About this article
Article Category: Review
Published Online: Jan 17, 2022
Page range: 987 - 1004
Received: Sep 24, 2020
Accepted: Jul 28, 2021
DOI: https://doi.org/10.2478/ahem-2021-0031
Keywords
© 2021 Dębska-Szmich et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Figure 1.
Studies evaluating the role of vitamin C in cancer treatment carried out in years 1978–2018
| Main author and year of publication | Study design | Results |
|---|---|---|
| Cameron 1978 [78] | Observational with matched controls; IV and oral vitamin C vs. no vitamin C; 1,100 patients (100 treated with vitamin C), advanced malignancies; concurrent treatment not defined; primary outcome: survival | Mean survival from the date of commencing best supportive care - 298 days in a vitamin C-treated arm vs. 38 days in controls (p= 0.01) |
| Murata 1982 [79] | Observational without a control group; IV and oral vitamin C at a high dose (≥ 5g/d) vs. IV and oral vitamin C at a low dose or no vitamin C; 99 patients with terminal cancer at the Fukuoka Torikai Hospital and 31 patients at the Kamioka Kozan Hospital; concurrent treatment not defined; primary outcome: survival | Cohort 1: the average time of survival after the date of designation as terminal was 43 days for 44 low-vitamin C patients and 246 days for 55 high-vitamin C patients; Cohort 2: the average survival time was 48 days for 19 control patients and 115 days for six high-vitamin C patients; no confidence intervals or any result of a test of significance reported, the administration of large doses of vitamin C seemed to improve the quality of life |
| Harris 2013 [80] | Observational, retrospectively assessed; vitamin C oral intake divided by quartiles, 3405 women diagnosed with breast cancer at all stages; concurrent therapy not described; primary outcome: survival regarding an vitamin C intake | The highest vs. lowest vitamin C intake prior to breast cancer diagnosis associated with benefit in mortality, HR 0.75 (0.57–0.99); no association between vitamin C intake following breast cancer diagnosis and mortality |
| Takahashi 2012 [75] | Observational, oral and IV vitamin C; 63 patients with newly diagnosed cancer, stage not defined, 34 patients undergoing concurrent chemotherapy; primary outcome: quality of life assessed using the QOL questionnaire developed by the European Organization of Research and Treatment of Cancer (EORTC) - EORTC-QLQ C30 | The global health/QOL score significantly improved from 44.6 ± 27.8 to 53.2 ± 26.5 (p < 0.05) at week 2 and to 61.4 ± 24.3 (p < 0.01) at week 4; a significant increase in physical, role, emotional, cognitive, and social functioning at week 4 (p < 0.05), observed a significant relief of fatigue, pain, insomnia, constipation, and financial difficulties, no adverse events reported |
| Yeom 2007 [76] | Observational; oral and IV vitamin C; 39 patients with metastatic cancer, no concurrent treatment; primary outcome: quality of life | An improvement in global health score from 36+/-18 to 55+/-16 after 1 week of vitamin C treatment |
| Vollbracht 2011 [81] | Observational retrospective study; IV vitamin C plus standard surgery, chemotherapy, radiation, and hormonal treatment (n=53) vs. standard therapy alone (n=72); 125 breast cancer patients (stages IIa-IIIb); primary outcome: quality of life (symptom intensity score, trial specific) | An improvement in quality of life in a vitamin C group based on intensity of complaints score (p =0.013); appetite, nausea, fatigue, depression, and sleep disorders during and after adjuvant therapy significantly improved in the vitamin C group; no validated ‘intensity of complaints’ scale used; no survival outcomes reported |
| Gunes-Baiyr 2015 [73] | Retrospective; IV vitamin C 2.5 g/d (n=15) vs. chemotherapy (n=15) vs. control (n=9); 39 patients with bone metastases, all the patients were radiotherapy-resistant; primary outcome: pain intensity, performance status, and survival | An increase in performance status in four patients of a vitamin C group and in one patient of chemotherapy group, in control group a decrease was observed; a median 50% reduction in pain in the vitamin C group; median survival 10 months in the patients receiving vitamin C vs. 2 months in the chemotherapy and control groups |
| Lv 2018 [13] | Retrospective; IV vitamin C 2 g for four or more days after initial hepatectomy (n=339) vs. control (n=274); 613 HCC patients who received curative liver resection; primary outcome: survival | 5-year disease-free survival (DFS) for patients who received IV vitamin C was 24% vs. 15% for controls (p< 0.001); Median DFS for IV vitamin C users 25.2 vs. 18 mo. for control (p<0.001); multivariate analysis demonstrated that IV vitamin C was an independent factor for improved DFS (adjusted HR = 0.622, 95% CI 0.487 to 0.795, p<0.001) |
| Hoffer 2008 [82] | Phase I; oral and IV vitamin C dose-escalating + oral multivitamin; 24 patients with advanced malignancies; primary outcome: dose finding; secondary - toxic effects, antitumor effects, quality of life using the Functional Assessment of Cancer Therapy — General (FACT-G) questionnaire, effects of different IV doses on the plasma vitamin C profile | 1.5 g/kg vitamin C infused >90–120 min three times weekly is free of risk and important side-effects when simple precautions are taken; response rate: 0%; adverse events and toxicity were minimal at all dose levels; patients in the 0.4 g/kg cohort experienced a significant deterioration in physical function over the course of the study, however, there was no deterioration in physical function among the patients in the higher dose cohorts; no changes in the social, emotional or functional parameters of quality of life in any cohort |
| Stephenson 2013 [77] | phase I; multivitamin and eicosapentaenoic acid (EPA); IV vitamin C 30–110 g/m2; 17 patients with advanced solid tumors; primary outcome: pharmacokinetics, safety and tolerability | Toxicity: grade 3–4 hyponatremia, hyperkalemia; in three patients stable disease, in 13 progressive disease observed; recommended dose of vitamin C 70–80 g/m2 |
| Kiziltan 2014 [83] | Pilot study; IV vitamin C; 11 patients with bone metastases who were unresponsive to standard cancer treatments; primary outcome: efficacy, toxicity | The mean reduction in pain was 55%; median survival: ten months; toxicity: 40% grade 1 gastrointestinal toxicity and 30% urinary toxicity |
| Polireddy 2017 [84] | Phase I/IIa; IV vitamin C + gemcitabine; 14 pancreatic cancer patients; primary outcome: safety and pharmacokinetic interaction | Twelve of 14 patients completed phase I pharmacokinetic evaluation and entered Phase IIa; median survival: 15.1 months; median progression-free survival: 3 months; significant adverse events: none were deemed related to IV vitamin C; adverse events attributable to IV vitamin C were grade 1 nausea and thirst |
| Welsh 2013 [85] | Phase I/II; IV vitamin C + gemcitabine; 11 advanced pancreatic adenocarcinomas; primary outcome: toxicity | Data only for nine patients who completed the study; two patients progressed and were excluded from the analysis; mean survival: 13 +/-2 months; time to progression: 26 +/- 7 weeks; no dose limiting adverse effects |
| Pinkerton 2017 [86] | An open-label pilot study; oral vitamin C in conjunction with opioids and standard adjuvant therapy; 34 patients with chronic pain secondary to cancer and/or its treatment; primary outcome: efficacy in the management of chronic cancer pain | Seven patients failed to complete the trial; 17 evaluable patients; the median daily opioid consumption was 360 mg oral morphine equivalents on the days prior to vitamin C and 390 mg when administered with vitamin C |
| Schoenfeld 2018 [70] | Phase I; following maximum safe surgical resection or biopsy (if unresectable), subjects received radiation (daily), temozolomide (daily), and IV vitamin C (three times a week) for approximately seven weeks, for each subsequent subject, vitamin C doses were escalated during the radiation phase (15–125 g) with 20 mM target plasma concentration; 13 glioblastoma multiforme patients; primary outcome: safety and tolerability | Following completion of the radiation phase, all subjects were dose escalated to achieve ≥ 20 mM plasma vitamin C in combination with temozolomide for approximately 28 weeks; the desired mean therapeutic blood level was achieved in all the subjects; vitamin C was safe and well tolerated with minimal grade 3 and 4 toxicities; two subjects were excluded from a long-term analysis due to non-adherence to the protocol therapy because of unrelated comorbidities; all the subjects maintained their performance status throughout the treatment; median progression-free survival: 9.4 months; median survival: 18.2 months.; in 73% of patients MGMT promoter methylation was absent and median survival in this group was 23.0 months |
| Monti 2012 [8] | Phase I/II; gemcitabine and erlotinib and IV vitamin C with dose escalation design; 14 patients with stage IV pancreatic adenocarcinoma; primary outcome: safety | Two patients who decided to withdraw from the study, and three patients who died from rapid disease progression were excluded from the survival analysis; mean OS: 182 days, (standard deviation 155 days); mean PFS: 89 days; response rate: 0%; stable disease rate: 50%; multiple toxicities, all grades, however, not related to vitamin C |
| Berenson 2009 [87] | Phase I/II; bortezomib, melphalan and oral AA; 35 newly diagnosed multiple myeloma patients; primary outcome: response rate and safety | Median survival: not reached at time of the publication (range 2–231 months); median progression-free survival: 13 months (range 2–221 months); response rate 74%; toxicity related to bortezomib and melphalan, not to vitamin C; grade 2 side effects predominantly hematological; the author stated that results were inferior to those obtained with other agents |
| Riordan 2005 [88] | Phase I/II; IV vitamin C vs. no; 24 patients with advanced malignancies; primary outcome: safety | Response rate: one stable disease (4%); toxicity: four grade 3–4 events (renal calculi, hypokalemia) |
| Tareen 2008 [53] | Phase I/IIa study; vitamin C 5000 mg: K350 mg (Apatone) oral; 17 patients with 2 successive increases in PSA after unsuccessful standard local therapy; primary outcome: safety and efficacy | PSAV decreased and PSADT increased in 13 of 17 patients (p ≤ 0.05); there were no dose-limiting adverse effects |
| Nielsen 2017 [89] | Phase II; IV vitamin C weekly infusions (week 1.: 5 g; week 2.: 30 g, and week 3–12. 60 g) with ongoing androgen-deprivation therapy with castration-level of testosterone; 23 patients with chemotherapy-naive, metastatic castration-resistant prostate cancer; primary outcome: the efficacy (reduction of prostate-specific antigen – PSA level) and safety; secondary endpoints: changes in health-related quality of life, biomarkers of bone metabolism, inflammation and bone scans | Twenty patients completed the study; no patient achieved a 50% PSA reduction; instead, a median increase in PSA of 17 μg/L; among the secondary endpoints, no signs of disease remission were observed; 53 adverse events, including 11 serious adverse events; three events were directly related to vitamin C (fluid load) |
| Zhao 2018 [90] | Randomized controlled trial, A-DCAG (IV vitamin C plus DCAG: decitabine, cytarabine, aclarubicin) [n = 39]) vs. DCAG (n = 34); 73 elderly patients with acute myeloid leukemia (AML); primary outcome: efficacy | Patients who received A-DCAG presented a higher complete remission (CR) rate than those who received DCAG (79.9% vs. 44.1%; p = 0.004) after first induction; median survival was longer in a A-DCAG group as compared to a DCAG group (15.3 months vs. 9.3 months, p = 0.039); similar toxicity |
| Goel 1999 [91] | Randomized controlled trial; oral vitamin C plus CMF chemotherapy vs. chemotherapy; 30 patients with stage IIIb/IV breast cancer; primary outcome: response in breast | 60% (vitamin C+ chemotherapy) vs. 33.3% (chemotherapy) measured by Vernier calipers, criteria for response not defined; change in tumor size by Vernier calipers 3.53 cm (vitamin C) vs. 1.93 cm (placebo); results of tests for significance not reported |
| Ma 2014 [74] | Randomized controlled trial; IV vitamin C plus chemotherapy (carboplatin and paclitaxel) vs. chemotherapy alone; 27 patients with stage III-IV ovarian cancer, primary outcome: toxicity | Statistically significant decrease in grade 1–2 toxicities in vitamin C group based on Common Terminology Criteria for Adverse Events, |
| Yeon 2016 [92] | Randomized controlled trial; IV vitamin C 50 mg/kg vs. placebo immediately after induction of anesthesia; 100 patients undergoing laparoscopic colectomy; primary outcome: effect of vitamin C on opiate consumption assessed at 2, 6, and 24 h after the completion of surgery | Ninety-seven patients included in the analysis; patients who received vitamin C had higher plasma concentrations of vitamin C at the end of surgery, significantly lower morphine consumption 2 h after the surgery, and significantly lower pain scores at rest during first 24 h after surgery; there were no significant differences between the groups in side effects, fatigue score, or pain score on coughing |
| Creagan 1979 [93] | Randomized controlled trial; oral vitamin C vs. placebo; 123 patients with advanced cancer; primary outcome: survival | No significant difference in survival, and no difference in symptoms of disease |
| Moertel 1985 [94] | Randomized controlled trial; oral vitamin C vs. placebo; 100 patients with advanced colorectal cancer; primary outcome: survival | Median survival: 2.9 months (vitamin C) vs. 4.1 months (placebo); no significant difference in quality of life |
| Zemskov 2000 [95] | Randomized controlled trial; IV and oral vitamin C plus Ukrain (anticancer drug based on the extract of the plant Chelidonium majus L.) vs. IV and oral vitamin C alone; 42 patients with advanced pancreatic adenocarcinoma, two patients had surgery; primary outcome: survival | Median survival 17 months in Ukrain plus vitamin C arm vs. 6.97 months in a vitamin C arm (p=0.001); response rate: 14.3% in a Ukrain group, vs. 0%, respectively; criteria for response not defined |