bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypertensison is a significant adverse effect of bevacizumab treatment
Authors: Lowery M. A. , Power D. G. , Behbehani A. T. , Carney D. N. , McCaffrey J. A.
Published: March 2020

14134

Introduction: Vascular endothelial growth factor (VEGF) is upregulated in many tumours. Bevacizumab (BV) is a recombinant, humanised monoclonal antibody against the VEGF receptor and has shown promising results in phase II / III trials in colorectal cancer, non-small cell lung cancer, renal cell carcinoma, and breast cancer. Hypertension (HT) has been reported in all studies involving BV and management of this is not well established. Methods: The records of patients treated with BV in our institution were analyzed from January to August 2006. Indications for BV therapy, incidence and management of HT, and resulting outcomes were assessed. Results: 71 patients (45 male, 28–84 years) were treated with BV, at a dose of 5mg/kg every two weeks. 87% (n=60) had colon cancer. Lung cancer, renal cell carcinoma, melanoma, and pancreatic cancer accounted for the rest. 20% (n=14) had pre-existing HT. In all of these cases HT was well controlled with medication. 10 patients developed new-onset HT, and 7 patients experienced exacerbation of existing HT. Using the CTCAE(v3.0) guidelines for grading of HT, 5 had grade II and 10 had grade III. HT developed after a median of 15 weeks of BV (range 6–36 weeks), and a median cumulative BV dose of 20mg/kg (range 10 - 85 mg/kg). In the new onset HT cases 8 patients were controlled (BP= 140/90) with a single anti-HT, and one patient needed two or more agents (BP<160/100). In the pre-existing HT cases who needed an adjustment of anti-hypertensives, 3 were controlled (BP=160/100) with two or more agents and 4 patients required dose escalation of a single agent. In 2 patients BV was permanently discontinued. Anti-HT agents used included beta-blockers, ACE-inhibitors and Ca++- channel blockers. Conclusions: HT may develop at any point during treatment with BV. BP should be measured regularly. In this study 14% of patients developed HT de novo, and 50% experienced exacerbation of pre-existing HT. Median time to BV-induced HT was 15 weeks. There is currently no data to define which anti-HT is the best to use. BV is now becoming widely used, and as with all new targeted therapies, it is important that oncologists recognise relatively unusual side effects, and develop appropriate practice guidelines.

No significant financial relationships to disclose.
Pre-clinical evidence for an anti-tumor activity of defibrotide, a DNA-based, endothelium stabilizing drug
Authors: Echart C. , Iacobelli M. , Richardson P. , Mitsiades C. , Ignoni T. , Ferro L. , Eissner G.
Published: March 2020

14144

Background: Defibrotide (DF) is a mixture of polydeoxyribonucleotides with anti-thrombotic activity. Next to endothelium stabilization, recent data suggest anti-neoplastic properties of DF modulating interactions of tumor cells with their microenvironment. We investigated whether DF regulates expression and activity of heparanase, an enzyme critically involved in breaking down extracellular barriers and releasing growth factors linked to tumor invasion and angiogenesis. Methods: Heparanase expression was tested by RT-PCR and flow cytometry with multiple myeloma (MM) and microvascular endothelial cells. Heparanase activity was measured in cellular extracts with a heparan-degrading enzymatic assay. Serum degradation products of DF were identified by SEC-HPLC. The anti-angiogenic potential of DF was tested in vitro using a kit with human microvascular endothelial cells forming tubes across a layer of fibroblasts. In vivo, DF was tested in the dorsal skin-fold chamber assay in mice after inoculation of human gastric cancer cells. Proliferation was assessed by trypan blue exclusion. Results: We demonstrate a striking downregulation of expression and enzymatic activity of heparanase in endothelial as well as MM cells. In contrast, the degradation products of DF failed to exert any biological activity, suggesting that the intact mixture of deoxyoligonucleotides is responsible for the anti-tumor effect. We could also show that DF prevents (tumor) angiogenesis in vitro and in vivo. Western blots suggest that DF reduces phosphorylation-activation of p70S6 kinase, a key target in the mTOR pathway linked to angiogenesis. In addition, DF does not influence proliferation of vascular or tumor cells, rather acts via selective inhibition of tube formation of endothelial cells. Conclusion: In the present report we provide evidence for an anti-tumor activity of DF. DF inhibits (tumor) vessel formation and heparanase activity, and thus should be considered as an anti-cancer agent.

[Table: see text]
Phase I evaluation of OXi4503, a vascular disrupting agent, in patients with advanced solid tumours
Authors: Patterson D. M. , Ross P. , Koetz B. , Saleem A. , Stratford M. , Stirling J. , Padhani A. , Asselin M. , Price P. , Rustin G. J.
Published: March 2020

14146

Background: OXi4500, the active product of OXi4503, is a vascular disrupting agent acting at the colchicine binding site on the β subunit of tubulin. OXi4503 has greater anti-tumour activity in human cancer cell lines, causes a greater reduction in tumour blood flow than combretastatin A4P and has single agent activity in human tumour xenograft models. A phase I trial has commenced to examine the safety, tolerability and pharmacokinetics of OXi4503, with the primary objective being determination of MTD. FDG-PET scans were performed prior to and 28 days after the first infusion of OXi4503. Several other pharmacodynamic endpoints are also being assessed including DCE & BOLD MRI, circulating endothelial progenitor cells and cytokeratin 18. Methods: OXi4503 is administered by 3 weekly iv infusions to a maximum of 6 cycles. Starting dose was 0.06mg/m2. 100% dose escalation in single patient cohorts proceeded to 3.84mg/m2, when cohorts were expanded to three patients and 30% escalation due to emergence of grade 2 drug-related toxicity (thrombocytopaenia). Results: 11 patients have so far received OXi4503 (5F 6M, median age 54, range 33–68); median cycles received was 2 (range 1–4). Common AE’s include hypertension, pyrexia and anaemia. PK profiles show a dose-dependent linear increase in peak plasma concentrations and AUC of both OXi4503 and OXi4500. OXi4500 concentrations at current dosing (5 mg/m2) are close to that seen at the MTD in rats and dogs. DCE-MRI showed significant reduction in Ktrans in one patient (0.24mg/m2). In the 2 patients studied to date, PET images showed a decrease in the standardised uptake value (SUV) in 3 out of 4 metastases for one subject (1.92mg/m2) and in 5 out of 7 metastases for the other subject (3.84mg/m2) demonstrating a reduction in FDG uptake following drug treatment. Of 10 patients assessed, 2 have stable disease and 8 disease progression. Conclusions: OXi4503 has been tolerated at doses up to 5mg/m2 with no DLT observed, but changes in functional activity have been seen in 3 patients. MTD has not been reached and recruitment is ongoing.

[Table: see text]
In silico design of novel anticancer antibody mimetic molecules targeting HER2
Authors: Nakajima H. , Tanuma S. , Fujiwara I. , Mizuta N. , Sakaguchi K.
Published: March 2020

14149

Background: HER2 is a unique receptor molecule for which no ligand has been found and functions as a coreceptor to form homo-and hetero-dimers with other three HER (1, 3 and 4) family members. The dimerization results in the activation of HER tyrosine kinase. This, in turn, promotes the tyrosine phosphorylation of certain proteins, leading to the stimulation of cell proliferation, invasion, and antiapoptosis. The overexpression of HER2 in breast cancer correlates with increased tumor growth and metastatic potential, and thereby poor long-term survival for the patient. A monoclonal antibody against HER2, named trastuzumab, is approved for breast cancer patients, while pertuzumab is currently in phaseIIclinical trial. The two antibodies bind to different epitopes in the extracellular domains of HER2. Trastuzumab binding mainly mediates the antibody-dependent cytotoxicity (ADCC). On the other hand, pertuzumab binding directly inhibits HER2 dimerization with its partner receptors, blocking the growth signaling and inducing apoptosis. Furthermore, the unique binding pockets on HER2 for trastuzumab and pertuzumab have been resolved and provide the important target domains for creation of new anticancer drugs. Methods: Based on these mechanisms, we are trying to design and create both antibodies-mimetic molecules using our in silico methodologies COSMOS (Conversion to small molecules through optimized-peptide strategy) and SARM (Self-assembling regulatory molecule). We design HRAP (HER2 reactive peptide)- SARM and HRAP- SARM- FAB (Fc?-binding peptide). HRAP-SARM may bind to HER2 pertuzumab binding site and sterically interferes with HER2 dimerization and induces apoptosis. HRAP- SARM- FAB is expected to induce both ADCC and apoptosis. Results and Conclusion: In this presentation, we will show the preliminary results and functions of the Ab-mimetics, HRAP- SARM and HRAP- SARM- FAB on human breast cancer cells overexpressing HER2, as compared to those of trastuzumab and pertuzumab. Since those Ab-mimetics are small molecules and cheap, the successful results are sure to promise the revolutionary therapy for refractory breast cancer.

No significant financial relationships to disclose.
Orexigenic and cytoprotective effects of a novel adenosine-enriched peptide nucleic acid compound: Implications for clinical application
Authors: D’Olimpio J. T. , Elliston S. , Dediego M. , Sodum R.
Published: March 2020

14154

Background: There is a major unmet need for new non-toxic orexigenic and cytoprotective agents that can ameliorate intractable symptoms in cancer such as anorexia, poor wound healing/ulcerations and poor QoL. Underlying causes of these clinical problems include excessive inflammatory/cytokine responses to either treatment related or tumor related processes, or to both at once. AVR118, a novel remarkably non-toxic peptide/nucleic acid formulation has been shown in many anecdotal reports and in small clinical trials, to stimulate appetite, improve fatigue, and assist in more rapidly reversing toxic side effects of chemotherapy, radiation and interferon therapy. It has now been re-characterized to better explain these multiple effects. It binds to adenosine receptors in vitro and increases cAMP release in HEK293 cell lines expressing A2 receptors, mechanistically involving targeted receptor binding, most likely in the gut and in the functional pathway of orexin A. Methodologies: HPLC, co-chromatography with standards, UV and mass spectrometry. Receptor binding/functional assays in vitro, animal models for anti-inflammatory and wound healing studies. Results: AVR 118 consists of a mix of 14 nucleoside derivatives, including available adenosine at a concentration of 2.1mM in stable solution. Also present is a complex aggregate of peptides showing high proline and tyrosine content. AVR 118 binds to adenosine receptors in vitro and increases cAMP release in HEK293 cell lines containing A2 receptors and enhances smooth muscle relaxation mediated by A2 and others such as NK2 and NTS1 in vitro. AVR 118 shows 20% enhancement of epithelialization when compared to saline controls in a controlled porcine wound healing model. Conclusions: AVR 118 may prove to play a major role in palliation of anorexia symptoms associated with serious debilitating diseases such as cancer or AIDS and as adjunctive therapy for these patients. [Table: see text]

No significant financial relationships to disclose.
Angiogenesis index (AI) as a predictor of tumor burden in lymph nodes in colon cancer (Cca) patients (pts) undergoing sentinel lymph node (SLN) mapping (M)
Authors: Grewal S. , Saha S. , Patel M. , Sehgal R. , Parker R. , Mechetner E. , Wiese D. , Yestrepsky B. , Yee C. , Barber K.
Published: March 2020

14509

Background: Lymph Node (LN) status is the most important prognostic factor in colon cancer (Cca). Angiogenesis Index (AI) has been studied as a prognostic marker in various solid tumors with conflicting results. Hence, a retrospective analysis was done to evaluate the role of AI as a prognostic marker in Cca. Methods: Pts with Cca who underwent SLNM to determine LN status were included. A portion of tumor was sent for tumor marker analysis including p53, Thrombospondin-1 and CD31 by IHC. AI was derived for each specimen by summing the biomarker specific score for the three tumor markers. AI of -ve 6 was taken as cut off for significance based on previous studies on solid tumors. Metastatic foci in SLNs and non-SLNs were measured in greatest diameter by ocular micrometer; and were added for each pt to estimate overall tumor burden in SLNs and non-SLNs. Results: A total of 111 consecutive pts with Cca were included in the study. SLNM was successful in 100% pts. Pts with distant metastasis (mets) (n=18), Tis (n=1) and skip mets (n=9) were excluded from final analysis. Out of the remaining 83 pts, an AI of -6 or less was found in 22 pts (26.5%) while 61 pts (73.5%) had AI of more than (>) -6. Of the 61 pts with AI > -6, 37.7% pts were SLN +ve while 62.3% pts were SLN -ve (p=0.05)( Table 1A ). Of the 22 pts with AI less than or -6, 45.5% pts were SLN +ve and 54.5% pts were SLN -ve (p=0.65). Size of the metastatic tumor burden in lymph nodes was available in 69.7% of SLN +ve pts. Total average tumor burden for pts with AI > -6 (n=15) was 2.04cm as compared to 1.48cm in pts with AI of -6 or less (n=8)(p=0.66). Average SLN met size was 0.73cm in pts with AI > -6 and 0.63cm in pts with AI of -6 or less (p=0.66)( Table 1B ). Conclusions: AI did not correlate with nodal positivity or tumor burden in LNs in pts with Cca. LN status remains the most important prognostic marker in Cca. Further larger trials are required to determine the role of AI as a prognostic marker in Cca.

[Table: see text] [Table: see text]

No significant financial relationships to disclose.
Outcome of colorectal cancer (CRC) patients resected for brain metastases (BM)
Authors: Zanon E. , Aprile G. , Tuniz F. , De Pauli F. , Iaiza E. , Pella N. , Saman M. , Skrap M. , Fasola G. , Piga A.
Published: March 2020

14530

Background: Advances in systemic treatment for metastatic CRC confer survival advantage, allowing patients to reach a median survival of almost 2 years. As a consequence of this remarkable life extension, the incidence of BM from CRC, though still low, is increasing over time. The presence of BM is considered an index of poor prognosis, even when surgical resection is possible. Methods: To determine if an aggressive approach to BM from CRC could provide patients with clinical benefit or survival advantage, we retrospectively collected data from 29 CRC patients who underwent neurosurgical resection of BM between March 1998 and July 2006. Results: The median age at the time of surgical procedure was 65 years, median ECOG PS was 1, and the majority of patients (26 out of 29) had concomitant metastases at other sites. Lung and liver metastases were both common. Median number of previous chemotherapy regimens was two, with almost all of the patients being exposed both to oxaliplatinum and irinotecan-based regimens. After resection, 30 Gy of external whole-brain radiotherapy were administered to the majority of the patients. At the time of the analysis, 26 out of 29 patients had died, with a median survival time after brain metastasectomy of 210 days (8–682). Only 2 patients died within a month from surgery. We did observe prolonged survival for patients who received post-surgical radiotherapy (Kaplan Maier, p=0.033). Although death due to encephalic progression was reported for the patients with brain as the sole metastatic site, intracranial disease progression was not a clear predictor for poor survival in the whole cohort (p>0.05). Conclusions: Surgical resection of BM from CRC, whether followed by radiotherapy or not, is a feasible and safe technique, offering a chance of prolonged survival. Patients who received radiotherapy after complete neurosurgical resection have a better outcome.

No significant financial relationships to disclose.
Early analysis of toxicity and surgery in patients treated with cetuximab single agent followed by 5-fu, cetuximab and pelvic radiotherapy as neo-adjuvant treatment for operable, locally advanced rectal cancer (rc)
Authors: Bertolini F. , Zironi S. , Malavasi N. , Dealis C. , Bertoni F. , Losi L. , Chiara S. , Sonaglio C. , Luppi G. , Conte P. F.
Published: March 2020

14531

Background: Pre-operative chemo-radiotherapy in locally advanced RC has been used to improve local control and to facilitate sphincter-sparing surgery for distal tumors. Cetuximab, an anti EGFR monoclonal antibody, has proved efficacy in advanced colorectal cancer. Methods: Study design provided: 1) tumor biopsy to confirm diagnosis and to measure tumor biomarkers (EGFR, TS, p53, MAP kinase, Ki 67, p21, bcl-2; immunological cell profile at the tumor level: CD45RO, CD68, CD56 CD4+/CD25+, CD31, HLA-A, -B and -C), 2) Cetuximab single agent (400 mg/sqm loading dose, then 250 mg/sqm weekly) for 3 doses, 3) a second biopsy to evaluate tumor biomarkers, 4) Cetuximab 250 mg/sqm weekly plus 5FU (225 mg/sqm in continuous infusion) concomitantly with RT (50 Gy), 5) surgery. Tumor biomarkers are measured again on tumor specimen in non pCR patients (pts). 66 pts with resectable uT3/uT4 N0/+ RC will enter the study. Primary aim is: toxicity and activity (pathologic complete response). Secondary aim is: evaluation of biological parameters, rates of sphincter sparing surgery and disease free survival. Results: Up to now 29 pts are valuable for toxicity (M/F= 22/5; median age: 61; range: 35–74). Ultrasound staging at diagnosis is: uT3N0: 7; uT3N1: 20; uT4N1: 2. Four pts (14%) withdrew neo-adjuvant treatment after 1 administration of Cetuximab: 2 for hypersensitivity reactions (1 G3; 1 G4), 1 for progression and 1 for purulent arthritis. Twenty-two pts (75%) presented acne-like rash; treatment with Cetuximab was interrupted or reduced in 4 pts (14%): in 2 for acne-like rash grade 3 (NCI-CTC) and in 2 pts for refuse. Grade 1–2 gastro-intestinal toxicity (unrelated to Cetuximab) was observed in 13 pts (proctitis: 4; diarrhoea: 9); in 1 case: diarrhoea G4. Twenty pts are valuable for surgery: 18 pts (90%) underwent conservative surgery. Two pts (10%) experienced post-surgical complications: 1 anastomotic fistula and 1 colonic necrosis. Conclusions: Pre-operative treatment with 5FU, Cetuximab and pelvic RT is well tolerated and does not increase surgical complication rate. An update on efficacy data and biological markers evaluation will be presented at the meeting.

No significant financial relationships to disclose.
Bevacizumab (BV) related adverse events among various age groups of elderly patients with advanced colorectal cancer
Authors: Raman A. K. , Lombardo J. C. , Chandrasekhar R. , Fakih M. G.
Published: March 2020

14546

Background: Hypertension (HTN), arterial thrombosis (ATE), venous thrombosis (VTE), and gastrointestinal perforation (P) are known BV related adverse events. The incidence of these events in different age groups of elderly patients (= 65 years) has not been well described. This study aimed at identifying the incidence of HTN, ATE, VTE, and P among three age groups: 65–69, 70–74 and =75 years. Methods: A retrospective chart review of CRC patients = 65 yrs treated with BV based chemotherapy during the period of January 2004 - July 2006 at Roswell Park Cancer Institute was performed. The incidence of grade (G) 3–4 HTN, ATE, VTE, and P was calculated. Results: Sixty patients = 65 yrs received BV during the study period: 20 patients were 65–69, 19 were 70–74, and 21 were = 75 years of age. The median age was 73 (range 65–90). Eight (13.3%) patients developed G3–4 arterial thromboembolic events, 7 (11.6%) developed G3–4 venous thromboembolic events, 10 (16.6%) developed G3 HTN, and 2 (3.3%) had a bowel perforation. The incidence of ATE was the highest in the = 75 age group (4/21, 19%) when compared to the 70–74 age group (2/19, 11%) and the 65–69 age group (2/20, 10%). Similarly, G3 HTN was more common in the = 75 years age group (6/21, 29%) when comparison to the 70–74 (2/19, 11%) and the 65–69 (2/20, 10%) age groups. VTE were evenly distributed in all 3 age groups while one P occurred in the 70–74 and = 75 age groups respectively. The trend of increasing incidence of ATE and HTN did not reach statistical significance using Odds Ratio analysis (SAS exact logistic regression method), likely due to the small sample size. Conclusion: The incidence of ATE and HTN is increased in the elderly population, especially in patients = 75 yrs. BV based therapy needs to be investigated further in this population to determine if BV clinical benefits outweigh the associated risks.

No significant financial relationships to disclose.
Phase I/II study of irinotecan, UFT, and leucovorin with hepatic arterial infusion in colorectal cancer patients with unresectable liver metastases: Preliminary results
Authors: Yamaguchi T. , Matsumoto H. , Takahashi K. , Yasutome M. , Mori T.
Published: March 2020

14549

Background: To determine the maximum-tolerated dose (MTD) and to evaluate the efficacy and tolerability of combination chemotherapy of irinotecan (CPT-11), UFT and leucovorin (LV) with hepatic arterial infusion (HAI) in colorectal cancer patients with unresectable liver metastases. Methods: Patients who had unresectable liver metastases from colorectal cancer were treated concurrently with intravenous CPT-11 on day1 of each 14-day treatment cycle with dose escalation, with orally UFT and LV on day 1–7 of each cycle, and with HAI of 5-FU on day 8–14 of each cycle. The primary objective of this phase I study was to determine the MTD of biweekly intravenous CPT-11 and UFT/LV with HAI of 5-FU. In the phase II study, the primary endpoint was to determine the response rate. Results: In the phase I study, the recommended dose of CPT-11 for phase II study was 140 mg/m2 combined with UFT 300 mg/m2/day, LV 75 mg/body/day and 5-FU 2,000 mg/body/week. Sixteen patients were enrolled onto the phase II study. The six patients treated at the recommended dose during the phase I study also included in the phase II analysis (n = 22). Median number of liver metastases was 12 (range, 3 to 35). Median size of maximum diameter was 6.3 cm (range, 2.0 to 12.0 cm). The most common adverse event was neutropenia. The complete and partial response rate totaled 81.8%. Median survival time has not been reached yet. Eleven patients (50.0%) were ultimately able to undergo liver resection. Conclusions: The combination chemotherapy of CPT-11 and UFT/LV with HAI was safe, well tolerate and effective in current population of the patients with unresectable liver metastases from colorectal cancer. Updated toxicity and response data will be available in the spring of 2007.

No significant financial relationships to disclose.
A phase II trial of bevacizumab and capecitabine combination in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens
Authors: Zoran P. , Tarabar D. , Doder R.
Published: March 2020

14555

Background: This is a phase II study combination of capecitabine plus bevacizumab for patients with metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-containing regimens. Methods: The dose of capecitabine was 1000 mg/m2, administered twice daily for 14 days every 3 weeks. Bevacizumab was given at a dose of 5mg/kg on day 1 as i.v. infusion every 3 weeks. Treatment was repeated until the occurrence of disease progression or unaccepted toxicity. Results: Twenty-eight patients were enrolled. Of 28 patients, the overall response rate was 14.3% and the disease control rate was 42.9%. With a median follow-up period of 7 months, median time to progression and overall survival duration were 3 months and 14 months, respectively. The 1-year survival rate of all patients was 60.7%. The most common treatment-related grade 3/4 hematological toxicities included leukopenia/neutropenia in 4 patients and thrombocytopenia in 3 patients. Nonhematologic toxicities attributable to bevacizumab included bleeding in 3 patients, hypertension in 4 patients, thromboses in 3 patients, proteinuria in 5 patients, and gastrointestinal perforation in 1 patient. Conclusions: This drug regimen was well tolerated and combination of bevacizumab and capecitabine shows potential as third line chemotherapy in heavily pretreated patients with metastatic colorectal cancer.

No significant financial relationships to disclose.
Matrix metalloproteinase-1 is differentially expressed in signet ring cell, and intestinal colorectal carcinomas histotypes
Authors: Calascibetta A. , Gebbia V. , Cabibi D. , Martorana A. , Aragona F. , Rausa L. , Sanguedolce R.
Published: March 2020

14564

Background: Signet ring cell colorectal carcinoma ( SRCC) pure is an infrequent and highly malignant variant of colorectal cancer, while this histological component is present in 30% of all colorectal carcinomas. In our previous studies we compared the E- Cadherin, β- Catenin, Fibronectin, Ki 67 and Thymidylate Synthase (TS) expression of SRCC, the intestinal type of colorectal carcinoma (ICRC) to try to explain the pathogenesis, the aggressiveness and the low 5 Fluorouracil (5FU) responsiveness of these tumours. We found that all SRCCs had very low levels of all markers and were in the post- mitotic phase of the cell cycle. To understand their high metastatic capability we assessed the SRCC expression of Matrix Metallo Proteinase-1 (MMP1), a proteolytic enzyme, suspected to play an important role in the progression of various cancer and compared it to the ICRC one. Methods: We tested MMP1 expression immunohistochemically on formalin-fixed, paraffin-embedded samples of 32 SRCC and 70 ICRC. Differences in the distribution of the study variables, and associations between variables were assessed by means of the ?2 test. Results: SRCC showed a high expression of MMP1 over all in the invasion front of the tumour and in the neoplastic embolus rather then the ICRC (p<0.001). Conclusions: As MMPs seem to play important role in tumour invasion and metastasis, recently they have gained attention as targets for new anticancer therapy strategies. MMPs inhibitors have been shown to prevent tumour spread both in vitro and in vivo and to inhibit tumour angiogenesis and some of them are being developed for clinical use. In these study we demonstrated that SRCCs showed a different MMP1 expression pattern from the ICRC one, for this reason an anti-MMP therapy should be advisable in these patients, because of their bad prognosis.

No significant financial relationships to disclose.
Impact on therapeutic index of a chronomodulated infusion at conventional doses of oxaliplatin (OHP), 5-fluorouracil (5-FU) and folinic acid (AF) in not previously treated metastatic colorectal cancer patients: A multicentric observational study
Authors: Pirovano M. , Zambelli A. , Gherardi F. , Masseroni S. , Nasisi A. , Paraboni L. , Martignoni G. , Meregalli M. , Huscer C. S. , Tabiadon D.
Published: March 2020

14572

Background: FOLFOX4 schedule represents the standard treatment for metastatic colorectal cancer in EU, but is characterized by relevant adverse effects like G3–4 neutropenia in 42 % of patients (data from MOSAIC study). Adjustment of chemotherapy delivery schedule to the circadian timing system allows a significative improvement of tolerability. Objective of this multicentric observational study is the evaluation of therapeutic index of a OHP and 5-FU + AF based schedule at the same doses of FOLFOX 4, but administered according to a chronomodulated schedule (FLOX-1). Methods: From November 2005 to December 2006, we treated 41 metastatic colorectal cancer patients (19 male and 22 female, average age 65) with OHP 85 mg/m2/d1q14 sinusoidal 12 hour infusion with flow rate peak at 04.00 PM; 5-FU 1000 mg and AF 100 mg/m2/d1–2q14 sinusoidal 12 hour infusion with flow rate peak at 04.00 AM: a total of 258 cycles (5.5 average for patient) were administered using Melodie infusional programmable system (138 cycles) and CIP preprogrammed disposable system (128 cycles), all in homecare regimen. These data confirm a significative tolerability improvement of OHP, 5-FU and AF schedule when infused according to a chronomulated infusion prophile in metastatic colorectal cancer patients. Results: Overall average dose intensity was 39.1 mg/m2/w for OHP and 907.5 mg/m2/w for 5-FU respectively. No G3-G4 haematological, hepatic and neurological toxicity were observed. ORR (CR+PR) was 41%. No patient has been treated with G-CSF. Conclusions: These data confirm a significative tolerability improvement of OHP, 5-FU and AF schedule when infused according to a chronomulated infusion prophile in metastatic colorectal cancer patients.

No significant financial relationships to disclose.
Response to the combination of cetuximab, bevacizumab and irinotecan (cetux/bev/iri) in patients (pts) previously treated with 3rd-line panitumumab, following disease progression on oxaliplatin, irinotecan and a fluoropyrimidine
Authors: Tubb E. E. , Jacobs M. , Mitchell E. P.
Published: March 2020

14586

Background: There are 2 monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) available for the treatment of advanced metastatic colorectal cancer- panitumumab, a fully human IgG2 kappa mAb and cetuximab, a chimeric IgG1 mAb. The ability to administer one agent after prior treatment with the other is unknown and further, not trivial given the possibility for cross-reactivity. In our institution, we evaluated an exploratory treatment schedule. Methods: We report the status of 8 colon cancer pts treated with panitumumab monotherapy as 3rd-line and subsequently treated with cetux/bev/iri as salvage chemotherapy. All were initially treated on 1 of 2 multicenter phase 2 studies enrolling pts on panitumumab; all pts had documented progressive disease (PD) during or after fluoropyrimidine and adequate doses of irinotecan and oxaliplatin, and low (1–9%) or high (=10%) EGFR tumor membrane staining by IHC. Pts received panitumumab 6 mg/kg q2weeks (wks) until PD or intolerability. Following PD they received bev 5 mg/kg and iri 250 mg/m2 q2wks and cetux 400 mg/m2, then 250 mg/m2 qwk. The endpoint was time to tumor progression (TTP). Results: The 8 pts (2 men, 6 women) were among those enrolled in 1 center. Median age was 67 years (range 51–81); 6 pts had low and 2 pts had high EGFR tumor expression. The median number of cycles of panitumumab was 8 (range 3–14); 1 had a partial remission (PR) for 24 wks, 4 had stable disease (SD) for a median of 14 wks (range 12–16) and 3 pts had PD. Following PD on panitumumab pts received cetux/bev/iri. The median number of cycles was 13 (range 2–17+); 1 had a PR of 20 wks, 6 had SD for a median of 20 wks (range 8–32+) and 1 pt had PD after 4 cycles. Median TTP was 24 wks (range 7–36+). Conclusion: In these 8 pts, prolonged TTP to the combination of cetux/bev/iri was observed following PD on panitumumab and standard chemotherapy. This combination may provide a potential treatment strategy for these heavily pretreated pts with advanced colon cancer. However, further investigation is needed.

No significant financial relationships to disclose.
Yttrium-90 microsphere selective internal radiation treatment (SIRT) with concomitant chemotherapy (Chemo-SIRT) as first/second-line therapy in patients with colorectal cancer liver metastases
Authors: Pennington K. L. , Bruetman D. , Mesoloras G. , Hostetter R. , Gulec S. A.
Published: March 2020

14589

Background: Yttrium-90 (Y-90) microsphere selective internal radiation treatment (SIRT) has been studied in patients (pts) with colorectal cancer liver metastases (CRCLM) in combination with FUDR and 5FU-LV with promising results. This is a phase II trial of SIRT and concurrent contemporary chemotherapy in the frontline management of CRCLM. Methods: Pts with metastatic disease limited predominantly to the liver were eligible for the study. Other entry criteria included KPS 70 or >, 3 month life expectancy and adequate marrow and renal reserve. Pre-treatment evaluations included the assessment of liver function, CEA level, 18F-FDG-PET/CT imaging, an angiogram and a 99mTc-MAA (macroagregate albumin) scan. SIRT with Y-90 resin microspheres (Sirtex Medical, Lake Forest, IL) was administered on day 2 of the first chemotherapy (Fol-Fox or Fol-Firi) course in either lobar or whole-liver fashion. Chemotherapy was repeated on a biweekly schedule. CEA levels and 18F-FDG-PET/CT based anatomic and functional volume (Vf) changes were used to determine tumor response at 4, 8, and 12 weeks after therapy. CTC v3 toxicity grades were used to classify adverse events. Results: 6 pts were treated as first-line and 2 pts as second-line. 5 pts received single lobe and 3 pts received whole liver treatment. Administered activity of Y-90 microspheres ranged from 0.9 to 3.1 GBq (mean 2.3 GBq). Mean tumor radiation absorbed dose was 203.6 Gy (Range 91.0–351.4 Gy). Mean liver absorbed dose was 47.8 Gy (Range 7.9–85.9 Gy). 6/8 pts had complete/near-complete metabolic response with a mean tumor Vf decrease in target lobe(s) of 98%). The remaining 2 pts demonstrated > 50% reduction in Vf in target lobe(s). A parallel decrease in CEA level was observed in responding pts. Surgical downstaging was attained in 3/8 pts. 2 pts developed grade III toxicity (one gastric ulcer and one alkaline phosphatase elevation). Conclusion: Chemo-SIRT as first-line therapy has a high level of response in CRCLM as measured by reductions in functional tumor volume and CEA level. Further follow-up of these pts is needed to confirm that this response is of clinical significance in terms of improved surgical downstaging and survival.

[Table: see text]
A phase II trial of irinotecan, 5-fluorouracil and leucovorin in patients with previously untreated advanced colorectal cancer (CRC)
Authors: Lee N. , Bae S. , Lee S. , Kim D. , Kim K. , Kim H. , Kim C. , Lee K. , Won J. , Hong D. , Park H.
Published: March 2020

14599

Background: We prospectively conducted a phase II trial to test the efficacy and safety of irinotecan, 5-fluorouracil and leucovorin (FOLFIRI) regimens for the first-line treatment of previously untreated patients with recurrent or metastatic advanced CRC. Methods: Thirty-four previously untreated patients with advanced CRC were enrolled in this study from June 2001 to December 2006. Eligible patients had histologically confirmed adenocarcinoma, no prior systemic therapy in palliative setting, ECOG PS = 2, adequate organ function, written informed consent and at least one measurable disease. The patients received either irinotecan 180 mg/m2 on day 1 with a LV bolus of 200 mg/m2 and a FU bolus of 400 mg/m2, and this was followed by a FU continuous infusion of 600 mg/m2 on day 1 and day 2 (the classic FOLFIRI regimen), or they were treated with a LV bolus of 400 mg/m2 and a FU bolus of 400 mg/m2 followed by a FU continuous infusion of 2,400 mg/m2 for 46 hours (the simplified FOLFIRI regimen), and these treatments were repeated every 2 weeks until disease progression. Results: There were 13 females and 21 males with median age of 54 years (range: 41–79). The most common metastatic sites were lung and liver. A total of 262 cycles were administrated with median 6 cycles per patient (range: 1–22). All pts were evaluable for toxicity, and 30 pts for response to the treatment. The objective response rate was 26.4% with 2 complete responses respectively. Sixteen (47%) pts had stable disease and 7 (20.5%) had a progression. The tumor control rate was 73.4%. The median TTP was 5.3 months, and the overall survival was 10.1 months. The prognostic factor for longer TTP and survival was the ECOG performance status (PS). The type of regimens was not affected on response rate, TTP and survival. The chemotherapy was generally well tolerated and the most common grade 3–4 toxicities were neutropenia, diarrhea. The non- hematological toxicities were similar for both treatment groups, with more frequent grade =3 neutropenia being noted for the simplified FOLFIRI regimen. Conclusions: The FOLFIRI regimen was demonstrated to have a moderate antitumor activity with acceptable toxicity profiles, and tend to show more favorable outcome for patients with good ECOG PS.

No significant financial relationships to disclose.
Cetuximab and irinotecan in patients with colorectal cancer refractory to oxaliplatin and irinotecan
Authors: Gonzalez-Baron M. , Blanco M. , Feliu J. , Gómez C. , Casado E. , Castro J. , Belda-Iniesta C. , Garrido M. , Aguayo C. , Campos M. A.
Published: March 2020

14600

Background: Patients with chemotherapy-resistant metastasic colorectal cancer have a poor prognosis with few therapeutic options. The purpose of this work is to evaluate the results of treatment with cetuximab and irinotecan in this group of patients. Methods: Between January 01 and July 06, 24 patients were treated in our centre with cetuximab. 19 patients received irinotecan 180 mg/m2 every two weeks with cetuximab at standard doses: 400 mg/m2 loading dose over 2 hours, then 250 mg/m2 over 1 hour weekly, and 5 patients received FOLFIRI schedule and cetuximab at the same doses as previously. Results: Characteristics of the 24 patients were: male/female 15/9; median age 63 years old (range 48–75); performance status 0–1 (10 patients), and 2–3 (14 patients). The median number of chemotherapy regimens preceding first cetuximab administration was 2 (range 1 to 4).12% had received one chemotherapy line, 64% two chemotherapy lines, 16% three chemotherapy lines and 8% received four chemotherapy lines. EGFR status was positive in all patients. The median of administrated cycles was 7.5 (range 2–26). There were 4 objective responses (16%; 95% CI: 5–38.5%) and 7 patients with stable disease (29%). The median progression free survival was 3.2 months and median overall survival was 7.8 months (95% CI: 3–14). The treatment was well tolerated. 6% of the patients had not cutaneous toxicity with the cetuximab treatment, 14 (25%) had a cutaneous toxicity grade 1 or 2 while 25% had a grade 3 or 4 toxicity, that lead to dose reduction in three cases and treatment drop out in one case. Other adverse effects with the treatment included four cases (17%) with diarrhoea grade 3, all of them in treatments with irinotecan, two patients (8%) suffered vomits grade 3, and one patient with grade 3 trombopenia. Conclusions: This therapeutic survey in an unselected population is in accordance with the results of the BOND survey for OS, tumour responses and toxicity.

No significant financial relationships to disclose.
Does histology influence outcome in advanced oesophagogastric (OG) cancer? Individual patient data from 1,680 patients on three randomised controlled trials (RCT)
Authors: Chau I. , Starling N. , Cunningham D. , Oates J. , Iveson T. , Nicolson M. , Hawkins R. , Hickish T. , Seymour M. , Norman A.
Published: March 2020

15001

Background: In advanced OG cancer, it is unclear whether squamous cell carcinoma (SCC) differs from adenocarcinoma (Ad) in its response to chemotherapy, as most phase III studies do not include both histology. The aim of this pooled analysis was to evaluate whether there is a differential chemotherapy effect on overall survival (OS), response rate (RR) and toxicity depending on tumour histology (SCC vs. Ad) using individual patient (pt) data. Methods: From 1994 to 2005, 3 RCTs were conducted assessing fluoropyrimidine ± platinum-based chemotherapy. This analysis was restricted to eligible pts with SCC or Ad histology who received =1 dose chemotherapy. Apart from OS and RR, a toxicity composite endpoint (TCE) was constructed - defined as occurrence of grades =3 diarrhoea, (febrile) neutropenia, infection, nausea & vomiting, grades =2 renal and neurotoxicity. Ad was used as the control group. Two-sided p values of <0.05 were considered significant. Results: Of the 1,836 pts randomised, 1,680 were included for this analysis of whom 1,536 (91%) had Ad and 144 (9%) had SCC. Locally advanced disease was present in 17% and 20% of Ad and SCC patients respectively. The median survival was 9.4 months with Ad and 7.7 months with SCC and one year survival rates were 38% and 29% respectively (log rank p= 0.115) and this remained non- significant on multivariate analysis (p=0.206). The RR was 40.4% (95% CI: 38–42.9%) in Ad and 33.3% in SCC (95% CI: 26.1–41.4%; p=0.109). TCE occurred in 45% and 44% of patients with Ad and SCC respectively (p=1.0). Time to TCE was not significantly different (log rank p=0.829). Conclusions: Although there was a trend towards worse survival with SCC, no significant differences in chemotherapy outcome were demonstrated, despite our large dataset. Molecular therapeutics targeting distinct biological pathways between the two histology subtypes may influence outcome more than cytotoxic combinations in the future.

No significant financial relationships to disclose.
Phase II trial of continuous/metronomic 5-fluorouracil infusion plus long acting Octreotide in advanced neuroendocrine carcinoma
Authors: Dogliotti L. , Brizzi M. P. , Ferrero A. , Milanesi E. , Ciuffreda L. , Castiglione F. , Bombaci S. , Perroni D. , Alabiso O. , Berruti A.
Published: March 2020

15003

Background: The administration of cytotoxic drugs on a metronomic schedule has shown antiangiogenetic properties. Well differentiated neuroendocrine carcinomas are notoriously highly vascularized and may be responsive to metronomic chemotherapy. A phase II study was designed to test the activity of protracted 5-fluorouracil (5FU) infusion in association with and long-acting release (LAR) octreotide in patients with advanced/metastatic neuroendocrine carcinoma. Patients and Methods: Twenty-nine patients (pts), with metastatic or locally advanced well differentiated neuroendocrine carcinoma not amenable to surgery with radical intent and not previously submitted to systemic treatments were enrolled. Treatment consisted of 5FU intravenous continuous infusion (200 mg/m2 daily) in association with Octreotide LAR (20 mg once every 4 weeks). 5FU treatment was administered until progression or for a maximum of 9 months. Octreotide LAR was administered until progression. Patients were followed for toxicity, objective response, symptomatic response, biochemical response, time to progression and survival. Results: According to RECIST criteria a partial response was observed in 7 patients (24.1%), a stable disease in 20 pts (69.0%) and a progression disease in only 2 pts (6.9%). A biochemical (chromogranin A) response was observed in 11/25 assessable patients (44.0%), 9/15 symptomatic patients (60.0%) obtained symptom relief. Post-treatment surgery was attempted in three patients, one of them was radically resected. The median time to disease progression was 25 months (range 2–69 months), median overall survival was not reached. Hematologic toxicity was rare and mild [grade 2 neutropenia in 2 pts (6.9%)]. Six cases (20.7%) suffered from grade 2–3 hand-foot syndrome. No patient withdrew from the study because of adverse events. Conclusions: Continuous/metronomic 5FU infusion plus octreotide LAR is well tolerated and shows promising activity in patients with advanced well differentiated neuroendocrine carcinoma. Additional studies with this combination are warranted.

No significant financial relationships to disclose.
A phase I study of the addition of weekly oxaliplatin to weekly gemcitabine during radiotherapy for unresectable pancreatic or biliary malignancies
Authors: O’Neil B. H. , Blackstock A. W. , Goldberg R. M. , Shearer H. , Sanoff H. K. , Aklilu M. , Bernard S. , Martinie J. , Kim H. J. , Tepper J. E.
Published: March 2020

15008

Purpose: Locally advanced pancreatic cancer (LAPC) leads to a poor survival, and current therapies are inadequate. External beam radiotherapy (EBRT) has been used to obtain local control, but the most effective systemic agent, gemcitabine(gem), can be used only at low doses with standard RT. Oxaliplatin (ox) has activity in PC, and has been delivered safely at doses near full systemic doses with EBRT for rectal cancer. We set out to define the maximum tolerated dose (MTD) of ox in combination with gem + upper abdominal EBRT. Methods: Patients (pts) with LAPC or biliary ca were eligible. Prior systemic therapy was allowed. A 3 + 3 design was employed with 4 dose levels (table). Gem + ox was given once weekly. EBRT was given in 1.8 Gy fractions to 50.4 Gy using a multi-field technique. DLT was defined as any grade 4 tox or grade 3 tox resulting in treatment delay > 1 wk. Results: 11 pts have completed therapy (Table). 10 pts had LAPC, 1 had ampullary ca. No pts in the first 2 cohorts had DLT. Pt #3 in cohort 3 had DLT (grade 3 elevated liver enzymes). Cohort 3 was expanded; patients 4 and 5 in the cohort have completed therapy without DLT; pt 6 is not yet evaluable. To date, 43 grade 3 toxic events have occurred in 11 evaluable patients. No grade 4 toxicities have occurred. The most common grade 3 tox are: nausea (63%), metabolic (54%), hyperglycemia (45%), neutropenia (36%), vomiting (27%). SD was best radiographic response in 8 of 8 evaluable pts. One patient with ampullary ca had regression of disease from vessels and was resected, but had positive retroperitoneal margin and died of a post-operative complication. Five pts have died (OS 2.6–12.2 mos). Median OS is currently 9 mos (95% CI 4.6, 12.3). Conclusions: Weekly oxaliplatin can be given safely with weekly gemcitabine (200 mg/m2) during EBRT for LAPC. The ox MTD in this combination is not yet defined, but is at least 30 mg/m2 weekly. Final dose results and updated efficacy results will be presented at the meeting. [Table: see text] [Table: see text]
Recent advances in the surgical treatment for esophageal cancer in Japan: An experience of 1000 cases who underwent an esophagectomy at a single institute
Authors: Morita M. , Yoshida R. , Ikeda K. , Honboh T. , Ohta M. , Egashira A. , Oki E. , Sadanaga N. , Kakeji Y. , Maehara Y.
Published: March 2020

15011

Background: Most cases of esophageal cancer are squamous cell carcinoma in Japan and the prognosis of such patients tends to be poor. However, the clinical results after an esophagectomy have recently been reported to improve. Methods: The mortality and morbidity as well as the patients’ prognosis were evaluated in 1000 cases of esophageal cancer who all underwent an esophagectomy in the Department of Surgery and Science (Department of Surgery II), Kyushu University, Japan from 1964 to 2006. The incidence of squamous cell carcinoma was 94 %. The patients were divided into three groups according to the operation period: Group I (n=197), Group II (n=432), and Group III (n=371) underwent an esophagectomy during the periods of ‘64-’80, ’81-’93, and ’93-’06, respectively. The incidences of TNM Stage 0 or I gradually increased (4, 19 and 24 %, respectively), while those of Stage IV decreased (28, 19 and 14 %). Results: The 5-yr overall survival rates (OSR) and cause-specific survival rate (CSR) after an esophagectomy for all 1000 cases were 30 and 37 %, respectively. The 5-yr OSRs of Groups I, II and III were 14, 27 and 46 %, while the 5-yr CSRs were 18, 36, and 52 %, respectively (P<0.01 between each group). When the prognoses were compared for each TNM stage, an improvement in the prognosis was observed at every tumor stage. A multivariate analysis (Cox proportional hazard model) revealed not only the age, depth of invasion, node metastasis, curability (each P<0.001) and extent of a lymphadenectomy (P<0.05) but also the operation period (P<0.001) to be independent prognostic factors. The morbidity rates of Groups I, II and III were 62, 38, and 33 %, and the incidences of pulmonary complications were 42, 13 and 14 %, respectively (P<0.01, Group I vs. II and I vs. III). The 30-day mortality rates were 8.1, 2.1 and 0 %, respectively (P<0.01 between each group). Conclusions: An analysis of a total of 1000 cases with esophageal cancer revealed that an esophagectomy has generally been safely performed without any critical pulmonary complications, while an increasingly favorable prognosis has been achieved due to recent advances in surgical techniques and treatment modalities.

No significant financial relationships to disclose.