Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.
Myrna Brind Center of Integrative Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy.
METHODS AND FINDINGS:
14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease.
These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration.
Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial.
Department of Surgery, 1528 JCP-UIHC, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models. A phase I clinical trial was performed to establish safety and tolerability of pharmacological ascorbate combined with gemcitabine in patients with biopsy-proven stage IV pancreatic adenocarcinoma.
Nine subjects received twice-weekly intravenous ascorbate (15-125 g) employing Simon’s accelerated titration design to achieve a targeted post-infusion plasma level of ≥350 mg/dL (≥20 mM). Subjects received concurrent gemcitabine. Disease burden, weight, performance status, hematologic and metabolic laboratories, time to progression and overall survival were monitored.
Mean plasma ascorbate trough levels were significantly higher than baseline (1.46 ± 0.02 vs. 0.78 ± 0.09 mg/dL, i.e., 83 vs. 44 μM, p < 0.001). Adverse events attributable to the drug combination were rare and included diarrhea (n = 4) and dry mouth (n = 6). Dose-limiting criteria were not met for this study. Mean survival of subjects completing at least two cycles (8 weeks) of therapy was 13 ± 2 months.
Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy. Further studies powered to determine efficacy should be conducted.
Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer.
Cancer Treatment Centers of America®, Zion, IL 60099, USA.
This phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of high-dose intravenous (i.v.) ascorbic acid as a monotherapy in patients with advanced solid tumors refractory to standard therapy.
Five cohorts of three patients received i.v. ascorbic acid administered at 1 g/min for 4 consecutive days/week for 4 weeks, starting at 30 g/m(2) in the first cohort. For subsequent cohorts, dose was increased by 20 g/m(2) until a maximum tolerated dose was found.
Ascorbic acid was eliminated by simple first-order kinetics. Half-life and clearance values were similar for all patients of all cohorts (2.0 ± 0.6 h, 21 ± 5 dL/h m(2), respectively). C max and AUC values increased proportionately with dose between 0 and 70 g/m(2), but appeared to reach maximal values at 70 g/m(2) (49 mM and 220 h mM, respectively). Doses of 70, 90, and 110 g/m(2) maintained levels at or above 10-20 mM for 5-6 h. All doses were well tolerated. No patient demonstrated an objective antitumor response.
Ascorbic acid administered i.v. at 1 g/min for 4 consecutive days/week for 4 weeks produced up to 49 mM ascorbic acid in patient’s blood and was well tolerated. The recommended dose for future studies is 70-80 g/m(2).
Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany.
Pascoe pharmazeutische Präparate GmbH, Giessen, Germany.
The aim of the study was to evaluate under praxis conditions the safety and efficacy of intravenous (i.v.) vitamin C administration in the first postoperative year of women with breast cancer.
PATIENTS AND METHODS:
Epidemiological multicentre cohort study, including 15 gynaecologists and general practitioners representatively distributed in Germany. Data from 125 breast cancer patients in UICC stages IIa to IIIb were selected for the study. A total of 53 of these patients were treated with i.v. vitamin C (supplied as Pascorbin® 7.5 g) additional to standard tumour therapy for at least 4 weeks (study group) and 72 without this additional therapy (control group). Main outcome measures were efficacy in regard to outcome and severity of disease- or therapy-induced complaints during adjuvant chemo- and radiotherapy and aftercare.
Comparison of control and study groups revealed that i.v. vitamin C administration resulted in a significant reduction of complaints induced by the disease and chemo-/radiotherapy, in particular of nausea, loss of appetite, fatigue, depression, sleep disorders, dizziness and haemorrhagic diathesis. After adjustment for age and baseline conditions (intensity score before adjuvant therapy, chemotherapy, radiotherapy), the overall intensity score of symptoms during adjuvant therapy and aftercare was nearly twice as high in the control group compared to the study group. No side-effects of the i.v. vitamin C administration were documented.
Oxidative stress and vitamin C deficiency play an important role in the etiology of adverse effects of guideline-based adjuvant chemo-/radiotherapy. Restoring antioxidative capacity by complementary i.v. vitamin C administration helps to prevent or reduce disease-, or therapy-induced complaints in breast cancer patients.
Complementary treatment of breast cancer patients with i.v. vitamin C was shown to be a well tolerated optimization of standard tumour-destructive therapies, reducing quality of life-related side-effects.
Depletion of L-ascorbic acid alternating with its supplementation in the treatment of patients with acute myeloid leukemia or myelodysplastic syndromes.
Cancer Center and Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. firstname.lastname@example.org
Purpose: L-ascorbic acid (LAA) modifies the in vitro growth of leukemic cells from approximately 50% of patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). To test the hypothesis that depletion of LAA, alternating with supplementation to prevent scurvy, would provide therapeutic benefit, a single-arm pilot trial was conducted (ClinicalTrials.gov identifier: NCT00329498). Experimental results: During depletion phase, patients with refractory AML or MDS were placed on a diet deficient in LAA; during supplementation phase, patients received daily intravenous administration of LAA. An in vitro assay was performed pretherapy for LAA sensitivity of leukemic cells from individual patients. Results: Of 18 patients enrolled, eight of 16 evaluable patients demonstrated a clinical response. Responses were obtained during depletion (four patients) as well as during supplementation (five patients) but at a pharmacologic plasma level achievable only with intravenous administration. Of nine patients for whom the in vitro assay indicated their leukemic cells were sensitive to LAA, seven exhibited a clinical response; compared with none of six patients who were insensitive to LAA. Conclusions: The clinical benefit, along with a conspicuous absence of significant adverse events, suggests that further testing of LAA depletion alternating with pharmacologic dose intravenous supplementation in patients with these and other malignancies is warranted.
Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects.
PMNT Unit, Louvain Drug Research Institute, Université Catholique de Louvain, 1200 Bruxelles, Belgium.
Recently, it has been proposed that pharmacologic concentrations of ascorbate (vitamin C) can be reached by intravenous injection. Because high doses of ascorbate have been described to possess anticancer effects, the therapeutic potential of these concentrations has been studied, both in vitro and in vivo. By using 2-h exposures, a protocol that mimics a parenteral use, we observed that pharmacologic concentrations of ascorbate killed various cancer cell lines very efficiently (EC(50) ranging from 3 to 7 mM). The mechanism of cytotoxicity is based on the production of extracellular hydrogen peroxide and involves intracellular transition metals. In agreement with what has been previously published, our in vivo results show that both intravenous and intraperitoneal administration of ascorbate induced pharmacologic concentrations (up to 20 mM) in blood. In contrast, the concentrations reached orally remained physiological. According to pharmacokinetic data, parenteral administration of ascorbate decreased the growth rate of a murine hepatoma, whereas oral administration of the same dosage did not. We also report that pharmacologic concentrations of ascorbate did not interfere with but rather reinforced the activity of five important chemotherapeutic drugs. Taken together, these results confirm that oral and parenteral administration of ascorbate are not comparable, the latter resulting in pharmacologic concentrations of ascorbate that exhibit interesting anticancer properties.
The prospects of vitamin C in cancer therapy.
Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul 110-744, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
Ascorbate (vitamin C) is a cofactor for a number of metabolic enzymes and is an indisputable essential vitamin C for humans. However, the potential of ascorbate as an anticancer agent has been a topic of controversy. A number of previous reports have addressed both positive aspects and limitations of ascorbate in cancer therapy. In this review, we briefly summarize the potential antitumor effects of ascorbate and its prospects for clinical use.
antioxidant, ascorbate, ascorbic acid, cancer, chemotherapy, cytotoxicity, intravenous, prooxidant, tumor growth, vitamin C
The controversial place of vitamin C in cancer treatment.
Unité de Pharmacocinétique, Métabolisme, Nutrition, et Toxicologie (PMNT), Département des sciences pharmaceutiques, Université Catholique de Louvain, Brussels, Belgium.
In 2008, we celebrate the 80th anniversary of the discovery of vitamin C. Since then, we know that vitamin C possesses few pharmacological actions although it is still perceived by the public as a “miracle-pill” capable to heal a variety of illnesses. Cancer is one of the most common diseases for which a beneficial role of vitamin C has been claimed. Thus, its dietary use has been proposed in cancer prevention for several years. Apart from this nutritional aspect, an extensive and often confusing literature exists about the use of vitamin C in cancer that has considerably discredited its use. Nevertheless, recent pharmacokinetic data suggest that pharmacologic concentrations of vitamin C can be achieved by intravenous injections. Since these concentrations exhibit anticancer activities in vitro, this raises the controversial question of the re-evaluation of vitamin C in cancer treatment. Therefore, the purpose of this commentary is to make a critical review of our current knowledge of vitamin C, focusing on the rationale that could support its use in cancer therapy.