bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual targeting of EGFR and HER-2 in breast cancer cell lines
Authors: O’Donovan N. , Crown J. P. , Clynes M.
Published: March 2020

13132

Background: ErbB2 is overexpressed in approximately 25–30% of breast cancers. Recent studies have shown that overexpression of ErbB2 is also frequently associated with expression of ErbB1 and that ErbB1 expression influences response to ErbB2 inhibition. The aim of this study was to investigate the effects of dual targeting of ErbB1 and ErbB2 in ErbB2 overexpressing breast cancer cell lines. Methods: Combinations of Trastuzumab (Herceptin), Gefitinib (Iressa) and Lapatinib (GW572016) were tested in two ErbB2 and ErbB1 positive breast cancer cell lines, SKBR3 and BT474. Proliferation assays were performed using the acid phosphatase assay and apoptosis was measured using the Cell Death Detection ELISA (Roche). The average combinations index (CI) values at ED25, ED50 and ED75 were determined using CalcuSyn. Results: With regard to inhibition of proliferation, dual targeting with Trastuzumab and Gefitinib is additive (CI=0.8) in SKBR3 cells and synergistic (CI=0.6) in BT474 cells. Combined treatment with Trastuzumab and Lapatinib is synergistic (CI=0.5) in SKBR3 cells and additive (CI=1.0) in BT474 cells. Dual targeting with Gefinitib and Lapatinib is antagonistic in both cell lines. Trastuzumab (10 nM) alone and Gefitinib (5 μM) alone did not induce significant apoptosis in SKBR3 cells whereas Lapatinib (0.75 μM) alone induced apoptosis and in combination with Trastuzumab enhanced apoptosis induction. Combined treatment with Trastuzumab (10 nM) and Gefitinib (5 μM) induced apoptosis comparable to Lapatinib alone (0.75 μM). Conclusions: Our results suggest that dual targeting of ErbB1 and ErbB2 with combinations of the monoclonal antibody, Trastuzumab and tyrosine kinase inhibitors may improve response to treatment in a sub-group of patients with ErbB2 overexpressing tumours that also express ErbB1. Interestingly, the apoptosis assays suggest that inhibition of both ErbB1 and ErbB2 is required to efficiently induce apoptosis in cells which express both receptors.

[Table: see text]
A phase 1 study of daily oral perifosine (P) with every 3-week paclitaxel (T)
Authors: Goggins T. F. , Nemunaitis J. J. , Shiffman R. , Birch R. , Berdeaux D. H. , Rettenmaier M. , Diaz-Lacayo M. , Henderson I. C.
Published: March 2020

13134

Background: Perifosine is a novel alkylphospholipid that has been shown to affect multiple signal transduction pathways including Akt, MAPK and JNK (Kondapaka, Mol. Canc. Ther 2: 1093–1103. 2003). Treatment with a taxane initially activates Akt, and persistent activation increases resistance to the drug (Vanderweele, Mol. Canc. Ther. 3: 1605–13, 2004). Methods: Twelve patients (pts) were enrolled on this study. T was given at a dose of 175 mg/m2 on day 8 (after 7 days of perifosine) of a 21 day cycle; this was to obtain a steady state level of P at the tumor before exposure to T. The intent of the protocol was to determine if full dose P could be delivered with 50 mg of perifosine given orally 1, 2 or 3 times a day on days 1–14 of each cycle. Results: Disease sites included lung 3, thyroid 3, breast 1, esophagus 1 and other 4, Median age was 66 (range 45 - 83); 6 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 2 regimens); 3 had prior treatment with a taxane. Three pts were entered at each dose level and the cohort expanded to 6 pts if 2 or more pts experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose level was toxic if 4 or more pts experienced a DLT during cycle 1. A total of 30 cycles and a median of 2 cycles (range 1–11) per patient were delivered. There were no grade 3/4 hematologic toxicities. Full dose T was given in all treatment cycles. P dose reductions were required in 6% of cycles (50 mg - 7%, 100 mg - 0%, 150 mg - 7%). One patient missed one dose due to nausea and one pt was stopped due to diarrhea. The grade 3 toxicities for each cohort are given in the table below. The elevated glucose value was 321. Nine pts were evaluable for response; two pts with thyroid cancer had stable disease by the RECIST criteria for 9 and 10+ months. Conclusions: In this study the usual single agent doses of P (150 mg daily) & T (175 mg/m2 q 3 weeks) were given together without increasing the toxicities that would be expected from using each drug alone. Phase II studies are warranted to define activity of the combination.

[Table: see text]

[Table: see text]
Modification in expression of EGFr, p53, and pTEN in non small cell lung cancer (NSCLC)
Authors: Bayle S. , Penault-Llorca F. , Robinet G.
Published: March 2020

13151

Background: Treatment inhibiting tyrosine kinase domain of EGFr have proved dramatically efficient in NSCLC. Even if several studies have revealed predictors of treatment response, - such as gender, adenocarcinoma histology, gene mutations, or Asian origin-, response to treatment remains random and is not correlated with an initial overexpression of EGFr by the tumor. The efficiency of those EGFr inhibitors was only shown in second- or third-line treatments, and studies using them in first-line treatments, particularly when combined, had no positive outcome. We have therefore assessed the expression of EGFr in NSCLC before and after cisplatin-based chemotherapy to see if it modified the level of expression of either EGFr, or of molecules including its chain of activation, such as P53 or pTEN. Methods: Tumor samples were obtained from patients treated for NSCLC. We retrospectively studied the bronchial samples of all the patients treated for NSCLC in Brest University Hospital for 6 months. Patients with treatment response whose control samples were negative were not included. We extracted paraffin embedded samples from NSCLC before and after cisplatin-based chemotherapy. For all cases EGFr expression has been assessed with the Ventana CONFIRM TM EGFr 3C6 antibody, P53 expression with the DAKO P53 D07 kit, and pTEN expression with Novocastra antibody. Intensity was scored 0, 1+, 2+, 3+. Results: Data on 30 patients are available, 27 males and 3 females. 70% of tumors show overexpression of EGFr before chemotherapy, and 63.3% after, which has no stastistical significance. The same was observed for pTEN and P53, whose level of expression is similar before and after treatment. The level of expression of P53, pTEN, and EGFr is not correlated with gender or histological type. However, EGFr expression tends to increase after chemotherapy for the subsets of adenocarcinoma and women, but this remains statistically non-significant. Conclusions: Cisplatin-based chemotherapy does not seem to modify the expression of EGFr nor its chain of activation. However, the level of expression, particularly for EGFr, seems to be higher after chemotherapy for the subsets of adenocarcinoma and women.

No significant financial relationships to disclose.
Sensitization of pancreatic cancer cells to ApoG2 induced killing by curcumin
Authors: Thoutreddy S. , Ali S. , Mohammad R. , Sarkar F. H.
Published: March 2020

13152

Background: In pancreatic cancer, several important survival molecules such as NF-kappa B and Bcl-2 or Bcl-XL are highly activated. Thus agents that inhibit NF-KappaB activation, together with agents that inhibit Bcl-2 or Bcl-XL protein function, may lead to enhanced cell killing. ApoG2, a new derivative of natural product gossypol, is a potent small molecule inhibitor of Bcl-2 and Bcl-XL proteins. Curcumin, an active ingredient from the rhizome of the plant, Curcuma longa, has anti-inflammatory and anti-cancer activities and works by inactivation of NF-Kappa B activity. In this study we have investigated the effects of curcumin on ApoG2 induced apoptosis. Methods: The BxPC-3 human pancreatic cancer cell line was used in this study. ApoG2 was dissolved in DMSO at 1 mM stock solution, and curcumin was dissolved in DMSO at 20 mM stock solution. Cell viability was determined by the standard MTT assay and apoptosis was measured by histone/DNA ELISA method. Results: Pretreatment of human pancreatic cell line BxPC-3 with curcumin sensitizes ApoG2 induced cell killing. In the dose escalation with ApoG2 at 48 hrs on MTT assay, 250 nM showed 75% cell viability, while 2.5 uM of curcumin at 72 hrs showed 80% cell viability. Pretreatment with curcumin for 24 hrs followed by ApoG2 at 48 hrs showed 55% cell viability (p = 0.0005). Apoptosis by histone/DNA ELISA showed 4-fold induction of cell death with ApoG2 at 48 hrs, 7-fold induction of cell death with curcumin at 72 hrs. However, pretreatment with curcumin for 24 hrs followed by ApoG2 at 48 hrs showed 10-fold induction in apoptosis compared to the control. Conclusions: From these results, we conclude that curcumin enhanced ApoG2 induced cell growth inhibition and apoptosis of BxPC-3 cells.

No significant financial relationships to disclose.
Response to EGFR inhibitors in fibroblast cell lines and its association with germline polymorphisms
Authors: Liu W. , Montenegro R. C. , Zhang W. , Ratain M. J.
Published: March 2020

13167

Background: Only a small number of cancer patients benefit from therapy with EGFR inhibitors. It is therefore important to understand the mechanism of action of these drugs and to find predictive markers for drug response. Although somatic mutations and gene amplification have been correlated with the efficacy of EGFR-targeting therapy, cancer cells and/or patients with normal EGFR expression are also sensitive to these drugs. We then aim to further understand the mechanism underlying the predisposition to sensitivity to EGFR inhibitors in germline cells. Methods: We chose 70 human normal fibroblasts cell lines as an in vitro model. Cytotoxicity studies were performed on these cells using two EGFR inhibitors, gefitinib (G) and AG1478 (AG). Cells were incubated with serial concentrations of the drugs (10, 20, 40 and 60 μM for G and 5, 10, 15 and 20 μM for AG) dissolved in DMSO. Growth inhibition was measured by Alamar Blue. Three polymorphisms, −216G/T, R497K and intron 1 (CA)n, were genotyped in these cells. EGFR expression was measured with real-time PCR. Results: There was considerable variability in drug response in a dose-dependent manner among these cells. The two drugs behaved quite differently. The fibroblasts had a much more variable response to G (mean of coefficient of variance of survival rates under all 4 concentrations, 61%) when compared to the response to AG (26%). Drug response was not correlated with EGFR expression. A significant correlation was observed between the R497K polymorphism and the survival rate of cells treated with AG at 5 μM (p<0.01) and 10 μM (p<0.05) with higher growth inhibition in K allele-carriers. No correlation was observed between any of the three EGFR polymorphisms and G cytotoxicity. Conclusions: These observations suggest that the cytotoxic effects of G and AG are due to different mechanisms, and that other genes such as transporters may also contribute to drug response. The R497K polymorphism may be useful as a predictive marker for response to AG and/or similar agents.

No significant financial relationships to disclose.
Fluorescent antibody tagging of colon cancer in the nude mouse; a model for improved surgical accuracy in the oncologic patient
Authors: Luiken G. A. , Xu M. , Quigley M. M. , Hoffman R. M. , Chan A. D.
Published: March 2020

13501

Background: Induced fluorescence of malignant tumors has the potential to improve the surgeon’s ability to accurately identify and excise all malignant tissue. Tumors can be made fluorescent using fluorophore-tagged anti-tumor antigen antiboies. We present here our results using a human colon cancer cell line in the nude mouse model. Methods: HCT 116 colon cancer cells were subcutaneously or orthotopically implanted in 16 nude mice (12 study mice and 4 control mice). Two to 8 weeks after injection, tumor nodules were easily detectable. Using the tail vein method, all mice were injected with fluorophore-tagged anti-CEA or fluorophore-tagged IgG. Mice were examined using a small animal imaging system with a 470 nm light source and appropriate filters. They were also examined using a simple blue LED flashlight fitted with a fixed 470 nm band pass filter for illumination and were observed through filtered goggles. Results: All tumor nodules in the study mice demonstrated green fluorescence when visualized through the skin. On dissection and exposure of the tumor nodules, this fluorescence was intense and clearly distinguishable from the surrounding normal tissue using either the imaging system or the blue LED. Very small (<0.5mm) metastatic nodules were easily identified. Bright tumor fluorescence remained visible up to 5 days after injection. Control mice injected with fluorophore-tagged IgG and examined in a similar manner revealed no tumor fluorescence. Minimal non-specific dull fluorescence was occasionally observed in gut mucosa and ovarian tissue but was easily distinguished from the bright tumor fluorescence. Conclusions: When tumor surface antigens are known and antibodies to those antigens are available, this technology is simple, easy to perform, requires no technically complex equipment or operator expertise and could be readily adapted for cancer surgery in the academic or community hospital setting. Major indications for this technology would be in those patients where tumor resection offers an excellent chance for cure or significantly improves survival. The implications for increased accuracy of procedures such as resection of primary colorectal cancer or resection of solitary hepatic or pulmonary metastases are clear.

No significant financial relationships to disclose.
Patterns of failure and outcomes in anal adenocarcinoma
Authors: Gonzalez R. J. , Chang G. J. , Skibber J. M. , Feig B. W. , Eng C. , Janjan N. , Crane C. H. , Rodriguez-Bigas M. A.
Published: March 2020

13503

Background: Adenocarcinoma of the anal canal is a rare malignancy with an aggressive natural history. The purpose of this study is to evaluate the outcomes of a multidisciplinary approach in patients with anal adenocarcinoma. Methods: A retrospective review was performed of patients with anal adenocarcinoma identified from the M.D. Anderson Cancer Center (MDACC) tumor registry between 1983 and 2004. Distal rectal cancers were excluded by pathologic review. Patients were classified according to treatment type: chemoradiotherapy (CXRT) ± local excision or radical surgery (RS) ± chemoradiation. Overall survival, and patterns of failure were assessed. Results: 41 candidate patients were identified. Thirteen patients were excluded (10 misclassified, 3 no treatment or followup at MDACC). Of the remaining 30 patients, 27 had localized disease and were treated with curative intent. 26 patients received radiation, 23 of the 26 with concurrent 5-FU based chemotherapy. Eleven patients (41%) received additional 5-fluorouracil-based adjuvant chemotherapy following primary treatment. Twelve patients were in the CXRT treatment group and 15 were in RS (1 did not receive chemoradiation). Median follow-up was 28 months (range 5–195). Median overall survival for the entire cohort was 59 months with an actuarial 5-year survival of 47%. Rates of recurrence are shown in the table below. Three patients with local failure were treated with salvage abdominoperineal resection and all developed subsequent failure (2 distant, 1 local). The fourth patient refused surgery and subsequently developed disease progression. Conclusions: Adenocarcinoma of the anal canal has a poor prognosis and accurate histologic diagnosis should be pursued. Although limited, our experience demonstrates that the most common pattern of failure is distant. An aggressive multimodal approach results in good local control but improvements in chemotherapeutic strategies are needed. [Table: see text]

No significant financial relationships to disclose.
Capecitabine plus oxaliplatin (XELOX) followed by capecitabine plus irinotecan (XELIRI) in a sequential schedule in first-line metastatic colorectal cancer (MCRC): a phase II multicenter study
Authors: Cassinello J. , Álvarez J. V. , García-López M. J. , Pujol E. , Colmenarejo A. , De Segovia F. , Marcos F. , Filipovich E. , García Castro I. , Arcediano A.
Published: March 2020

13516

Background: In phase II trials, XELOX and XELIRI were highly active and well tolerated in first-line MCRC. The aim of this study is to explore the efficacy and safety of XELOX followed by XELIRI as first-line treatment in MCRC. Specifically, we wanted to evaluate the impact of sequential scheduling on the dose-limiting neurotoxicity associated with oxaliplatin accumulation. Methods: Eligible patients (pts) had histologically or cytologically confirmed MCRC, ECOG PS ≤ 2 and adequate bone marrow, renal and hepatic function. Prior chemotherapy for MCRC was not allowed. Pts received 4 cycles of XELOX (capecitabine 1000mg/m2 orally bid d1–14 + oxaliplatin 130mg/m2 i.v. d1, q3w) followed by 4 cycles of XELIRI (capecitabine 1000mg/m2 bid d1–14 + irinotecan 240mg/m2 i.v. d1, q3w). This sequential schedule was repeated until unacceptable toxicity or disease progression. Results: Of the 35 pts analized to date: M/F (69%/31%); median age 68 years (range 41–78); ECOG PS 0–1 (94%); surgery (77%) and adjuvant chemotherapy (31%). 240 cycles (median 6, range 1–16) have been administered. 35 pts received XELOX (123 cycles, median 4), and 21 pts received XELIRI (83 cycles, median 4) in the first sequential schedule. In the second sequential schedule 6 pts received XELOX (22 cycles, median 4) and 4 pts received XELIRI (12 cycles, median 3.5). Median relative dose intensity was 88% for XEL, 96% for OX and 92% for IRI. In 27 efficacy evaluable pts, the ORR was 48% (95% CI, 29–67%). Eight pts were not evaluable due to adverse events (n=6), ongoing treatment (n=1) and lost of follow up (n=1). Conclusions: This sequential schedule is active and well tolerated in first-line MCRC. The improvement/recovery of the oxaliplatin-related neurotoxicity during the XELIRI phase is also promising and allows the re-treatment with oxapliplatin in the next sequence without accumulating neurotoxicity. Final results will be presented at the meeting. [Table: see text]

No significant financial relationships to disclose.
Survivorship patterns of a large nationwide cohort of elderly veterans with colorectal cancer
Authors: Virgo K. S. , Valentine M. P. , Dauz L. , Marietta L. H. , Adams B. , Devarajan S. , Longo W. E. , Johnson F. E.
Published: March 2020

13525

Background: Administrative databases are not designed to permit cancer researchers to readily follow patients from the period pre-diagnosis through initial curative intent treatment, adjuvant therapy, post-treatment follow-up, to either death or loss to follow-up. One major hurdle to cancer research using such databases has been the lack of data such as stage at diagnosis, and histopathologic type and grade. A second major hurdle is that many patients use more than one system of care, in this instance, Department of Veterans Affairs (VA) and Medicare-reimbursed care. These dual users would be inaccurately represented in the analysis if only one source of data were analyzed. Methods: A retrospective analysis of 13 years of nationwide Medicare and VA inpatient and institutional outpatient data beginning with the three years pre-diagnosis (1986–1990) through a minimum of five years post-diagnosis (1994–1998) was conducted. Death data were available through June 2005. Data were also extracted from tumor registry files, Computerized Patient Record System Files, and paper medical records at each VA. The population studied included all VA patients diagnosed with colorectal cancer and surgically treated for cure during the five-year period 1989–1993, who were Medicare-eligible at diagnosis, and survived the index admission. Results: Of the 6612 patients treated with curative intent during the five-year period, 4924 (74%) could be staged. Of these, 4551 (92%) were deemed eligible for the study. Of the eligible patients, 77% were diagnosed with colon cancer and 23 percent with rectal cancer. The majority (89%) had adenocarcinoma. The histopathologic grade was moderately differentiated for 54% and well differentiated for 19%. As of June 2005, 77% had died. Including all stages (0- IV), the average survival in months after treatment was 86 (median=61). Survivorship differed significantly by stage at diagnosis (p < .001). Conclusions: This rich database provides a wealth of data for subgroup analyses of survivorship, recurrence patterns, and health services utilization patterns within and across systems of care. Identifying predictors of survivorship within subgroups of this population is currently under way

[Table: see text]
Influence of the department on the resection rate in palliative treatment of metastatic colorectal cancer (CRC)
Authors: Wein A. , Liersch T. , Hofheinz R. , Fahlke J. , Wilke J. , Brueckl W. M. , Maennlein G. , Boxberger F. , Kohnen R. , Hahn E. G. , Hohenberger W.
Published: March 2020

13528

Background: During the last years due to the application of Irinotecan, Oxaliplatin and “biologicals” for the first- and secondline treatment of CRC in palliative situation the efficacy of palliative treatment has considerably improved with an acceptable toxicity. The achievements of secondary metastatic resection after downsizing by palliative treatment have increasingly become the focus of interest in palliative patients and opened up new ways in terms of curative options (Folprecht et al. 2005; Wein et al. 2001). Here, we analyse the influence of different departments on the resection rate after palliative treatment. Methods: A prospective phase III trial in metastatic CRC with systemic treatment by 5-FU/sodium FA as a 24h-infusion (AIO) versus AIO plus Oxaliplatin followed by secondary metastatic resection. Trial start: 2000; end of trial: 2005. Randomized patients: n = 240 by 5 centers experienced in clinical trials. In order to achieve a homogeneous patient group, non-resectability of distant metastases was required according to pre-defined criteria. Stratification characteristics: In accordance to the participating departments; ECOG index 0.1 vs 2. Involvement of the hepatic tumour extension 25% vs other localisation; organ manifestation 1 vs > 1. Inclusion criteria: Definitively non-resectable metastases. Palliative first-line treatment: Histologically proven adenocarcinoma of the colon or rectum, unambiguous enlargement of metastatic masses in objective imaging procedures. At least one bidimensionally measurable tumour lesion. Age: > 18, < 75 years. Exclusion criteria: Concomitant treatment with other anti-neoplastic substances. Sensoric neuropathy. Results: Resected/randomized patients of 176 currently evaluable patients, both treatment groups combined: department (dep.) 01: 0/26 (0%), dep. 02: 10/27 (37.0%), dep. 03: 21/68 (30.9%), dep. 04: 8/43 (18.6%), dep. 05: 1/12 (8.3%), total: 40/176 (22.7%). Although in the total population, a remarkable resection rate could be achieved, the variation between the departments is high (p=.0043 for differences between departments). Conclusions: The resection rate after palliative CRC treatment essentially depends on the department.

No significant financial relationships to disclose.
Influence of palliative surgical resection on overall survival in patients with Advanced Colorectal Cancer: A retrospective single institutional study
Authors: Kaufman M. S. , Radhakrishnan N. , Roy R. , Thomas A. , Gecelter G. , Tsang J. , Caramalis A. , Nissel-Horowitz S. , Mehrotra B.
Published: March 2020

13532

Background: The role of palliative surgical resection in patients presenting with locally advanced or metastatic colorectal cancer (CRC) is unclear. Resection is often limited to symptomatic management of bleeding, obstruction, perforation or for relief of pain, in patients with an adequate performance status and an expected life span of over several weeks. An exploratory analysis to evaluate the influence of a palliative surgical resection on survival outcome in patients with advanced CRC is reported. Methods: A retrospective review of medical records of all patients diagnosed with advanced CRC at our institution between the years 1998–2003 was undertaken. Tumor registry data were reviewed to identify age, gender, modalities of therapy (i.e. surgery (S), chemotherapy (C), radiation), and overall survival. IRB approval was obtained for this study. Results: 185 patients were identified. Mean age was 67 years (range 30–99). M: F ratio was 1:1. 62% of patients (115/185) underwent a palliative surgical intervention. Mean survival of patients who underwent S and those that did not undergo S was 27.7 months (mo) and 8.7 mo respectively (p<0.0001). 48% of patients (79/185) underwent systemic C. Mean survival of patients who received C + S, and patients who received C alone was 39 mo and 17.3 mo respectively (p<0.0004). 51% of patients who underwent S, received C; 30% of patients who did not undergo S, received C. Chemotherapy data were available on 46 of 79 patients. Patients treated with S + C, and C without S, received a median of 9 mo and 6 mo of therapy respectively. The median number of regimens used were similar in both. Conclusions: These exploratory data suggest a positive influence of a palliative resection performed during the disease course of patients with advanced CRC. The increased frequency of utilization and the more prolonged duration of C in the surgically treated patients may in part contribute to this improved survival . This may also be reflective of performance status at the time of diagnosis. Future trials enrolling patients with advanced CRC should prospectively stratify for surgical intervention to further clarify the influence of this modality on the outcome of systemic therapy in this disease.

No significant financial relationships to disclose.
Investigations of oral uracil and tegafur(UFT)-based adjuvant chemotherapy in patients with colon cancer
Authors: Noshima S.
Published: March 2020

13535

Background: Surgical resection plays a major role in the treatment of colon cancers. However, surgical resection alone has limitation in its use and it is necessary to administer adjuvant therapy and it would be important to define clinical significance of adjuvant chemotherapy. Methods: A total of 95 patients diagnosed with colon carcinoma were randomly assigned to one of two groups, i.e., treatment-group or non-treatment group. UFT (400 mg/day) was administered daily to 40 patients (treatment-group), one week before surgery. 55 patients (non-treatment group) received no medication before undergoing surgery. In the present study, we have investigated how adjuvant chemotherapy inhibited proliferation of colon cancer cells in vivo through monitoring cell proliferative activities (using MIB-1 antibody), expression of abnormal p53 protein and apoptosis-assays. Two groups were subjected to analyses of these study parameters. Results: Effects of preoperative administration of UFT on cellular proliferative activities: MIB-1-positive rates were 21.21 ± 2.89 (%) for treatment group and 39.02 ± 2.27 (%) for non-treatment group, and there was significant difference in MIB-1-positive-rates between the two groups (P<0.0001). Effects of preoperative administration of UFT on mutated p53 protein expression: The incidence of mutated p53 protein was 20.27 ± 4.28 (%) for treatment group and 49.06 ± 4.46 (%) for non-treatment group, and there was significant difference in the incidence of mutated p53 protein expression between the two groups (P<0.0001). Effects of preoperative administration of UFT on apoptosis: Apo.I. was 1.24 ± 0.20 (%) for treatment group and 0.49 ± 0.06 (%) for non-treatment group, and there was significant difference in Apo.I. between the two groups (P<0.001). Conclusions: Taken together, these findings indicate that UFT-based adjuvant chemotherapy is potentially useful for treatment of colon cancer patients undergoing surgical resection.

No significant financial relationships to disclose.
Randomized single institute pilot study of vaccinia-CEA(6D)-tricom and fowlpox-CEA (6D)-tricom with GM-CSF (V) in combination with docetaxel (D) in patients with colorectal cancer (CC)
Authors: He A. R. , Hwang J. , Malik S. , Park S. , Schlom J. , Marshall J.
Published: March 2020

13538

Background: Our previous study demonstrated 40% patients with CC achieved stable disease at 4 months with V (JCO, 23(4):720–31, 2005.). Preclinical studies showed taxene enhanced tumor vaccine in delaying tumor growth and increasing the antigen-specific T cells. We report the results of a Randomized phase II pilot study of V in combination with docetaxel (D) in CC patients. Methods: 27 patients with metastatic CC were randomly assigned to 3 arms, stratified for HLA-A2. All patients received a ‘prime’ dose of vaccinia-Tricom on Day 0, followed by ‘boost’ doses of fowlpox-Tricom on Days 21 and q 21 days for 4 months; all vaccinations were followed by local GM-CSF (100 μg) for 4 days. Arm 1 received V; Arm II and III received V and D on D1, D8 during each fowlpox vaccination at 10mg/m2 and 30mg/m2, respectively. Patients with stable disease continued vaccinations monthly after study completed. Safety data was evaluated. Primary endpoints included the impact of varying doses of D on CEA-specific T cell immune responses (CTL) using the ELISPOT assay, the recommended dose for further study as defined by the best immune response with acceptable toxicity, and objective clinical response. Results: The most common AE related to the vaccines was grade (g) 1 injection site reactions. Other common AEs were g1 fatigue, nausea, vomiting, fever, headache, and myalgia. There were 1 g3 fever and 1 g3 abdominal pain. The AE from the combination arm were contributed by D as expected, included g3: hyperglycemia (1), fatigue (1), elevation of liver function tests (2), pulmonary infection (1), abdominal pain (1), vomiting (1) or diarrhea (1). 6/ 27 patients have died 17 months after starting V. Patients received 2 to 12 cycles of therapy before disease progression. Observed clinical benefit was significantly lower than the 40% previously documented with V alone. The immune data is to be presented. Conclusions: Inferior clinical benefit as compared to our previous experiment could be explained by more heavily pretreated patients in this trial or negative impact of D on V. CTL data should explain this observation.

No significant financial relationships to disclose.
Toxicity and efficacy of four schedules of intensified neoadjuvant chemoradiotherapy (RCT) with irinotecan and 5-Fu or Capecitabine in patients with locally advanced rectal cancer (LARC)
Authors: Klautke G. , Ludwig K. , Klar E. , Freund M. , Fietkau R.
Published: March 2020

13550

Background: After neoadjuvant RCT in patients with LARC the rate of complete response (pCR), nearly complete response (nCR)and also the ypN0 category influences survival. So four different schedules of neoadjuvant RCT with irinotecan and 5-Fu or Capecitabine were compared in efficacy (pCR, nCR, ypN0) but also in the main toxicity (diarrea III/IV CTC). Methods: Conventional radiation was given at daily fractions of 1.8Gy to a total dose of 50.4Gy and 5.4Gy boost in all schedules. In our first schedule 5-Fu (250mg/m2, d1–43) and irinotecan (40mg/m2, d1,8,15,22,29,36) (group A), in our next schedule capecitabine (1500mg/m2, d1–43) and irinotecan (40mg/m2, d1,8,15,22,29,36) (group B), and then next capecitabine (1500mg/m2, d1–14, 22–35) and irinotecan (50mg/m2, d1,8,22,29) (group C) and now capecitabine (1500mg/m2, d1–14, 22–35) and irinotecan (60mg/m2, d1,8,22,29) (group D) was applicated concurrently. Surgery was performed 4–6 weeks after RCT. Results: Group A-B-C-D: number of patients: 37 - 28 - 20 - up to now 11; clinical state UICC II/III: 6/31 - 2/28 - 5/15 - 1/10; diarrhea (III+IV): 12/37(32%) - 11/28(39%) - 2/20(10%) - 1/11(9%); pCR: 9/37(24%) - 4/26(15%) - 0/20(0%) -3 /9(33%); nCR: 10/37(27%) - 3/26(12%) - 5/20(25%) - 1/9(11%); ypNo: 25/37(68%) - 15/26(58%) - 12/20(60%) - 6/9(67%). Conclusions: Neoadjuvant RCT with 5-Fu or capecitabine in combination with irinotecan is high effective. The splitting of capecitabine with a break in the third week of radiation reduces toxicity but not efficacy. In our trials during RCT a total dose of 240mg/m2 irinotecan in combination with 5-Fu/capecitabine must be applicated to receive a high rate of pCR.

No significant financial relationships to disclose.
Docetaxel and capecitabine for previously treated metastatic colorectal cancer
Authors: O’Brien T. E. , Newton E. , Trey J. , Crum E.
Published: March 2020

13579

Background: Docetaxel (D) induces human colon cancer cell lines to upregulate thymidine phosphorylase, an enzyme which activates capecitabine (C) to its cytotoxic form. This provided rationale for adding low dose D to C in patients with colorectal cancer (CRC). Although this combination has been established in metastatic breast cancer, it has not been evaluated in CRC. Because of concerns of toxicity in a pretreated population, we performed a phase I trial in patients with previously treated CRC. Methods: Eligibility: At least 1 prior treatment for metastatic disease; ECOG PS 0–1; adequate organ function. Design: Phase I, dose escalation. D, IV, days 1 & 8, and C, PO BID days 5–18, repeated q21days. Dose Level 1: D=15mg/m2, C=1000mg/m2; Level 2: D= 15 mg/m2, C= 1100 mg/m2; Level 3: D= 20 mg/m2, C= 1100 mg/m2; Level 4: D=20mg/m2, C=1250mg/m2. Results: 13 patients have thus far been treated. 11 are evaluable for toxicity and 10 for response (1 at dose level 4 was taken off study due to non-compliance before completion of cycle 1; another died of progressive cancer before completing cycle 1 at dose level 4; another is evaluable for toxicity but not yet for response). 9 with colon, 4 with rectal primary sites. Median follow-up= 5 mo (1–19 mo). Med age= 59 (30–75); #prior regimens for met disease 1–2, all of which were 5-FU based. Toxicities No dose limiting toxicities (DLT) until Dose Level 4. Dose Level 1: 1/3 developed grade 2 diarrhea and hand-foot syndrome and delayed grade 3 hand-foot; Dose Level 2: 2/3 developed grade 2 toxicities (hand-foot in one and diarrhea in the other); Dose Level 3: 1/3 developed delayed grade 2 hand-foot; Dose Level 4: 1 patient with delayed grade 2 hand-foot and grade 1 eye tearing; another developed DLT (grade 4 stomatitis/dehydration). Response 6/10 patients progressed after 2 cycles; 2 pts had stable disease, one lasting 4.6 mo; 2 patients had a partial response, one of which lasted 9 mo. The latter case had refractory disease to FOLFOX 4 but a 78% reduction in her liver metastases to D+C. Conclusions: The combination of low dose docetaxel, used as chemosensitizing agent, with capecitabine in this pretreated group of patients with metastatic CRC appears to be well tolerated, with no DLTs seen until Dose Level 4, and has modest activity. MTD determination awaits further accrual.

No significant financial relationships to disclose.
Surgical salvage of pelvic recurrences from colorectal tumors
Authors: Chacon M. , Varela M. , Huertas E. , Roca E. , Sanchez Loria F. , Kaplan J. , Pairola A. , O’Connor J. , Chacon C. , Chacon R. D.
Published: March 2020

13580

Background: The morbidity of pelvic recurrences from colorectal tumors (PRCT) represents a challenge for the oncology multidisciplinary team. Surgical treatment is the best option for palliation and in several series it offers long term local control in 30% of the cases. Objective: To perform a retrospective analysis of patients (pts) surgically resected for PRCT in terms of: time to progression after surgical salvage (TP) and specific suvival (SS). Correlatives studies were performed with clinic and pathologic factors, surgical procedures (SP), and postoperative complications in terms of TP and SS. Methods: 64 pts treated (June 1994 - February 2005) were identified (women: 30), median age 63 years, site of the primary: rectum 48, sigmoid 16; Median number of resected nodes: 8 (r: 2 - 20) in pts with negative nodes and 15 (r: 6 - 42) in pts with positive nodes; primary treatment: surgery (S): 22 pts, S + chemotherapy (CT): 18, S + radiotherapy (RT): 4, S + CT/RT: 17, CT + S: 2 pts, QT/RT + CX: 1; in 7/64 a Miles procedure was performed as primary therapy, median disease free interval: 15 months; site of initial recurrence: locoregional 58 (90%), locoregional + systemic 10%. Pain and bleeding were the most frecuent symptoms. Results: The strategy in PRCT was: S: 29 pts, S + RT: 15, S + CT/RT: 9, CT/RT + S: 7, S + CT: 2, CT + S: 1, RT + S:1; IORT: 18/64; external beam RT: 17/64, 6 pts required Miles; type of resection: R0: 50/64 (78%), R1: 8/64 (12%), R2: 3/64 (5%) and 3 (5%) unknown. Median duration of surgery: 4 hours, abscesses and fistulas were the complications most frequently observed. Median time to progression (TP): 12 months, site of recurrence (56/64 pts) post salvage surgery: pelvic: 22 pts, extrapelvic: 6 pts, combined: 10 and unknown 18. Eleven pts are free of disease. In 16 pts more than one surgical salvage was perfomed. The specific survival was 21 months (IC 95% 37 - 61 m). Conclusions: In this serie surgical salvage of PRCT showed one year of local control disease, even in pts with R2 and with moderate morbidity. The surgical decision must be individualized and in the context of a trained surgical team.

No significant financial relationships to disclose.
Combined regimen of Irinotecan (Iri), Fluorouracil (FU), Leucovorin (LV) with Oxaliplatin (Oxa), FU/LV, in elderly patients with metastatic colorectal cancer (MCRC) treated in second line therapy
Authors: Botto H. G.
Published: March 2020

13583

Background: In previous trials in elderly patients (pts) with MCRC, treated with Iri-FU/LV combination in first line therapy (1st line therapy), we reported: Overall Response Rate (ORR) of 38%, (ASCO 343,2004) and with Oxa-FU/LV combination in 1st line therapy: ORR of 34%, (ASCO 3743,2005). The purpose of this trial was to study the feasibility, toxicity and response, with the combined regimen of Iri-FU/LV with Oxa-FU/LV in elderly pts with MCRC, treated in second line therapy (2nd line therapy), all of them recurrent after the 1st line therapies mentioned before. Methods: Sixteen pts with MCRC; M/9, F/7; PS: 0=9, 1=5, 2=2; median age 74,5 years (65–84 y), with normal hematological, cardiac and renal functions. Sites of disease: hepatic, 9 pts; locoregional, 7 pts. After the employment of Iri-FU/LV combination in 9 pts, and Oxa-FU/LV combination in 7pts, they have all shown recurrent disease. Treatment: Iri, 100 mg/m2, FU 350 mg/m2, LV 20 mg/m2, iv, day 1º and Oxa 75 mg/m2 and increases dosis of FU 550 mg/m2, LV 50 mg/m2, iv, day 8°, every 28 days. Pts evaluation was performed every two cycles, the median number of cycles was 5 (range 3–8), the total number of cycles was 84. All pts were examined for response, toxicity and survival. Results: PR: 31.2%; SD: 31.2%; PD: 37.5%. ORR: 31.2% (hepatic metastasis 19% and locoregional disease 12.2%). Toxicity: Gr 2/3, neutropenia 43.7%; anemia 37.5%; thrombocitopenia 12.5%; diarrea 12.5%; paresthesia 6.25%. The median time to progression was 6 months (range 2–12 m), the median survival time was 14 months (range 7–25 m). Conclusions: The combined regimen of Iri-FU/LV with Oxa-FU/LV, following this shedule in second line therapy, in elderly pts with recurrent MCRC proved feasibility, good activity, acceptable toxicity and good survival time.

No significant financial relationships to disclose.
Correlation between the number of positive nodes, number of dissected nodes and survival of patiens with colorectal cancer
Authors: Marin Marmolejo J. C. , Villegas Mejia C. R. , Cardona Arcila J. P. , Mulett Vasquez E. , Osorio Chica M. , Osorio G. F. , Correa Ramirez L. A. , Chacon Cardona J. A.
Published: March 2020

13585

Background: According to the TNM classification, the prognosis of patients suffering from colon and rectal cancer has been defined taking into account the number of nodes reported positively. Objective: This work is intending to establish a relation between the number of positive nodes and the number of dissected nodes, relating it with the overall survival. Methods: 5500 medical records of patients were reviewed. 771 out of these corresponded to gastrointestinal cancer (14%) from which 351(6.38%) corresponded to colorectal cancer. From this group, 291 patients (82.9%) underwent a surgery. A relation between the number of positive nodes and the number of dissected nodes was established and called proportion of positivity (positive nodes/ dissected nodes × 100) and this was in turn related to a five year overall survival. Two groups were analyzed: proportion of positivity > than 50% and proportion of positivity < than 50%. Results: A report of 209 patients showing nodes was obtained (59.5%), with a means of 10.4 (rank 0–31) of dissected nodes per patient and a means of positive nodes of 2.4 (rank 0–22). Comparing the two groups the statistic significance starts to be obvious from the 18 months and the difference between the two groups continues increasing until the five years. The survival to five years for the group with the proportion > than 50% was 39% (IC 95%:13.4–64.5) compared to the survival for the group with a proportion < than 50% that was 75.7% (IC 95%:67.6–83.7) p<0.05. Conclusions: The proposal shows that not only is the absolute number of positive dissected nodes as only prognostic indicator (TNM) but also that before nodes dissections with low number of them, it is possible to establish a reliable prognostic relationship by calculating the proportion of positivity. The above said does not consider that the nodal dissection can be less than recommended, on the contrary obtaining the biggest number of nodes will mean bigger equivalence of the proposal and a bigger possibility to detect positive nodes.

No significant financial relationships to disclose.
A Phase II study of gemcitabine plus zoledronic acid in subjects with Stage IV pancreatic cancer
Authors: Cox J. V. , Cartwright T. H. , Neubauer M. , McCollum D. , Sandbach J. , Monticelli M. A. , Boehm K. A. , Ilegbodu D. , Asmar L.
Published: March 2020

14002

Background: Gemcitabine, the standard chemotherapy for advanced pancreatic cancer (APC), produces low response rates and short time to progression. Preclinical studies suggest that zoledronic acid inhibits pancreatic cell lines by interfering with the p21ras/raf-1/MEK1/ERKL signaling pathway. We conducted this trial to evaluate the efficacy and toxicity of gemcitabine and zoledronic acid in subjects with APC. Methods: Eligible subjects had histological or cytological diagnosis of metastatic pancreatic adenocarcinoma (Stage IV) not amenable to resection with curative intent. Gemcitabine 1000 mg/m2 IV was given on Days 1, 8, 15, and 22 in Cycle 1 and Days 1, 8, and 15 in subsequent cycles. Zoledronic acid 4 mg IV was given on Day 1 every 4 weeks. Toxicity was assessed at each visit. Results: Between December 2004 and July 2005, 35 subjects were enrolled. Baseline characteristics: 20 males (57%), median age 66.7 years (range, 40–83.5), and KPS of 70/80/90/100 = 8%/29%/34%/29%, respectively. Four patients had locally advanced disease (3 stage IIB and 1 stage III), 86% of subjects had Stage IV disease at diagnosis; 91% of subjects had adenocarcinoma. Prior therapy included surgery (n=15, 43%), chemotherapy (n=3, 9%), and radiotherapy (n=2, 6%). To date, there has been 1 PR and 9 SD; the clinical benefit rate (PR+SD≥6 months) was 14%. Grade 3 and 4 treatment-related toxicities included: neutropenia (22%); thrombocytopenia and fatigue, (12.5% each); and anemia, nausea/vomiting, dehydration, and diarrhea (6% each). Seven treatment-related SAEs have been reported; 28 subjects are off study. Patients discontinued treatment due to: progressive disease (PD) (n=15), toxicity (n=4, 1 each DVT, infection, back pain, and generalized weakness), withdrew consent (n=3), MD decision (n=2), patient request (n=2), and death (n=2), To date, 21 subjects have died; deaths were attributed to PD (n=16), CVA (n=1), and unknown (n=4). Conclusions: Pancreatic cancer, typically advanced at diagnosis, remains a major treatment challenge. Zoledronic acid in combination with gemcitabine was well-tolerated in this study. Future genomic testing is proposed for responders. Updated toxicity, response, and survival data will be presented. Supported by Novartis Pharmaceuticals Corp., East Hanover, NJ.

No significant financial relationships to disclose.
Dose-finding study using oxaliplatin (Ox) in combination with fixed dose gemcitabine (Gem) and radiotherapy (RT) in patients with locally advanced pancreatic or biliary tract cancer (PBCa)
Authors: Peeters M. , Boterberg T. , Monsaert E. , Borbath I. , Demols A. , Polus M. , Scalliet P. , Berrevoet F. , Derre T. , Van Laethem J.
Published: March 2020

14028

Background: Prognosis of inoperable PBCa is poor. Large randomized studies in pancreatic cancer showed a better survival in patients (pts) with locally advanced (LA) in comparison with metastatic disease. Data on radiochemotherapy are scarce in pts with LA disease. Therefore, we performed this multicenter, phase I study on the combination of radiotherapy and Gem/Ox. This regimen showed superior activity to Gem alone in pancreatic cancer (Louvet C et al. JCO 2005;23:3509–16.) Methods: After signed informed consent, pts with LA pancreatic cancer (n = 14) or biliary tract cancer (n=1) were included. They received two cycles of Gem/Ox1 followed by 5 weeks of RT (25 fractions of 1.8 Gy up to a total dose of 45 Gy) in combination with a weekly fixed dose of Gem (300 mg/m2 in 30’) and an escalating weekly dose of Ox (levels: 40/50/60 mg/m2). NCI-CTC 2.0 was used weekly to score treatment-related toxicity in all pts. Results: Today, 15 pts. with a median age of 61 y (range: 44–74), median Karnofsky performance score 90 (range: 70–100) and M/F = 8/7 were included. Upto 60 mg/m2 Ox, no disease limiting toxicity (DLT) occured. Grade 3 toxicity included nausea (n = 1), neutropenia (n = 3) and thrombocytopenia (n = 1). This latter patient was treated with 40 mg/m2 Ox and subsequently also experienced a grade 4. One patient receiving 50 mg/m2 Ox developed a grade 4 thrombocytopenia. Most frequent grade 1/2 toxicity was nausea (n = 8, 53%), thrombocytopenia (n = 5, 33%) and diarrhea (n = 5, 30%). Fourteen out of 15 received the full course of radiotherapy. Median time to progression (TTP) is 6.7 months (95% CI: 3.7–13.5). Thirteen out of 15 pts. are still alive. Conclusions: Combination of radiotherapy and Gemcitabin/Oxaliplatin in pts with LA pancreaticobiliairy cancer is feasible and well-tolerated. The long TTP underlines the potential activity of this regimen. As no DLT has been reached, we will use a dose of 60 mg/m2 Ox for further evaluation.

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