bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative study of six cycles versus twelve cycles of adjuvant temozolomide post concurrent chemoradiation in newly diagnosed glioblastoma.
Authors: Bhandari Menal , Gandhi Ajeet K , Julka Pramod Kumar , Sarkar Chitra , Sharma Dayanand , Rath Goura Kishor
Published: March 2020

e13034

Background: This study assesses the impact of 6 cycles of adjuvant TMZ (conventional arm) versus 12 cycles (Extended arm) on Progression free survival (PFS), evaluate the toxicity and correlate the outcome with EGFR, P53 and MIB I labelling Index. Methods: Between December 2010 to October 2012, 36 post operative patients of Glioblastoma between age 18-65 years and Karnofsky Performance Score (KPS) ≥ 70 were included. Patients were randomized to receive Radiation with a dose of 60 Gray in 30 fractions over 6 weeks at 2 gray/fraction with concomitant TMZ (75 mg/m2/day) and Adjuvant therapy with either 6 or 12 cycles of TMZ(150 mg/m2 for 5 days, 28 days cycle). Patients were then assessed monthly clinically and imaged with MRI/CT every 3 monthly or when symptomatic. Toxicity was assessed using CTCAE version 3.0. Statistical Analysis was done using SPSS version 17.0.Kaplan Meier method was used for analysis of survival and log rank test was used for assessing the impact of variables on survival. Results: Of 36 patients, 18 patients were treated in each arm. Median age and KPS in both the arms was 47 years and 80 respectively. 44 % patients in the conventional arm and 50% patients in the Extended arm underwent complete surgical resection. 22% patients in the conventional arm and 28% in the extended arm did not complete their intended treatment. Grade ¾ Thrombocytopenia was seen in 16% in the extended arm and 0% in the conventional arm.EGFR, P 53 and MIB 1 >20% was seen in 26%, 45% and 20% patients respectively, overall. Median follow up was 18 months for both the arms (Range 10-23 months).At last follow up,8 patients in each arm had progression. Median PFS was 10 months vs.18.4 months (p 0.47) in conventional and extended arm respectively. On Univariate analysis, patients with KPS ≤ 80 had poorer survival than those >80 (Median PFS 9.5 Months vs. 16.9 Months; p 0.02).Age, extent of resection, EGFR, P53, MIB 1 did not significantly alter survival in the two treatment groups. Conclusions: Our study showed that schedule of extended Temozolomide is well tolerated by patients and tend to have better progression free survival. Further prospective randomized studies are needed to validate the findings of our study.
Prognostic value of the EGFR gene amplification by chromogenic in situ hybridization (CISH) in adult patients with glioblastoma.
Authors: Bella Santiago Rafael , Theaux Ricardo Alejandro , Lingua Alejo , Llugdar Jose Roberto , Papalini Francisco , Olocco Ricardo , Ferraris Gustavo Alberto , Magri Ignacio , Lerda Daniel
Published: March 2020

e13036

Background: Prognosis of patients with glioblastoma is based on clinical characteristics: age, performance status (PS), neurological deficit and extent of surgery. Two prognostic scores have been developed: Medical Research Council and RTOG scores. Molecular features of the tumor may also be accurate to determine the prognosis. Amplification of EGFR is found in 35% to 40% of patients, being more common as age increases. Researches of EGFR gene amplification by PCR and FISH have reported contradictory results. Methods: Research was carried out retrospectively to determine the prognostic value on survival of EGFR gene amplification by CISH in patients with glioblastoma, as well as age, extent of resection and post-surgery neurological PS. Results: EGFR gene amplification was analyzed in 42 patients. Average age: 56 years. 12 patients were under 50 years old and 30 patients were 50 years of age or older. 20 patients (48%) underwent complete resection, 10 patients (23%) partial resection and 12 patients (29%) biopsy. Of all patients, 12 (28.6%) had EGFR gene amplification. Only 1 of the 12 patients less than 50 years old presented amplification, while 11 of the 30 patients (36.6%) older than 50 years had such amplification. There were no significant differences in survival according to age groups, extent of resection and post-surgery neurological performance status. During follow-up, 11 of 12 patients (92%) with amplification died, while 20 of the 30 patients (67%) without amplification had died. There was a difference in survival with statistical significance for patients without EGFR gene amplification: equal test survival distributions for different levels of EGFR, Log Rank (Mantel-Cox) Chi Cuadrado 7,054, Gl 1,k, Sig 0,008. Conclusions: EGFR gene amplification in adult patients with glioblastoma negatively impacts patient survival.
Metabolic profiles of ketolysis and glycolysis in malignant gliomas: Possible predictors of response to ketogenic diet therapy.
Authors: Chang Howard T. , Olson Lawrence Karl , Schwartz Kenneth A.
Published: March 2020

e13048

Background: The enzymatic differences in energy metabolism between normal brain tissues and malignant gliomas formed the basis for animal model studies that showed increased survival in mice with orthotopically transplanted glioblastoma multiforme (GBM) treated with energy restricted ketogenic diet (ERKD). To test the hypothesis that human brain tumors may also be sensitive to ERKD, we used immunohistochemistry reactions on formalin fixed paraffin embedded tumor samples to evaluate for the presence of enzymes important for the metabolism of ketones and glucose. Methods: Immunoreactivities were graded using a semi-quantitative scale based on the percentage of positive cells: low positive<5% (LOW); intermediate (INT) 5-20%; and highly positive (HIGH) >20%. Focal non-neoplastic “normal” brain tissue present within the specimens served as positive internal controls. Results: Succinyl CoA: 3-oxoacid CoA transferase (OXCT1) and 3-hydroxybutyrate dehydrogenase 1 (BDH1) are mitochondrial enzymes important for metabolizing beta hydroxy butyrate, the main ketone in blood. Both of these enzymes were either decreased or absent (INT or LOW) concordantly in 14 of the 17 (82%) GBMs, and in 1 of 6 (17%) anaplastic astrocytomas (AA). Two of the enzymes in the glycolytic pathway hexokinase-2 and pyruvate kinase M2 were concordantly LOW or INT in only 3 of the 17 GBMs that also were LOW or INT for both OXCT1 and BDH1. The remaining brain tumors were positive for at least one of these glycolytic enzymes. Mitochondrial enzymes were not globally deficient. The mitochondrial enzyme acetyl CoA transferase (ACAT1) was present in 9 of the 14 GBM specimens that were LOW or INT for the mitochondrial enzymes OXCT1 and BDH1. Conclusions: Our data showing that many, but not all, malignant gliomas lack ketolytic enzymes, support the rationale of ERKD as investigational treatment for patients with malignant gliomas. Moreover, we hypothesize that it is important to test individual tumor samples for the expression of these enzymes prior to ERKD, as patients with malignant gliomas that have diminished capacity to metabolize ketones likely may derive the most benefit from ERKD.
Final results of a phase I study evaluating the combination of linsitinib, a dual inhibitor of insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor (IR) with weekly paclitaxel (PAC) in patients (Pts) with advanced solid tumors.
Authors: Harb Wael A. , Sessa Cristiana , Hirte Hal W. , Kaye Stanley B. , Banerjee Susana N. , Christinat Alexandra , Simantov Ronit , Singh Margaret , Sternberg David W. , Light Rebecca , Poondru Srinivasu , Naumann R. Wendel
Published: March 2020

e13502

Background: Linsitinib (OSI-906) is an oral inhibitor of IGF-1R and IR. Increased IGF-1R and IR activity is observed in human cancers and implicated in resistance to chemotherapy. In preclinical studies, linsitinib blocked IGF-1R/IR-AKT pathway activity evoked by PAC treatment. This study combines linsitinib + a cytotoxic agent. Methods: Pts with advanced solid tumors received weekly IV PAC (80mg/m2) in 21-day cycles with intermittent linsitinib (Arm A, d1-3q7d) or continuous linsitinib (Arm B, B2 and B3, twice daily (BID) d1-21). The primary objective was to determine the maximum tolerated dose (MTD) of linsitinib + PAC using a standard 3+3 phase I design. Results: 58 pts were treated (49F:9M, median age 58 yrs). Linsitinib doses of 300mg to 600mg daily (QD) d1-3q7d in Arm A and 75mg to 150 mg BID in Arm B were evaluated. Dose limiting toxicities in Arm A (n=27) were grade G3 neutropenia, G2 neuropathy and G3 deep vein thrombosis (DVT), and in Arm B (n=31) were G3 hyperglycemia, G3 fatigue (n=2) and G4 pulmonary embolism (PE). DVT and PE were reported as unrelated to linsitinib. MTD: Arm A = 600mg QD d1-3q7d Arm B = 150mg BID. Most common drug-related toxicities in ≥20%were (any grade; G3): fatigue (60%; 15.5%), nausea (48%; 0%), alopecia (48%; 0%), diarrhea (36%; 5%), drug eruption (21%; 2%), neuropathy (26%; 2%) and dysgeusia (24%; 0%). The median duration of exposure (days) for Arm A was 64.5, 91.0, 132.0 and 159.5 for the 300mg, 400mg, 450mg and 600mg doses, respectively. In Arm B, median duration of exposure (days) was 232.0 and 87.5 for the 75mg and 150mg doses, respectively. Partial response was achieved in 6 pts (10%)-3 ovarian, 1 primary peritoneal, 1 endometrial, and 1 esophageal. Stable disease was achieved in 25 pts (43%) - 10 ovarian, 2 primary peritoneal, 1 endometrial, and 12 pts in other tumor types. Pharmacokinetic (PK) results suggested no substantial PK interaction when linsitinib was administered 2 hours prior to PAC. Conclusions: Linsitinib + PAC did not show any unexpected safety concerns given the known mechanism of action, at doses up to the single agent MTDs. Clinical trial information: NCT00889382.
Effect of treatment with hedgehog inhibitor, PF-04449913, on leukemia-initiation potential in acute myeloid leukemia cells.
Authors: Minami Yosuke , Fukushima Nobuaki , Naoe Tomoki
Published: March 2020

e13520

Background: Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in a variety of cancers, and required for maintenance of the leukemic stem cell population in several experimental systems. PF-04449913 (PF) is a novel oral small molecule inhibitor that targets Smoothened (SMO) in the Hh pathway. Treatment with PF has shown promising results regarding safety, tolerability, and early signs of efficacy in a phase 1 study of hematologic malignancies including acute myeloid leukemia (AML) (Jamieson C, et al. ASH, 2011). Methods: We used AML cell lines and primary AML cells in order to elucidate mechanisms and biomarkers in PF treatment. We also used a co-culturing system with HS-5 stromal cells, and an immunodeficient NOD/SCID/IL2rγnull (NOG) mouse model serially xenotransplanted with primary AML cells to evaluate effects of PF on AML propagation. Results: In vivo-treatment with PF attenuated leukemia-initiation potential in acute myeloid leukemia cells through the serial transplantation system, while limiting reduction of tumor burden in the primary leukemia system. Ex vivo-treatment with PF inhibited proliferation and minimally induced cell death in leukemia cell lines and primary AML cells increased expression of the myeloid differentiation marker, CD11b. In addition, PF treatment down-regulated mRNAs encoding downstream effector GLIs in the canonical Hh pathway using RQ-PCR assays and decreased nuclear expression of GLI-2 using immunofluorescence assays. Moreover, combined treatment with PF abrogated resistance to Ara-C in MOLM-14 cells co-cultured with HS-5 stromal cells. We are also investigating biomarkers in these models including CD markers (such as CD44) as well as the toxicity for normal cord blood cells with PF treatment. Conclusions: These results imply that PF treatment can attenuate leukemia-initiation potential in acute myeloid leukemia cells and improve AML therapy through overcoming the resistance to chemotherapy in the bone marrow microenvironment.
Personality disorders as a result of symptom of chemotherapy-related cognitive impairment (CRCI) antiangiogenic treatment for metastatic renal cancer: A case report of 71-year-old women.
Authors: Wachula Ewa , Zok Jolanta , Ziomek Marzenna , Wysocki Piotr Jan , Rogowski Wojciech
Published: March 2020

e13560

Background: Chemotherapy-related cognitive impairment, known also as chemo brain, is defined as cognitive changes experienced by patients undergoing chemotherapy, especially in aspects of visual and verbal memory, attention and psychomotor functions. Cognitive changes and dysfunction after common cancer chemotherapy and recently appearing after biologic agents are increasing as a disturbing side-effect in cancer survivors. The etiology of this phenomenon is not well understood. Methods: We present the case of 71-year- old female, with metastatic renal cancer who are exposed to anti-angiogenic treatment for years.From 2005 to 2009 the patient was treated by combination therapy which consisted of bevacizumab and INF-alfa.The anti-angiogenic therapy was discontinued prematurely because of cardiac toxicity. Partial response of metastatic lesions was achieved as a result of the treatment. In 2010, new metastases were found, and a second line therapy by m-TOR inhibitor everolimus was commenced. Because of hematological toxicity of CTC grade 3, the patient required a 50% dose reduction. During anti-angiogenic treatment some psychiatric symptoms such as paranoid personality disorders, memory impairment, dementia, emotional coldness and social withdrawal were observed. Results: In laboratory tests any electrolytes and metabolic imbalance were noticed. The CT and the MR imaging of the head excluded any structural damages and focal brain parenchymal lesions. Psychotherapy and pharmacotherapy were suggested.The patient is still on everolimus until now in order to maintain stabilization. Conclusions: The chemotherapy-related cognitive impairment can be problematic for survivors. Better understanding factors that contribute to chemotherapy-related cognitive dysfunction is important because this information could identify patients at risk and inform treatment.
Pharmacologic differences in taxanes leading to difference in clinical activity and toxicity.
Authors: Deshmukh Chetan Dilip , Divekar Ganesh , Jain Minish Mahendra , Bondarde Shailesh Arjun , Bhatt Niraj
Published: March 2020

e13567

Background: Paclitaxel and docetaxel share major parts of their structures and mechanism of action, but differ in several aspects. Both paclitaxel and docetaxel act at microtubule causing tubulin polymer generation but exhibit pharmacodynamic differences. These pharmacological differences may account for the differences observed between taxanes in their clinical activity and toxicity. Methods: Review of articles providing details of taxane pharmacology was conducted to evaluate pharmacological basis. Results: Greater uptake and slower efflux of docetaxel from tumor cells leads to longer retention time; whereas equal uptake and efflux of paclitaxel shorter retention time for paclitaxel. Hence, apoptotic and mitotic responses of paclitaxel is complete within 4 days implying that more frequent (weekly) administration of paclitaxel will be superior. High affinity to β-tubulin with docetaxel (1.9) than with paclitaxel (1.0) allows higher inhibition of tumor growth. Secondly, drug concentration causing maximum polymerization is 0.2 µM and 0.4 µM for docetaxel and paclitaxel, respectively; indicating that docetaxel is twice as potent as paclitaxel in causing microtubule polymerization. Docetaxel arrests cells in the radiosensitive G2/M phase of the cell cycle making it a potent radiosensetizer than paclitaxel. Mechanisms consistent with allosteric modulation of the reductases increase doxorubicinol formation at clinically relevant concentrations of paclitaxel when it is administered with doxorubicin. Enhanced formation of doxorubicinol aglycone, a metabolite potentially involved in the reversible phase of cardiotoxicity causes higher cardiotoxicty when doxorubicin is administered with paclitaxel than with docetaxel. Non linear pharmacokinetics and hypersensitivity with paclitaxel and fluid retention with docetaxel is attributed to excepient of the drug rather than drug itself. Conclusions: Influx and efflux mechanism support superior weekly administration of Paclitaxel. Pharmacological differences between taxanes justify the incomplete resistance seen between taxanes. The incomplete cross resistance is specifically related to docetaxelactivity in paclitaxel resistant cases.
Incidence of mucositis in patients treated with mTOR inhibitor-based regimens and correlation to treatment response.
Authors: Liu Xiaochun , Hong David S. , Fu Siqing , Piha-Paul Sarina Anne , McQuinn Lacey , Falchook Gerald Steven , Williams Jessica , Karp Daniel D. , Subbiah Vivek , Tsimberidou Apostolia Maria , Janku Filip , Zinner Ralph , Wheler Jennifer J. , Wolff Robert A. , Kurzrock Razelle , Naing Aung
Published: March 2020

e13575

Background: Mucositis is a well-known side effect of mTOR inhibitor (temsirolimus) treatment of cancer patients, limiting the use of mTOR inhibitors. We investigated whether combination treatment of temsirolimus with another agent that was not known to cause mucositis would result in a higher or lower incidence of mucositis. We further investigated if there was an association between the severity of mucositis and tumor response to the temsirolimus-based combination treatment. Methods: This retrospective data review was approved by IRB and conducted in the department of Investigational Cancer Therapeutics at MD Anderson Cancer Center. We reviewed the electronic medical records of 87 patients who were enrolled in temsirolimus-based combination phase I trials (n=3), including physician notes from the date they enrolled on the study to the date they came off treatments. We first examined the incidence of mucositis during the course of study and its severity. We assessed patient response to the study treatment with severity of the mucositis. Results: The overall incidence of mucositis in the 3 temsirolimus-based combination trials was 46%, similar to the published data for the single agent of 41%. The grades of mucositis were: for grade 1 (n=14), grade 2 (n=17) and grade 3 (n=9). No grade 4 mucositis was observed. Neither gender nor ethnicity altered the incidence of mucositis. The median onset time was 14 days after the start of the studies. Of 87 patients, 20 responded to the study treatments with at least stable disease for longer than 6 months or a partial or complete response. The incidence of the mucositis was not associated with the response to temsirolimus-based treatment. Severity of mucositis did not correlate with response to the temsirolimus-based regimen. (grades 1/2 vs. ≥ grade 3; p=0.512). Conclusions: The incidence of mucositis did not increase significantly in patients who received a temsirolimus-based regimen compared to single-agent temsirolimus. Severity of mucositis did not correlate with tumor response to the temsirolimus-based regimen. Future study is warranted to optimize management for mTOR inhibitor-induced mucositis.
Paclitaxel in combination with AT-101 induces apoptosis via supressing Bcl-2, bcl-XL, mcl-1 proteins in human breast cancer cells.
Authors: Cakar Burcu , Gursoy Pinar , Atmaca Harika , Kisim Asli , Bozkurt Emir , Uzunoglu Selim , Sezgin Canfeza , Sanli Ulus Ali , Karabulut Bulent , Uslu Ruchan , Karaca Burcak
Published: March 2020

e13578

Background: Paclitaxel, a microtubule stabilizing agent, has been a standard of care for breast cancer. AT-101, is an -/- enantiomer of gossypol, inhibits the Bcl-2 family proteins which contain BH3 domain. We reported previously that Paclitaxel in combination with AT-101 showed strong synergistic cytotoxic and apoptotic effects in human breast cancer cells. In this study, to elucidate the molecular mechanisms involved in the apoptotic effect of AT-101/Paclitaxel combination treatment in breast cancer cells, we investigated the possible roles of anti-apoptotic Bcl-2, Bcl-XL and Mcl-1 proteins which contain BH3 domain. Involvement of caspase 3 and 7 activation was also investigated. Methods: Human breast cancer cells were treated with increasing concentrations of drugs alone or with the synergistic combination doses of AT-101 and Paclitaxel. Cell Death Detection Elisa Plus Kit (Roche) was used to detect apoptosis. Caspase 3/7 activity was evaluated by Caspase-Glo 3/7 (Promega, Madison, WI) kit. Changes in the mRNA levels of Bcl-2, Bcl-XL and Mcl-1 genes were evaluated by qRT-PCR. Expression levels of these proteins were also investigated by Western blot analysis. Results: Combined treatment was shown to have strong synergistic apoptotic effects in MCF-7 and MDA- MB-231 human breast cancer cells. mRNA levels of Bcl-2, Bcl-XL and Mcl-1 molecules were reduced by the combination treatment in both cell lines. In parallel with mRNA levels, Bcl-2, Bcl-XL and Mcl-1 protein levels were significantly reduced after this novel drug combination. Combined treatment also induced caspase 3/7 activation in breast cancer cells. Conclusions: These preliminary data suggest that anti-apoptotic proteins such as Bcl-2, Bcl-XL and Mcl-1 may play important role in the underlying mechanistic rationale of apoptotic effect of AT-101/paclitaxel combination, while pro-apoptotic Bcl-2 related genes (Caspase-3 and Caspase-7) also seem to regulate this synergistic interaction.
The radiosensitization effect of mTOR inhibitior in human tongue squamous cell carcinoma.
Authors: Su Yu-Chieh , Hung Shih-Kai , Yu Chi-Chia , Lee Ching-Chih , Li Szu-Chin , Lai Hung-Chih
Published: March 2020

e13585

Background: mTOR plays a critical role in malignant phenotype in many tumors. Everolimus [RAD001 (40-O-(2-hydroxyethyl)-rapamycin)] is a rapamycin rapalog that is being developed as an antitumor agent and is approved for various cancers. Recently, RAD001 has also been reported to increase the radiosensitization following for amplifying the autophagic pathway; however, it could promote an alternative mechanism that leads to apoptosis. In HNSCC, radiation therapy is a common form of cancer treatment, but locoregional recurrence and/or distant metastasis is the most cause of failure after RT and it results in HNSCC significant morbidity. Evidence from previous studies showed that RAD001 enhanced the cytotoxic effects of radiation in HNSCC cell lines. The molecular mechanism of radiosensitization by RAD001 in HNSCC has not cleared.Our aim is to evaluate the role of molecular mechanism of RAD001-mediated radiosensitization in HNSCC. Methods: Radiosensitivity effects of RAD001 were assays on human oral squamous cell carcinoma cell lines (SCC4 and DuFa). RAD001 (30 and 300 nM)and radiation (0~8 Gy) alone and in combination were evaluated for antitumor activity in the clonogenic assay. Next, we also evaluated the RAD001 on radiation-induced signal transduction by western blot analysis. Results: Here, we show that 300nM RAD001 plus 6 Gy cohort with significant HNSCC cell line growth suppression compared to 6 Gy alone (p=0.004) or 30n MRAD001 plus 6 Gy (p=0.008). RAD001 treatment effectively reduces mTOR downstream effector p-S6 protein compared with the vehicle or irradiated alone. RAD001 + 6 Gy significantly increases p53 and PARP cleavage, which facilitates apoptosis. Unexpectedly, autophagy pathway, such as beclin 1 and LC3II were not affected by RAD001. Addiationlly, we discover that Akt phosphorylation (Ser473) is up-regulated after RAD001/and irradiation of HNSCC cells. Conclusions: These findings suggest radiosensitization by the RAD001 involves the induction of apoptosis in HNSCC. Notwithstanding, Akt signaling is increased under RAD001 and it could attenuate anticancer efficacy instead, contribute to the development of resistance.
Patient compliance to oral anticancer chemotherapy evaluated in breast and colorectal cancer patients receiving capecitabine: The OCTO study.
Authors: Henin Emilie , Bourmaud Aurelie , Colomban Olivier , Schwiertz Vérane , Regnier Veronique , You Benoit , Ranchon Florence , Guitton Jerome , Maraval-Gaget Raymonde , Girard Pascal , Chauvin Franck , Freyer Gilles , Tod Michel , Rioufol Catherine , Trillet-Lenoir Veronique N.
Published: March 2020

e13594

Background: Given the expanding use of oral chemotherapies, optimal compliance to treatment is critical to achieve the best clinical outcome in terms of efficacy and safety. The aim of the OCTO clinical study was to measure patient compliance, either electronically or by self-assessment, to capecitabine-based treatment. Methods: A cohort of patients with either locally advanced or metastatic, breast or colorectal, cancer were monitored for 6 cycles, and ambulatory treated with monotherapy of capecitabine (Xeloda). Treatment was prescribed at 1250 mg/m² as a combination of 500 and 150 mg pills, taken twice daily for 14 days every 3-week cycle. Tumor response was evaluated after 3 and 6 cycles using the RECIST criteria. Toxicity was evaluated using the NCI CTC scale. Compliance was assessed in all patients by self-completed questionnaires on disease, treatment and ambulatory management of side effects; and in half of the cohort by electronic medication event monitoring systems (MEMS) recording the opening times of the pill bottle. Results: Forty patients were enrolled between November 2008 and September 2011 and treated by capecitabine for an average of 4.75 cycles (range: 1-6). 63% patients completed 6 cycles, 22% and 15% patients discontinued due to respectively disease progression and adverse events. Best tumor response was evaluable in 35 patients: 23% had partial response, 54% stable disease and 23% progressed. Hand-foot syndrome was the most reported toxicity (77% patients), and to a lesser extent diarrhea (45%), nausea (30%) and vomiting (30%). In the MEMS cohort, 20 patients were included. Patient compliance was excellent with very few missing occasions (23/2272 records). Timing of morning doses was less variable (p=0.03) than timing of evening ones. Thirty-eight questionnaires were returned. Autonomy of ambulatory oral treatment was appreciated by 54% patients, while resulting in anxiety in 6%. Only 39% patients were concerned by the potential impact of non-compliance while 45% declined answering the question. Conclusions: Compliance to oral anticancer chemotherapy was found excellent in this population, with few deviations from prescription.
Pharmacodynamic effects of regorafenib in metastatic colorectal carcinoma (mCRC).
Authors: Wong Andrea Li Ann , Sinha Arvind , Gopinathan Anil , Lim Robert S.C. , Tan Chee Seng , Soh I Peng Thomas , Venkatesh Sudhakar , Titin Christina , Soong Richie Chuan Teck , Pang Brendan , Sapari Nur Sabrina , Wang Ting Ting , Zee Ying Kiat , Chuah Benjamin , Jeffers Michael , Lathia Chetan , Trnkova Zuzana , Wilhelm Scott , Goh Boon C.
Published: March 2020

e14507

Background: Regorafenib, an oral multikinase inhibitor of VEGFR2/3, PDGFRb, KIT, FGFR, RET, RAF and TIE2, is efficacious in refractory mCRC but its mechanism of action is unclear and predictive biomarkers are lacking. Methods: We assessed tumor and circulatory biomarkers in a phase 2 study of regorafenib in refractory mCRC patients. Regorafenib was administered orally at 160mg/d for 3 out of 4 weeks. Post cycle 2 response was assessed by RECIST 1.1. Subjects were scheduled for FDG PET-CT scans (pre + D15) and paired core needle tumor biopsies for IHC analysis (pre + D21) in cycle 1. Archival tumor mutations were evaluated using Sequenom MassARRAY OncoCarta Panel V1.0 assay. Results: 35 patients were treated; 49% received > 4 prior therapies and 43% had prior bevacizumab. Median PFS was 3.45 mths (95% CI: 3.40-3.49), ORR was 3% and disease control rate [DCR] (PR + SD at 8 wks) was 57%. Early PET responses (EORTC criteria) were seen in 49%, but did not predict for DCR (p=1.0). Fatigue, hand foot skin reaction (HFSR), voice change and diarrhea occurred in > 30% of subjects. Grade 3-5 toxicities occurred in 46%, the commonest being HFSR and rash (17% each). Median relative dose intensity was 92%; 43% required > 1 dose reduction, 60% required > 1 dose interruption. KRAS (29%), BRAF (9%), EGFR (9%), NRAS (6%) KIT (3%), PIK3CA (3%), PDGFRA (3%) and CDK (3%) mutations were detected in archival tumors. None predicted for ORR or DCR; PFS was identical in KRAS mutant vs wt patients (3.45 mths, p=0.39) and similar in BRAF mutant vs wt patients (3.48 vs 3.45 mths, p=0.10). The patient with the longest PFS (12.6 mths) had a BRAF mutation. Amongst the 10 paired tumor samples available, IHC markers upregulated in >50% cases were pMEK, pERK, pJun and pJNK, whilst those downregulated/ unchanged in >50% were pKIT, pVEGFR2, CD31 [vascular endothelial cells (ECs)] and podoplanin (lymphatic ECs). The greatest change was observed in podoplanin expression, corresponding to a 60% reduction in lymphatic vessel density. Conclusions: FDG-PET responses in cycle 1 did not predict for regorafenib clinical benefit in mCRC patients. Targeting lymphatic/vascular ECs in the tumor microenvironment may be a more significant antitumor mechanism of regorafenib than MAP kinase pathway inhibition. Clinical trial information: NCT01189903.
Early prediction of therapeutic efficacy of bevacizumab (Bmab) by measuring plasma concentration of βmab-unconjugated free VEGF-α in patients with recurrent or metastatic colorectal cancer (CRC).
Authors: Cho Yukiko , Fujieda Shinji , Ozeki Mizuharu , Amagai Kenji , Kojima Hiroshi
Published: March 2020

e14510

Background: Although Bmab plus chemotherapy is widely accepted as the standard treatment for recurrent or metastatic CRC, some patients (Pts) are eventually poor responders. We hypothesized that monitoring of Bmab-unconjugated free VEGF-A concentration (conc.) in plasma is useful for predicting the therapeutic efficacy. Methods: Plasma samples were obtained from 20 (13 males & 7 females) recurrent or metastatic CRC Pts with informed consent before Bmab administration and at 1- and 2-M of the 1st administration. VEGF-A conc. was measured by ELISA. For measuring Bmab-unconjugated free VEGF-A, Bmab-conjugated VEGF-A was immuneprecipitated by using protein A/G-Agarose. VEGF inhibitory ratio (%) was calculated by free VEGF-A / total VEGF-A. Clinical response was evaluated according to RECIST, and Pts achieving CR/PR and remaining NC more than 6 months were defined as good responders. Results: Baselineplasma conc. of VEGF-A was 78.45 ± 113.67 pg/ml (mean ± SD), which was significantly higher than that of healthy volunteers. Administration of Bmab did not result in significant decrease in the conc. of total VEGF-A (1- and 2-M: 85.26 ± 41.42 & 99.63 ± 44.87 pg/ml, respectively). In contrast, Bmab-unconjugated free VEGF-A conc. decreased significantly (30.24 ± 91.94 & 45.22 ± 51.23 pg/ml, respectively) (p<0.05), and each inhibitory ratio was 70.18 ± 25.67 and 65.12 ± 32.15%. We then set inhibitory ratio of 70% as the cut-off level, and analyzed the correlation between inhibitory ratio and therapeutic efficacy. Among 11 Pts whose inhibitory ratio reached ≥70% at both 1- and 2-M, 9 Pts (81%) were good responders. Contrary, among the remaining 9 Pts, only 3 Pts (33%) were good responders. There was no correlation between therapeutic efficacy and total or free VEGF-A conc. Conclusions: We consider that early prediction of therapeutic efficacy of Bmab is possible by monitoring the inhibitory ratio of VEGF-A, and that future prospective study for validating its usefulness was warranted.
Survival benefit associated with the number of chemotherapy/biologic treatment lines in 5,129 elderly metastatic colon cancer patients.
Authors: Hanna Nader , Zheng Zhiyuan , Woods Corinne , Onukwugha Ebere , Bikov Kaloyan A. , Seal Brian S. , Mullins C. Daniel
Published: March 2020

e14524

Background: Metastatic colon cancer (mCC) patients often receive multiple lines of chemotherapy/biologics treatment to improve survival, yet the "real world" benefits and risks of multiple treatment lines have not been fully examined. Methods: The National Cancer Institute’s SEER-Medicare data was analyzed to determine the association between the number of treatment lines and 5-year survival in mCC patients. Patients were at least 66 years old, diagnosed with mCC in 2003-2007 and followed until death or 12/31/09. Only patients who survived at least 3 months from diagnosis were included. Cox proportional hazards regression was used along with inverse probability weighting method to adjust for the probability of receiving treatment. Results: Of 5,129 elderly Medicare mCC patients, the 5-year survival rate was 12.9% (n=664). Each incremental treatment was significantly associated with an increase in the average five-year survival by 5.4 months, 7.2 months and 2.7 months for 1st-line, 2nd-line and subsequent treatments, respectively. Significant variables associated with increased mean survival times were receipt of 1st-line, 2nd-line or subsequent treatment compared to no treatment (hazard ratio HR=0.58, 0.36 and 0.32, respectively, p<.01); resection/ablation of liver metastases (HR=0.80, p<.01) and primary site surgery (HR=0.52, p<.01). Significant variables associated with lower survival times were poorly-graded tumor (HR=1.53, p<.01), Charlson Comorbidity Index score of at least 3 compared to 0 (HR=1.15, p=.016), female (HR=1.07, p=.043) and age (in 10-year increments, HR=1.06, p=.011). Conclusions: Among elderly Medicare mCC patients who survived at least 3 months from diagnosis, receipt of 1st-line, 2nd-line and subsequent treatments was associated with incremental increases in the average survival time. However, this may reflect physician treatment patterns in healthier patients who are more likely to receive treatment. Additional factors that significantly increased survival time were primary site surgery (by 5.5 months), resection/ablation of liver metastases (by 1.9 months) and a tumor not poorly-graded (by 3.6 months).
FDG-PET/CT (PET) in the early prediction of benefit from first-line chemotherapy plus bevacizumab (bev) in metastatic colorectal cancer (mCRC).
Authors: Salvatore Lisa , Loupakis Fotios , Cremolini Chiara , Schirripa Marta , Antoniotti Carlotta , Marmorino Federica , Zoratto Federica , Bergamo Francesca , Brunetti Isa Maura , Pfanner Elisabetta , Masi Gianluca , Genovesi Dario , Filidei Elena , Giorgetti Assuero , Falcone Alfredo
Published: March 2020

e14531

Background: The conventional assessment of response according to RECIST seems not optimal to estimate the actual benefit from antiangiogenic agents. A recent experience suggests the potential role of PET in the early prediction of benefit from first-line chemotherapy in mCRC. The objective of the present study was to evaluate the metabolic PET response to one single cycle of chemotherapy plus bev in mCRC patients (pts). Methods: PET was carried out at baseline and on day 13 in 51 unresectable mCRC pts, treated with biweekly bev-containing regimens; computed tomography (CT) scan was performed at baseline and every 2 months. PET response was defined by >15% decrease in FDG uptake in the dominant proportion of lesions, in the absence of metabolically progressive lesions. CT response was defined according to RECIST 1.0. Results: PET response rate was 73%. PET responders achieved longer PFS compared to PET non-responders (median PFS: 11.0 vs 8.3 months; HR=0.45 [95%CI 0.14-0.93] p=0.035). RECIST CT response rate was 62% and 57%, in PET responders and non-responders, respectively (p=0.76). At an exploratory analysis, among pts (N=15) reporting a RECIST-defined stable disease (SD), those with a percentage decrease in FDG uptake higher than the median value (>33%) had significantly longer PFS in comparison to those with a lower PET response (median PFS: 9.4 vs 7.4 months; HR=0.2 [95%CI 0.005-0.24] p=0.0006). Conclusions: Early PET response, assessed after one single cycle of chemotherapy plus bev, predicts PFS, while it does not correlate with traditional RECIST response. In the subgroup of pts reporting a RECIST SD, the early reduction in FDG uptake correlates with PFS. On the basis of our results, early PET response on day 13th could representan early predictor of benefit from bev plus chemotherapy in mCRC.
Disparities between young and elderly patients in the first course of treatment for stage II and III rectal cancers.
Authors: Tilahun Yaphet , Arnoletti Juan Pablo , De La Fuente Sebastian G.
Published: March 2020

e14546

Background: The use of neoadjuvant chemoradiation for stage II and III rectal cancers is associated with higher rates of resectability, sphincter preservation and improved local control. In elderly patients, however, the feasibility and benefits of this approach are less understood. In this study, we determined disparities in the first course of therapy between young and elderly patients with rectal cancer using the National Cancer Data Base (NCDB). Methods: The NCDB was queried for cases of rectal cancer diagnosed from 2000-2009. Analyzed variables included tumor staging, age group and first course of treatment. For analytical purposes, study groups were divided in young (≤ 69 years of age) or elderly patients (≥ 70 years of age). Results: A total of 8,237 patients that received chemoradiation as the first treatment approach were identified from the NCDB during the study period. During the same time, 15,468 patients were treated with surgery first. Fifty-eight percent of patients in the neoadjuvant-first treatment group were equal or younger than 69 years of age. Subgroup analysis showed that elderly patients were treated with surgery first more frequently than with neoadjuvant chemoradiation therapy (surgery-first 72% vs. chemoradiation first 28%, p<0.04). In the contrary, no differences were noted in the first course of treatment received among younger patients (surgery-first 53% vs. chemoradiation first 47%, p=NS). Conclusions: This data shows that there is an age-bias after the age of 70 for surgery only as the first treatment approach for patients with stage II and III rectal cancers. This is probably confirmatory that patients are brought to surgery without neoadjuvant therapy because they are perceived as not being able to tolerate chemoradiation.
Neoadjuvant treatment response as a tumor necrosis grade for patients with rectal cancer.
Authors: Shim Byoungyong , Jung Ji Han , Cho Hyun Min , Kim Hyung Jin , Hong Ji Hyung , Kim Sung Whan
Published: March 2020

e14563

Background: Neoadjuvant chemoradiotherapy for rectal cancer results in prevention of local recurrence and may achieve sphincter conserving surgery. Association between pathologic response evaluated after radical tumor resection and patient prognosis was well established. The object of this study was to assess the association between the degree of tumor necrosis after chemoradiotherapy and oncologic outcomes. Methods: In all, 225 patients with locally advanced rectal cancer (stage II and III by endorectal ultrasonography, CT and MRI) had 50.4 Gy over 5.5 weeks, plus 5-fluorouracil and leucovorin and surgery was performed at 7 to 10 weeks after completion of all therapies. Pathologic tissue necrosis after chemoradiotherapy was reviewed and scored as follows: Grade 0, no response; Grade 1, necrosis or disappearance of tumor cells less than 2/3; Grade 2, necrosis or disappearance of tumor cells more than 2/3; and Grade 3, no viable cells (ypCR). Correlation analysis was performed using Pearson’s Chi square or Fisher’s exact test, as appropriate. Recurrence-free survival and overall survival were calculated using the Kaplan-Meier method. Results: This study included cStage II (101 patients) and cStage III (124 patients) rectal cancer patients, and down stage rate was 57.3% and pCR was 16.9%. The pathologic tumor response ( pStage 0 v I v II v III) was associated with 5-year RFS (97.4 % v 81.5% v 76.6% v 50.0%; p<0.001). The tumor necrosis (Grade 0 & 1 v 2 v 3) was associated with 5-year RFS (64.4% v 76.8 v 97.4%; p=.002). Conclusions: The tumor necrosis to neoadjuvant chemoradiotherapy is a surrogate marker for recurrence and oncologic outcomes in rectal cancer patients treated with 5 flurouracil and leucovorin neo-adjuvant chemoradiotherapy.
Neoadjuvant pelvic perfusion may facilitate resection of pelvic recurrent rectal cancer.
Authors: Wanebo Harold J. , Begossi Giovanni , Belliveau James , Gustafson Eric
Published: March 2020

e14599

Background: Pelvic recurrence of rectal cancer is a persisting therapeutic challenge in spite of wide spread use of adjuvant/neoadjuvant chemo radiation and wide resection isolated pelvic perfusion (IPP) may facilitate pelvic resection in selected high-risk patients.IPP was done in 42 patients with locally advanced previously irradiated rectal cancer, 26 as a preoperative therapy and 16 for palliation. A comparative larger non-perfused group included 63 patients with pelvic resection only for recurrent rectal cancer. Methods: Isolated pelvic perfusion (60 min) utilized pump oxygenation (Temp>41°C)with chemo agents – 5 FU 1500mg/m2, Cisplatin/Oxaliplatin 100/ 150mg/m2, Mitomycin 10-20 mg/m2, which was done in 42 patients (26 as preoperative and 16 as palliative therapy). Results: Palliative IPP in 16 advanced rectal cancer patients (pts)resulted in significant relief (1-4 months) of narcotic resistant pain (in 70%). Preoperative IPP in 26 locally advanced rectal cancer pts achieved a clinical pathologic complete response (CR) in 2 patients, and significant regression in 11 patients rendering them resectable. Seven pts had R0 pelvic resections,(6 abdominal sacral resection (ABSR) and 1 extended APR).Of 8 other patients, 3 responders refused surgery, 5 were excluded.(medical or disease related ). Median survival was 22.5 months in 15 resectable and 32 mos in 7 resected pts (2 pts were 5 year survivors). This is compared to outcome in 63 patients amenable to having pelvic resection alone: 57% had R0 resection (median OS 36 mos), 28% had R1 resection (med OS = 15 mos) and 15% had R2 resection (med OS 21 mos). Conclusions: Neoadjuvant IPP may facilitate selection of recurrent rectal cancer by identifying therapeutic responders likely to benefit from major pelvic resection and excluding non-responders most likely to benefit from non-surgical therapy. The potential to induce regression and facilitate R0 resection merits further exploration.
Phase II study of first-line combined chemotherapy bevacizumab with modified RPMI regimen for elderly or frail patients with unresectable or metastatic colorectal cancer (OGSG0802) update analysis.
Authors: Satoh Taroh , Kato Takeshi , Yoshida Motoki , Miyake Yasuhiro , Iwamoto Shigeyoshi , Nakamura Masato , Sakai Daisuke , Matsuoka Masaki , Otsuji Toshio , Furukawa Hiroshi ,   Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG)
Published: March 2020

e14601

Background: The first-line combined chemotherapy RPMI regimen with bevacizumab (Bmab) in AVF2192g tri al were active. According to the results of efficacy and safety, a fluoropyrimidine (FU) + Bmab regimen is regarded as one of treatment options for 1st-line chemotherapy in many guidelines. We planned a phase II study of modified RPMI regimen with Bmab especially for elderly or frail Pts. Methods: Pts with confirmed unresectable/metastatic colorectal cancer without previous chemotherapy, and not suitable for intensive chemotherapy were enrolled. Pts received modified RPMI regimen (5-FU 600 mg/m2 and l-leucovorin 200 mg/m2 bolus day 1, 8, 15) and Bmab 5 mg/kg day 1, 15, q4w) until disease progression or study withdrawal. The primary endpoint was overall response rate (ORR), and the secondary endpoints were PFS, OS and safety. Results: 41 Pts were enrolled from 13 institutions. Pts characteristics were as follows; median age 76 (range 56-90); male/female, 18/23; ECOG performance status 0/1/2, 21/19/1. The ORR, the rate of best response, the disease control rate (CR+PR+SD) were 36.6%, 56.1%, 85.4%, respectively. Median follow-up period was 14.4 months(Updated results will be presented). 28 Pts (68%) had objective progression and a patient (2.4%) died without progression. The median PFS and OS were 9.0 months (95%CI, 7.5–19.6) and 24.0 months (95%CI, 20.1–NR). The incidences of grade 3 or 4 adverse events were: leukopenia (7%), neutropenia (24%), thrombocytopenia (2%), diarrhea (5%), anorexia (10%), fatigue (5%), stomatitis (7%) and hypertension (5%). Grade 3 febrile neutropenia and grade 4 pulmonary embolism was observed in one pt. Five pts (12%) discontinued the treatment due to severe or uncontrollable adverse event. Conclusions: The modified RPMI regimen with Bmab showed promising activity, and was well tolerated for elderly or frail Pts. ORR and the median PFS of this regimen were similar to historical data with FU + Bmab. This regimen may be a good option for patients with poor PS or elderly with advantages of not requiring percutaneous port placement nor compliance or oral agents. Clinical trial information: UMIN000002182.
Expression and methylation profiles associated with recurrent mutations in stage II colorectal cancer.
Authors: Pare-Brunet Laia , Sanz-Pamplona Rebeca , Lopez-Doriga Adriana , Berenguer-Llergo Antoni , Ausso Susanna , Cordero David , Closa Adria , Moreno Victor
Published: March 2020

e14613

Background: Aberration of normal genetic and epigenetic patterns occurs at early stages of colorectal cancer (CRC) and accumulates throughout cancer progression. To characterize pre-metastatic tumors, a series of stage II, microsatellite stable, colon tumors and their paired mucosa were profiled on RNA expression and DNA methylation microarrays ( www.colonomics.org ). Our aim is to define molecular subtypes based on recurrent gene mutations, methylation and expression profiles, and explore if these molecular subtypes are associated to patients’ prognosis. Methods: We have sequenced exomes (Illumina Genome Analyzer) of a subset of 42 COLONOMICS normal-tumor paired samples (21 good and 21 bad prognosis). Variants identified in normal tissue were used to filter SNPs. DNA methylation (Infinium Human Methylation 450k) and RNA expression (Affymetrix U219) data from those samples were used in this analysis. Correlation was used to assess the association between tumor mutations and differentially expressed/methylated genes. Significant genes were subsequently used to perform tumor clustering. Results: Exome analysis revealed a mean of 150 somatic mutations per sample. From these, 12 variants were recurrently mutated (KRAS, TP53, etc) in more than 3 tumors that were used to define tumor subtypes based on gene methylation/expression patterns. We obtained 12 profiles that clearly identified the cluster of mutated samples. For some profiles, the cluster only includes those tumors with the mutation. Interestingly, some clusters included the mutated samples and additional tumors showing the same phenotype despite not having the mutation. For each mutation, the overlapping between the differently methylated/expressed genes ranged from 14 to 200 common genes. When combining data from the three platforms two main CRC molecular subtypes emerge; each of which shows molecular heterogeneity but no association with prognosis. Conclusions: Mutational status is associated with gene methylation and expression patterns in CRC patients. Although none of these clusters was associated with prognosis, different groups of tumors could be related to distinctive pathways, which may reveal useful as therapeutic targets.