Open Access

Total lymphocyte count in cancer patients with lymphopenia treated with intravenous vitamin C: Results of an observational study

  • Dolores Margarita Rodríguez1Email author,
  • Mery Elizabeth Guerrero1,
  • Bárbara Marisol Maldonado1,
  • Claudia Vollbracht2, 3 and
  • Sandra Aracely Herrera1
Translational Medicine Communications20172:3

https://doi.org/10.1186/s41231-017-0012-x

Received: 5 July 2016

Accepted: 16 February 2017

Published: 10 March 2017

Abstract

Background

Lymphopenia commonly occurs in cancer patients and predicts poor prognosis. It is caused by radio- and chemotherapy, with malnutrition and treatment-related oxidative stress playing key roles in its pathogenesis. Tumour-related morbidity is reported to be associated with reduced plasma ascorbate, which is a key physiological antioxidant and essential factor in immune function.

Method

A prospective observational study was conducted on 48 cancer patients with lymphopenia (<1500/μL) to investigate the total lymphocyte count (TLC) during four weeks of elective adjuvant treatment with intravenous (iv) vitamin C 7.5 g (Pascorbin®7.5 g) once a week. TLC values at baseline (just prior to start of treatment) and after 4 weeks treatment were compared using descriptive statistics.

Results

After 4 weeks iv vitamin C 7.5 g, TLC increased by a mean of 211/μL (p = 0.0018). Subgroup analyses showed that, in patients with severe lymphopenia (n = 25) (TLC <1000/μL), the increase in TLC was greater with a mean rise of 368/μL (p = 0.0004), than in patients (n = 23) with an initial TLC of 1000–1500 (mean rise of 40/μL) (p = 0.6105). TLC increased by at least 240/μL in half of the patients with severe lymphopenia and by more than 610/μL in 25% of patients.

Conclusion

Our data indicate that iv high-dose vitamin C treatment increases TLC, which strongly implies improvement of immune function, especially in patients with severe lymphopenia. Appropriately-powered, randomized, placebo-controlled trials of iv high-dose vitamin C are now needed to define more precisely its role in the treatment of cancer-related lymphopenia and how this impacts on the patients’ clinical prognosis.

Keywords

AscorbateLymphopeniaTLCNeoplasms

Background

Severe treatment-related hematological toxicities, such as lymphopenia, occur commonly in many cancers [1]. Drastically reduced TLC increases the risk of various forms of infections [2]. Recent studies reveal an association of post-treatment lymphopenia and decreased survival in patients with solid tumours who underwent chemo- or radiotherapy [1, 35]. Adjuvant treatment options are needed to restore this reversible prognostic factor.

Ascorbate, the absorbed form of dietary vitamin C, is an essential factor for immune cells and enhances the immune system in many ways [6, 7]. It enhances leukocyte function and innate immune responses via modulation of chemokinesis and chemotaxis [8]. Leukocytes actively accumulate ascorbate to achieve intracellular concentrations that exceed plasma concentrations by up to 80-fold [9].

Cancer patients are often reported to be vitamin C deficient [1018]. Particularly serious are the deficiencies in patients with advanced cancer [15, 19, 20], where decreased plasma ascorbate levels are associated with shorter survival and impaired quality of life [21].

Intravenous (iv) instead of oral administration of ascorbate is required in order to achieve the high plasma concentrations [22] that have been shown to have potential therapeutic effects [23, 24]. Ten years ago, high dose vitamin C (as sodium ascorbate) was found to have selective tumour cytotoxic effects [25] and its chemotherapeutic potential is still undergoing investigation [26]. Several phase I/IIa studies examined the chemotherapeutic effects of iv high-dose vitamin C as an adjuvant to standard treatment in patients with advanced tumours [2729]. Another potential benefit of iv vitamin C treatment is the favourable effect on the quality of life of cancer patients [3032]. Although iv high dose vitamin C is a popular complementary treatment in the management of cancer conditions [23, 24, 33], there is, as far as we are aware, no published data on its effects on lymphopenia.

The aim of this observational study was the evaluation of the effects of iv high-dose vitamin C on lymphopenia in cancer patients.

Methods

The objective of this prospective observational study was to document the use of Pascorbin® 7.5 g (licensed, proprietary medicinal product containing 7.5 g ascorbate for iv infusion; license owner: Pascoe Pharmazeutische Präparate GmbH, Germany) in patients with advanced cancer and lymphopenia, and to monitor its effect on their TLC. Data were collected from those cancer patients attending the ambulatory service of the Clinical Nutrition Department at SOLCA Cancer Hospital, Guayaquil, Ecuador, from February 2012 to October 2014, and who received elective iv ascorbate treatment as an adjuvant to tumour therapy. It was the physicians’ decision to use the infusion in accordance to the indication as an adjuvant to tumour therapy with the aims of to speed up postoperative recovery, to reduce the side effects of conventional oncological therapy (such as chemotherapy, radiotherapy), to reduce periods of hospitalization, to prolong the tumour- and recurrence-free intervals and to improve quality of life. As lymphopenia is a chemotherapy or radiation related hematological side effect, the treatment with iv vitamin C is covered by the approved indication.

The study included 48 cancer patients (aged ≥18 years) with lymphopenia, defined as a TLC below 1500/μL blood [2, 34]. Diagnosis of cancer was previously confirmed and documented by the attending physician. Malignant neoplasm of cervix uteri (n = 11) was the most common (22.9%) cancer documented in the study group, followed by breast cancer (14.6%), with between 2.1 and 8.3% for other cancer types. The study was a non-interventional study aimed to document the routine clinical use of iv vitamin C. Patients agreed, in a signed statement, to study participation and to release of their data. The criteria for patient selection are listed in Table 1.
Table 1

Patient data eligibility criteria

Inclusion criteria

 Aged ≥18

 Vitamin C deficiency (due to the underlying cancer disease or treatment)

 Previously confirmed cancer diagnosis with previous or current radiation- and/or chemotherapy

 Total lymphocyte count <1500/μL

 Treatment with iv vitamin C 7.5 g once a week, for a total of 4 doses

 Patient's statement of agreement to use and publish their data for the observational study

Exclusion criteria (anamnestic)

 Patients who received colony-stimulating factor

 Patients not completing all four doses of iv vitamin C

 Oxalate-urolithiasis, nephrolithiasis

 Renal insufficiency

 Iron-storage disease (thalassemia, hämochromatosis, sideroblastic anaemia)

 Erythrocytic glucose-6-phosphate-dehydrogenase-deficiency

 Pregnancy and lactation

Once a week, patients received iv vitamin C 7.5 g (Pascorbin®), diluted in a suitable carrier solution, such as 100 mL NaCL 0.9%. Data were collected before the start of vitamin C treatment (visit 1, baseline) and after 4 weeks of treatment.

Total lymphocyte count (TLC)

The main study parameter was the change in TLC from baseline to 4 weeks. A quantitative multi-parameter automated hematology analyser (xn 3000 series, sysmex) was used for all patients to measure TLC in peripheral blood samples obtained by venipuncture. The one-sample t-test (two-sided, with α = 0.05) was used to test for significance of the mean change. Additional, separate analyses were carried out on data from patients with TLC of <1000/μL (severe lymphopenia) and patients with TLCs of 1000–1500 lymphocytes/μL before start of treatment. The statistical analyses were performed by an independent statistician.

Nutritional status

Due to the lack of an universally accepted definition of malnutrition, our classification of the nutrition status (Table 2) is based on a combination of patient’s body mass index (BMI) [35] together with a scored Patient-Generated Subjective Global Assessment (PG-SGA) [36], and the Nutritional Risk Screening (NRS) [37]. The BMI allows us to classify overweight or obese patients. Risk of malnutrion (BMI < 20.5) is defined by NRS and the combination of BMI with the PG-SGA allows us to differentiate further to mild, moderate or severe malnutrition.
Table 2

Baseline demographic and clinical characteristics of patients

Characteristics

Baseline/Visit 1 (n = 48)

Age, years mean ± SD; range

 Total

56.4 ± 15.7; 17–84

 Male

53.8 ± 15.4; 17–73

 Female

57.1 ± 15.9; 24–84

Sex, n (%)

 Male

10 (20.8%)

 Female

38 (79.2%)

Nutrition status, n (%)

 Normal

0 (0.0%)

 Risk of malnutrition

10 (20.8%)

 Mild malnutrition

3 (6.3%)

 Moderate malnutrition

17 (35.4%)

 Severe malnutrition

12 (25.0%)

 Overweight

2 (4.2%)

 Obesity Grade 1

4 (8.3%)

The safety of the vitamin C treatment was assessed by the attending physician in terms of adverse events and possible relatedness of such events to vitamin C treatment.

Results

A total of 48 patients (mean ± standard deviation of age, 56.4 ± 15.7 years; 79.2% female) with previously confirmed neoplasms were included in the study and all were included in our analysis. Of note, more than half of the patients (60.4%) displayed moderate or severe malnutrition (Table 2). The mean TLC increased significantly (p = 0.0018) from 902.0/μL (±414/μL) at baseline to 1113/μl (±466/μL) after 4 weeks treatment. This was a mean increase in TLC of 211/μL (±442/μL). In patients with <1000 lymphocytes/μL (severe lymphopenia), the mean increase at 4 weeks was 368/μL (±449/μL) (p = 0.0004) compared to an increase of 40/μL (±372/μL) (p = 0.6105) in patients with an initial TLC of 1000–1500 lymphocytes/μL (n = 23) (Table 3).
Table 3

Total lymphocytes count (TLC) at start and at end of treatment

 

TLC at start of treatment [cells/μL]

TLC at end of treatment [cells/μL]

Difference (end – start)[cells/μL]

probability estimatea

All patients n = 48

 Mean value ± SD;

 range

902 ± 414;

130–1499

1113 ± 466;

220–1135

211 ± 442;

−1110–1900

p = 0.0018

 25% Percentile

532.5

742.5

25.0

 50% Percentile (Median)

920.0

1135.0

115.0

 75% Percentile

1315.0

1440.0

395.0

Patients with severe lymphopenia (lymphocytes < 1000/μL) n = 25

 Mean value ± SD;

 range

551 ± 212;

130–960

919 ± 447;

380–2420

368 ± 449;

−110–1900

p = 0.0004

 25% Percentile

390.0

585.0

30.0

 50% Percentile (Median)

540.0

820.0

240.0

 75% Percentile

705.0

1180.0

610.0

Patients without moderate lymphopenia (lymphocytes 1000–1500/μL) n = 23

 Mean value ± SD

 range

1283 ± 161; 1000–1499

1323 ± 396;

220–1870

40 ± 372;

−1110–660

p = 0.6105

 25% Percentile

1120.0

1150.0

20.0

 50% Percentile (Median)

1320.0

1400.0

100.0

 75% Percentile

1180.0

1620.0

180.0

SD standard deviation

aThe one-sample t-test (two-sided) with α = 5% was applied for statistical testing of the null hypothesis that the mean changes between start and after 4 weeks of treatment are equal to 0

Patients in our study group who were at risk of malnutrition or mild malnutrition had initial TLC values of >1000/μL (mean TLC 1046.9/μL and 1270.0/μL, respectively), whereas the initial mean TLC in patients with moderate or severe malnutrition was <1000/μL (846.5/μL and 774.2/μL, respectively) (Table 4, Fig. 1). TLC at begin and at end of treatment for each patient are available in Table 5.
Table 4

Mean total lymphocytes counts (TLC) for patients of differing nutritional status

Nutrition status

Lymphocytes before therapy mean [cells/μL]

Lymphocytes after therapy mean [cells/μL]

Difference in Lymphocytes mean [cells/μL]

Normal = 0

Risk of malnutrition n = 10

1046.9

1334.0

287.1

Mild malnutrition n = 3

1270.0

1096.7

−173.3a

Moderate malnutrition n = 17

846.5

1013.5

167.1

Severe malnutrition n = 12

774.2

1013.3

239.2

Overweight n = 2

615.0

1620.0

1005.0

Obesity Grade 1 n = 4

1025.0

1035.0

10.0

Valid data

48

48

48

Missing data

0

0.0

0

anegative values means a decrease of lymphocytes

Fig. 1

Total lymphocytes count (TLC) before and after 4-week iv high-dose vitamin C treatment. The Box Plot displays the data of the study group with initial TLC < 1000 μL. Vertical bar indicates standard deviation, box indicates 25%, median, 75% percentile

Table 5

TLC at begin and end of treatment for each patient

Lymphocytes at begin

Lymphocytes at end

Lymphocytes - Difference (post - pre)

Lymphocytes - status

1430

1450

20

≥1000

1330

220

−1110

≥1000

880

1460

580

<1000

520

2420

1900

<1000

1499

1620

121

≥1000

1300

1400

100

≥1000

680

920

240

<1000

700

740

40

<1000

1250

1320

70

≥1000

1440

1620

180

≥1000

1350

1630

280

≥1000

1130

460

−670

≥1000

420

880

460

<1000

810

770

−40

<1000

1410

1330

−80

≥1000

550

1280

730

<1000

130

510

380

<1000

1060

910

−150

≥1000

290

1030

740

<1000

1490

1580

90

≥1000

440

1080

640

<1000

660

680

20

<1000

960

1060

100

<1000

1120

1230

110

≥1000

580

750

170

<1000

1420

1710

290

≥1000

760

1310

550

<1000

370

380

10

<1000

1080

1690

610

≥1000

280

1410

1130

<1000

830

720

−110

<1000

630

1290

660

<1000

1250

1380

130

≥1000

1030

1180

150

≥1000

1000

1120

120

≥1000

1420

1670

250

≥1000

530

570

40

<1000

1100

1150

50

≥1000

380

400

20

<1000

490

510

20

<1000

710

820

110

<1000

400

440

40

<1000

540

940

400

<1000

1210

1870

660

≥1000

1320

1400

80

≥1000

1450

1500

50

≥1000

1420

990

−430

≥1000

240

600

360

<1000

In the study group, no adverse effects related to iv vitamin C were observed.

Discussion

Our non-interventianal study provides evidence that iv high-dose vitamin C reverses lymphopenia in cancer patients. We included radiotherapy- or chemotherapy-treated cancer patients with a TLC of <1500/μL, which was our definition of lymphopenia [2]. The data indicated a significant increase in the mean TLC value for the whole group while a subgroup analysis revealed a more significant effect in patients with a TLC of <1000/μL.

Several published reports suggest that lymphopenia is a reversible, predictive factor for earlier tumour progression/relapse and reduced survival, as indicated in several retrospective studies [35, 38, 39]. Poor prognosis of cancer patients is indicated by a TLC value of <1000/μL [39] [38] and is more evident with TLC values of <500/μL [3, 5]. More than 35% of our patients with an initial mean TLC of 551/μL (±212) had a TLC of >1000/μL after 4 weeks of iv vitamin C treatment. Given the increased risk of progression and mortality in severe lymphopenia, a TLC increase to >1000/μL is a clinically relevant and significant improvement.

The reasons for lymphopenia can be diverse [40]. In our study group, it is presumably lymphocyte depletion primarily due to radiotherapy and chemotherapy [40]. Severe stress, malnutrition and protein-energy under-nutrition can also cause lymphopenia [2]. Moderate-to-severe malnutrition was evident in more than half of the patients (60.4%) in our study group and was probably a contributory factor to the lymphopenia. The small size of our study group may explain the absence of statistical significance of any association between nutritional status and lymphocyte counts at the start of treatment. However, we did observe a correlation between risk of malnutrition and lymphopenia in our study group (Table 4 and Fig. 1).

The beneficial effect of iv vitamin C on TLC values in cancer patients is most likely due to its antioxidant actions counteracting treatment-induced oxidative stress. This was also suggested to explain the positive clinical effects of iv high-dose vitamin C observed in other cancer patients [29, 30, 41]. Oxidative stress is considered to be an underlying cause of lymphopenia of different etiologies [42], such as that caused by intensive exercise [43], end-stage renal disease patients [44] and AZT (3′-azido-2′,3′-dideoxythimidine) (an AIDS treatment). This notion is supported by animal data showing that high-dose antioxidants abrogate experimentally-induced lymphopenia [45].

A contributory factor for the favourable effect of vitamin C could be its function as a cofactor in the synthesis carnitine [46], which supports immune cell function, s predominantly through carnitine-dependent energy metabolism of fatty acids. Carnitine deficiency has been demonstrated in patients with impaired immune responses [47]. The ability of vitamin C to increase endogen carnitine synthesis and thereby improving energy metabolism is supported by animal data [46].

The supportive effect of iv vitamin C on the immune system that we have observed is supported by other published findings (such as, stimulation of natural killer cell activity by high dose vitamin C [48]). Furthermore, our data may relate to the increased quality of life and prolonged survival time observed in in phase I/IIa clinical trials of cancer patients treated with iv vitamin C [28, 29].

Intravenous high-dose vitamin C treatment was well tolerated by our patients, which is consistent with data from other clinical studies and comprehensive clinical surveys indicating the good tolerability of iv high-dose vitamin C up to 0.5 g/kg body weight (in phase-I-trials even up to 1.5 g/kg) when contraindications are complied with [23, 27, 33, 49, 50].

As we are aware, our study provides the first evidence that iv high-dose vitamin C treatment improves the immune status of cancer patients treated in daily clinical practice, and that the treatment is well-tolerated by this patient group. However, the clinical interpretation of our data is limited by the absence of a control group and the small size of our study group.

Conclusion

This study provides “real-life” observational evidence of the use of iv high-dose vitamin C in daily practice in the treatment of cancer patients with lymphopenia. Patients with severe lymphopenia seem to particularly benefit from iv vitamin C with a clinically significant increase in TLC. Appropriately-powered, randomized, placebo-controlled trials of iv high-dose vitamin C are now needed to define more precisely its role in the treatment of cancer-related lymphopenia and how this impacts on the patients’ clinical prognosis.

Abbreviations

iv: 

Intravenous

NIS: 

Non-interventional stud

TLC: 

Total lymphocyte count

Declarations

Acknowledgements

The authors thank Professor Gerard Patrick McGregor PhD (OmniScience SA) for his scientific editing of the manuscript.

Funding

Laboratory determination of TLC was part of routine labor. Charges for the independent statistician and the language editing service as well as the article-processing charge for the open-access journal were sponsored by Pascoe Natural Medicine, Germany.

Availability of data and materials

TLC at begin and at end of treatment for each patient are available in Table 5 without patient number, because of data protection purposes.

Authors’ contributions

DRV conceived and initiated the study and carried out data evaluation. GTM, MMV, and SHM participated in study design, coordination and data evaluation. CV drafted the manuscript and participated in data evaluation. All authors read and approved the final manuscript. The statistical analyses were performed by an independent statistician (Gesellschaft für Therapieforschung mbH, www.gkm-therapieforschung.de, Munich, Germany).

Competing interests

DRV, GTM, MMV, and SHM declare that they have no competing interests and received no funding for this observational study. CV is employed by Pascoe Pharmazeutische Präparate GmbH (Giessen, Germany).

Consent for publication

Not applicable.

Ethics approval and consent to participate

The objective of this prospective observational study was to document the use of an authorized medicinal product. Data were collected from those cancer patients who received elective iv ascorbate treatment as an adjuvant to tumour therapy (non-interventional study; NIS). Because this type of study documents the effects of medical routine without given intervention an ethics committee vote is not necessary. According to the ICMJE definition of a clinical trial purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator) will not require registration.

Patients agreed with the study participation and data processing, which was assured by a signed statement.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Clinical Nutrition Department, SOLCA Cancer Hospital
(2)
Hochschule Fresenius, University of Applied Sciences
(3)
Pascoe Pharmazeutische Präparate GmbH

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