D Melnychuk

McGill University, Montréal, Quebec, Canada

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Publications (11)172.43 Total impact

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    ABSTRACT: Background: The treatment of patients with metastatic colorectal cancer (mCRC) has evolved during the past 2 decades, and patient survival has increased. Consequently, patients are exposed to more chemotherapeutic agents and regimens. Little is known about therapeutic drug sequencing and the factors influencing these choices. Materials and methods: An observational, retrospective medical record review was conducted of patients with newly diagnosed adult mCRC from January 2002 to September 2013 identified in the McGill University-Jewish General Hospital's local tumor registry. All patients presented with mCRC (stage IV) and received ≥ 2 cycles and/or ≥ 28 days of first-line chemotherapy. The patient demographics, CRC characteristics, treatment patterns, and outcomes were recorded. The reason for changing or halting therapy was also reported. Results: Of the 215 patients who underwent treatment, 74.4% received second-line, 36% third-line, and 16.3% fourth-line treatment. In total, 88% received ≥ 3 classes of cytotoxic chemotherapy and 80% received ≥ 1 biologic agent. The most common first-line treatment was FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) (47.4%) or CAPOX (capecitabine, oxaliplatin) (28.8%), and more than one half received bevacizumab (56%). Among the second- and third-line treatments, FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) was the most common (40.3% and 30.3%, respectively), and bevacizumab was the most frequently used biologic agent (48.1% and 39.2%, respectively). For fourth-line treatment and beyond, most patients participated in clinical trials (45.7%) or received panitumumab monotherapy (31.4%). Across the first 4 therapy lines, disease progression was the primary motive for discontinuation (39.5%, 53.8%, 58.2%, and 37.1%). Conclusion: FOLFOX was the most common first-line and FOLFIRI the most common second- and third-line mCRC therapy. Bevacizumab was the most frequently used targeted therapy across all 3 treatment lines. Therapy discontinuation was primarily due to disease progression.
    No preview · Article · Nov 2015 · Clinical Colorectal Cancer
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    ABSTRACT: Background: Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC) could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail. Methods and findings: We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement. Conclusions: Despite IVC's biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC's value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify specific clusters of cancer type, chemotherapy regimen and IVC in which exceptional responses occur frequently enough to justify appropriately focused clinical trials. Trial registration: ClinicalTrials.gov NCT01050621.
    Full-text · Article · Apr 2015 · PLoS ONE
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    ABSTRACT: Ascorbic acid is frequently administered intravenously by alternative health practitioners and, occasionally, by mainstream physicians. Intravenous administration can greatly increase the amount of ascorbic acid that reaches the circulation, potentially increasing the risk of oxalate crystallization in the urinary space. To investigate this possibility, we developed gas chromatography mass spectrometry methodology and sampling and storage procedures for oxalic acid analysis without interference from ascorbic acid and measured urinary oxalic acid excretion in people administered intravenous ascorbic acid in doses ranging from 0.2 to 1.5 g/kg body weight. In vitro oxidation of ascorbic acid to oxalic acid did not occur when urine samples were brought immediately to pH less than 2 and stored at -30 degrees C within 6 hours. Even very high ascorbic acid concentrations did not interfere with the analysis when oxalic acid extraction was carried out at pH 1. As measured during and over the 6 hours after ascorbic acid infusions, urinary oxalic acid excretion increased with increasing doses, reaching approximately 80 mg at a dose of approximately 100 g. We conclude that, when studied using correct procedures for sample handling, storage, and analysis, less than 0.5% of a very large intravenous dose of ascorbic acid is recovered as urinary oxalic acid in people with normal renal function.
    Full-text · Article · Mar 2009 · Metabolism: clinical and experimental
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    ABSTRACT: Ascorbic acid is a widely used and controversial alternative cancer treatment. In millimolar concentrations, it is selectively cytotoxic to many cancer cell lines and has in vivo anticancer activity when administered alone or together with other agents. We carried out a dose-finding phase I and pharmacokinetic study of i.v. ascorbic acid in patients with advanced malignancies. Patients with advanced cancer or hematologic malignancy were assigned to sequential cohorts infused with 0.4, 0.6, 0.9 and 1.5 g ascorbic acid/kg body weight three times weekly. Adverse events and toxicity were minimal at all dose levels. No patient had an objective anticancer response. High-dose i.v. ascorbic acid was well tolerated but failed to demonstrate anticancer activity when administered to patients with previously treated advanced malignancies. The promise of this approach may lie in combination with cytotoxic or other redox-active molecules.
    Full-text · Article · Jul 2008 · Annals of Oncology
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    ABSTRACT: 2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) is a novel chloroethylnitrosourea that demonstrates selective cytotoxicity in athymic mice bearing human glioma. SarCNU demonstrates selective cytotoxicity in vitro against human glioma at least in part because of the selective SarCNU uptake by the extraneuronal monoamine transporter. The purpose of this phase I study was to determine the maximum-tolerated dose (MTD), the toxicity profile, the pharmacokinetics profile, and recommended phase II dose. Forty-three eligible patients with advanced solid tumors were enrolled. SarCNU was administered orally on days 1,5, and 9 every 28 days. The dose ranged from 30 to 1,075 mg/m2. Pharmacokinetic evaluation was done on the first cycle (one dose was given intravenously on day 1 or 5 of the first cycle to determine bioavailability). Delayed myelosuppression (thrombocytopenia and neutropenia occurring 4 to 6 weeks after administration) was the dose-limiting toxicity (DLT). Anemia occurred but was mild. Nonhematologic toxicity was generally mild, but one patient died with pulmonary toxicity that was probably secondary to SarCNU. There were no partial or complete responses, but eight patients had stable disease for 19 to 46 weeks. The oral bioavailability of SarCNU was 80% +/- 37%. The terminal phase half-life was similar after intravenous (58.4 +/- 23.5 minutes) or oral (64.0 +/- 34.8 minutes) administration. The total plasma clearance was 20.4 +/- 8.8 L/h/m2, and the apparent volume of distribution was 29.9 +/- 17.6 L/m2. The area under the plasma concentration-time profile increased proportionally with the dose, and the pharmacokinetics seemed to be independent of the route of administration and the number of doses. SarCNU was well tolerated and the MTD was 1,075 mg/m2. The recommended starting dose for phase II trials is 860 mg/m2 orally on days 1, 5, and 9 every 6 weeks.
    Preview · Article · Feb 2003 · Journal of Clinical Oncology
  • L C Panasci · V Sandor · D Melnychuk

    No preview · Article · Jan 1999 · New England Journal of Medicine
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    L C Panasci · D Melnychuk

    Preview · Article · Dec 1997 · JNCI Journal of the National Cancer Institute
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    ABSTRACT: Glutathione S-transferase (GST) represents a multifunctional enzyme family consisting of four known cytosolic isoforms (alpha, mu, pi, and Phi) that detoxify a variety of xenobiotic chemicals and may confer resistance to both chemotherapeutic drugs and carcinogens in various experimental models. GST-pi has already been extensively studied in clinical specimens, including breast cancer. We studied the immuno-histochemical distribution and relative immunopositivity of GST-alpha and GST-mu, based on a grading system for immunointensity, in samples of 51 neoplastic and 46 normal breast samples and 12 lymph node metastases from patients treated with intensive chemotherapy and bone marrow transplant. In normal breast tissue, GST-alpha localized predominantly to the cytoplasm of scattered cells lining the luminal aspects of the ducts. Occasional cells showed both cytoplasmic and nuclear GST-alpha immunoreactivity. GST-mu was stained in myoepithelial cells preferentially as well as in occasional ductal cells (including apocrine epithelium), vascular smooth muscle, and plasma cells. GST-alpha and GST-mu were detected in 22 of 51 (43%) and 24 of 48 (50%) invasive cancers, respectively. In paired samples of normal and malignant tissue from the same patient, GST-alpha immunostaining in cancers was significantly less intense compared to that of normal breast tissue in 13 of 41 (32%) cases. No such trend was found for GST-mu in paired samples. Neither GST-alpha nor GST-mu immunopositivity in tumor or nonneoplastic breast was found to correlate with relapse-free or overall survival in this clinical context; however, the apparent decreased expression of GST-alpha in malignant versus normal breast epithelial cells could have important implications in breast carcinogenesis.
    Full-text · Article · Jun 1997 · Clinical Cancer Research
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    ABSTRACT: Glutathione (GSH) is known to play a role in cellular sensitivity to some chemotherapeutic agents and to radiation. Depletion of cellular glutathione increases toxicity of these drugs, and this approach is being explored in the clinic as a form of biochemical modulation using the drug buthionine sulfoximine. The fact that some drug-resistant cell lines have increased GSH levels, and that enhancing glutathione concentrations in animal tissues protects against a variety of xenobiotic agents, suggests a different potential approach to improve anticancer therapy. We previously showed a selective enhancement by the cysteine "pro-drug," L-2-oxothiazolidine-4-carboxylate (OTZ), of GSH concentration in some normal tissues of tumor-bearing rats, whereas there is a paradoxic GSH depletion in tumor. OTZ has been shown to protect animals from a variety of toxins, and in vitro studies showed a selective increase in GSH in normal cells that results in reduced sensitivity to some chemotherapy drugs. This report describes evidence that OTZ provides this effect in an in vivo rat mammary tumor model. We have examined the OTZ "activating" enzyme, 5-oxoprolinase, in these tumors and found it to be 4-fold lower than that of normal rat liver. This may explain at least the lack of increased GSH in tumor in response to OTZ. A limited number of human breast cancer samples show similar activity.
    No preview · Article · Apr 1996 · Journal of Pharmacology and Experimental Therapeutics
  • D Melnychuk · L C Panasci

    No preview · Article · Oct 1994 · New England Journal of Medicine
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    ABSTRACT: . One may conclude that the total dose is the underlying basis for the observed differences, whereas the authors prefer to postulate a nonlinear dose-response or intensity-response effect . If the survival benefit of adjuvant chemotherapy mostly accrues to patients who are incurable sbecause of a drug- resistant minority clone, then both theory' and laboratory models' suggest that total dose is indeed the important de- terminant up to the point at which the sensitive cell popula- tion is eliminated in the majority of patients . If so, the con- clusion that doses "should not be reduced" is unsound and may lead to inappropriate risk taking in the face of excessive toxicity . Although it is good clinical practice to give the maximal well-tolerated dose, it may be possible to compen- sate for dose reductions or delays with additional therapy to achieve the target total dose .
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