bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of sorafenib plasma concentrations and clinical toxicity: A prospective population pharmacodynamic and pharmacokinetic study
Authors: Billemont B. , Hornecker M. , Ropert S. , Blanchet B. , Jais J. , Blanchard P. , Meric J. , Alexandre J. , Tod M. , Goldwasser F.
Published: August 2020

e14585

Background: Sorafenib is an angiogenesis inhibitor recently approved for the treatment of metastatic renal cell carcinoma and hepatocarcinoma. This oral multi-targeted kinase inhibitor blocks the VEGF, PDGF receptors, BRAF and c-kit. In clinical trials, severe toxicities included rash, hand-foot syndrome and diarrhea. We investigated the relationship between severe toxicity and sorafenib plasmatic exposure. Patients and methods: From February 2008 to December 2008, 32 patients (pts) were treated with sorafenib (800 mg given daily). Clinical and blood exams were performed at baseline and every 2 weeks. Toxicity events were graded according to National Cancer Institute Common Toxicity Criteria 3.0. The sorafenib area under the plasma concentration-time curve over 12 hours (AUC0–12) was determined every 2 weeks by gradient elution liquid chromatography, data analysis with one-compartment disposition and a population approach using NONMEM software. Grade 3 toxicity free survival was estimated by Kaplan-Meier method. Results: Pts (23 males), ECOG 0–1 (27 pts), median age 62.8 years (range 37–78), with metastatic hepato-carcinoma (11), melanoma (6), thyroid cancer (8), renal cell carcinoma (7), received a median treatment duration of 94 days (range : 7–330). 20 pts experienced grade 3 toxicities with 33 events: hand-foot hyperkeratosis (14), diarrhea (5), cutanous rash (4), asthenia (2), anorexia (2), dyspnea (1), scrotal toxicity (1), post surgical complication (1), hypertension (1), increase creatinine level (1), digestive hemorrhage (1). The median AUC0–12 was 62.4 mg/L.h, ranging from 28.7 to 202.2 mg/L.h. Amongst pts experiencing grade 3 toxicity, two groups of 16 pts were defined with the median AUC0- 12 as cut off: low exposure (Lw) and high exposure (Hi). Six Lw pts experienced grade 3 toxicity versus 14 Hi pts (exact Fisher Test p=0.009). The probability of free grade 3 toxicity survival was higher for Lw (Logrank test p=0.004). Conclusions: These results show that grade 3 toxicity occurrence may be related to high plasma sorafenib exposure. This supports the need for therapeutic drug monitoring to prevent toxicity grade 3 occurrence and therefore optimize the clinical management of patients under sorafenib.

No significant financial relationships to disclose.
Single-agent and combination activity of suberoylanilide hydroxamic acid (SAHA, vorinostat) in small cell lung cancer (SCLC) cell lines
Authors: Cubitt C. , Zhang S. , Chiappori A.
Published: August 2020

e14586

Background: SCLC represents a major therapeutic challenge. Histone deacetylase inhibitors (HDAC-I) are a new class of drugs. Exposure to HDAC-Is results in hyperacetylation of core histone proteins, with subsequent chromatin decondensation, and increased topoisomerase inhibitor (TI) DNA binding, with potentiation of DNA damage and apoptosis. This synergy is only observed when the HDAC-I precedes the TI. We investigated the activity of SAHA, an HDAC-I with broad activity in different cancer cell lines, and the potential synergy between SAHA and TIs, in SCLC cell lines. Methods: TIs were obtained from chemical supply companies and SAHA from Merck. Four different cell lines (DMS-114, NCI-H69, NCI-H82, and NCI-H526) were grown and cryopreserved in the recommended media. Drug activity was determined by a high-throughput CellTiter-Blue cell viability assay. A luciferase based assay (Caspase-Glo 3/7) was used to confirm apoptosis as the cause of cell viability reductions. The Chou and Talalay method was used to optimize the drug doses to use in a combination, and to determine the influence of drug sequencing on any additive or synergistic anti- tumor effect. Results: The 72 hours inhibitory concentration 50 (IC50) values corresponding to each drug and cell line is reported in the Table . Using the CellTiter-Blue cell viability assay, the combination index (CI) for SAHA with each of 2 TIs (topotecan and etoposide) was calculated concurrently and sequentially. The strongest synergism was always detected when SAHA and the TI were combined sequentially (SAHA first). This observation was reproduced when the CI was calculated using the Caspase-Glo 3/7 luciferase based assay. Conclusions: The anti-tumor activity of SAHA in SCLC cell lines is comparable to that of common TIs. The synergism observed between SAHA and TIs is sequence specific and highest when drugs are used sequentially (SAHA first). Clinical confirmation of this synergism is warranted in patients with SCLC. [Table: see text]

No significant financial relationships to disclose.
Ex-vivo analysis of the isoform selective histone deacetylase inhibitor entinostat in triple-negative breast cancer tumors
Authors: Ordentlich P. , Tee L. , Huynh Y. , Mee S. , Mamuszka H. , Lee G.
Published: August 2020

e14597

Background: Triple-negative (ER, PR, HER2 negative) breast cancer represents an unmet need for which novel agents and approaches are essential. Entinostat is an orally available, class 1 isoform selective histone deacetylase inhibitor currently in multiple phase 2 clinical studies including advanced NSCLC and breast cancer. Studies in vitro and in vivo in the triple negative cell line model MDA-MB-231 have established single agent activity of entinostat in inhibiting tumor growth as well preventing bone metastases. In addition, entinostat induces expression of ERα in MDA-MB-231 in vivo and is synergistic with endocrine therapy agents to inhibit tumor growth of ER negative cancer cells. The aim of these studies was to confirm the activity of entinostat in triple negative breast cancers using human breast tumor explants. Methods: Cytotoxicity of entinostat was determined by the Oncotech Extreme Drug Resistance (EDR) proliferation assay using ten cryopreserved breast tumor explants known to lack estrogen receptor, progesterone receptor and HER2/neu expression (i.e. Triple negative) by immunohistochemistry. Results: Dose response curves of entinostat were analyzed and compared to paclitaxel at 2.45 μM in ten triple negative breast tumor explants in the EDR assay. Entinostat was broadly effective in all of the tumors tested, with most samples showing dose-dependent response for the range of concentrations analyzed (0.003 - 10 μM). Two of the breast tumors that were most sensitive to entinostat (IC50 30- 100nM) were also sensitive to paclitaxel. In contrast, entinostat effectively inhibited (IC50 10–270nM) the growth of eight of the tumors that were resistant to paclitaxel (i.e. < 50% growth inhibition). Overall, all breast tumors tested were sensitive to entinostat at clinically achievable concentrations regardless of paclitaxel resistance indicating entinostat may improve the treatment outcome of triple negative breast cancer patients. Conclusions: Entinostat is an effective agent at inhibiting the growth of triple negative breast tumors with clinically relevant IC50's ranging from 10nM to 270nM. A pre-surgical clinical study to assess the activity of entinostat in triple negative breast cancer patients is planned.

[Table: see text]
Activity of dasatinib with chemotherapy in triple-negative breast cancer cells
Authors: Tryfonopoulos D. , O'Donovan N. , Corkery B. , Clynes M. , Crown J.
Published: August 2020

e14605

Background: Triple-negative breast cancers (TNBC) lack expression of oestrogen, progesterone, and are HER-2 normal. TNBC cell lines have displayed greater sensitivity to growth inhibition by the multi-target kinase inhibitor, dasatinib, than luminal or HER- 2 positive breast cancer cell lines. The aim of this study was to assess the direct anti-tumor effects of dasatinib in combination with chemotherapy in TNBC. Methods: Four TNBC cell lines (MDA-MB-231, HCC-1143, HCC-1937, MDA-MB-468) were treated with dasatinib in combination with docetaxel, cisplatin or 5'-5' DFUR. IC50 values were calculated for each drug alone by determining response in a 5-day proliferation (acid phosphatase) assay. Combination index (CI) values were determined, using CalcuSyn, to assess the interaction between drugs. Results: Three of the cell lines (MDA-MB-231, HCC- 1143, HCC-1937) were sensitive to dasatinib (IC50 < 1 μM) whereas MDA-MB-468 was resistant (IC50 > 1 μM) (Table). In MDA-MB-231 and HCC-1143 cells, combined treatment with dasatinib and 5'-5'-DFUR displayed synergy (CI<1.0), whereas the combination was additive in HCC-1937 cells (CI=0.98). Combined treatment with dasatinib and cisplatin was synergistic in the three dasatinib sensitive cell lines (CI<1.0). Dasatinib in combination with docetaxel displayed moderate synergy in MDA-MB-231 and HCC-1937 cells (CI<1.0), but was antagonistic in HCC-1143 cells (CI>1.0). Conclusions: Our findings show that the combination of dasatinib with either 5'-5'-DFUR or cisplatin is synergistic in TNBC cell lines, and suggest that combinations of dasatinib with chemotherapy may improve response in triple negative breast cancer patients. [Table: see text]

No significant financial relationships to disclose.
Plasma concentration of amrubicinol in gamma phase in patients treated for 3 days with amrubicin and hematological toxicities
Authors: Kimura T. , Kudoh S. , Mitsuoka S. , Tanaka H. , Kyoh S. , Suzumura T. , Yoshimura N. , Asai K. , Tochino Y. , Hirata K.
Published: August 2020

e14606

Background: Amrubicinol (AMR-OH) is an active metabolite of amrubicin (AMR), a novel synthetic 9-amino-anthracycline derivative. The time-concentration profile of AMR-OH exhibits a continuous long plateau slope in terminal phase. To determine the relationships between the steady-state plasma concentration of AMR-OH and treatment effects and toxicities associated with AMR therapy, we performed a PK/PD study of AMR in patients with lung cancer treated with AMR alone or the combination of AMR + cisplatin (CDDP). Methods: AMR was given at a dose of 30 or 40 mg/m2 on days 1 to 3. Plasma samples were collected at pretreatment, 24 hours after the 1st injection (day 2), and 24 hours after the 3rd injection (day 4). Plasma concentrations of AMR, AMR-OH, and CDDP were determined by HPLC and AAS. Percent change in neutrophil count (dANC) and the plasma concentration of AMR-OH were evaluated using a sigmoid Emax model. Results: A total of 35 patients with a median age of 65 years (range 40–78), including 10 with small cell lung cancer (SCLC), 23 with non-small cell lung cancer (NSCLC), 1 with thymic cancer, and 1 with neuroblastoma were enrolled. A total of 107 plasma samples were available for study. Mean concentrations of AMR on day 2, AMR on day 4, AMR-OH on day 2, and AMR-OH on day 4 were 8.52ng/mL+4.63, 16.55ng/mL+11.92, 7.28 ng/mL+3.56 SD, and 13.35ng/mL+5.56 (mean ± SD), with significant increase from day 2 to day 4 for both AMR (p<0.0001) and AMR-OH (p<0.0001). Significant relationships were observed between AMR-OH on day 4 and the toxicity grades of leukopenia, neutropenia, and anemia (p=.018, p=.012, and p=.025). Thrombocytopenia grade exhibited a tendency toward relationship with AMR-OH on day 4 (p = .081). No relationships were observed between drug concentrations and responses. The plasma concentration of AMR-OH on day 4 was positively correlated with dANC in the group of all patients, as well as in patients treated with AMR alone and in patients with co-administration with CDDP using a sigmoid Emax model. Conclusions: The plasma concentration of AMR-OH on day 4 was correlated with hematological toxicities in patients treated with AMR. Assessment of plasma concentration of AMR-OH at one time point might enable prediction of hematological toxicities.

No significant financial relationships to disclose.
A strategy for clinical guidance using PD biomarkers revealed from human primary (HuPrime) tumors transplanted in nude mice
Authors: Chen T. , Liu C. , Song X. , Zhang L. , Liu Y. , Wery J. , Chen Y.
Published: August 2020

e14612

Background: Most anticancer drug candidates, currently in clinical trials, have clear targets in molecular and cellular systems. However, such molecular targets are not always affected (or not correlated with efficacious endpoints) when the candidate is evaluated in a clinical setting. There is an urgent need to develop better biological tools and models to ease the transition between in vitro and in vivo, and between preclinical and clinical settings. Activation of tyrosine kinases in tumor cells has been recognized as key driving force in malignancy; therefore inhibitors of tyrosine kinases (TKI) have often shown efficacy in preclinical in vivo models and beneficial responses in clinical trials. An increasing number of TKI has been approved as anticancer drugs in selected cancer types. Methods: We have developed a unique platform combining our novel HuPrime™ xenograft models with our PD biomarker technologies. This platform is used to better understand the efficacy of novel drug candidates and generate information critical to maximize the chance of a successful clinical development. To illustrate the usefulness of our platform, we have applied it to understand the pharmacodynamic changes (at the molecular level) which are associated with the activity of sunitinib and sorafenib in our sensitive esophageal HuPrime models. Tumor tissues from sensitive esophageal HuPrime models treated with single dose of the respective drugs (and a vehicle control) have been collected at time-points 4, 8, 16, and 24 hour. Results: We have successfully applied immunohistochemistry (IHC) assays on many molecules covering most pathways including proliferation, apoptotic, necrotic, and cell cycle regulation, G2M phase arrest, DNA damage response, etc. Additional markers including angiogenesis can also be included for certain therapeutic compounds. These tissues have been analyzed with our platform and we have uncovered key molecular events which correlate with the efficacy and potency of the drugs. Conclusions: The PD biomarkers validated in this approach have potential for clinical application and patient stratification.

[Table: see text]
Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism
Authors: Karimdjee B. S. , Cambien Miss B. , Richard Mrs P. F. , Bereder J. , Scoazec Mr J. , Birnbaum Mr D. , Mounier Mr N. , Schmid Mrs H. A. , Schmid Mrs A. A.
Published: August 2020

e14619

Background: Liver and lung metastases are the predominant cause of colorectal cancer (CRC) related mortality. Recent research has indicated that CXCR3/chemokines interactions that orchestrate hematopoetic cell movement are implicated in the metastatic process of malignant tumors, including that of CRC cells to lymph nodes. To date, however, the contribution of CXCR3 to liver and lung metastasis in CRC has not been addressed. Methods: To determine whether CXCR3 receptors regulate malignancy-related properties of CRC cells, we have used CXCR3-expressing CRC cell lines of human (HT29 cells) and murine (C26 cells) origins that enable the development of liver and lung metastases when injected into immunodeficient and immunocompetent mice, respectively, and assessed the effect of CXCR3 blockade using AMG487, a small molecular weight antagonist. Results: In vitro, activation of CXCR3 on human and mouse CRC cells by its cognate ligands induced migratory and growth responses, both activities being abrogated by AMG487. In vivo, systemic CXCR3 antagonism by preventive or curative treatments with AMG487 markedly inhibited metastasis of human and mouse CRC cells to the lung without affecting that to the liver. Also, we measured increased levels of CXCR3 and ligands expression within lung nodules compared to liver tumors. Conclusions: Altogether, our findings indicate that CXCR3 is a key mediator for lung metastasis of colon carcinoma and identify CXCR3-blocking approaches as promising strategies against established lung metastases.

No significant financial relationships to disclose.
TKI258, a novel, multitargeted tyrosine kinase inhibitor for the treatment of breast cancer
Authors: Liu H. , Schulz C. O. , Regierer A. C. , Dieing A. , Possinger K. , Eucker J.
Published: August 2020

e14625

TKI258 (4-amino-5-fluor-3-[5-(4-metylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one, formerly known as CHIR258) is an ATP-competitive inhibitor with activities against class III or IV receptor kinases, which include FGFR, VEGFR, PDGFR, FLT3, and KIT. It has been demonstrated to possess strong anti-tumor and anti-angiogenetic activities in different tumor models, and, therefore, this compound is currently being clinically assessed for the treatment of diverse malignancies. In this study, we chose the breast cancer cell line MDA-MB-231, a cell line with high invasive capacities, as an in vitro model to analyze the effect and functional mechanism of TKI258 on the breast cancer invasiveness. Treatment of MDA-MB-231 cells with TKI258 resulted in reduced invasive capacities in a dose-dependent manner. In association with this effect, we observed that TKI258 down-regulated the phosphorylation of ERK1/2 and STAT3 and inhibited the VEGF production in the cell supernatants. Most interestingly, we found TKI258 had influence on the inflammatory chemokines CCL5 and CCL2 level if MDA-MB-231 cells were co-cultured with breast cancer stroma cells. We found that CCL5/CCL2 mRNA level in MDA-MB-231 cells, in stroma cells, or in co-culture of MDA-MB-231/breast cancer stroma was strongly inhibited by TKI258 as detected with real-time PCR. Parallel to this result, the dramatically elevated CCL2/CCL5 level in the media supernatants from co-cultured MDA-MB-231/stroma cells was reduced by TKI258 effectively. Furthermore, we demonstrated that the invasion-promoting effect of the tumor stroma cells was antagonized by TKI258 significantly. CCL5 stimulated invasion of MDA-MB-231 cells could be partially abrogated by TKI58 and/or by CCL5-neutralizing antibody. Therefore, it is most likely that the inhibitory effect of TKI258 on invasion of MDA-MB-231 cells in the presence of stroma cells is achieved, at least in part, by antagonizing the invasion-promoting effect of CCL5. Overall, our data show that TKI258 inhibited invasive capacities of aggressive breast cancer cell line MDA-MB-231, either in the absence or presence of tumor stroma cells in vitro.

No significant financial relationships to disclose.
Antisense oligonucleotides targeting the large subunit (R1) of human ribonucleotide reductase synergistically increase the cytotoxicity of doxorubicin and paclitaxel to MCF-7 breast cancer cells
Authors: Jiang X. , Elliott R. L. , Head J. F.
Published: August 2020

e14626

Ribonucleotide reductase (RR) is an essential enzyme that catalyzes the reduction of ribonucleotides to deoxyribonucleotides for use in DNA synthesis. Human RR consists of two subunits, a large subunit (R1) and small subunit (R2). RR provides an attractive target for anticancer therapy. In the present study, we synthesized phosphorothioated antisenses oligonucleotides (RR1AS1, RR1AS2, RR1AS3, RR1AS4 and RR1AS5) that target the R1 subunit of RR. We treated the human breast cancer cell line MCF-7 with antisenses, and doxorubicin or paclitaxel for 72 hours. Cell proliferation was measured by 3[H]- thymidine incorporation. The effects of the drug combinations were analyzed with Biosoft Calcusyn software. The levels of RR mRNA were measured by RT-PCR. We found two antisenses, RR1AS2 and RR1AS4, inhibited the proliferation of MCF-7 cells in a dose-dependent pattern (IC50s: 5.32+1.64μm and 2.57+2.72μm, respectively, 72 hours incubation). Also, RR1AS2 and RR1AS4 significantly suppressed the expression of RR1 mRNA. When MCF-7 cells were incubated in media with a mixture of antisense and doxorubicin or paclitaxel, both RR1AS2 and RR1AS4 synergistically increased the cytotoxicity of doxorubicin and paclitaxel. Calcusyn analysis showed that averaged combination index (CI) were 0.59+0.04, 0.66+0.22, 0.83+0.16 and 0.88+0.03, when MCF-7 cells were treated with the mixtures of RR1AS2 + doxorubicin, RR1AS2 + paclitaxel, RR1AS4 + doxorubicin and RR1AS4 + paclitaxel, respectively (CI<1 indicates synergism). These results suggest that the combination of RR antisenses and chemotherapeutic agents, such as doxorubicin or paclitaxel, may decrease both the dosages and side effects of both antisense oligonucleotides and chemotherapeutic agents (doxorubicin and paclitaxel) in cancer therapy.

No significant financial relationships to disclose.
Effect of sunitinib on TRAIL-induced apoptosis in preclinical colon cancer models
Authors: Mahalingam D. , Medina E. , Swords R. T. , Kelly K. R. , Carew J. S. , Robbert C. H. , Szegezdi E. , Francis G. J. , de Jong S. , Nawrocki S. T.
Published: August 2020

e14633

Background: Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis, however not all cancers respond to TRAIL, which may be due to activation of survival signals. Sunitinib is a potent inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). These receptors and their signaling cascades promote cell survival and drug resistance. Inhibition of these pathways with sunitinib may augment TRAIL-mediated apoptosis. Aims: 1) Determine sensitivity of colon cancer cell lines to the combination of TRAIL and sunitinib, 2) identify mechanism by which sunitinib enhances TRAIL-mediated apoptosis, and 3) investigate the anticancer activity of this drug combination in xenograft models. Methods & Results: Sunitinib enhanced the anticancer activity of TRAIL in HCT116 and HCT15 colon cancer cell lines, with increased caspase cleavage and DNA fragmentation using western blot analysis and propidium iodide staining, respectively. Overexpression of Bcl-2 in HCT116 cells reduced TRAIL+sunitinib-mediated apoptosis, suggesting that sunitinib enhances TRAIL-induced apoptosis via activation of the mitochondrial apoptotic pathway. Sunitinib enhanced TRAIL-induced JNK activation, which may play a role in TRAIL+sunitinib-mediated apoptosis. Xenograft models of HCT116 and HCT15 were established in nude mice and treated with TRAIL, sunitinib, or the combination. The TRAIL+sunitinib combination significantly reduced tumor burden in both xenograft models compared to either treatment alone. The reduction in tumor volume correlated with increased apoptosis and decreased tumor proliferation and angiogenesis as determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunohistochemistry for Proliferating Cell Nuclear Antigen and VEGF. Conclusion: These results are the first to demonstrate that simultaneous treatment with TRAIL and sunitinib reduced cell viability, induced apoptosis, inhibited tumor proliferation and angiogenesis in both in vitro and in vivo models of colon cancer, and warrants further investigation.

No significant financial relationships to disclose.
The incidence of non-melanoma skin cancer after a single field treatment with aminolevulinic acid and blue light photodynamic therapy
Authors: Kozyreva O. N. , Konnikov N.
Published: August 2020

e14646

Background: Non-melanoma skin cancer (NMSC) is the most common form of human cancer. Aminolevulinic acid photodynamic therapy (ALA PDT) is a safe and effective treatment for NMSC precursors. It is unknown if ALA PDT treatment will affect incidence of NMSC in high risk patients (pts). Methods: A retrospective study was undertaken using a Veteran Affairs Boston Health Care System Medical Record Database. Study population included immunocompetent pts with history of NMSC, multiple actinic keratosis (AKs), and moderate to severe dermatoheliosis (DH). Study pts received a single application of 20 % ALA to the face or scalp following by exposure to blue light at 10 J/cm2. Differences in incidence of NMSC two years prior and two years after ALA PDT were tested using the Wilcoxon rank sum test. Data were analyzed by the median and interquartile range (IQR). Results: 43 Caucasian males (range 59- 87 yrs), 37 (87%) had history of NMSC on the face or scalp, 32 (78%) had basal cell carcinoma (BCC), 11 (22%) squamous cell carcinoma (SCC), 100% of patients had multiple (>4) AKs prior to treatment and 23 (75% ) had moderate to severe DH determined by Griffiths scale. Prior to ALA-PDT 74 NMSC's were documented: 40 (54%) BCC and 34 (46%) SCC. 46 NMSC's were documented following ALA-PDT: 22 (48%) BCC and 24 (52%) SCC. Prior to ALA-PDT, the frequency of BCC averaged 2 [IQR 1 to 3, max=4], and the frequency of SCC averaged 1 [IQR 1 to 1, max=3]. Following ALA-PDT, the occurrence of BCC averaged 1 [IQR 0 to 1, max=5], and that of SCC averaged 1 [IQR 0 to 2, max= 4]. The difference between BCC frequency before and after ALA-PDT treatment shown a significant reduction in BCC incidence (P = 0.0018). No such differences were observed between the frequency of SCC before and after ALA-PDT (P=0.6230) Conclusions: A single ALA-PDT treatment to the face or scalp in high risk patients significantly reduces the incidence of BCC, the incidence of SCC was not reduced. The potential role of ALA PDT as a NMSC chemopreventive modality warrants further investigation in larger samples with an alternative treatment protocols.

No significant financial relationships to disclose.
The number of lymph node metastases as a prognostic indicator of disease-specific survival in the era of sentinel lymph node mapping in colon cancer
Authors: Saha S. , Sirop S. , Korant A. , Chakravarty B. , Krishnaiah N. , Wiese D. , Soni M. , Arora M. , Nagpal S. , Singh T.
Published: August 2020

e15000

Introduction: Sentinel Lymph Node Mapping (SLNM) in colon cancer (CCa) is shown to be successful, sensitive and accurate. We aimed to evaluate the survival of patients (pts) undergoing SLNM in addition to the standard colon resection, compare it to pts without SLNM and correlate it to the number of LN metastasis. Methods: Staging and survival analysis from our prospective database (gpA, 195 pts) were compared to the Surveillance, Epidemiology, and End Results (SEER) database (gpB, 126,484 pts) between 1996–2003. All pts had invasive CCa. GpA pts underwent SLNM plus complete resection. The minimum follow up (F/U) was 5 years. The primary outcome was cancer-specific survival. Exclusion criteria were stage IV disease, 2nd malignancy, or lost to F/U. Cancer specific survival of gpA was then analyzed according to the number of positive LNs. Results: In gpA (195 pts), SLNM was successful in 99.7%, of pts with a sensitivity, negative (-ve) predictive value, and false -ve rates of 86.3%, 91.7% and 14.6% respectively. In 15.1% of node +ve pts, the disease was upstaged because of micrometastasis (0.2–2mm). In gpA, 128 pts were included, of which 17(13.3%) lost to F/U as compared to 89,483 pts included in gpB, of which 47,168 (52.7%) lost to F/U. The average number of LNs examined per pt was 15 in gpA as compared to 12.4 in gpB (p=<0.0001). The 5 year-cancer specific survival of pts in gpA vs gpB was 100% vs 94.9% in stage I, 91.2% vs 83.5% in stage II and 81.8% vs 63% in stage III disease. For gpA pts, the 5 year cancer-specific survival decreased from 95.0% in node -ve disease to 92.8% when 1 LN was +ve, 83.3% when 2 LNs were +ve and 71.4% when 3 or more LNs were +ve (Table). Conclusions: A significant number of pts with CCa are being upstaged and the true node -ve disease is being identified when SLNM is performed at the time of surgery leading to improved survival as compared to conventional surgery. Our study showed that the number of LN metastasis is a predictor of cancer specific survival even after SLNM in CCa. [Table: see text]

No significant financial relationships to disclose.
Safety summary of panitumumab (pmab) in combination with chemotherapy (ctx) from four clinical trials in patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Price T. J. , Peeters M. , Douillard J. , Mitchell E. , Cohn A. , Strickland A. H. , Rivera F. , Xu F. , Gansert J. , Siena S.
Published: August 2020

e15005

Background: Pmab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody approved in the US and EU (wild-type KRAS) as monotherapy for pts with mCRC. Safety data from 4 studies (Siena et al ASCO 2008; Peeters et al ASCO 2008; Cohn et al ASCO 2008; Mitchell et al WORLD GI 2008) of pmab in combination with ctx are summarized. Methods: Two studies are single-arm, phase II trials and two are randomized, phase III trials with pooled, blinded safety data that include ctx-controls. All studies were multicenter. Common pt eligibility criteria included: diagnosis of mCRC with measurable disease per modified RECIST criteria, age ≥ 18 years, and adequate hematologic, renal, hepatic, and metabolic function. All studies required pts to receive FOLFOX, FOLFIRI, or irinotecan ctx in combination with pmab. Pts received pmab 6.0 mg/kg Q2W with FOLFOX Q2W or FOLFIRI Q2W, or pmab 9.0 mg/kg Q3W with irinotecan Q3W. Results from planned interim analyses are available for 3 studies, and results from the final analysis are available for one study. Results: Among the 4-study safety data, 1213 pts received pmab + ctx; 703 pts received pmab + FOLFIRI, 455 pts received pmab + FOLFOX, and 55 pts received pmab + irinotecan. Approximately 1,200 pts were enrolled in each phase III study, and data are available from 1,003 pts who received pmab + ctx and 997 pts who received ctx alone. All pts in the phase III studies, regardless of treatment group, were included in the pooled, blinded interim analysis sets monitored by the data monitoring committee for each study. Safety results for the two phase II studies of pmab + ctx and two phase III studies of pmab ± ctx are summarized (Table). Conclusions: Phase II data are consistent with expectations, and phase III trials are ongoing. A consistent safety profile was observed across studies.

[Table: see text]

[Table: see text]
FOLFIRI + bevacizumab as first-line treatment in advanced colorectal cancer (ACC): Final results (prot. GOIM 2601)
Authors: Giuliani F. , De Vita F. , Lorusso V. , Cinieri S. , Nugnes I. , Orditura M. , Maiello E. , Del Prete S. , Leo S. , Colucci G.
Published: August 2020

e15007

Background: The addition of Bev to IFL obtained better OS and RR than chemotherapy alone. However IFL is not considered an optimal regimen and is certainly more toxic than FOLFIRI. To investigate the activity and efficacy of the addition of Bev to FOLFIRI, the GOIM started the following phase II study. Methods: seventy-two untreated pts with histologically/citologically confirmed diagnosis of colorectal cancer, with at least one measurable disease, age > 18 yrs, PS < 2 (ECOG), adequate bone marrow reserve and hepatic and renal function, with no history of cardiovascular disease, thromboembolic events or coagulative disorders and who signed informed written consent, were enrolled and received the following treatment: CPT-11 at 180 mg/m/mq on day 1, FA at 100 mg/mq as 2h infusion on days 1–2, FU at 400 mg/mq bolus on days 1–2 and FU at 600 mg/mq as 22h infusion on days 1–2 (FOLFIRI) plus Bev at 5 mg/Kg on day 1, every two weeks. A maximum of 12 cycles of chemotherapy was planned and a maintenance with Bev for 6 months was permitted. The evaluation of activity (Recist criteria) was performed every 4 cycles Results: all the enrolled pts were evaluable for activity and safety. Their main characteristics were M/F: 38/34; median PS: 0; median age 60 (range 33–73); primary site colon/rectum: 50/22 (69.4%/30.6%); main sites of disease liver: 50 (69.4%), lung: 18 (25%), lymph nodes: 19 (26.4%); synchronous/metacronous disease: 55/17 (77.7%/22.3%); multiple/single lesions: 40/32 (55.5%/44.5%).Seven (9.6%) CR, 25 (34.8%) PR, 33 (45.8%) SD and 7 PRO were observed for an ORR of 44.4% and a disease control of 90.3%. The response rate according to the main sites of disease were: liver 25/50 (50%), lung 6/18 (33.3%). The median number of administered cycle were 9 and the median TTP was 10.0 months. The main haematologic side-effects (% G3–4 NCI criteria) were: neutropenia 11%, thrombocytopenia 2.7% and anemia 4.7%, while diarrhea affected only 2.7% of pts; hypertension, thromboembolic and bleeding events were observed in 2.7%, 1.3% and 1.3% respectively. Conclusions: the addition of Bev to FOLFIRI is an active and effective first-line treatment in ACC with a good safety profile. Survival data will be presented during the meeting.

No significant financial relationships to disclose.
Activity and tolerance of biweekly CapeOx-cetuximab in 1st line therapy of metastatic colorectal cancer (mCRC): Relation to K-ras mutation status
Authors: Yuan Y. , Ma H. , Cohen D. J. , Ryan T. , Choi H. , Love‘ E. , Awad M. , Khambata-Ford S. , Mauro D. , Hochster H.
Published: August 2020

e15018

Background: This novel q2w schedule trial combined oxaliplatin (Ox), flat dose capecitabine (Cape) and cetuximab(C) in first line therapy of mCRC. C was given weekly initially and then q2w. We report the response rate, toxicity and influence of K-ras mutation status in first-line patients treated with biweekly CapeOx-C in this phase II trial. Methods: Pts with previously untreated, histologically confirmed, metastatic colon adenocarcinoma, ECOG PS 0–1, and adequate organ function were eligible. Pts were treated with C (initially 250mg/m2 q week and later amended to 500mg/m2 q2w) and Ox (85mg/m2) combined with flat dose Cape (2500mg po bid x 7days) q2w. Endpoints included response (RECIST), toxicity (CTCAE v3) and relationship to K-ras mutation status as determined in codons 12/13 of exon 2 in genomic tumor DNA by PCR, blinded to clinical data. Results: Between 8/04 and 8/08, 27 pts were enrolled. One pt failed screening, 1 withdrew prior to rx and 2 too early for assessment. 25 pts were treated: M/F (15/10), PS 0/1 (13/12), median age 65 yrs (37–80). 12 pts were treated weekly with C and 13 q2w. 23 pts were eligible for both toxicity and efficacy analysis. The most common grade 3/4 toxicities (N=23) were diarrhea (26%), thrombosis (22%), neuropathy (17%), rash (13%), hand-foot syndrome (9%), hypersensitivity reaction (9%), stomatitis (9%). Toxicity profiles between the two C schedules were comparable. Of 23 pts evaluable for response, there were 2 CR, 12 PR, and 3 SD (ORR 61%; disease control rate (DCR) 74%). K-ras status was determined in 18 pts: 9 were K-ras wild-type (WT) and 9 mutant (MT) with ORR and DCR = 66%, 89% for WT vs. 44%, 44% MT. Time on study was 6 mon for WT vs 3 mon for MT (p<0.05). Grade 0–1 vs. 2–3 skin rash was 33% vs. 67% for WT and. 89% vs. 11% in MT pts. Conclusions: The novel combination of biweekly CapeOx-C, with flat dose Cape was well tolerated and very active (regardless of K-ras status) as first line treatment in mCRC. C 500 mg/m2 q2w appears equal to weekly dosing. Analysis of the K-ras mutation status showed a trend toward increased benefit by response rate and time on study, with more cutaneous toxicity in K-ras WT pts. [Supported in part by grant from BMS.]

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Relation between long-term blood pharmacokinetics (PK), pharmacogenomics (PG), and severe neurotoxicity in patients undergoing an oxaliplatin (O)-based regimen
Authors: Bastian G. , Chibaudel B. , Maindrault-Goebel F. , Garcia-Hejl C. , Bonnetain F. , Rebischung C. , Hebbar M. , Yataghene Y. , de Gramont A.
Published: August 2020

e15024

The aim of the study was to investigate the residual blood level of O before each cycle of various oxaliplatin (O)-based protocols, and to explore its predictive value for potential occurrence of a severe neurotoxicity. Methods: Between 11/2005 and 06/2008, 220 Pts were included in a prospective cohort, in 7 French centers. Patients received a minimum of 7 cycles of O. Blood samples were taken before each cycle with a maximum of 12 cycles. In parallel neurotoxicity was assessed by the modified Levi score (grade 0 to 3) and by the Von Frey filament exam. Saliva was collected before the first cycle for genomics analysis. The O concentration was obtained by Atomic Absorption Spectrometry assay. Polymorphism of different targets were investigated (carrier proteins: MRP2, OCT1, OCT2, GSTP1, adducts repair system: ERCC1, ERCC2). Time to first severe neurotoxicity occurrence (TTSN Events: Grade 2 or3) was estimated using Kaplan-Meier. Predictive value of severe neurotoxicity was explored using univariate and multivariate logistic or Cox regressions. Harrel C index was produced. Results: 206 pts with gastro-intestinal cancer had, at the time of analysis, completed follow-up and 171 pts were eligible. 84% received FOLFOX regimen (85mg/m2every 2 weeks), the others GEMOX or XELOX (100mg/m2 every 3 weeks). After cycle 1, 2 and 10, median residual level of O was respectively 0.23 mg/L, 0.40 mg/L and 0.58 mg/L. The maximal concentration was obtained between cycle 5 and cycle 9. Respectively 83 Pts (40%) and 15 pts (7%) had a Gr2 and a Gr3 neurotoxicity. Median time TTSN was 141 days (95% CI: 132 - 161). O concentration before 2nd (HR = 1.39, p = 0.34, C =0.53) or 3rd cycle (HR = 1.00, p = 0.99, C =0.54) were not associated with TTSN. Multivariate logistic and Cox analyses confirmed these results. Conclusions: Despite a trend, which needs to be confirmed, the residual blood level of O is not predictive of a Gr 2 or Gr 3 neurotoxicity in patients with an O based-regimen. With updated data, further statistical analyses will be done to be presented at the next ASCO meeting. They will take into account more precise data as the cycle delay or the dose-intensity of O received by the patients.

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Dose escalating study of 5-FU/folinic acid (FA)/oxaliplatin/irinotecan (FOLFOXIRI) and cetuximab in first-line therapy of patients with metastatic colorectal cancer
Authors: Trarbach T. , Schuette K. , Stoehlmacher J. , Goekkurt E. , Guenther H. , Ubbelohde U. , Stroszczynski C. , Ehninger G. , Folprecht G.
Published: August 2020

e15025

Background: Highly active chemotherapy schedules are necessary in several clinical situations, i.e. for conversional chemotherapy in order to resect liver metastases. Adding oxaliplatin or cetuximab to 5-FU / FA / irinotecan was shown to increase the efficacy of chemotherapy in patients with metastatic colorectal cancer (Falcone et al, JCO 2007, Van Cutsem et al, ASCO 2008). Methods: We performed a phase I study in patients (pts) with metastatic colorectal cancer, WHO PS 0–1 who had not been pretreated for metastatic disease. They received cetuximab (500 mg/m2, 2h), oxaliplatin (85 mg/m2, 2h), folinic acid (400 mg/m2, 2h), irinotecan (95, 125, or 165 mg/m2, 1h), 5-FU (3200 mg/m2, 46 h), each on day 1 in biweekly cycles. Dose was escalated if dose limiting toxicities (DLT) were absent in the first three pts per cohort, or if <2 DLTs in six pts. Non-evaluable pts were replaced. Pts were not selected for EGFR IHC or KRAS status. Results: Twenty-one pts were enrolled into the study between Jan 2007 and June 2008, six evaluable pts per each cohort. Two pts who had adverse events deemed unrelated to study during the first cycle (morphine overdosing, mechanical ileus) were replaced, one patient (port dysfunction during first dose) was excluded from analysis. Patient characteristics were as follows: median age 59 (33–72) years, 16 pts WHO PS 0, 15 pts male, 10 pts rectal cancer primary, 3 pts previous adjuvant chemotherapy. In the first two cohorts, 95 and 125 mg/m2 irinotecan, one DLT occurred per dose level (neutropenia gr. 4 and diarrhea gr. 3). In the 165 mg/m2 cohort, 2 DLTs were observed (neutropenia grade 4). Most common grade ≥ 3 toxicities were neutropenia (40%), diarrhea (25%), skin toxicities (15%), thrombopenia (10%) and infections (15%). One patient had a confirmed complete response, 14 pts had confirmed partial response (ORR 75%, 95% CI: 51–91%), 5 pts stable disease. Median progression free survival has not yet been reached. Conclusions: With the combination of FOLFOXIRI/cetuximab, the recommended dose of irinotecan is 125 mg/m2 for further investigation in clinical trials in patients with good performance status. The observed response rate of 75% is very promising.

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Phase I trial of zalutumumab and irinotecan in metastatic colorectal cancer patients who have failed irinotecan- and cetuximab-based therapy
Authors: Mano M. , Hendlisz A. , Machiels J. , Ehrnrooth E. , Aladdin H. , Van Laethem J.
Published: August 2020

e15028

Background: Zalutumumab is a novel human IgG1 anti-EGFR mAb. We investigated the safety of zalutumumab and irinotecan in heavily pretreated mCRC patients. Methods: Metastatic CRC patients with documented progression (PD) during or within 6 months of stopping cetuximab and irinotecan based therapy were eligible. No prior treatment with anti-EGFR antibodies other than cetuximab was allowed. Patients received weekly doses of zalutumumab 8mg/kg and 16 mg/kg respectively in combination with irinotecan (180 mg/m2) every second week until PD or unacceptable toxicity. Results: The maximum tolerated dose was not reached and no patients experienced any dose limiting toxicity. At data cut-off (18-Dec-08) 4 patients had died (no cases of death were considered related to zalutumumab), 4 were off study due to PD and 1 was still ongoing ( Table 1 ). In total, 6 patients experienced one or more grade 3/4 toxicities (diarrhea 2; neutropenia 2; leucopenia 1; abdominal pain 1; pulmonary embolism 1; alopecia 1). Conclusions: Zalutumumab can be safely administrated in doses up to 16mg/kg in combination with irinotecan in mCRC patients failing cetuximab and irinotecan based therapy. Zalutumumab and irinotecan resulted in durable stable disease warranting further investigation of this regimen.

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Neoadjuvant cetuximab, capecitabine, and radiotherapy (RT) in locally advanced resectable rectal cancer: results of a phase II trial
Authors: Velenik V. , Ocvirk J. , Oblak I. , Anderluh F.
Published: August 2020

e15029

Background: Preoperative chemoradiotherapy (CRT) with capecitabine is a treatment of choice for locally advanced rectal cancer. The radiosensitizing effect of cetuximab, an EGFR-targeting monoclonal antibody, may further enhance the tumor response. The aim of this prospective, nonrandomized, open-label phase II study was to establish the efficacy and safety profile of cetuximab combined with capecitabine and concurrent RT for locally advanced resectable rectal cancer. Methods: Patients (pts) with stage II or III rectal cancer confirmed by MRI were treated with capecitabine 1250 mg/m2 twice daily for 2 weeks. Cetuximab 400mg/m2 was intravenously administered on week 3, followed by cetuximab 250mg/m2/week and capecitabine 825 mg/m2 bid including weekends during RT. The RT dose was 45 Gy (25×1.8 Gy, 3D conformal technique), starting on week 4. Total mesorectal excision was scheduled 4–6 weeks after completion of CRT. Tumor regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was complete pathologic response (pCR). Results: Thirty-seven pts were eligible for safety and efficacy analyses. Median age was 55 (range: 33–72) years, 81% of pts were male. Three pts (8.1%) had T3N0 tumors, 1 pt (2.7%) T2N1, 13 pts (35%) T3N1, 1 pt (2.7%) T2N2, 15 pts (40.5%) T3N2 and 4 pts (11%) T4N2. The median tumor distance from anal verge was 6 (range: 1–11) cm. All pts received 45 Gy RT. Dose reduction/treatment interruption was necessary for 9/37 (24.3%) pts owing to hypersensitivity reaction (n=4), hepatotoxicity grade 3 (n=1) or diarrhea grade 3 (n=4). Other grade 3 toxicities included dermatitis (n=6, 16.2%), anorexia (n=1, 2.7%) and infection (n=1, 2.7%). TRG 4 (pCR) was recorded in 3 pts (8.1%) and TRG 3 in 7 pts (18.9%). T-, N- and overall downstaging rates were 56.8%, 81.1% and 73.0%, respectively. The total sphincter preservation rate was 75.7%; in 17 pts whose tumors were located ≤5 cm of the anal verge, the rate was 53%. Conclusions: Preoperative CRT with cetuximab and capecitabine is safe and feasible. A high pathologic downstaging rate was achieved, although the pCR rate appeared to be in the range previously reported for CRT with capecitabine.

No significant financial relationships to disclose.
Functional and prognostic influence of receptor polymorphisms in the vascular endothelial growth factor system in colorectal cancer
Authors: Hansen T. , Spindler K. G. , Olsen D. A. , Andersen R. F. , Lindebjerg J. , Brandslund I. , Jakobsen A.
Published: August 2020

e15032

Background: The vascular endothelial growth factor (VEGF) system plays a key role in the angiogenic process ensuring a sufficient blood supply to the growth of malignant tumours. The clinical importance of single nucleotide polymorphisms (SNP's) in the VEGF receptors is still unknown. The aim of this study was to investigate the functional and prognostic influence of the V297I C/T and the -604 T/C SNP's in the VEGFR-2 gene, in tumour and normal tissue from colorectal cancer patients. Methods: Blood samples and tissue were collected from 110 patients, surgically resected for colorectal cancer. Genomic DNA was isolated from whole blood, and SNP's were analysed by PCR. Gene expression analysis was performed by RT-PCR and protein analysis was performed by ELISA. Progression free survival according to genotypes was compared using the Kaplan-Meier method and the logrank test. Results: Median gene expression according to the CC genotype of the -604 T/C SNP, were significantly higher than the median gene expression of the TT genotype (p = 0.045) and the TC genotype (p = 0.033) in CRC tissue. Regarding the V297I C/T SNP, median protein concentration according to the CT genotype was significantly higher than the median protein concentration of the CC genotype, p = 0.005. The CC genotype held prognostic information compared to CT and TT genotypes for both SNP's, p<0.05. Conclusions: The V297I C/T SNP seems to have a functional influence on the VEGFR-2 protein level, and the -604 T/C SNP on the gene expression level in CRC patients. The results furthermore indicate a prognostic influence of both SNP's on progression-free survival.

No significant financial relationships to disclose.
Evaluation of stool melting curve analysis of methylated CpG island promoters as an alternative for early noninvasive diagnosis of colorectal tumors
Authors: Azuara D. , Rodriguez-Moranta F. , Soriano-Izquierdo A. , Guardiola J. , de Oca J. , Biondo S. , Blanco I. , Esteller M. , Capella G.
Published: August 2020

e15036

Background: Previous studies have shown that assessment of promoter hypermethylation of a limited number of genes in tumor biopsies may identify all colorectal tumors analyzed. The aim of the present study was to assess the clinical usefulness of a panel of methylation biomarkers in stool DNA in the diagnosis of colorectal tumors using Methylation Curve (MC) analyses, a technique that simultaneously analyze all CpG residues within a promoter. Methods: Promoter methylation status of 5 tumor-related genes (RARB2, p16INK4a, MGMT, p14ARF and APC) was analyzed in DNA stool samples and corresponding tissues in an initial set of 12 newly diagnosed patients with primary colorectal carcinomas and 20 with colorectal adenomas using Methylation-specific PCR (MSP). Results were validated in a set of 88 patients (20 healthy subjects, 17 inflammatory bowel disease, 23 adenomas, 28 carcinomas) using MC analyses. Median age for every group was 63, 51, 66 and 67 y respectively. Results: In the initial set, the majority [10 of 12 (83%) carcinomas and 18 of 20 (90%) adenomas] of biopsies were positive for at least one marker. In stool DNA prevalence was 75% for carcinomas (9 of 12) and 60% for adenomas (12 of 20) with no false positive in stools. In the validation set MC was used. Analytical sensitivity of MC was 5% of methylated alleles for p16INK4a, p14ARF, RARB2 and APC and 10% for MGMT. In the validation set MC analyses of biopsies showed that at least one marker was positive in 22 of 28 (79%) carcinomas and 16 of 23 (70%) adenomas. In stool DNA, these percentages were 64% (18 of 28) for carcinomas and 42% (9 of 23) for adenomas. No aberrant methylation was observed in healthy subjects and in 2 of 15 (13%) of IBD patients aberrant RARB2 methylation was detected. Conclusions: Melting Curve analysis of a panel of methylation markers in stool DNA is a good alternative for the early non-invasive diagnosis of colorectal tumors.

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