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A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies.
Harding, JJ, Do, RK, Dika, IE, Hollywood, E, Uhlitskykh, K, Valentino, E, Wan, P, Hamilton, C, Feng, X, Johnston, A, et al
Cancer chemotherapy and pharmacology. 2018;(3):429-440
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Abstract
PURPOSE Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways. Preclinical data indicates that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. METHODS This is a single-center, open-label, phase 1 trial of ADI-PEG 20 and modified FOLFOX6 (mFOLFOX6) in treatment-refractory hepatocellular carcinoma (HCC) and other advanced gastrointestinal tumors. A 3 + 3 dose escalation design was employed to assess safety, tolerability, and determine the recommended phase 2 dose (RP2D) of ADI-PEG 20. A RP2D expansion cohort for patients with HCC was employed to define the objective response rate (ORR). Secondary objectives were to estimate progression-free survival (PFS), overall survival (OS), and to explore pharmacodynamics and immunogenicity. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m2 (Cohort 2 and RP2D expansion). RESULTS Twenty-seven patients enrolled-23 with advanced HCC and 4 with other gastrointestinal tumors. No dose-limiting toxicities were observed in cohort 1 or 2. The RP2D for ADI-PEG 20 was 36 mg/m2 weekly with mFOLFOX6. The most common any grade adverse events (AEs) were thrombocytopenia, neutropenia, leukopenia, anemia, and fatigue. Among the 23 HCC patients, the most frequent treatment-related Grade ≥ 3 AEs were neutropenia (47.8%), thrombocytopenia (34.7%), leukopenia (21.7%), anemia (21.7%), and lymphopenia (17.4%). The ORR for this group was 21% (95% CI 7.5-43.7). Median PFS and OS were 7.3 and 14.5 months, respectively. Arginine levels were depleted with therapy despite the emergence of low levels of anti-ADI-PEG 20 antibodies. Arginine depletion at 4 and 8 weeks and archival tumoral argininosuccinate synthetase-1 levels did not correlate with response. CONCLUSIONS Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m2 weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCC patients.
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A process and mechanism of action evaluation of the effect of early and intensive nutrition care, delivered via telephone or mobile application, on quality of life in people with upper gastrointestinal cancer: a study protocol.
Furness, K, Huggins, CE, Hanna, L, Silvers, MA, Cashin, P, Low, L, Croagh, D, Haines, TP
BMC cancer. 2018;(1):1181
Abstract
BACKGROUND Cancers of the upper gastrointestinal tract commonly result in malnutrition, which increases morbidity and mortality. Current nutrition best practice lacks a mechanism to provide early and intensive nutrition support to these patients. A 3-arm parallel randomised controlled trial is testing the provision of a tailored, nutritional counselling intervention delivered using a synchronous, telephone-based approach or an asynchronous, mobile application-based approach to address this problem. This protocol outlines the design and methods that will be used to undertake an evaluation of the implementation process, which is imperative for successful replication and dissemination. METHODS A concurrent triangulation mixed methods comparative analysis will be undertaken. The nutrition intervention will be provided using best practice behaviour change techniques and communicated either via telephone or via mHealth. The implementation outcomes that will be measured are: fidelity to the nutrition intervention protocol and to the delivery approach; engagement; acceptability and contextual factors. Qualitative data from recorded telephone consultations and written messages will be analysed through a coding matrix against the behaviour change techniques outlined in the standard operating procedure, and also thematically to determine barriers and enablers. Negative binomial regression will be used to test for predictive relationships between intervention components with health-related quality of life and nutrition outcomes. Post-intervention interviews with participants and health professionals will be thematically analysed to determine the acceptability of delivery approaches. NVivo 11 Pro software will be used to code for thematic analysis. STATA version 15 will be used to perform quantitative analysis. DISCUSSION The findings of this process evaluation will provide evidence of the core active ingredients that enable the implementation of best practice nutrition intervention for people with upper gastrointestinal cancer. Elucidation of the causal pathways of successful implementation and the important relationship to contextual delivery are anticipated. With this information, a strategy for sustained implementation across broader settings will be developed which impact the quality of life and nutritional status of individuals with upper gastrointestinal cancer. TRIAL REGISTRATION 27th January 2017 Australian and New Zealand Clinical Trial Registry ( ACTRN12617000152325 ).
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Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy with lobaplatin and docetaxel improves survival for patients with peritoneal carcinomatosis from abdominal and pelvic malignancies.
Wu, HT, Yang, XJ, Huang, CQ, Sun, JH, Ji, ZH, Peng, KW, Zhang, Q, Li, Y
World journal of surgical oncology. 2016;(1):246
Abstract
BACKGROUND This work was to evaluate the perioperative safety and efficacy of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) with lobaplatin and docetaxel in patients with peritoneal carcinomatosis (PC) from gastrointestinal and gynecological cancers. METHODS Patients were treated by CRS + HIPEC with lobaplatin 50 mg/m(2) and docetaxel 60 mg/m(2) in 6000 mL of normal saline at 43 ± 0.5 °C for 60 min. Vital signs were recorded for 6 days after CRS + HIPEC procedures. Perioperative serious adverse events (SAE), hematological, hepatic, renal, and electrolytes parameters, the changes in serum tumor markers (TM) before and after operation, patient recovery, and overall survival (OS) were analyzed. RESULTS One hundred consecutive PC patients underwent 105 CRS + HIPEC procedures and postoperative chemotherapy. The median CRS + HIPEC duration was 463 (range, 245-820) min, and the highest temperature and heart rate during six postoperative days were 38.6 °C (median 37.5 °C) and 124 bpm (median 100 bpm), respectively. The 30-day perioperative SAE occurred in 16 (15.2 %) and mortality occurred in 2 (1.9 %) patients. Most routine blood laboratory tests at 1 week after surgery turned normal. Among 82 cases with increased preoperative TM CEA, CA125, and CA199, 71 cases had TM levels reduced or turned normal. Median time to nasogastric tube removal was 5 (range, 3-23) days, to liquid food intake 6 (range, 4-24) days, and to abdominal suture removal 15 (range, 10-30) days. At the median follow-up of 19.7 (range, 7.5-89.2) months, the median OS was 24.2 (95 % CI, 15.0-33.4) months, and the 1-, 3-, and 5-year OS rates were 77.5, 32.5, and 19.8 %, respectively. Univariate analysis identified five independent prognostic factors on OS: the origin of PC, peritoneal cancer index, completeness of CRS, cycles of adjuvant chemotherapy, and SAE. CONCLUSIONS CRS + HIPEC with lobaplatin and docetaxel to treat PC is a feasible procedure with acceptable safety and can prolong the survival in selected patients with PC. TRIAL REGISTRATION ClinicalTrials.gov, NCT00454519.
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A dose-finding study for oxaliplatin, irinotecan, and S-1 (OIS) in patients with metastatic or recurrent gastrointestinal cancer.
Han, B, Jung, JY, Kim, HS, Cho, JW, Kim, KC, Lim, H, Kang, HS, Ha, HI, Kim, MJ, Kim, JH, et al
Cancer chemotherapy and pharmacology. 2016;(5):949-958
Abstract
PURPOSES To determine the maximum tolerated dose (MTD), recommended dose (RD), and activity of combined oxaliplatin, irinotecan, and S-1 chemotherapy for metastatic or recurrent gastrointestinal (GI) cancer. METHODS Oxaliplatin and irinotecan were administered intravenously on day 1, and S-1 was administered orally on days 1-7, every 2 weeks. This phase I study used the following dose levels for oxaliplatin/irinotecan/S-1: level 1, 85/120/60 mg/m2; level 2, 85/120/80 mg/m2; level 3, 85/120/100 mg/m2; level 4, 85/150/100 mg/m2; and level 5, 85/180/100 mg/m2. Treatment was repeated for a maximum of 12 cycles, until disease progression, or until unacceptable toxicity. RESULTS Twenty-four patients were enrolled between October 2012 and February 2014 (median age 59 years). During the first cycle, one of the six patients in levels 1, 3, and 4 developed a dose-limiting toxicity (grade 3 febrile neutropenia), and none of the three patients in level 5 developed a dose-limiting toxicity. As the planned maximum dose did not reach the MTD, the level 5 dose was defined as the RD. Twenty-one patients were evaluated for response, which included 2 cases of complete response and 8 cases of partial response, with an overall response rate of 47.6 %. CONCLUSIONS The combination of oxaliplatin, irinotecan, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced GI cancer. The RD was 85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan, and 100 mg/m2 of S-1 every 2 weeks.
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Partial splenic embolization to permit continuation of systemic chemotherapy.
Luz, JH, Luz, PM, Marchiori, E, Rodrigues, LA, Gouveia, HR, Martin, HS, Faria, IM, Souza, RR, Gil, RA, Palladino, AM, et al
Cancer medicine. 2016;(10):2715-2720
Abstract
Systemic chemotherapy treatments, commonly those that comprise oxaliplatin, have been linked to the appearance of distinctive liver lesions that evolves to portal hypertension, spleen enlargement, platelets sequestration, and thrombocytopenia. This outcome can interrupt treatment or force dosage reduction, decreasing efficiency of cancer therapy. We conducted a prospective phase II study for the evaluation of partial splenic embolization in patients with thrombocytopenia that impeded systemic chemotherapy continuation. From August 2014 through July 2015, 33 patients underwent partial splenic embolization to increase platelets count and allow their return to treatment. Primary endpoint was the accomplishment of a thrombocyte level superior to 130 × 109 /L and the secondary endpoints were the return to chemotherapy and toxicity. Partial splenic embolization was done 36 times in 33 patients. All patients presented gastrointestinal cancer and colorectal malignancy was the commonest primary site. An average of 6.4 cycles of chemotherapy was done before splenic embolization and the most common regimen was Folfox. Mean platelet count prior to embolization was 69 × 109 /L. A total of 94% of patients achieved primary endpoint. All patients in need reinitiated treatment and median time to chemotherapy return was 14 days. No grade 3 or above adverse events were identified. Aiming for a 50% to 70% infarction area may be sufficient to achieve success without the complications associated with more extensive infarction. Combined with the better safety profile, partial splenic embolization is an excellent option in the management of thrombocytopenia, enabling the resumption of systemic chemotherapy with minimal procedure-related morbidity.
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Phase I trial of combination of FOLFIRI and pasireotide, a somatostatin analogue, in advanced gastrointestinal malignancies.
Mahipal, A, Shibata, D, Siegel, E, Springett, G, Almhanna, K, Fulp, W, Williams-Elson, I, Kim, R
Investigational new drugs. 2015;(5):1093-9
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Abstract
INTRODUCTION Pasireotide (SOM230) is a somatostatin analog with high binding affinity for somatostatin receptors including sst1, 2, 3 and 5 and inhibit insulin like growth factor-1. Blocking of IGF-1 receptor (IGF-1R) in combination with cytotoxic chemotherapy has demonstrated additive or synergistic activity in pre-clinical models. This study aimed to evaluate the maximum tolerated dose (MTD) of pasireotide in combination with standard FOLFIRI (5-fluorouracil, leucovorin and irinotecan) regimen in patients with gastrointestinal malignancies. METHODS This was a phase 1, 3 + 3 design, open-label dose escalation study conducted in sequential cohorts to determine the MTD of pasireotide in combination with FOLFIRI. All patients had gastrointestinal malignancies and were previously treated. Sixteen patients enrolled in five dose cohorts at pasireotide doses of 40, 60, 80, 100 and 120 mg were evaluated for safety and tolerability of the combination. RESULTS The tumor types of the enrolled subjects included esophageal (n = 5), biliary tract (n = 3), colon (n = 3), gastric (n = 2), pancreatic (n = 1), anal (n = 1) and small bowel (n = 1). No dose limiting toxicities were observed. The most common adverse events related to the study treatment included hyperglycemia (81 %), neutropenia (62 %), thrombocytopenia (44 %), anorexia (44 %), dehydration (25 %) and elevated alkaline phosphatase (25 %). Two patients had partial response and 7 patients had stable disease. Plasma levels of IGF-1 and IGFBP-3 were significantly reduced after treatment with pasireotide. DISCUSSION Combination of pasireotide and FOLFIRI has manageable safety profile and is feasible in patients with gastrointestinal malignancies. Preliminary signals of activity were observed. Larger phase II trials are warranted.
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A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors.
Grem, JL, Kos, ME, Evande, RE, Meza, JL, Schwarz, JK
Cancer. 2015;(21):3862-8
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Abstract
BACKGROUND Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU). METHODS Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m(2) on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m(2) /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase. RESULTS Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity. CONCLUSIONS The recommended dose of PDX was 148 mg/m(2) . A subset of heavily pretreated patients had PFS durations of ≥6 months with this regimen.
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Influence of acupuncture on bioelectrical impedance measures in patients with gastrointestinal cancer: results of a pilot study.
Grundmann, O, Yoon, SL, Williams, JJ
Acupuncture in medicine : journal of the British Medical Acupuncture Society. 2015;(1):16-22
Abstract
BACKGROUND Patients with gastrointestinal cancers often suffer from malnutrition and cachexia caused by inflammatory processes due to malignancy and therapeutic intervention. Evaluation of nutritional status and well-being of patients is essential to prevent or slow down the progression of cachexia. In addition, acupuncture as a complementary intervention may help reduce cachexia and unintentional weight loss. METHODS Seven patients with cancers of the gastrointestinal tract enrolled in this pilot study were provided with eight acupuncture sessions in addition to their regular treatment schedule. Bioelectrical impedance analysis (BIA) measurements were taken at every other acupuncture session to evaluate the body composition of patients. BIA is a fast, inexpensive and non-invasive method for evaluating fluid, fat and muscle mass distribution which correlates with nutritional status. RESULTS All patients enrolled in the pilot study completed the acupuncture intervention and BIA measurements. The average weight loss and reduction in body weight was 1.3%, which is less than the average weight loss of 5% reported in the literature. Both phase angle and fat-free mass decreased in patients, indicating a worsening of the condition. However, a shift from intracellular to extracellular fluid was not observed, which is usually associated with a loss of cell integrity. CONCLUSIONS This pilot study indicates that patients tolerate acupuncture treatments well. The BIA results should be interpreted with caution due to the small sample size. A larger randomised placebo-controlled study is currently being conducted to further investigate the influence of acupuncture and to provide insights into BIA as a reliable tool for evaluating body composition in patients with gastrointestinal cancers.
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A phase I study of farletuzumab, a humanized anti-folate receptor α monoclonal antibody, in patients with solid tumors.
Sasaki, Y, Miwa, K, Yamashita, K, Sunakawa, Y, Shimada, K, Ishida, H, Hasegawa, K, Fujiwara, K, Kodaira, M, Fujiwara, Y, et al
Investigational new drugs. 2015;(2):332-40
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Abstract
Farletuzumab is a humanized monoclonal antibody against folate receptor α (FRA). The purpose of the study is to assess safety and tolerability, the pharmacokinetic (PK) profile, and preliminary antitumor effect. Patients with ovarian cancer (OC) or FRA-expressing solid tumors who are resistant to standard treatments were eligible for the study. After single-dose administration for PK assessment, farletuzumab was administered by intravenous injection, repeating every week until disease progression. Dose-limiting toxicities (DLTs) were defined as grade 4 hematological and grade 3/4 nonhematological toxicities. Dose escalation was planned in 4 cohorts (50, 100, 200, and 400 mg/m(2)). Fourteen patients with OC and two patients with gastric cancer (GC) received farletuzumab infusion. Neither DLTs nor grade 3/4 toxicities were reported in all cohorts. Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8%), headache (seven patients, 43.8%), and nausea and decreased appetite (five patients each, 31.3%), were observed and medically managed. AUC and Cmax increased dose-dependently and linear PK profiles were observed. No tumor shrinkage was recorded, but long-term disease stabilization for 25 and 20 months was observed in one patient with clear cell OC (100 mg/m(2)) and one patient with GC (400 mg/m(2)), respectively. No cumulative toxicity occurred in any patient. Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population. Long-term disease stabilization was observed in a subpopulation of clear cell OC and GC; both of them were resistant and progressive after standard chemotherapies (ClinicalTrials.gov Identifier: NCT01049061).
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Detection of hepatic metastases from carcinoid tumor: prospective evaluation of contrast-enhanced ultrasonography.
Hoeffel, C, Job, L, Ladam-Marcus, V, Vitry, F, Cadiot, G, Marcus, C
Digestive diseases and sciences. 2009;(9):2040-6
Abstract
The purpose of our study was to prospectively compare unenhanced ultrasonography (US) to contrast-enhanced US (CEUS) in the detection of hepatic metastases from carcinoid tumor. Thirty patients with carcinoid tumor prospectively underwent US, CEUS, and magnetic resonance imaging (MRI). Differences in sensitivity at US and CEUS were compared using a combination of the results of MR imaging, fine-needle biopsy, and follow-up imaging. Lesion conspicuity was assessed subjectively for US and CEUS. Seventeen patients had a total of 69 hepatic metastases. The addition of CEUS improved the detection of individual metastases from 47 (Se 68%; 95% CI: 57.0, 79.0) to 68 (Se 99%; 99% CI: 96.7, 100.0). Contrast enhancement improved the subjective conspicuity of metastases in 85% of patients. CEUS showed one more metastasis than did MRI in one patient, and MRI showed one more than did CEUS in one patient. CEUS is more sensitive than US in the detection of carcinoid liver metastases.