using multivariate analysis, BL PWV was an independent determinant of the delta brachial SBP (β= -1.36 [-2.61; 0.11], p=0.034) with age (β=0.25 [0.04; 0.47], p=0.02). Conclusions: AAD induce functional alterations of large arteries, increasing arterial stiffness, independently of BP increase. In addition, pre-AAD administration arterial properties influence the hypertensive response to AAD.
Suppression of tumor progression and angiogenesis in two Lewis lung carcinoma mouse models by shRNA knockdown of fibroblast activation protein.
Authors: Xian Shuang , Peng Feng , Wang Chunting , Cai Fan , Wei Yuquan
Published: March 2020

e13592

Background: Fibroblast activation protein (FAP), a transmembrane serine peptidase, is expressed by tumor-associated fibroblasts. As an important factor in tumor microenvironment, it has been reported that FAP plays a dual role in tumor progression, both positive and negative. In a mouse model of breast cancer, FAP increasing microvessel densities had been experimentally demonstrated. The aim of the study was to determine the effect of FAP in tumor growth and tumor microenvironment in LLC mouse models, especially in lung metastasis model. Methods: Female C57 mice received i.v injection of LLC cells into tail vein or s.c into right flank to establish lung metastasis model or subcutaneous xenograft model. 21 mice were randomly divided into 3 groups (n=7, per group) and treated with 5% GS,control-shRNA or FAP-shRNA, respectively. Xenograft tumor size and weight, numbers of pulmonary metastatic nodules and lung weight were measured. FAP expression, microvessel density and collagen fiber were evaluated. Data were analyzed using one-way analysis of variance (ANOVA), and a value of P <0.05 was considered to be statistically significant. Results: FAP-shRNA decreased significantly in the number of metastases on the lung surface and average lung weight, compared with 5%GS and control-shRNA (P<0.05).The size of metastases in treatment group was large than those of the controls (P<0.05). Moreover, FAP-shRNA showed a significant reduction of 44% in tumor volume and tumor weight, relative to other groups (P<0.05). In both models, FAP expression and microvessel density were lower in treatment group compared to the controls. And FAP-shRNA indicated an increase in the accumulation of collagen fiber. Conclusions: The study suggests that shRNA targeting FAP inhabit tumor growth in LLC mouse models, especially in lung metastasis model. We hypothesize that the anti-tumor mechanism is related to angiogenesis reduction and alteration of collage fibro accumulation, which eventually change tumor microenvironment. These findings indicate the potential of FAP as a new therapeutic strategy for lung cancer.
Uptake of adjuvant chemotherapy (AC) for colon cancer in older and younger patients (pts) in the Irish population.
Authors: Rehman Zia , Coyle Seamus , Sui Jane Sze Yin , Jordan Emmet , Lee Chalen , Deady Sandra , Comber Harry , O'Connor Miriam , Calvert Paula , Horgan Anne M.
Published: March 2020

e14515

Background: The use of AC in older patients with colon cancer in clinical practice is uncertain. We examined uptake of AC and it’s impact on survival in older pts with stage II and III colon cancer in a national cohort. Methods: Using the National cancer Registry of Ireland, 3,486 pts with stage II and III colon cancer treated with curative resection from 2004-2009 were identified. Clinopathological features and AC use were compared between those ≥70 yrs and those < 70 yrs. Data from a single institution were reviewed to determine drivers of treatment decisions. Results: 2,026 pts with stage II disease were identified, 60% ≥ 70 yrs. AC was utilized in 10% and 40% of ≥ 70 and <70 yrs, respectively (p<0.0001). A benefit for AC over observation was seen in older [HR 0.36; p <0.0001] and younger pts [HR 0.43; p<0.0004]. Of 46 stage II pts from a single institution there were no significant differences between ≥ 70yrs (n=26) and <70yrs (n=23) in terms of ECOG PS, Charlson comorbidity scores (CCI), tumor grade, T3/T4 disease, R0/R1 resections, obstruction/perforation, lymphovascular invasion or nodal yield. However, only 12% ≥ 70yrs received AC compared to 57% of <70yrs (p=0.0002). Of 1,460 pts with stage III disease, 51% were ≥ 70 yrs. 34% of older and 83% of younger pts received AC (p<0.0001). A benefit from AC compared to observation was seen in pts ≥ 70yrs [HR 0.30; p <0.0001] and <70yrs [HR 0.22; p<0.0001]. Of 65 stage III pts from the single institution there were no differences in CCI, ECOG PS, tumor grade, R0/R1 resections between >70yrs (n=20) and <70yrs (n=45). There was a difference in those receiving AC: 75% ≥ 70yrs compared to 96% <70yrs (p=0.02). Conclusions: Adoption of AC is associated with a survival benefit in older pts (age ≥ 70 yrs), however, is still underutilized in clinical practice. Age impacts the decision to treat in our cohort.
North American (NA) subgroup results from VELOUR: Ziv-aflibercept versus placebo plus FOLFIRI in mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen.
Authors: Mitchell Edith P. , Guarino Michael J. , Andria Michael L. , Bhargava Pankaj , Kirshner Jeffrey J.
Published: March 2020

e14528

Background: Ziv-aflibercept (known outside the US as aflibercept) is a multiple angiogenic factor inhibitor that prevents VEGF-A, VEGF-B, and PlGF from binding their receptors. Ziv-aflibercept in combination with FOLFIRI was FDA approved for metastatic colorectal cancer (mCRC) patients who are resistant to or have progressed following an oxaliplatin-containing regimen. Approval was based on the multinational phase 3 VELOUR trial (N=1226) showing statistically significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with ziv-aflibercept/FOLFIRI. Detailed analyses of the NA subgroup are presented here. Methods: Patients were randomized 1:1 to ziv-aflibercept 4 mg/kg + FOLFIRI or placebo (pbo) + FOLFIRI q2wks. Patients had ECOG PS ≤2 and 1 prior oxaliplatin-based regimen; prior bevacizumab was allowed. Primary endpoint was OS. NA analysis was prespecified but not powered to compare within or between subgroups. Results: NA patients (n=138) were randomized to ziv-aflibercept/FOLFIRI (n=63) or pbo/FOLFIRI (n=75). Baseline characteristics were similar in both arms (ziv-aflibercept: median age 61 y; 60% male; 96% PS 0-1; 56% >1 metastatic organ; 74% prior bevacizumab) and were similar to the worldwide population. Median OS for ziv-aflibercept vs pbo was 17.94 vs 12.88 mos; median PFS was 6.01 vs 4.17 mos; ORR was 12% vs 9%. On average, patients received more cycles (median 8.5 vs 7.0), had longer duration of exposure (median 20 vs 14 wks), and more treatment modifications with ziv-aflibercept vs pbo. Most severe AEs (grade ≥3) with ziv-aflibercept were grade 3, including hypertension, venous thromboembolic events, proteinuria, diarrhea, fatigue/asthenia, infection, stomatitis/ulceration, and neutropenia; there were few grade 4 AEs. Conclusions: Ziv-aflibercept/FOLFIRI in mCRC patients previously treated with an oxaliplatin-based regimen showed improvements in OS, PFS, and ORR with an acceptable safety profile. NA results are consistent with the VELOUR worldwide population. Clinical trial information: NCT00561470.
Survival benefits of adjuvant chemotherapy in high-grade stage II and III colon cancer.
Authors: Tsang Walter , Ziogas Argyrios , Nangia Chaitali Singh , Zell Jason A.
Published: March 2020

e14529

Background: High-grade (HG; poorly differentiated and undifferentiated) colon carcinoma has an increased risk of recurrence after surgical resection compared to low-grade tumors. However, the benefits of adjuvant chemotherapy (AC) in this patient population remain unclear. Using a large population-based database, we examined survival outcomes of HG stage II/III colon cancer patients treated with or without AC. Methods: Stage II/III adult colon cancer patients with HG tumors who have undergone resection were identified in the California Cancer Registry from 1989 to 2006, with follow-up through 2009. Estimates of Colorectal Cancer Specific Survival (CRC-SS) were generated using Kaplan-Meier methods. CRC-SS multivariate analyses were performed using Cox proportional-hazard regression models adjusted for age, gender, race/ethnicity, histology, tumor site, chemotherapy, time period of diagnosis (1989-1994, 1995-2000, 2001-2006) and socioeconomic status. Results: Significant CRC-SS improvements were observed in stage III patients treated with AC (n=3,793) versus no AC (n=2,582) in univariate (Table) and multivariate analyses (HR=0.89, 95% CI 0.82-0.96). In contrast, among stage II patients treated with AC (n=1,232) vs. no AC (n=3,470), no differences were observed in univariate analyses (Table); furthermore, an increased risk of CRC-specific mortality was observed in multivariate analyses (HR=1.23, 95% CI 1.06-1.44). Conclusions: In high-grade colon cancer, despite significant survival benefits of adjuvant chemotherapy to stage III patients, adjuvant chemotherapy was independently associated with increased mortality in stage II patients. These findings invoke new questions about the utility of adjuvant chemotherapy among patients with high-grade stage II colon cancer. [Table: see text]
Adjuvant systemic chemotherapy with or without bevacizumab in patients with resected pulmonary metastases from colorectal cancer.
Authors: Turan Nedim , Dane Faysal , Unal Olcun Umit , Benekli Mustafa , Kara Hasan volkan , Koca Dogan , Balvan Ozlem , Eren Tulay , Tastekin Didem , Dogan Erkan , Helvaci Kaan , Demirci Umut , Berk Veli , Ozturk Selcuk Cemil , Kucukoner Mehmet , Gumus Mahmut , Oztop Ilhan , Coskun Ugur , Ozet Ahmet , Buyukberber Suleyman
Published: March 2020

e14533

Background: To determine impact of modern chemotherapy regimens after pulmonary metastasectomy from colorectal cancer (CRC). Methods: A total of 122 consecutive patients who curatively resected for pulmonary metastases of CRC in eleven oncology centers were retrospectively analysed between January 2000 and April 2012. Results: Of 122 patients, 108 who received chemotherapy with fluoropyrimidine-based (n = 12), irinotecan-based (n = 56) and oxaliplatin-based (n = 40) combinations were analyzed. Among these, 52 patients received bevacizumab (BEV) while 56 did not (NoBEV). With a median follow-up of 14 months after metastasectomy, median recurrence-free survival (RFS) was 17 months, overall survival (OS) was not reached. Three and 5-years OS rates were 66% and 53%, respectively. There was no significant difference among cytotoxic regimens in respect to RFS and OS. Similarly, no significant difference was seen between BEV and NoBEV arms in respect to OS and RFS. In univariate analysis prior liver metastasectomy (p = 0.045), positive pulmonary margin (p = 0.028), disease-free interval < 12 months (p = 0.013), and KRAS mutation (0.009) were negative significant prognostic for RFS. Thoracic pathological lymphatic involvement (p = 0.006) and higher prethoracotomy carcinoembryonic antigen (p = 0.038) were negative significant prognostic for OS. In multivariate analysis, positive pulmonary margin was the only negative independent prognostic for RFS, while thoracic lymphatic involvement was the only negative independent prognostic for OS. Conclusions: Chemotherapy type and addition of bevacizumab have no impact on both RFS and OS in the adjuvant setting following complete resection of colorectal pulmonary metastases.
Cetuximab with irinotecan or oxaliplatin for first-line metastatic colorectal cancer: Effectiveness in the EREBUS cohort compared to pivotal trials.
Authors: Fourrier-Réglat Annie , Rouyer Magali , Noize Pernelle , Bignon Emmanuelle , Le Monies Alise , Jove Jeremy , Monnereau Alain , Sa Cunha Antonio , Francois Eric , Mitry Emmanuel , Smith Denis Michel
Published: March 2020

e14542

Background: Cetuximab (CTX) has demonstrated improved survival outcomes in metastatic colorectal cancer (mCRC) but information from real-life use is sparse. Here, CTX survival and safety outcomes in real-life are compared to those observed in OPUS and CRYSTAL trials. Methods: EREBUS is a French multicenter cohort study that included over two years (2009-2010) patients with unresectable mCRC and wild-type KRAS initiating CTX as 1st-line therapy in 65 centres and followed for 12 months from treatment initiation. Results: We included 389 patients treated with a combination of CTX with irinotecan-based (56.0%) or CTX with oxaliplatin-based (37.8%) chemotherapy. The main characteristics, safety, response rate, and one year survival of this cohort are presented in the Table below in parallel with results obtained in pivotal trials. Conclusions: Despite differences in baseline characteristics between real-life and pivotal trials (such as ECOG status), the response rate and PFS were comparable in mCRC patients with wt KRAS treated with 1st-line CTX. The nature of adverse events was in-line with the trials but the frequency was lower probably owing to under-notification in real-life. [Table: see text]
Pooled survival analysis of series using the liver-first approach to the management of colorectal cancer with synchronous liver-limited metastases demonstrates wide variation in outcome.
Authors: Jegatheeswaran Santhalingam , Siriwardena Ajith K.
Published: March 2020

e14547

Background: Options for the management of patients with colorectal cancer with synchronous liver-limited metastatic disease include synchronous (liver and bowel) resection or sequential surgery: either the classic bowel-first approach or the newer liver-first strategy. This latter approach is popular but has little evidence underlying it. This study undertakes a pooled analysis of protocol and outcome of all reports of the liver-first approach for synchronous metastases. Methods: PubMed, Embase, science citation index, social sciences citation index and the Derwent innovations index were searched using terms describing colorectal cancer, liver metastases and surgery. The literature search identified 417 articles of which 4 cohort study reports described the liver-first approach and reported survival data and constitute the study population. A pre-defined protocol for data extraction was utilised to retrieve data on design, distribution of primary and hepatic metastatic disease, chemotherapy, surgery, patients completing treatment algorithm, outcome and survival. Data were extracted to populate a PRIZMA quality-control chart. Results: The 4 studies comprised 121 patients starting treatment of whom 90 (74%) completed the specified treatment protocol (83 rectal primary, 33 colon primary and primary site unreported in 5). Disease progression during the protocol period occurred in 23 (19%). Ninety six (79%) of the starting cohort of 121 reached the stage of liver resection with disease progression or death during chemotherapy being the principal causes of failure. Preferred algorithm was systemic chemotherapy (median 3 to 6 cycles) followed by hepatectomy with colorectal resection as the last step. There was wide variation between the reports in terms of their survival data. Conclusions: The liver-first approach is technically feasible in patients with colorectal cancer and synchronous hepatic metastases. About 20% will fail to complete the full treatment protocol because of disease progression. To date, there are no data to suggest superiority of outcome over the classic approach or synchronous surgery.
Functional polymorphism in the microRNA-367 binding site as a prognostic factor for colonic cancer.
Authors: Chae Yee Soo , Lee Soo Jung , Kim Jong Gwang , Kang Byung Woog , Lee Yoo Jin , Park Ho Yong , Choi Gyu Seog , PARK JUN Seok
Published: March 2020

e14549

Background: As microRNAs play important roles in cancer development and progression by regulating the expressions of oncogenes and tumor suppressor genes though interacting with the 3′ untranslated region (UTR) of target genes, we aimed to evaluate the association between genetic variants of miRNAs and their binding sites and prognosis in patients with colorectal cancer (CRC). Methods: Three miRNA variants and four variants in the miRNA binding sites were selected based on allelic frequencies and potential impact described in previous studies. DNA was extracted from fresh-frozen tissues of 344 patients with CRC who underwent curative surgery and genotyping analyses were performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Results: Among seven target variants, rs1044129 at the miR-367 binding site of calcium channel ryanodine receptor gene 3 (RYR3) was associated with relapse-free survival (RFS) for colon cancer patients as a recessive model in a univariate analysis. Moreover, a multivariate analysis revealed that patients carrying the GG genotype had poor RFS compared to those with the AA or AG genotype (hazard ratio, HR=2.864; p=0.005), yet there was only a marginal trend for disease-specific survival (HR=2.226; p=0.087) regardless of the patient and tumor characteristics. Conclusions: The current study suggests that the functional variant (rs1044129) in the miR-367 binding site of RYR3 may be a potential marker for prognosis in patients after curative surgery for CRC.
The efficacy and safety of XELOX plus bevacizumab with oxaliplatin stop-and-go strategy in first-line treatment for metastatic colorectal cancer: Final report of CCOG-0902 study.
Authors: Hayashi Naomi , Nakayama Goro , Ishigure Kiyoshi , Yokoyama Hiroyuki , Yaguchi Toyohisa , Kojima Hiroshi , Tsuboi Kenji , Ito Akihiro , Deguchi Tomohiro , Sekiya Masanori , Tanaka Chie , Uehara Keisuke , Ando Yuichi , Kodera Yasuhiro ,   Chubu Clinical Oncology Group
Published: March 2020

e14552

Background: XELOX plus bevacizumab (BEV) is an established first line therapy for metastatic colorectal cancer (mCRC). However, the cumulative neurotoxicity of oxaliplatin often requires therapy to be discontinued while the patient is still responding. The aim of this study was to evaluate efficacy and safety of XELOX plus BEV with oxaliplatin stop and go strategy. Methods: Fifty four patients with unresectable mCRC were enrolled as first line treatment. They were treated with four cycles of XELOX plus BEV, followed by maintenance therapy with capecitabine (Cape) plus BEV. Reintroduction of oxaliplatin was scheduled after eight cycles of Cape plus BEV or upon tumor progression. The primary endpoint was progression free survival (PFS). Results: Forty nine patients (90%) achieved to the maintenance therapy and thirty two patients (59%) were reintroduced oxaliplatin. After a median follow-up time of 24.2 months, median PFS was 13.4 months (95%CI: 11.7-15.1), median duration of disease control was 13.8 months (95%CI: 11.6-16.0) and median overall survival was 29.0 months (95%CI: 23.1-34.9). The response rate and disease control rate were 57.4% and 96.3% in the initial XELOX plus BEV therapy, 6.1% and 73.5% in Cape plus BEV maintenance therapy, and 0% and 72.4% in reintroduced XELOX plus BEV therapy. The incidence of neuropathy was 38% in initial therapy, 33% in maintenance therapy and 43% in reintroduced therapy. Conclusions: XELOX plus bevacizumab therapy with oxaliplatin stop-and-go strategy was feasible to maintain long disease control without increasing severe neurotoxicity in first-line treatment for mCRC. Clinical trial information: UMIN000006478.
Are XELOX and FOLFOX equivalent in colorectal cancer? Dose intensity, toxicity, and treatment duration in clinical practice.
Authors: Gao Ya Ning , Mamo Aline , Palumbo Michael Ostaric , Batist Gerald , Chaudhury Prosanto , Melnychuk David , Metrakos Peter , Panasci Lawrence , Kavan Petr ,   McGill Oncology Group
Published: March 2020

e14556

Background: Xelox and Folfox regimens have been shown to be equivalent in clinical trials for colorectal cancers. However, concerns about toxicity induced by Xelox in clinical practice have been reported, resulting in reduced dose intensity. In this retrospective analysis, we compared the dose intensity of Xelox to Folfox in relation to toxicity. Methods: 208 patients were treated in adjuvant (Xelox: n=56, median age 65 years; Folfox: n=40, median age 66 years) or metastatic (Xelox: n=65, median age 66 years; Folfox: n=47 median age 62 years) settings. 90% of patients had ECOG 0-1. Results: In the adjuvant setting, 86% of patients treated with Xelox received a lower dose of the drug up front, compared to only 10% of Folfox-treated patients. Additional dose reductions occurred in subsequent cycles in 23% of Xelox-treated patients (mean relative dose intensity (RDI) Oxaliplatin: 72%; Capecitabine: 74%) but not Folfox-treated patients (mean RDI Oxaliplatin: 85%, 5-FU: 86%). A higher percentage of Folfox-treated patients had toxicities compared to Xelox-treated patients: nausea (30% vs 18%), diarrhea (47% vs 24%), and peripheral sensory neuropathy (32% vs 3%). Treatment delays were more frequent in Folfox (40%); mean cumulative delay, 9.4 (range 2.1-52.4) weeks, compared to Xelox (20%); mean cumulative delay, 10.2 (3.1-48.1) weeks. Mean treatment duration was equal (Xelox: 22.8 (3.0-78.1); Folfox: 22.6 (2.3-64.4) weeks). In the metastatic setting, results followed a similar pattern. 75% of Xelox-treated patients received a lower dose up front compared to 33% of Folfox-treated patients. Further dose reductions occurred in 31% of Xelox-treated patients (mean RDI Oxaliplatin: 70%; Capecitabine: 67%) compared to 20% of Folfox-treated patients (mean RDI oxaliplatin: 75%; 5-FU: 69%). Treatment delays occurred in 60% of Folfox-treated patients and 43% of Xelox-treated patients becauseof toxicities. Mean treatment duration was 24.9 (3.0-65.0) and 26.1 (4.0-60.1) weeks respectively. Conclusions: The higher dose reduction of Xelox compared to Folfox appeared to enable treatment completion with less toxicities. The impact on survival and cost of treatments will be presented.
Is adjuvant oxaliplatin (Ox) overutilized in colon cancer (CC): 408 cases from the practices of 102 oncologists.
Authors: Ziel Kathryn , Grothey Axel , Venook Alan Paul , Hussein Atif Mahmoud , Moss Jonathan , Love Neil
Published: March 2020

e14564

Background: Recent long-term clinical trial follow-up suggests that adding Ox to a fluoropyrimidine (FP) may provide less benefit in adjuvant CC than originally believed (Tournigand JCO 2012). In addition, emerging data on tissue biomarkers such as microsatellite mismatch repair (MMR) and the 12-gene Recurrence Score (RS) suggest these assays may be helpful in better defining treatment benefit, and a new report provides evidence that RS may specifically predict the value of Ox (O'Connell ASCO 2012). In view of these developments we sought to document current use of adjuvant chemotherapy and physician perceptions about these decisions. Methods: U.S.-based oncologists were recruited to complete a survey and contribute treatment data for their last three patients (pts) with stage II disease and last pt with a stage III tumor. Results: 25 gastrointestinal cancer clinical investigators and 77 practicing oncologists participated, providing data from a total of 408 cases (92% treated since 2011). Findings from the two groups are similar and are presented in aggregate. A median of 9 and 15 pts annually were evaluated with Stage II and III tumors, respectively. Clinicians stated that they require a median of a 5% absolute reduction in relapse rate to use a FP alone and an additional 5% reduction to add Ox. Ox/FP was administered to 95 of 102 pts with stage III tumors (93%) and 85 of 306 pts with stage II disease (28%), particularly to those under age 70 or with T4 tumors (Table). MMR was evaluated in 127 pts (42%) with stage II and 20 pts (20%) with stage III disease. RS was obtained for 46 pts (15%) with stage II tumors, but only 2 pts (2%) with stage III. Conclusions: Adjuvant Ox is employed widely in spite of the fact that it may provide less benefit than many oncologists report requiring to initiate its use. However, several recent research developments may be laying the groundwork for a change in this treatment practice. [Table: see text]
Nodal status after preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer: Prognostic evaluation of number of resected lymph nodes (LNs), metastatic resected LNs, and LN ratio in the National Cancer Institute of Brazil.
Authors: Vieira Fernando Meton , Araujo Rodrigo Otavio , Victorino Ana Paula , Oliveira Maria de Lourdes , Ferreira Carlos G. M.
Published: March 2020

e14568

Background: For accurate colon cancer staging, 12 or more LNs must be resected. However, in rectal cancer, preoperative CRT can decrease the number of evaluable LNs, and the cutoff for a minimum number of LNs retrieved is unclear, as well as the prognostic value of LN ratio. Methods: We evaluated all locally advanced rectal cancer that received CRT followed by standard surgery (TME) from 2002 to 2009. External radiotherapy consisted of 45 to 50.4 Gy in 5 weeks and concomitant chemotherapy was bolus 5-Fu/LV. Pre-treatment staging included abdominal and pelvic CTs, chest RXs, CEA, and physical examination. Clinical data was collected from medical records and surgical specimens were pathologically evaluated accordingly to Quirke's method. LN ratio was defined as the ratio of the number of positive LN and total number of LN examined. Kaplan-Meier overall survival (OS) and disease free survival (DFS) curves were obtained and compared using the Long-rank test. Categorical variables were assessed using Fish's exact test. Results: Of 202 patients included, 125 (62%) were low rectal cancers (5cm or less from anal verge). Surgery was performed in a mean time interval from CRT of 3.95 months (0.28-24), and the type of resection was a low anterior resection in 139 (64%) and abdominoperineal resection in 63 (36%). Only 42.5% received postoperative chemoterapy. LN metastasis at the vascular stump level were more frequent in cancers lying more than 5 cm above the anal verge (p=0.02). Median number of LNs found in the specimens was 12 (0-56). The number of resected LNs had no impact in prognosis within the cutoff levels of 7 or 12, neither when considering only ypN0 cases. A LN Ratio >0.15 was found in 33% of our patients, and associated to a decrease in OS (p<0.001) and DFS (p=0.01), and was the only variable associated to distant metastasis (p=0.048). Conclusions: Positive LNs after CRT severely impaired prognosis in patients treated with rectal cancer. A prognostic cutoff value for LN dissection were not achieved, but a LN ratio >0.15 seems to be a strong predictor of recurrence and cancer related death.
Risk for developing brain metastases from colorectal cancer in long-term survivors with lung metastases and KRAS mutations.
Authors: Zoratto Federica , Loupakis Fotios , Cremolini Chiara , Salvatore Lisa , Schirripa Marta , Antoniotti Carlotta , Marmorino Federica , Campenni Giuseppe , Bergamo Francesca , Zagonel Vittorina , Lonardi Sara , Tomao Silverio , Cortesi Enrico , Allegrini Giacomo , Lucchesi Sara , Morvillo Manfredi , Savi Roberta , Marcucci Lorenzo , Minuti Gabriele , Falcone Alfredo
Published: March 2020

e14574

Background: Brain metastases (BM) occur in 1-4% of metastatic colorectal cancer (mCRC) patients (pts). Retrospective series evidence that pts with a long survival from the diagnosis of mCRC are more frequently affected. Moreover, BM seem to be associated with lung metastases and KRAS activating mutations. The identification of clinical and molecular features correlated with BM may allow to define a subgroup more likely to develop BM, thus to benefit from neuroimaging follow up and early treatment. Methods: We prospectively tested the hypothesis that a higher incidence of BM occurs in a population of mCRC pts with a survival time from the diagnosis of mCRC ≥10 months, lung metastases and KRAS exons 2 and 3 mutations. Given a reported incidence of BM in unselected mCRC of around 3% (H0) and expecting an incidence in an “at risk” population selected on the basis of the 3 above reported features of 10% (H1), setting α and β errors to 0.05 and 0.10 respectively, we adopted the Fleming single-stage design for calculating the sample size of our analysis. The null hypothesis would have been rejected if at least 7 out of 104 “at risk” pts had developed BM. Results: 623 pts, enrolled in clinical trials treated with first-line chemotherapy and bevacizumab, were included in the overall study population in order to identify 105 (16.9%) pts who simultaneously had a survival time from the diagnosis of mCRC ≥10 months, lung metastases and KRAS exons 2 and 3 mutations. 26 (4.2%) out of 623 pts developed BM. 14 out 518 (2.7%) not “at risk” pts presented BM, while 12 out of 105 (11.4%) “at risk” pts did. The incidence of BM in the two groups differed significantly (Fisher’s exact test, p=0.0004). The null hypothesis was rejected according to the original design. Conclusions: This analysis confirms the hypothesis that the concomitant presence of the 3 analyzed risk factors increases the probability of developing BM in mCRC patients. Based on these data, the opportunity to consider a neuroimaging exam, such as brain CT scan or MRI, in this specific population might be taken into account in order to provide an early diagnosis of BM and therefore the most appropriate therapy in an asymptomatic phase.