关于vc抗癌--从两个临床试验谈起

VC抗癌说由来已久，众说纷纭；但大多是细胞、动物试验或个例报告，不足为凭。

现搜集整理两个VC抗癌的临床试验如下，据此加以研判：
/ H! t" \7 L* Q9 Z
: g6 v6 J- o+ w1 ]
8 l9 [2 q$ [+ G1、《A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study)》
2 b, ~. b/ _  v# j7 _0 b% Y1 q# _
这应该是到目前为止，涉及到VC抗癌的，规模最大的一个随机对照试验。
" W9 ~: M5 x/ d6 v3 l- u) y
8 \/ @7 S# N0 A- lPatients and methods: Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription.

* D, s: T" _/ V5 s; q/ p" w试验结果：The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively.
/ H) |; _3 P9 ]  u* p+ F
这个临床试验结果意味着即便是采用了静脉注射的给药方式，即便是用了1.5 g/kg/d这么高的剂量（一个50公斤的患者一天要静脉注射75克之多的VC），从整体而言，传统化疗靶向抗癌治疗增加IVC，也没有给疗效带来有统计学意义上的改善。

( _5 M$ ]8 o7 q8 o) h3 ]* U1 Q但是，“In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only.”
* t& k. ^* b9 C8 w5 b9 \# _$ y
( L" F3 c" j, v" @; _4 j+ H* v在RAS突变（kras、hras、nras）患者中，应用静脉注射大剂量VC，却带来了PFS的统计学意义上的显著改善。
. b5 D4 X. ?* ]2 M* E- A
* A- S9 r- I& B/ ^' _( x$ V- \研究者认为这个结果也是跟临床前研究结论相符的 ：“It suggested that the oxidized form of vitamin C, dehydroascorbate, was the pharmaceutically active agent resulting in an energy crisis and colorectal cancer cell death, and the selective cytotoxicity of vitamin C stemmed from high expression of GLUT1 glucose transporter combined with RAS oncogene-induced glycolytic addiction”

9 }9 Y% C9 y$ Z* h- T( m# W另外在超过55岁的老年患者中也带来了PFS上的益处。这或许跟老年患者中VC缺乏比例高（88%）有一定的关系。

5 X2 P2 h, B# N) A; i研究者认为临床设计上有两个不足：“First, the patients received intravenous high-dose vitamin C for 3 days of every treatment cycle, which might not be enough for vitamin C to show its antitumor effect.”“Second, high-dose vitamin C discontinued at 6 months before the majority of patients progressed, and the true impact of high-dose vitamin C in mCRC may thus be underestimated.”
3 x* B% b# y% e7 u3 y( p- M
核心意思就是尽管IVC的单日剂量不小，但是打的天数不多，治疗积累的总量并不算很多，有可能没有让VC发挥出应有的作用来。

- H3 I4 _; F' s从这个临床试验结果来看，VC要发挥抗癌作用，关键在于患者的基因突变情况，在于患者的VC缺乏情况，在于VC的给药方式、剂量、剂型、给药频率的情况。不能脱离这些具体条件去得出什么结论。
! {7 w3 b+ B/ ~( i2 p3 T; \; l
下面这个临床试验也说明了这点。
" p6 P, K7 W5 b
2、《Randomized trial of topical ascorbic acid in DMSO versus imiquimod for the treatment of basal cell carcinoma》
$ c/ Y& H% Z" Z, H" W: P
这是到目前为止，VC抗癌疗效最好的一个临床试验。
& d5 }! C8 M9 X% O! F3 x& o- e
“The objective of this study was to compare efficacy of a topical solution consisting of 30% ascorbic acid in 95% dimethylsulfoxide with topical imiquimod in the treatment of basal cell carcinoma. Twenty-five patients with 29 biopsy confirmed basal cell carcinomas were randomly assigned to receive either the topically applied ascorbic acid treatment twice daily for 8 weeks or topical imiquimod, a standard and well characterized topical treatment. ”
) @5 v$ t% s5 P3 t6 M
& b. k6 Y$ f  G8 W2 P3 `; ?7 g试验结果：“After 8 weeks, post-treatment biopsy of lesions showed complete resolution of 13/15 (86.7%) in the ascorbic acid group, while 8/14 (57.1%) lesions in the IMQ group were resolved (p < 0.05 Chi Square). Topical ascorbic acid was superior at 8 weeks, and non-inferior at 12 weeks to topical imiquimod in the treatment of low risk nodular and superficial lesions. In addition, ascorbic acid was associated with fewer adverse effects than imiquimod. 70% of patients in the imiquinod group showed residual hypopigmentation at 30mo follow up versus 0% in the ascorbate group.”

剂型上把ascorbic acid 溶在 DMSO这个渗透力极强的无毒的佐剂里，给药方式上采用涂抹这种药物直接接触病灶的方式，这样保证了药物在病灶内的局部高浓度，这是临床试验成功的关键。
) @2 u7 n+ C/ `) ?- Q1 ]" L
8 Q" e& z7 |* U5 O5 M按照这两个临床试验的思路，完成可以拓展VC-DMSO药液对RAS突变患者或者严重缺乏VC患者病灶实施病灶表面给药或者瘤体内直接给药的治疗。
+ c8 L* D' {" a# ~# @