Background

Intravenous vitamin C (IV vitamin C) is used as an adjunctive therapy that contributes to antitumor effects by increasing immunity while reducing the side effects of anticancer therapy (nausea, vomiting, decrease in the number of white blood cells, decreased immunity, stomatitis, diarrhea, etc.) in cancer patients. However, the Group of Public Involvement in NECA (PIN) found that unconfirmed information of IV vitamin C has been spreading via digital media, which could cause confusion to patients and their families. Thus, the aim of this review is to evaluate the effectiveness and safety of IV vitamin C in cancer patients.

Methods

We conducted, overview of Systematic Reviews (SRs) to evaluate the scientific evidence of IV vitamin C in cancer patients. All assessment methods were finalized after review by the Effectiveness and Safety of IV Vitamin C in Cancer Patients Sub-committee (hereinafter Sub-committee) in consideration of the purpose of the assessment.

The key question was “Is IV vitamin C clinically safe and effective in cancer patients?” and literature search was performed from 3 international databases and 5 domestic databases. Two reviewers independently selected SRs according to the predefined inclusion/exclusion criteria, assessed risk of bias with. A MeaSurement Tool to Assess Systematic Reviews-2 (AMSTAR 2) and performed data extraction. For data analysis, qualitative review was performed and conclusion was determined via discussion with the Sub-committee.

Results

A total of 5 SRs were included in the analysis. Van Gorkom et al. (2019) and Fritz et al. (2014) demonstrated “moderate” risk of bias, Jacobs et al. (2015) had “low”, and Hoppe et al. (2021) and Nauman had “very low”, respectively.

Safety

IV vitamin C-related toxicity included osmotic load, headache, dizziness, and temporary nausea due to dry mouth, which were generally mild symptoms. In controlled studies, there was no report of adverse events that occurred more frequently than the control group. However, in Phase 1/Phase 2 clinical trials and case reports, serious adverse events (SAEs) such as kidney stones, hypokalemia, and hypernatremia were reported. In all of the five SRs, adverse events due to IV vitamin C were mild, and accordingly, it was reported to be safe. 

Effectiveness

The effectiveness of IV vitamin C in cancer patients was largely divided into anticancer effects and supplementary effect to anticancer treatment. Anticancer effect was examined based on the survival rate and tumor response rate and the supplementary effect to anticancer treatment was evaluated based on quality of life (QoL) and the effect on adverse events to anticancer therapy. In addition, drug interactions between IV vitamin C and chemotherapy were reviewed.

① Anticancer effect

There were two randomized controlled trials (RCT) that reported on survival rates. In the case of overall survival (OS), Ma et al. (2014) reported no significant difference depending on IV vitamin C administration, whereas Zhao et al. (2018) reported prolonged OS in the intervention group compared to the control group. Among the five SRs, two articles, van Gorkom et al. (2019) and Fritz et al. (2014), reported a positive trend in relation to the survival rate according to IV vitamin C. However, in the other three SRs (Hoppe et al., 2021; Nauman et al., 2018; Jacobs et al., 2015), the evidence of a positive effect of IV vitamin C on survival time could not be confirmed or the findings were inconsistent.

There was one RCT that reported on the response rate (Zhao et al., 2018), and the complete remission rate was significantly higher in the intervention group including IV vitamin C after the first cycle of anticancer therapy compared to the control group. After the second cycle, however, the difference between groups in complete remission rate disappeared.

In other single-arm studies, tumor response was reported in patients receiving combined therapy of IV vitamin C and chemotherapy, but the results were inconsistent and it was difficult to determine whether the effect was due to IV vitamin C administration. All four SRs that examined the response rate reported that the effect of IV vitamin C on the improvement of the tumor response rate could not be confirmed.

② Supplementary effect to anticancer treatment

Regarding the effect on QoL and anticancer therapy-related adverse reactions, Jeon et al. (2016) reported in their RCT study that when IV vitamin C was administered before laparoscopic colectomy, postoperative pain at rest was decreased compared to the control. In another controlled study by, Vollbracht et al. (2011) reported that a combination of radiotherapy/chemotherapy and IV vitamin C showed decrease in the adverse events from the anticancer treatment, such as nausea, loss appetite, fatigue, depression, sleep disorders, dizziness, etc. compared to the control group. Among the four SRs that examined the effect on QoL and adverse effects of anticancer treatment, van Gorkom et al. (2019), Hoppe et al. (2021), and Jacobs et al. (2015) argued that the level of evidence is low and therefore it was not available to conclude that IV vitamin C had a positive effect on improvement of quality life or reduction in adverse events from anticancer therapy. However, Fritz et al. (2014) reported that IV vitamin C had a positive effect on maintaining or improving the QoL of patients.

③ Drug interactions

Fritz et al. (2014) reviewed, the interactions between IV vitamin C and other anticancer agents. When IV vitamin C was used in combination with anticancer agents such as gemcitabine, paclitaxel, carboplatin, and erlotinib, there was no toxicity related IV vitamin C occurred, while adverse effects of chemotherapy were reduced. Fritz et al. (2014) suggested that the evidence for drug interactions with IV vitamin C in cancer patients is limited and that further study is necessary. Also, in the Sub-committee, there was a discussion on whether IV vitamin C reduces the efficacy of bortezomib, but this was not confirmed in the SRs included.

Conclusion and Suggestions

In this report, the safety and effectiveness of IV vitamin C in cancer patients were examined through an overview of SRs. However, it was difficult to draw a definitive conclusion due to the heterogeneity of the patient, treatment regimen (combination or monotherapy, dosing, etc.) of the intervention group, and the dose regimens of IV vitamin C.

As a result, IV vitamin C-related toxicity in cancer patients was generally mild, and there were no adverse events that occurred more frequently than in the control group in the controlled studies. Although serious adverse events including kidney stones, hypokalemia, and hypernatremia, have been reported, all of the five SRs demonstrated that the adverse events of IV vitamin C were mild, and the Sub-committee determined it generally safe as well. 

The effectiveness of IV vitamin C in cancer patients was categorized into anticancer effect, indirect supplementary effect to anticancer treatment, and drug interactions. As a result of the anticancer effect of IV vitamin C based on survival rate and tumor response rate, 2 out of 5 SRs reported that survival rate showed a positive trend with IV vitamin C. In 4 SRs, it was reported that the effect of IV vitamin C on tumor response rate could not be confirmed. For supplementary effects to anticancer treatment, 3 out of 4 SRs reported that a definitive conclusion on the positive effect of IV vitamin C on improving QoL or decreasing adverse effects of anticancer treatments could not be drawn. Drug interactions were examined in one SR, and it was reported that at present, the evidence of drug interactions to IV vitamin C in cancer patients was limited, and further research was necessary. 

Accordingly, the Sub-committee determined that IV vitamin C was relatively safe with little known toxicity in cancer patients. Regarding effectiveness, the following was determined: First, there was insufficient evidence to support that IV vitamin C improves the survival time or tumor response rate of cancer patients. Second, there was insufficient evidence to draw a conclusion of the effect QoL or adverse effects of anticancer therapy. 

Based on the review by the Sub-committee, the 4th Health Technology Reassessment Committee in 2021 (April 15, 2022) drew the following conclusion regarding “Effectiveness and Safety of Intravenous Vitamin C in Cancer Patients” in accordance with Article 4, Paragraph 10 of the Health Technology Reassessment Guideline: 

Although IV vitamin C is relatively safe with low known toxicity in cancer patients, there is insufficient evidence to support the effects of IV vitamin C on survival time or tumor response rate, and to conclude that IV vitamin C improves QoL or adverse effects from anticancer treatments. 

Based on the results, information notice for the public was separately prepared and provided to support rational and scientific choices on healthcare for general public. 

Keywords

Neoplasms, intravenous Vitamin C injection, Ascorbic Acid, Safety, Effectiveness

요약문 (국문) i

알기 쉬운 의료기술재평가 I

Ⅰ. 서론 1

 1. 평가배경 1

  1.1 평가대상 의료기술 개요 1

  1.2 질병 특성 3

  1.3 국내외 임상진료지침 3

  1.4 체계적 문헌고찰 현황 3

  1.5 일차연구 5

  1.6 평가대상 의료기술의 국내외 보험 및 행위등재 현황 6

 2. 평가목적 8

Ⅱ. 평가 방법 9

 1. 체계적 문헌고찰 9

  1.1 개요 9

  1.2 핵심질문 9

  1.3 문헌검색 10

  1.4 문헌선정 11

  1.5 비뚤림위험 평가 11

  1.6 자료추출 12

  1.7 자료합성 12

  1.8 근거수준 평가 12

Ⅲ. 평가결과 13

 1. 문헌선정 결과 13

  1.1. 문헌선정 개요 13

  1.2. 선택문헌 특성 14

  1.3. 비뚤림위험 평가 18

  1.4. 선택문헌의 비교 18

 2. 검토 결과 23

  2.1. 안전성 23

  2.2. 효과성 30

  2.3. 국내 문헌 47

Ⅳ. 결과요약 및 결론 50

 1. 평가결과 요약 50

  1.1 안전성 50

  1.2 효과성 50

  1.3 고찰 및 향후 전망 52

 2. 결론 52

 3. 대국민 정보문 54

Ⅴ. 참고문헌 56

Ⅵ. 부록 60

 1. 의료기술재평가위원회 60

 2. 소위원회 61

 3. 문헌검색현황 62

 4. 비뚤림위험 평가 및 자료추출 양식 68

 5. 최종선택문헌 72