S0-called alternative medicine (SCAM) is often promoted for improving the quality of life (QoL) of cancer patients. Women with early-stage breast cancer often opt for trying SCAM. One such option is vitamin C. Its effectiveness in cancer treatment remains, however, unproven. On this background, this first-ever randomized clinical trial aimed to explore the effects of intravenous vitamin C (IVC) on symptoms and adverse events associated with conventional breast cancer treatment.
This single-center, parallel-group, single-blind study was conducted in the oncology ward of a tertiary care hospital in Pakistan. After informed consent, breast cancer patients with Union for International Cancer Control stages IIA to IIIb were included in the study. Three hundred and fifty patients were randomized into two groups at a ratio of 1:1. The study group received 25 grams per week of IVC at a rate of 15 grams per hour for four weeks in addition to their current standard treatment, and the control group received a placebo in addition to their current standard treatment.
In patients who had received IVC, there were significant decreases in the severity scores after 28 days for the following symptoms:
- nausea, loss of appetite (2.26 ± 0.51 vs. 2.11 ± 0.52; p-value: 0.007),
- tumor pain (2.22 ± 0.45 vs. 1.99 ± 0.40, p-value: <0.0001),
- fatigue (3.11 ± 0.32 vs. 2.87 ± 0.29; p-value: <0.0001),
- insomnia (2.59 ± 0.35 vs. 2.32 ± 0.36, p-value: <0.0001).
The authors concluded that this study shows an improvement in the mean severity score of nausea, fatigue, tumor pain, loss of appetite, and fatigue. More studies are also needed to assess the long-term effects of IVC in the cancer management. This shall help incorporate the use of IVC in standard practice to make the journey of cancer management comfortable for the patients.
This new study does not stand alone. A 2014 review summarised three prospective studies as well as case reports and retrospective studies concluding that intravenous (IV) vitamin C alleviates a number of cancer- and chemotherapy-related symptoms, such as fatigue, insomnia, loss of appetite, nausea, and pain. Improvements in physical, role, cognitive, emotional, and social functioning, as well as an improvement in overall health, were also observed.
What about the mechanism of action? The authors of the new study offer the following explanation:
The role of vitamin C in reducing symptoms in cancer patients can be explained by its antioxidant properties. It is known that radiation and chemotherapy along with tumor cell metabolism increase oxidative stress in cancer patients. This stress is combated by the intrinsic antioxidants of the body including vitamin C. It is seen that patients with cancer have low levels of vitamin C in their bodies. This is because uncontrolled oxidative stress in cancer leads to high consumption of intrinsic body reserves resulting in vitamin C depletion. If not replenished duly, this deficiency eventually leads to the unopposed production of reactive oxygen species (ROS). The gut mucosa and the neural tissues, being the most sensitive to ROS, are affected the most. This leads to mucosal irritation of the gastrointestinal tract causing symptoms of nausea, vomiting, and loss of appetite. The neural irritation may trigger mental disorders including insomnia, tumor pain, and fatigue. Thus, replenishment of the intrinsic reserve by parenteral vitamin C administration may help combat the unopposed ROS production and play a vital role in alleviating cancer symptomatology, and hence QoL in these patients, as witnessed in our current study.
This explanation may be somewhat simplistic; moreover, the new study is far from flawless, and the totality of the evidence seems less than compelling. Nonetheless, the subject is, in my view, interesting and would seem to deserve further rigorous study.
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The authors suggest that the symptomatic improvements seen in the vitamin C treated group might be due to correction of a deficiency that was making them more susceptible to the symptoms examined. However, they don’t seem to have measured any vitamin C levels, either at the start of the trial or at any other time, to establish whether this was actually the case.
The methods section gives very little detail at all about how the trial was conducted or the treatment administered. We are told:
“The study group was randomized to receive 25 grams per week of IVC at a rate of 15 grams per hour for four weeks in addition to their current standard treatment”
What does this mean? Were they given a single weekly dose of 25 grams over 100 minutes, or was it 5 grams daily on weekdays over 20 minutes or something else entirely. How did the timing of the vitamin C infusion relate to their conventional cancer treatment? Was it the same day as chemotherapy? Was it before or after radiotherapy?
What chemotherapy regimens were used? Was it the current gold standard of FEC+docetaxel, or perhaps the older and much cheaper (and less toxic) CMF? What about radiotherapy – what was the dose and the scheduling? Vitamin C might be expected to have a greater effect with a hypofractionated protocol.
In fact it seems rather odd to me that about 75% of patients in the trial received chemotherapy but only 30% received chemotherapy. This suggests that either breast-conserving surgery in combination with radiotherapy was not routinely used (this has been the gold standard for my entire career, replacing mastectomy except for those patients where a lesser operation is not possible) or else radiotherapy was not given to patients who should have had it. Either way the oncology treatment seems to have been rather sub-optimal.
This is worrying in itself, since we are told that the 350 or so patients in the trial were undoing adjuvant treatment, which means that the intention was long-term cure.
Much more worrying, however, is the known interaction between free radical scavenging antioxidants and radiation. Radiotherapy works by ionising oxygen atoms to generate oxygen free radicals. These then react with cellular DNA, damaging it and ultimately leading to cell death; normal cells can repair the damage quite effectively, but cancer cells have lost this capability on the way to becoming malignant in the first place, which is why radiotherapy is a useful treatment. However, in the absence of oxygen, radiotherapy loses much of its effect, and approximately three times the dose is required in order to achieve the same level of cell kill. This is a problem with all radiotherapy as tumours on the whole have a poor blood supply, with many of their constituent cells being short of oxygen, and a lot of radiotherapy research has been into ways of getting around this problem. In the case of adjuvant radiotherapy, the visible tumour has already been removed surgically, and the radiation is given to kill any remaining cells in the surrounding tissue which are likely to be well enough oxygenated; fractionating the radiotherapy (i.e. dividing it into many doses) also improves that chance that cells that are hypoxic one day will be better oxygenated on another, as well as facilitating better DNA repair in non-malignant cells.
If the high-dose intravenous vitamin C as given in this protocol is a good scavenger of free radicals, then effectively it will reduce the radiotherapy dose. It would be no surprise, then, that treatment-related symptoms are improved. However, even a slight reduction in radiation dose has quite a large impact on the number of malignant cells killed, so my worry is that any improvement in side-effects comes at the expense of the benefits of giving radiotherapy in the first place.
The authors don’t seem to have considered this question at all. At the very least it seems to me that they should have made arrangements for long-term follow-up to see if the cancer recurrence rates differ between the treatment and the control groups. Although it will be decades before any differences become apparent, it is nevertheless unethical given the possibility that the study intervention may have compromised their subjects’ cancer treatment. Indeed, I wonder whether any mention of this was made in the consent forms.
Nor have they made any attempt to analyse their results according to what cancer treatment was given. Radiotherapy and chemotherapy are quite different from each other and to lump them together in this way makes no sense. In particular, if the stated benefits of vitamin C were greater with radiotherapy than with chemotherapy this would be particularly worrying given its radioprotective effect. Of course such subgroup analysis after the fact (as opposed to being written into the protocol) is fraught with danger as it is very prone to generating spurious chance correlations. Though the authors seem to have erred in the other direction and not even given enough demographic information for us to judge whether the two groups were matched with regard to age and co-morbidity, for instance.
I am not familiar with Cureus as a journal. It claims to be peer-reviewed, but that its review process is both crowdsourced and post-publication. They say this removes barriers and delays to the dissemination of medical knowledge, though I’m not sure that this is necessarily an advantage if the research is of poor quality.