Table 1.
Baseline characteristic of included studies
| First author, year | Country | Design | Participants(n), age(year), gender(M/F), case/control(n) | Cancer type | Follow up (year/month) | Intervention (Case/ control) |
Dose/duration | Main findings | JADAD score |
|---|---|---|---|---|---|---|---|---|---|
| Vitamin C (VC) | |||||||||
| Ou et al. 2020 [29] | China | Phase II, RCT | 97, 42–72 yrs, M:75/F:22, 49/48 |
Stage IIIB, IV non-small-cell lung cancer (NSCLC) |
Up to 24 mo |
IVC + modulated electrohyperthermia (mEHT) + best supportive care (BSC) vs. BSC |
1 g/kg/d 3 times/w for 25 treatments |
-Safe -↑sig. PFS: median 3 mo -↑sig. OS: median 9.4 mo -↓sig. 3-mo disease progression |
3 |
| Allen et al. 2019 [30] | US | Phase I, Open-label | 11, 53 (25–68), M:6/F:5, all cases | Newly diagnosed Glioblastoma | Up to 168 d | AA + standard therapy | 15, 25, 50, 62.5, 75, 87.5 g 2–3 times/w until concentration reached to ≥ 20 mmol/L |
-Safe -Median PFS: 9.4 mo -Median OS: 18 mo |
2 |
| Mikirova et al. 2019 [31] | US | Phase I, Open-label | 24, ≥ 19 yrs., M:12/F:12, all cases | Colon with/without metastases | Up to 8 w | 5 groups of various dosage of high-dose IVC + chemotherapy |
Group1:150 Group2:290 Group3:430 Group4:510 Group5:710 mg/kg/d for 8w |
-continuous IVC infusion is safe until 300 mg/kg/d -↓disease progression -↓neutrophil/ lymphocyte (↑survival rate) |
2 |
| Wang et al. 2019 [32] | China | Open-label | 36, 53 (27–75) yrs, M:21/F:15, all cases | metastatic colorectal, gastric | 8.6 mo | AA + chemotherapy (mFOLFOX6 or FOLFIRI) |
Dose-escalation phase: AA (0.2–1.5 g/kg, 3-h infusion, once daily, days 1–3) + chemotherapy speed-expansion phase: AA (MTD or 1.5 g/kg/d for 3 consecutive days) + Chemotherapy/14 cycle days until 12 cycles |
-17 PFS (progression free survival) events (16 progression, 1 death) -Median PFS 8.8 months -Safe for combination |
2 |
| Zhao et al. 2018 [33] | China | Open-label | 73, 68.2 yrs ( 60–87), M:40/F:33, 39/34 | Acute myeloid leukemia | 2–6 cycles (18–54 d) | VC + chemotherapy vs. chemotherapy alone |
15 mg/m2 of decitabine |
-sig. complete remission -sig. higher median OS (15.3 vs. 9.3 mo) -↓sig. HR deaths: 0.47 [0.26–0.84] |
2 |
| Nielsen et al. 2017 [34] | Denmark | Uncontrolled phase 2 | 23,73.8 yrs. (69.2–79.6), only male, 23/0 |
Metastatic castration-resistant prostate cancer |
12 w | Infusion AA |
5 g/w week 1, 30 g/w week 2, 60 g/w weeks 3–12 |
Not disease remission | 2 |
| Polireddy et al. 2017 [35] | US | Phase I/II, single arm | 14, 36–80 yrs., 4 M, 10 F |
Locally advanced or metastatic prostate cancer |
Up to 44 w | IVC, gemcitabine |
-Escalating dose of IVC 25–100 g -Phase II: IVC 3 times/w |
Patients experienced a mix of stable disease,partial response and disease progression | 2 |
| Schoenfeld et al. 2017 [36] | US | Phase I, single arm | 13, 53 yrs. (25–71), 7 M, 6 F | Glioblastoma | 35 w |
IVC, radiation and temozolomide |
IVC (twice/ w, dose-escalation, around ~ 85 g infusion) |
-PFS 13.3 mo -Average OS 21.5 mo |
2 |
| Schoenfeld et al. 2017 [36] | US | Phase II, single arm | 14, 51–68 yrs., 9 M, 5 F |
Advanced stage non-small cell lung cancer |
Carboplatin, paclitaxel, and ascorbate |
two 75 g infusions/w up to 4 cycles |
partial response in 4, stable disease in 9, disease progression in 1 patient | 3 | |
| Hoffer et al. 2015 [37] | Canada | Open-label | 14, 47–73 yrs., M:7/F:7 | Various advanced cancers | 11–580 d | IVC + chemotherapy | 1.5 g/kg BID-TDS/w | Short time remission in two cases (< 2 mo) | 2 |
| Kawada et al. 2014 [38] | Japan | Open-label, single arm | 3, 57–72 yrs., M:2/ F:1 | Relapsed non-Hodgkin’s lymphoma | 18 d | IVC + chemotherapy | 75 g/twice/w | safe | 2 |
| Ma et al. 2014 [39] | US | Open-label | 25, NA, 13/12 | Stage III -IV ovarian cancer | 52 w | IVC + chemotherapy vs. chemotherapy alone | High dose VC twice/w/12 mo |
-↓ sig. Grade 1-II adverse events -↑non-sig. relapse time and OS -↑8.75 mo PFS |
2 |
| Stephenson et al. 2013 [40] | US | Open-label, single arm | 17, 59 yrs. (40–72), M:6/F:11 | Advanced various cancers | 4 w | IVC | 30–110 g/m2 for 4d/w/4 w |
-stable disease in 3, progress disease in 14 -safe: 70–80 gr/m2 |
2 |
| Welsh et al. 2013 [41] | US | Open-label, single arm | 11, 62 yrs. (50–69), M:6/F:5, all cases | Advanced pancreatic cancer | 6 mo | IVC | 15–125 g IVC twice w/4 w |
-safe, -mean survival 13 ± 2 mo |
2 |
| Mikirova et al. 2012 [42] | US | Single arm | 45, 68 yrs. (47–85), M:29/ F:16 | Various cancers | Average 7.2 yrs. | IVC + chemotherapy |
50 g 3 times/w for median 9 treatments (IQR = 5–18) |
-No objective tumor response -progression in 2 patients |
2 |
| Monti et al. 2012 [43] | US | Open-label, |
14, 64.4 ± 10 yrs. (47–81), M: 2/F:7, 3/3/3 |
Stage IV pancreatic cancer | 8 w | 3 groups of various IVC + chemotherapy | IVC (50,75,100 mg) three times/ w/8 w |
-safe -survival -↓10% tumor mass in 8 of 9 completed trial -5 progressed quickly (3 died) -PFS: 89 d -OS: 182d |
2 |
| Berenson et al. 2009 [44] | US | Single arm, phase II | 35, 70 (50–90) yrs, M:20/F:15 | newly diagnosed multiple myeloma | Up to 23 mo | Bortezomib + oral AA + melphalan | 1 gr oral AA | Well tolerated, disease control in 29 (94%), Median time to progress (19 mo), stable disease in 6 (19%) | 2 |
| Hoffer et al. 2008 [45] | US | Open-label, single arm | 24, 61 yrs. (21–88), M:16/F:8 | Advanced cancer | Up to 30 w | IVC | 0.4-1/5 IVC g/kg/3 times/w | stable disease in 2 patients | 2 |
| Yeom et al. 2007 [46] | South Korea | Uncontrolled phase II trial | 39, 53.5 ± 10.5 yrs, M:20/F:19 | Terminal cancer | 10 d | VC ( IV and oral) | 10 gr VC twice then 4 g oral/d for 1w | ↑health score | 2 |
| Riordan et al. 2005 [47] | Puerto Rico | Uncontrolled phase II | 24, > 19 yrs., 24/0 | Late stage cancer, mainly colorectal | 2 mo | IVC | 10, 30, 40, 50 g/d for 8w | stable disease in 1(4%), progression in others | 2 |
| Correa et al. 2000 [48] | Colombia | DRCT | 852, 51.1 yrs. (29–69), M: 392 (46%)/F: 460 (54%), 130 (AA), 117 (placebo) |
histologic multifocal atrophic gastritis with/without intestinal metaplasia |
6 yrs. | AA, β-carotene, combination vs. placebo | 1 g/twice/d/ oral |
-↑sig. RR regression: 3.3 [1.1, 9.5] -↓non-sig. RR progression: 0.5 [0.2, 1.1] |
5 |
| Moertel et al. 1985 [49] | USA | DRCT | 100, adult, M: 57/F:43, 51/49 | Advanced colorectal cancer | Up to 26 mo | oral VC vs. placebo | 10 g/d VC or lactose as placebo | Non-sig. difference in median OS (2.9 by AA vs.4.1 mo by placebo) | 5 |
| Poulter et al.1984 [50] | NA | Non-randomized clinical trial | 66, NA, 27/25 | Newly diagnosed breast cancer | 3 mo | Oral VC vs. placebo | 3 g/d |
-↑non-sig. RR deaths: 1.52 [0.72, 3.23] -no change in survival |
3 |
| Murata et al. 1982 [51] | Japan | Non-randomized clinical trial | 130, NA, 111/19 | Terminal cancer | NA | Low dose vs. high dose IVC and oral |
site 1: 6-30 g/d oral, 10-20 g/IV, site 2: 0.5-3 g/d or 5–30 g/d oral |
-site 1: average OS 246 d with high dose vs. 43 d low dose -site 2: average OS 115 d with high dose vs. 48 d low dose |
2 |
| Creagan et al. 1979 [52] | US | DRCT | 123, children and adult, M:76/F:47, 60/63 | Advanced cancer | 11 mo | VC vs. placebo | 10 g/d VC | -non-sig difference in OS between groups | 5 |
| Cameron et al. 1978 [53] | US | Non-randomized trial | 1100, 38–93 yrs, M:517/F:583, 100/1000 | Advanced cancer | 12 mo | IVC and oral VC | 10 g/d IVC for 10 days and then oral | ↑sig. survival (↑300 d) | 2 |
| Vitamin E (VE) | |||||||||
| Thomsen et al. 2019 [54] | Denmark | Phase II | 23, 70 (41–81) yrs., all women |
refractory ovarian cancer |
NR (until progression grade 3 toxicity, or patient wish to discontinue) |
Bevacizumab + oral tocotrienol | 300 mg/3 times/d |
-stable disease 70% -very low toxicity -Median PFS: 6.9 mo -Median OS: 109 mo |
3 |
| Springett et al. 2015 [55] | US | Phase I | 25, 65.3 yrs. (49–84), M:16/ F:9, |
Resectable pancreatic exocrine neoplasia |
14 d before surgery | VE α-tocotrienol | 200–3200 mg/d |
-except in one patient with 3200 mg, safe -↑sig. apoptosis by 400–1600 mg/d |
2 |
| Nesaretnam et al. 2010 [56] | Malaysia | Double blind-non-random trial | 240, 40–60 yrs., all women | Breast cancer | 5 yrs. | Tocotrienol or placebo + tamoxifen | 200 mg/d |
5-yrs cancer survival: VE: 98.3% vs. placebo: 95%, 5-yrs cancer free survival: VE: 86.7%, placebo: 83.3 -↓non-sig. adjusted HR deaths: 0.40 [0.08, 2.05] -↓non-sig. HR recurrence: 0.84 [0.43, 1.65] |
4 |
|
Lippman et al. 2009 [57] (SELECT study) |
US, Canada, Puerto Rico | RCT | 35,533 with high PSA, ≥ 50 yrs., all men, 8737 VE, others selenium with/without VE, and placebo | Prostate, colorectal, lung, other primary cancers | 7–12 yrs | VE, Selenium, both vs. placebo | 400 IU/d VE | ↓non-sig. HR deaths: 0.84 [0.60, 1.18] vs. non-VE | 4 |
| VC + VE | |||||||||
| McKeown-Eyssen et al. 1988 [58] | Canada | DRCT | 185, average 60 yrs., M: 121, F:64, 96 case/89 control | After removal at least one colorectal polyp | 2 yrs. | VC + α-tocopherol vs. placebo | 400 mg VC + α-tocopherol |
-recurrence in 41% of 70 case, and 50.7% of 67 control -↓non-sig. adjusted RR for any polyp 0.86 [0.51, 1.45] -↓non-sig. adjusted RR for neoplastic polyp 0.93 [0.48, 1.83] |
5 |
Legend: PFS: Progression-free survival; OS: Overall survival; HR: Hazard ratio; NA: Not access full text; IVC: Intravenous vitamin C; AA: Ascorbic acid; DRCT: Double-blind randomized controlled trial; F: Female; M: Male; W: week; D: day; Yrs: Years