Table 4.

Characterization of the included studies with lower level of evidence

References	Diagnosis	N	Concurrent therapy	Endpoints	Dose	Results
Bruemmer et al. (2003)	Breast cancer, leukemia, myelodysplastic syndrome	1 182	Radio- and/or chemotherapy	1. Non-relapse mortality	0.03–12.5 g every day, oral	1: ALL and AML: At dose ≥ 500 mg daily, significant increase compared with no intake: RR (95% CI): 2.25 (1.33–3.83), p = 0.01
				2. Relapse		2: Mamma carcinoma: With a dose of ≥ 500 mg per day less relapse compared to no intake: RR (95% CI): 0.11 (0.02–0.89), p = 0.03
				3. Mortality or relapse		3: Mamma carcinoma: With a dose of ≥ 500 mg per day less relapse or mortality: RR (95% CI): 0.41 (0.17–1.02), p = 0.04; ALL and AML: At doses < and ≥ 500 mg daily, significant increase:  < 500 mg/day: RR (95% CI): 1.40 (1.03–1.92), ≥ 500 mg/day: RR (95% CI): 1.63 (1.09–2.44), p = 0.01
Gunes-Bayir and Kiziltan (2015)	Different types of cancer with bone metastases	39	Radiotherapy	1. Pain	2.5 g 1 h daily, intravenous	1: Vitamin C arm: 1 × complete relief, 3 × no change, 7 × 50–80% relief, 2 × slight relief, 2 × increase in pain; Chemotherapy arm: 3 × no change, 2 × 50–80% relief, 4 × slight relief, 6 × increase in pain; Control arm: 100% increase in pain
				2. PS (ECOG: 0–5)		2: Vitamin C arm: before treatment (T0): PS = 3, increase in PS in 4 out of 15 cases after treatment (T1), otherwise no change; Chemotherapy arm: T0: PS = 4, T1: Improvement in 1 person, 14 without change; Control arm: T0: PS = 4, T1: in all 9 no change
				3. OS		3: Vitamin C arm: median: 10 months, range: 2–36 months; Chemotherapy arm: median: 2 months, range: 1–10 months, p < 0.001; Control arm: median: 2 months, range: 1–6 months
Hoffer et al. (2008)	Different types of cancer	24	No	1. Toxicity	0.4, 0.6, 0.9, .5 g/kg, intravenous, 3 times a week, for 4 weeks	1: Only mild side effects Grade 1 or 2
				2. Tumour response		2: No patient with an objective response of the tumour—all with progression, 2 × in 0.6 g/kg arm with stable disease
				3. QoL		3: In 0.4 g/kg arm deterioration in physical function: MV: 5.4 (SD = 4.2) vs. MV: 13.4 (SD = 1.1), p < 0.01; No deterioration in the higher dose groups
Hoffer et al. (2015)	Different types of cancer	14	Chemotherapy	1. Toxicity	1.5 g/kg body weight, 90 min at dose up to 90 g and 120 min at dose > 90 g, 3 × every week during chemo, otherwise every 2 days, intravenous	1: No side effects due to vitamin C
				2. Tumour response		2: 2 × very severe courses (probably unrelated to vitamin C), 6 × no change, 6 × temporary stabilization, but not long lasting, 3 × better course than expected
Kawada et al. (2014)	Non-Hodgkin lymphoma	3	Chemotherapy	1. Toxicity	15 g (0.5 g/min) on the first day, then 75 g (1 g/min), intravenous, 6 days	1: Good tolerated, no obvious side effects
Kiziltan et al. (2014)	Different types of cancer with bone metastases	11	Palliative Radiotherapy	1. Pain	2.5 g in 1 h, intravenous, 1-week intervals with 3–10 infusions	1: 48.5% reduction of pain (SD = 39.7), median: 55%, 6 × 50–100% reduction, 1 × 25% reduction, 2 × no change, 2 × aggravation
				2. PS		2: 1-year survival: 45%, 2-year survival: 17.5%
				3. Toxicity		3: 40% Grade 1 gastrointestinal toxicity, 30% Grade 1 urinary toxicity
Monti et al. (2012)	Pancreas carcinoma	9	Chemotherapy with gemcitabine or erlotinib	1. Toxicity	50 g, 75 g, 100 g per infusion, intravenous, 3 times a week, for 8 weeks	1: mild lightheadedness or nausea, 8 of 23 side effects were serious and likely due to disease progression or treatment
				2. Tumour response		2: 8 of 9 patients showed a reduction in primary tumour, 7 with stable disease, 2 with progressive disease
				3. PFS		3: MV: 89 days (SD = 77)
				4. OS		4: MV: 182 days (SD = 155)
Nielsen et al. (2017)	Prostate cancer	23	No	1. ≥ 50% PSA-level reduction	1st week: 5 g, 2nd week: 30 g, 3.-12. week: 60 g, 1 × every week, intravenous, 500 mg, oral, for 26 weeks	1: No patient achieved a 50% reduction, 75% increase in the PSA level, increase by 17 µg/L, 5 × lower PSA value than at baseline (> 2 µg/L)
				2. QoL		2: 16 × with no change, 2 × improved, 2 × worsened; changes after 12 weeks only in the physical functional level, otherwise no improvements
				3. Toxicity		3: 5 × no side effects, 4X only one side effects—in total 53 side effects (11 severe): hypertension, anaemia, pulmonary embolism
Park et al. (2009)	Leukemia, myelodysplastic syndrome	18	No	1. Toxicity	10 g-60 g/m2 for 2 h every day, intravenous	1: Grade 1 or 2 side effects, 1 × Grade 3 fatigue
				2. Tumour response		2: 8 × good response to therapy (1 × complete remission with incomplete recovery of the blood count, 6 × hematological reaction, 1 × hematological improvement)—8/18 (44%)
Pinkerton et al. (2017a)	Different types of cancer	17	Adjuvant therapy	1. Pain: opioid dose	1 g 2 × every day, oral, for 3 days	1: Unchanged or increased
				2. Toxicity		2: 21 side effects, that were stronger than baseline—none attributable to vitamin C
Polireddy et al. (2017)	Pancreatic cancer	12	Chemotherapy with gemcitabine	1. OS	3 × every week, intravenous	1: 50% (6/12) survived longer than a year, 8.3% (1/12) survived longer than 2 years; median: 15.1 months
				2. PFS		2: 6 × progress of disease; median: 3 months
				3. Toxicity		3: 1st Grade nausea and thirst, all others unrelated to vitamin C
Riordan et al. (2005a, b)	Different types of cancer	24	No	1. Tumour response	150, 300, 430, 570, 710 mg/kg every day, intravenous, for 8 weeks	1: 1 × stabile disease, 23 × progression
				2. Toxicity		2: 2 × Intervention discontinued due to grade 3 and 4 side effects (2 of 4 related to vitamin C), majority of side effects grade 1 or 2 (especially nausea, dry skin/mouth, oedema, fatigue)
Stephenson et al. (2013)	Different types of cancer	17	No	1. Toxicity	30, 50, 70, 90 or 110 g/m2 on 4 consecutive days, intravenous, for 4 weeks	1: Good safety even at high doses, mostly mild side effects and only possible through treatment; nausea and headache in all cohorts
				2. Tumour response		2: No objective tumour response, 3 × stabile course, 13 × progressing disease
				3. QoL		3: Constant over the first 2 weeks, then improvement in the 3rd and 4th week
Tareen et al. (2008)	Prostate cancer	17	No	1. PSA velocity	500 mg + 5 mg vitamin K3, 10 × every day, oral, for 12 weeks	1: Decrease in PSA velocity in 13/17 (76%): Before treatment: 1.05 to 696 ng/ml/year (median: 21.6 ng/ml/year), during treatment: -12 bis 256 ng/ml/year (median: 6.39 ng/ml/year)
				2. PSA doubling times		2: Increase in PSA doubling time in 76% Before treatment: 2.0 to 54.4 months (median: 3.12 months), during treatment: -39 bis 57.1 months (median: 7.88 months)
				3. Toxicity		3: No side effects, no discontinuation of therapy
				4. Symptoms		4: Tendency to have fewer symptoms: Before therapy: 7.9, after 12 weeks: 7.2, p = 0.07
				5. Pain		5. Intermittent improvement followed by decline: Before therapy: 3.2, after 6 weeks: 2.3, after12 weeks: 3.2
Vollbracht et al. (2011)	Breast cancer	125 (53/72)	Chemo- or radiotherapy	1. Intensity of symptoms	7.5 g, intravenous, 1 × every week, for at least 4 weeks	1: Mean values of the intensity in arm A smaller than in arm B, during treatment (p = 0.013) and after (p = 0.021)
				2. PS		2: Higher PS in arm A than in arm B: During treatment: arm A: 80%, arm B: 71%, p < 0.001; after: arm A: 87%, arm B: 78%, p < 0.001; ECOG: during treatment: arm A: 1.596, arm B: 2.067, p = 0.002; after: arm A: 1.11, arm B: 1.71, p < 0.001
				3. Toxicity		3: No side effects (Safety: 86.8% excellent and 13.2% good)
Welsh et al. (2013)	Pancreatic cancer	9	Chemotherapy with gemcitabine	1. Toxicity	15 g, intravenous, for 30 min, increase dose, 1 × every week, for 4 weeks	1: No severe side effect (Grade 3, 4), nausea (6×) and diarrhoea (4×), thirst and dry mouth (4×)
				2. PS		2: 6 of 9 maintained or improved PS
				3. PFS		3: 26 ± 7 weeks
				4. OS		4: 13 ± 2 months

ALL acute lymphocytic leukaemia, AML acute myelogenous leukaemia, MV mean value, PS performance status, QoL quality of life, SD standard deviation