Micronutrients in Oncological Intervention.

1. Introduction

According to estimates from the International Agency for Research on Cancer (IARC), there were 14.1 million new cancer cases in 2012 worldwide, of which 8 million occurred in economically developing countries, which contain about 82% of the world’s population. The most common types of malignancy include colorectal cancer, lung cancer, and, depending on gender, breast or prostate cancer. The corresponding estimates for total cancer deaths in 2012 were 8.2 million. By 2030, the global burden is expected to grow to 21.7 million new cancer cases and 13 million cancer deaths simply due to the growth and aging of the population. However, the estimated future cancer burden will probably be considerably larger due to the adoption of lifestyles that are known to increase cancer risk, such as poor diet, physical inactivity, and smoking. Cancers related to these factors, such as breast, lung, and colorectal cancers, are already on the rise in economically-transitioning countries [ 1 , 2 ].

After a long period of stagnation, the conventional medical management of cancer has improved considerably in recent years, with better treatment outcomes and even prolonged survival in some forms of malignancy. New approaches with drug therapy has been mainly responsible for this, but improved diagnostic methods and radiotherapy techniques have also contributed. At the same time, the treatment of cancer has become more intensive and sometimes aggressive, with a corresponding increase in adverse reactions [ 3 , 4 ]. In parallel, the oncology patient’s needs for both gentle therapeutic procedures and complementary measures have increased greatly over the past 15 years. Today, many cancer patients take vitamins and other micronutrients (e.g., selenium, vitamin D) with the aim of improving their standard therapy or reducing the adverse effects of treatment and the underlying disease. Depending on the type of malignancy and the gender of the patient, 30%–90% of people with cancer supplement their diets with antioxidant and immune system stabilizing micronutrients, often without the knowledge of the treating physician [ 5 , 6 ].

Data collected between 2003 and 2010 within the Intergroup Phase III Breast Cancer Chemotherapy trial (S0221) found 48% of patients were taking multivitamins, 20% were taking vitamin C, D, and omega-3 fatty acids, 15% were taking vitamin E, B6, and folic acid, and 34% were taking calcium. Clinicians advised one third to start taking a supplement during treatment, 10% to stop taking one, and 7% to stop all except a multivitamin. 51% of all patients received no advice [ 7 ]. From the oncological viewpoint, there are justifiable concerns that dietary supplements decrease the effectiveness of chemotherapy or radiotherapy [ 5 , 7 , 8 , 9 , 10 ]. Recent studies, however, have provided increasing evidence of improved patient compliance, fewer adverse effects and, subsequently, a lower rate of treatment discontinuations, when selected micronutrients (e.g., selenium, l -carnitine, and vitamin D) are added as appropriate to the patient’s medication. There is a better response to the cancer therapy, which in turn improves the prognosis and also the patient’s quality of life [ 4 , 11 , 12 , 13 ]. The micronutrients used in complementary oncology have to be selected appropriately and taken at the right time so as not to reduce the effects of the cytoreductive therapy [ 4 , 5 , 11 ].

There is a need to develop an open and non-judgmental dialogue between oncologists and cancer patients, addressing the needs of the patient while dealing with issues related to the efficacy and safety of micronutrients. Referral of patients to an integrative medicine consultant may help achieve these goals, providing both parties with the option of reaching an informed and respectful decision about treatment. In this review article, we assess the value of specific micronutrients, with an overview of the latest publications and specific recommendations for clinical practice. The review is by no means exhaustive, but presents a selection of the latest findings on important micronutrients used in complementary oncology.

2. Malnutrition: The Overlooked Link to Micronutrient Deficiency

The success of treatment and healing processes in people with cancer are greatly influenced by the nutritional status of the patient. This is particularly relevant in clinical practice since, depending on the nature, site, and stage of the malignancy, 30%–90% of patients have an inadequate diet [ 14 , 15 ]. The most severe form of cancer-associated deficiency is seen physically as cachexia. It occurs especially in cases of bronchial, gastric, pancreatic, and prostate cancer ( Table 1 ) [ 16 , 17 ].

An inadequate diet has detrimental effects on the immune status and tolerance of treatment, as well as on various organ and metabolic functions. The effectiveness of measures intended to destroy the cancer (chemo- and radiotherapy) may be reduced, as well as the response to such therapy, while the rate of adverse effects and the risk of treatment-associated complications are increased. This in turn impacts the patient’s quality of life and the prognosis [ 9 , 15 , 17 ]. Cancer patients with deficient diets have a higher morbidity and mortality: the mortality in malnourished cancer patients is about 30% higher [ 18 , 19 , 20 , 21 , 22 , 23 ].

Up to 50% of cancer patients suffer from a progressive atrophy of adipose tissue and skeletal muscle, called cachexia, resulting in weight loss, a reduced quality of life, and a shortened survival time. Anorexia often accompanies cachexia, but appears not to be responsible for the tissue loss, particularly lean body mass [ 24 ]. The pathogenesis of cancer-associated malnutrition is multifactorial. In addition to the tumor’s direct consumption, anorexigenic mediators, as well as hormone- and cytokine-induced metabolic disorders also contribute. Pro-inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6), catabolic hormones (e.g., glucagon and cortisol), and catabolic proteins secreted by the tumors themselves (such as proteolysis-inducing factor, lipid-mobilizing factor, and zinc alpha-glycoprotein), all shift the metabolic equilibrium in the direction of muscle protein and fat breakdown ( Figure 1 ) [ 4 , 24 , 25 , 26 , 27 ].

Malnutrition affects not only the macronutrients that supply energy (carbohydrates, proteins, and fats) but also the biocatalytic and immunomodulating micronutrients. As macronutrients are the natural carriers of micronutrients, malnutrition is one of the main reasons that cancer patients have an inadequate micronutrient status [ 4 , 5 , 26 ].

According to the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines on enteral nutrition, it can be assumed that all patients with cancer who consume less than 60% of their daily energy requirements for more than 7–10 days have an inadequate supply of micronutrients [ 3 ]. In addition, the consumption and requirements for micronutrients may be increased by the adverse effects of chemo- or radiotherapy (e.g., vomiting, diarrhea, alterations in taste; Table 2 ) and inflammatory processes. Loss of appetite and aversion to particular foods as a result of anorexia also contribute to a micronutrient deficiency [ 4 , 18 , 27 ].

3. Micronutrient Status in Patients with Cancer

Even at the time of diagnosis and before there are any clinically-relevant changes in the nutritional status, but certainly after the start of treatment, the supply of various vitamins (e.g., vitamin D, vitamin C, and B-group vitamins) and trace elements (e.g., selenium, zinc) is worse in patients with cancer than in healthy people [ 5 , 25 , 28 ]. Supplies of immunomodulatory and antioxidant micronutrients (e.g., vitamin D, selenium, l -carnitine) and of those with little storage or reserve capacity (e.g., vitamin B1, vitamin C, folic acid, and vitamin K) are particularly critical [ 27 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ].

An inadequate supply of antioxidant micronutrients in patients with cancer is reflected, among other things, in raised markers of oxidative stress [ 29 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. Bleeding has also been reported in association with severe zinc deficiency in cancer patients with a poor nutritional status [ 46 ].

As cancer- and/or treatment-induced micronutrient deficiency impacts the course of disease and the effectiveness of cytoreductive measures, as well as increasing the risk of complications (e.g., impaired immunocompetence, delayed wound healing, fatigue, and depression), it is necessary to ensure that the patient has an optimal supply of immunostabilizing micronutrients, such as selenium and vitamin D, in addition to an adequate supply of energy substrates (proteins, fats, and carbohydrates). Together with nutrition therapy, the laboratory-validated administration of micronutrients appropriate to the patient’s cancer therapy is, therefore, becoming an important aspect of the concept of adjuvant and complementary oncological treatment [ 3 , 4 , 7 , 10 , 11 , 17 , 18 , 47 ].

4. Micronutrient Supplements for Patients with Cancer

Micronutrient deficiencies have, basically, a negative effects on the course of malignant disease and the efficiency of treatment intended to destroy tumors, as it impairs immunocompetence, increases the risk of complications, and impacts on the patient’s physical and mental quality of life [ 7 , 18 , 48 , 49 , 50 , 51 , 52 , 53 ]. The results of several studies have demonstrated the importance of micronutrients as adjuvants to nutrition therapy, and provided evidence that taking a multivitamin/mineral preparation can improve both the quality of life and the prognosis of patients with cancer.

A cohort study of 1129 patients with lung cancer, carried out at the Mayo Clinic (USA), showed that mortality was reduced by 26% in patients taking a micronutrient preparation compared with those not taking any such supplements (95% confidence interval (CI): 0.44–0.65; p < 0.01). The mean survival in patients taking micronutrients was 4.3 years compared with two years in patients not taking multivitamin/mineral supplements. Taking a micronutrient preparation was associated with a better quality of life (mean score difference of 3 (95% CI: 0.8–5.1; p < 0.01) [ 52 ].

In a study on patients with ovarian cancer, who were treated with cyclophosphamide and cisplatin, oral supplements with multiple antioxidants including selenium led to a significant improvement in the immune status and a reduction in the frequency of chemotherapy-induced adverse reactions. In addition to the basic cytostatic therapy, patients ( n = 31) were given an antioxidant combination consisting of 200 μg selenium, 800 mg vitamin C, 144 mg vitamin E, 60 mg beta-carotene, 18 mg vitamin B2, and 180 mg vitamin B3, in four divided doses, every day for three months. After three months, these patients had significantly higher serum selenium levels (130.23 ± 64.30 compared with 51.41 ± 18.21 μg/L) and greater erythrocyte glutathione peroxidase activity ( p < 0.0038) than controls who took no antioxidant supplements ( n = 31). The leucocyte count (e.g., neutrophil granulocytes) was also significantly higher in the group that had taken regular antioxidant supplements ( p < 0.0001). The incidence of adverse reactions to the chemotherapy, such as loss of appetite, nausea, vomiting, stomatitis, hair loss, flatulence, abdominal pain, weakness, and malaise, was significantly lower in the antioxidant group than in the control group. Neurotoxic symptoms from cisplatin occurred in one woman taking antioxidants and two women in the control group [ 54 ].

Antioxidant supplements during cancer therapy are still controversial, as the cytoreductive effects of radiotherapy and some cytostatic agents partially involve the formation of free radicals [ 7 , 10 , 53 , 55 , 56 ]. The vast majority of cytostatics used in treatment today—antimetabolites (e.g., methotrexate), nitrogen mustard derivatives (e.g., cyclophosphamide), platinum complexes (e.g., cisplatin), vinca alkaloids (e.g., vinorelbine), taxanes (e.g., paclitaxel), and anthracyclines (e.g., epirubicin)—do not primarily act through oxidative stress [ 57 , 58 ]. If antioxidants were definitely to reduce the efficiency of standard anticancer therapy, patients would not be allowed to consume any antioxidant- or phytamine-rich fruit and vegetables or green tea (rich in epigallocatechin) during the treatment phase. The often uncritical blanket renunciation of dietary supplements with effective antioxidant and immunomodulating micronutrients during chemotherapy is therefore not justified [ 59 ].

Antioxidative micronutrients such as vitamin C, vitamin E, retinoids, and selenium do not act merely as radical scavengers but have many essential metabolic functions in addition to the antioxidant cell protection. They have immunomodulating and apoptosis-inducing properties, as well as regulatory effects on cell proliferation and differentiation. In vitro , animal, and human studies have shown that antioxidants reduce cancer cell growth through a variety of mechanisms, including an increase in cell differentiation and apoptosis, as well as the inhibition of protein kinase C and adenylate cyclase activity in neoplastic cells [ 55 , 60 , 61 , 62 ].

A systematic review of controlled randomized trials on the effects of antioxidants on chemotherapy concluded that antioxidant supplements do not act detrimentally on chemotherapy, but rather have a beneficial effect on the rate of adverse reactions and the tumor response [ 63 ]. None of the studies examined in this review demonstrated a significant impact on chemotherapy. On the other hand, many studies showed that antioxidant supplements increased survival time, the tumor response, or both; they also reduced the rate of adverse reactions in comparison with control groups. These data were confirmed by the results of a further publication from the same group of authors in 2008 [ 11 ]. They used a standardized procedure to search the literature published between 1996 and October 2007 in the following databases: Medline, Cochrane, CinAhl, AMED, Alt-HealthWatch, and EMBASE. They included only those randomized controlled clinical trials that had data on the effects of antioxidants on chemotherapy-associated toxicity. Only 33 of the 965 articles examined, with 2446 participants, met the criteria. In particular, evaluation of these trials showed that antioxidant supplements taken during chemotherapy reduced the dose-limiting toxicity of the cytostatic agents, allowing greater tolerability of a higher dose. This working group rightly suggested that further well-designed studies with large numbers of patients and clearly defined antioxidants were necessary to confirm the benefits of adjuvant supplements during chemotherapy [ 10 , 11 , 63 , 64 ].

The American Institute for Cancer Research (AICR) recommends that cancer patients undergoing treatment with chemo- and/or radiotherapy should not take multivitamin/mineral preparations that contain antioxidants in a daily dose greater than the corresponding tolerable upper intake level (UL) of the micronutrient concerned (e.g., vitamin C: 2000 mg per day; vitamin E: 250 mg tocopherol equivalent per day). According to the AICR, multivitamin/mineral supplements can generally be regarded as safe when the daily doses of the vitamins and minerals are in the range of the recommended daily allowance (RDA) [ 18 , 65 , 66 ].

Before supplements are prescribed or taken, all attempts are to be made to obtain needed nutrients through dietary sources according to the recommendations of the WCRF/AICR for cancer prevention. We recommend our cancer patients with nutritional problems or weight loss to take a multivitamin/mineral supplement based on the RDA, in order to cover the basic supply of essential micronutrients. This approach primarily compensates for potential deficiencies and is not a high-dose micronutrient therapy. In this article, however, we will review micronutrients, such as vitamin D, selenium, and l -carnitine, which may also benefit patients in supranutritive doses when given appropriately for the specific cancer treatment and based on the results of lab testing.

5. Vitamin D

5.1. Vitamin D: Sunlight and Cancer

Ecological studies provide the strongest evidence for reduced mortality rates with respect to solar UV-B, with vitamin D production the likely reason. A large body of evidence indicates that solar UV-B (UVB) irradiance and vitamin D reduce the risk of incidence and death for many types of cancer. For men, the UVB index was significantly inversely correlated with 14 types of internal cancer, bladder, breast, colon, gallbladder, kidney, laryngeal, liver, lung, oral, pancreatic, pharyngeal, prostate, rectal, and small intestine cancer. For women, the same UVB index was inversely correlated with bladder, breast, and colon cancer. The results of many studies provide support for the UVB-vitamin D-cancer hypothesis and suggest that the widespread fear of chronic solar UV (UV) irradiance may be misplaced [ 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ].

5.2. Vitamin D: Deficiency and Insufficiency

25(OH)D is the vitamin D metabolite that is measured to assess a patient’s vitamin D status. Vitamin D deficiency is diagnosed when 25(OH)D <20 ng/mL, vitamin D insufficiency is defined as 25(OH)D of 21–29 ng/mL, and 25(OH)D >30 ng/mL is considered sufficient, with 40–60 ng/mL being the preferred range. Vitamin D intoxication usually does not occur until 25(OH)D >150 ng/mL. Vitamin D intoxication is only to be expected at levels of 25(OH)D >150 ng/mL [ 85 , 86 , 87 ].

It is unrealistic to believe that outdoor activities in the summertime will be able to raise serum 25(OH)D levels to such a significant extent that can be sustained throughout the winter. Typically serum levels of 25(OH)D increase by approximately 10–20 ng/mL by the end of the summer in white Europeans into the range of 35 ng/mL for those exposed to upwards of 300 h of sunshine per month. Since the half-life for 25(OH)D is approximately 2–3 weeks, serum levels decline below the desired 30 ng/mL within 1–2 months after October when sunlight can no longer produce any vitamin D in the skin for those living above 34° north latitude. Vitamin D 3 supplementation with 2000 IU to 4000 IU vitamin D per day, respectively 40–60 IU vitamin D per kg bodyweight per day will increase serum 25(OH)D levels above 30 ng/mL [ 85 , 86 , 88 , 89 , 90 ].

5.3. Vitamin D Deficiency in Patients with Cancer

Vitamin D deficiency is common in cancer patients and correlates with disease progression. In observational studies, vitamin D deficiency is associated with increased incidence of breast and colon cancer, as well as with an unfavorable course of non-Hodgkin lymphoma [ 30 , 91 , 92 , 93 , 94 , 95 , 96 ]. A recent meta-analysis found a 12% (95% CI = 3%–22%) reduction of lung cancer incidence with respect to 25(OH)D concentrations for an increase from 20 to 50 nmol/L. Another meta-analysis found a relative risk of 0.83 (95% CI = 0.77–0.90; p < 0.001) for high versus low 25(OH)D concentration [ 96 , 97 ].

In both patients with colorectal cancer and those with breast cancer, the vitamin D status has been shown to be an independent predictor of survival [ 88 , 98 , 99 , 100 , 101 ]. There seems to be also an association between vitamin D receptor (VDR) gene polymorphisms and the breast cancer risk. A recent meta-analysis of high-quality studies demonstrated that the Fok1 polymorphism of the VDR gene was closely associated with breast cancer risk [ 102 ].

In a placebo-controlled, double-blind study of 1179 postmenopausal women aged over 55 years, the influence of 1400 mg of calcium daily, the combination of 1400 mg of calcium and 1100 IU of vitamin D 3 or placebo on the cancer risk was studied over a period of four years. In the woman who received the combination of calcium and vitamin D, the 25(OH)D level rose from 28.7 ng/mL to 38.4 ng/mL. Vitamin D status remained unchanged in the two other groups. At the end of the four-year period, the relative risk (RR) of developing cancer was reduced by 60% in the calcium + vitamin D 3 group as compared with the placebo group relative risk (RR) cancer (RR: 0.402, CI: 0.20, 0.82; p = 0.013), while in the group with calcium alone it was reduced by 47% (RR: 0.532, CI: 0.27, 1.03; p = 0.063). A reevaluation using logistic regression to cancer-free survival at 12 month showed that the relative risk in the calcium + vitamin D 3 group had been significantly reduced by 77% (RR 0.232, CI: 0.09, 0.60, p < 0.005). The data in the calcium group alone remained virtually unchanged (RR: 0.587, CI: 0.29, 1.21; p = 0.147) [ 86 , 89 , 103 ].

In a prospective cohort study, Canadian researchers from the Mount Sinai Hospital in Toronto observed the course of disease in 512 women with breast cancer for about 12 years from 1997 to 2008. The average age of the women was 50.4 years at diagnosis. 37.5% of the breast cancer patients had a vitamin D deficiency [25(OH)D <20 ng/mL or <50 nmol/L] when diagnosed. Only 24% of the affected women had an almost normal vitamin D status [25(OH)D >29 ng/mL or 72 nmol/L]. Vitamin D deficiency was associated with the occurrence of more aggressive forms of breast cancer. After 12 years, the risk of a metastasis in women with a vitamin D deficiency was increased by 94% compared with those with normal vitamin D status (hazard ratio (HR) = 1.94; 95% CI, 1.16 to 3.25). The probability of premature death due to the disease rose in the presence of a vitamin D deficiency by 73% (HR = 1.73; 95% CI, 1.05–2.86) [ 86 , 95 ].

A recent meta-analysis was performed of five studies ( n = 4443) of the relationship between 25(OH)D and mortality from breast cancer. Higher serum concentrations of 25(OH)D were associated with lower case-fatality rates after diagnosis of breast cancer. Specifically, patients in the highest quintile of 25(OH)D (~30 ng/mL) had approximately half the death rate from breast cancer as those in the lowest (~17 ng/mL) [ 88 ]. In another recent meta-analysis that evaluated eight prospective cohort studies from Europe and the USA with over 26,000 men and women (age: 50 to 79 years) and was carried out by the German Cancer Research Centre in Heidelberg an analysis of cancer mortality showed that cancer patients with a 25(OH)D ≤4 ng/mL (≤10 nmol/L) had a 1.7-fold increased risk of dying from the disease compared to cancer patients with a 25(OH)D ≥36 ng/mL (≥90 nmol/L) (risk ratio: 1.70; 95% CI 1.00–2.88) [ 89 , 100 ].

Basal serum 25(OH)D concentrations were retrospectively analyzed in a cohort of melanoma patients ( n = 324) and healthy controls ( n = 141) and the hypothesis was tested that serum 25(OH)D concentrations are predictive of melanoma risk, thickness of primary melanomas, and overall survival (OS). Median serum 25(OH)D concentrations were significantly lower ( p = 0.004) in melanoma patients (median = 13.6 ng/mL) as compared to controls (median = 15.6 ng/mL). Primary tumors of patients with low serum 25(OH)D concentrations (<10 ng/mL) had significantly ( p = 0.006) greater Breslow thickness (median: 1.9 mm) as compared to patients with higher levels (>20 ng/mL; median: 1.00 mm). Patients with 25(OH)D serum concentrations in the lowest quartile had inferior overall survival (median: 80 months) comparing with the highest quartile (median: 195 months; p = 0.049). These data support the concept that serum 25(OH)D concentrations are associated with risk and prognosis of melanoma [ 104 ].

5.4. Vitamin D and Cancer Therapy

In breast cancer patients under polychemotherapy with anthracycline and taxane, a significant drop in 25(OH)D levels was observed [ 105 ]. Some cytostatics (e.g., cyclophosphamide, paclitaxel) are ligands of the pregnane X receptor (PCR) and can, therefore, increase the enzymatic degradation of 25(OH)D and 1α,25(OH)2D via the induction of 24-hydroxylase in the course of chemotherapy [ 106 , 107 , 108 ]. This mechanism discussed by various authors that explains the abnormalities in bone metabolism under medication is the activation of pregnane X rececptor by some drugs, that may be responsible for the acceleration of vitamin D catabolism through the upregulation of CYP3A4 and CYP24A1, leading to vitamin D deficiency and, eventually, to osteopenia or osteomalacia. Human PXR (hPXR) is also named steroid and xenobiotic receptor (SXR). CYP24 is a multifunctional 24-hydroxylase and the major vitamin D catabolic enzyme that directs the side-chain oxidation and cleavage of 1α,25(OH)2D and 25(OH)D to catabolic carboxylic acid end products. Docetaxel is a known trigger for cutaneous adverse reactions and taste disorders. A vitamin D deficiency can lead to the occurrence of chemotherapy-induced mucositis and dysgeusia. There have been case reports of mucocutaneous side effects (e.g., stomatitis) and taste disorders occurring in cancer patients under polychemotherapy with TCH (T: docetaxel, C: carboplatin, H: trastuzumab), or FOLFOX6, which could be treated successfully with supplementation of vitamin D 3 [ 106 ]. Additionally, arthralgias and fatigue during treatment with aromatase inhibitors, such as letrozole, were significantly reduced by supplementation of vitamin D 3 (e.g., 50,000 IU vitamin D 3 /week for 12 weeks, PO) in breast cancer patients with vitamin D deficiency [ 109 , 110 ].

Similar results are on record for use of bisphosphonates. The osseous effectiveness of bisphosphonates is improved by an adequate vitamin D status (25(OH)D ≥33 ng/mL). This could be related to the fact that a cessation of the parathyroid hormone increase is not achieved until a 25(OH)D level ≥40 ng/mL is reached [ 111 ]. Necrotic bone exposure in the oral cavity has recently been reported in patients treated with nitrogen-containing bisphosphonates as part of their therapeutic regimen for multiple myeloma or metastatic cancers to bone. It is suggested that the pathophysiologic mechanism(s) underpinning osteonecrosis of the jaw may involve the interaction between bisphosphonates and compromised vitamin D functions in the realm of skeletal homeostasis and innate immunity [ 112 , 113 ]. In a recently published case-control study with 43 patients, 77% of patients with BRONJ were osteomalacic compared with 5% of patients without BRONJ, according to histomorphometry ( p < 0.001). Osteomalacia represents a new and previously unreported risk factor for the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Due to the high incidence of vitamin D deficiency and the low accuracy of clinical risk factors to predict vitamin D deficiency, screening for vitamin D deficiency before administration of bisphosphonates such as zoledronate may be appropriate. In vitamin D deficiency (until it is corrected) oral bisphosphonates should not be used [ 114 , 115 , 116 ].

Vitamin D deficiency is common among palliative cancer patients and has been connected to an increased risk for pain, infections and depressions. In a recent prospective, observational study in palliative cancer patients ( n = 100) low 25(OH)D-levels were associated with a significant increased opioid consumption in palliative cancer patients ( p = 0.02). A univariate cox regression analysis showed also a weak correlation between survival time and 25(OH)D levels ( p < 0.05) [ 117 ].

Vitamin D deficiency is a risk factor for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). In a recent study the impact and mechanisms of vitamin D deficiency on the outcome of elderly patients with diffuse large B-cell lymphoma was investigated. 359 pretreatment 25(OH)D serum levels from the RICOVER-60 study (six vs. eight cycles of biweekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-Cell lymphomas) and 63 from the RICOVER-noRTh study (an amendment to the RICOVER-60 study in which patients received six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone administered at an interval of two weeks, plus two cycles of rituximab (R-CHOP-14), but without radiotherapy) were determined by chemoluminescent immunoassay. Rituximab-mediated cellular cytotoxicity was assessed by lactate dehydrogenase release assay of CD20+ Daudi cells. RICOVER-60 patients with severe vitamin D deficiency (25(OH)D ≤8 ng/mL) and 25(OH)D levels more than 8 ng/mL treated with rituximab had three-year event-free survival of 59% and 79% and three-year overall survival of 70% and 82%, respectively. These differences were significant in a multivariable analysis adjusting for international prognostic index risk factors with a hazard ratio of 2.1 ( p = 0.008) for event-free survival and 1.9 ( p = 0.04) for overall survival. Event-free survival was not significantly different in patients with 25(OH)D levels ≤8 or more than 8 ng/mL (HR, 1.2; p = 0.388) treated without rituximab. This was confirmed in an independent validation set of 63 RICOVER-noRTh patients. Rituximab-mediated cellular cytotoxicity increased significantly ( p < 0.001) in seven of seven individuals with vitamin D deficiency after substitution and normalization of their vitamin D levels. That vitamin D deficiency impairs Rituximab-mediated cellular cytotoxicity and substitution of vitamin D improves Rituximab-mediated cellular cytotoxicity strongly suggests that vitamin D enhances rituximab efficacy [ 118 ].

One vitamin D mechanism not widely discussed is the reduction of cancer cachexia, which is characterized by systemic inflammation, weight loss, body-fat atrophy, and muscle wasting. Up to 50% of cancer patients suffer from cancer cachexia and up to 30% may die from it. Several mechanisms associated with cancer cachexia involve cytokines, such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor-α. Vitamin D affects many of these factors, especially those associated with inflammation. IL-6 seemed to be a key mediator of muscle wasting in cancer cachexia. IL-6 is one cytokine that vitamin D suppresses. Vitamin D regulates also the hepcidin-ferroportin axis which may facilitate the bioavailability of iron. Therefore it could also be of importance in the treatment of cancer anemia [ 18 , 19 , 20 , 21 , 24 , 119 , 120 , 121 , 122 , 123 , 124 ].

Radiation-induced injury to normal tissues is a common complication of radiation therapy in cancer patients. Considering the role of vitamin D in mucosal barrier hemostasis and inflammatory responses in a recent prospective observational study it was investigated if vitamin D deficiency is associated with the severity of radiation-induced acute proctitis in cancer patients. 98 patients (57.1% male) with a mean age of 62.8 ± 9.1 years were studied. Vitamin D deficiency was found in 57 patients (58.1%). Symptoms of acute proctitis occurred in 72 patients (73.4%) after radiation therapy (total received radiation dose of 50 Gy). RTOG grade was significantly higher in patients with vitamin D deficiency than in normal cases (median interquartile range of 2 (0.5–3) vs. 1 (0–2), p = 0.037). Vitamin D deficiency was associated with RTOG grade of ≥2, independent of possible confounding factors (odds ratio (OR) = 3.07, 95% CI: 1.27–7.50, p = 0.013) [ 125 ].

Some trials show the benefit of vitamin D supplementation in preventing or treating cancer. However, an alternative method can be used to evaluate the evidence obtained to date: Hill’s criteria for causality in a biological system. The Hill criteria relevant for vitamin D and cancer include the following: strength of association; consistent findings in different populations; temporality; biological gradient (dose–response relation); plausibility (e.g., mechanisms); coherence (no serious conflict with known natural history and biology); experiment (e.g., RCT); analogy. Confounding factors should also be accounted for. Not all criteria need be satisfied to claim causality; however, the more they are, the stronger the case. Researchers have evaluated these criteria for cancer in general, and breast cancer in particular. Readers of this article can evaluate how well they think the criteria have been satisfied now [ 126 , 127 , 128 , 129 ].

Recommendation for clinical practice:

Vitamin D status should be monitored in all cancer patients and treated by adequate vitamin D supplementation (e.g., 40–60 IU vitamin D per kg body weight per day, 25(OH)D target value: 40–60 ng/mL or 100–150 nmol/L). This applies, in particular to cancer patients with poor nutritional status, treatment with aromatase inhibitors, bisphosphonates, and chemotherapy regimens including anthracyclines, taxanes, and monoclonal antibodies, as well as in cases of muscular or mucocutaneous disorders, fatigue, and cancer-related anemia and cachexia.

6. Selenium

6.1. Selenium and the Risk of Cancer

Selenium is an essential micronutrient for human health whose biological activities and anti-carcinogenic properties likely result from its incorporation as the 21st proteinogenic amino acid selenocysteine in selenoproteins encoded by 25 separate human genes with roles in cell protection from oxidative stress, redox control, and the inflammatory response. Selenium-dependent glutathione peroxidases and thioredoxin reductases are necessary for optimal function of immune cells by controlling oxidative stress and redox regulation. Specific selenoproteins also have ROS-independent roles in modulating inflammatory responses [ 130 ]. Pharmacodynamics data suggest that selenite targets several key cancer-associated signaling pathways and induces multimodal regulated cell death pathways [ 131 , 132 ].

The trace element selenium has a long history as a cancer preventive agent. A few human trials addressing total cancer incidence have been published [ 133 , 134 , 135 , 136 ]. Some of these studies show a correlation between low serum selenium levels and increased incidence of mainly breast cancer [ 137 ], gastrointestinal cancers [ 138 , 139 ], and prostate cancer [ 140 ]. The major effects of supplementation have been observed in the incidences of colorectal-, lung, and prostate cancers along with a drastic decrease in the total cancer mortality by 50% [ 141 ]. There is also a clear correlation to dose and the base line selenium status of the study population [ 141 ]. In the case of prostate cancer beneficial effects are clear only in populations with a low baseline selenium level and a low intake [ 142 , 143 , 144 ].

A Cochrane review published in 2011 investigated whether there was a relationship between the selenium supply and the risk of cancer, and also the effectiveness of selenium supplements in cancer prevention [ 145 ]. The analysis included 49 prospective non-interventional studies and six randomized clinical trials. The epidemiological studies showed that people with a better selenium supply had a reduced incidence of cancer (OR 0.69; 95% CI 0.53–0.91) and a reduced mortality from cancer (OR 0.55; 95% CI 0.36–0.83). The effects on the incidence of cancer was more pronounced in men than in women (OR 0.66; 95% CI 0.42–1.05 and OR 0.90; 95% CI 0.45–1.77, respectively). The randomized clinical trials, however, did not find any effects of selenium supplements, using either selenium yeast to prevent non-melanoma skin cancers or l -selenomethionine to prevent prostate carcinoma. Although an inverse association between selenium exposure and the risk of some types of cancer was found in some observational studies, this cannot be taken as evidence of a causal relation, and these results should be interpreted with caution [ 145 , 146 ].

A critical observation at this point is that the evaluation of the epidemiological data included studies carried out around the world, while merely two studies were considered in the assessment of the preventative effects of selenium, namely the Nutritional Prevention of Cancer Trial (NPCT; selenium yeast for the prevention of non-melanoma skin cancers) [ 133 ] and the Selenium and Vitamin E Cancer Prevention Trial (SELECT; l -selenomethionine for the prevention of prostate carcinoma) [ 147 ]. It is known, however, that the SELECT participants from the USA, Canada, and Puerto Rico had a median selenium serum level of about 135 µg/L at the start of the study and were therefore already adequately supplied with selenium at baseline. This is one reason why the expected effects of selenium supplements were not seen [ 147 ]. In Europe, including Germany, healthy people have mean selenium serum levels about 84 µg/L, while the levels in cancer patients are often even below 70 µg/L [ 137 ]. The results of a long-term non-interventional study with 13,887 adult USA citizens demonstrated that an optimal selenium supply gives serum levels between about 110 µg/L and 130 µg/L [ 148 , 149 ]. Above and below this range there was a tendency towards increased mortality from cancer and increased mortality in general. This supports the view that serum selenium levels that are too high (>150 µg/L) do not provide any long-term protection against cancer, as was also the case in the SELECT study. A relevant secondary result of the NPCT study, which primarily investigated the effects of selenium supplements on the risk of skin cancer, is that not only the overall incidence of cancer but also the overall mortality was significantly lower after selenium yeast supplements (200 µg/day) in comparison with placebo [ 133 ]. The incidence of prostate cancer was also reduced in the selenium group (relative risk 0.51; 95% CI: 0.29–0.87) with the greatest effect being seen in the men who initially had the lowest selenium supplies (serum selenium levels <123 µg/L) [ 143 , 150 , 151 , 152 ].

Note: Against this background, both in healthy patients and in those with cancer, the selenium status should always be checked first whenever supplements are being considered. Only when selenium deficiency has been confirmed should supplements be given until a concentration in the optimal range is achieved (serum selenium level: 130 to 150 µg/L). People whose serum selenium concentration is already 122 µg/L or higher should not supplement with selenium [ 148 , 149 ]. The converse is also important: there are various health benefits, and more importantly, no extra risk, for persons with serum concentrations less than 122 µg/L associated with rising their selenium status (e.g., selenium containing supplement) to 130–150 µg/L, a selenium level associated with minimal mortality [ 3 , 4 , 149 ].

6.2. Use of High-Dose Selenium during Chemo- or Radiotherapy

Five randomized trials have looked at the question of whether the concomitant use of high-dose selenium reduces the toxicity of chemo- or radiotherapy without impairing the main effects of oncological treatment. The five available studies on the use of selenium are all randomized but not blinded or placebo-controlled ( Table 3 ). In a Chinese study by Hu et al. ( n = 41), the concomitant use of high-dose selenium significantly reduced the hematotoxicity and nephrotoxicity of cisplatin in the treatment of various solid tumors; survival rates were not given in this publication [ 153 ]. Sieja et al. ( n = 31) gave selenium to accompany chemotherapy with cisplatin and cyclophosphamide in patients with ovarian cancer, and found a significant reduction in hematotoxicity, as well as alopecia; survival data were not given here either [ 54 ].

In patients with non-Hodgkin’s lymphomas ( n = 50) and chemotherapy according to the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) regimen, the concomitant use of selenium led to a significant reduction in hematotoxicity, a significant improvement in the remission rate, and in the median overall survival [ 154 , 155 ]. A German study ( n = 39) in which patients took selenium in parallel to radiotherapy for head and neck cancers showed a significant reduction in the rate of dysphagia in the last week of radiotherapy (week 7) [ 156 ].

In another German study ( n = 81) on patients with cervical or uterine cancer, taking selenium at the same time as adjuvant irradiation caused a significant reduction in the rate of radiogenic diarrhea (grade ≥ 2) from 44.5% to 20.5% ( p = 0.04) [ 49 , 157 , 158 ]. After 10 years, the disease-free survival in the selenium group was 81.5%, versus 82.3% without selenium ( p = 0.87); the overall survival at this point in time was 58.4% in the selenium group, versus 44.8% without selenium ( p = 0.13). We can conclude, therefore, that the administration of sodium selenite is safe and does not reduce the main biological effects of the oncological treatment. In view of its positive effects on RT-induced diarrhea, we consider Se supplementation to be a meaningful and beneficial adjuvant treatment in Se-deficient cervical and uterine cancer patients while undergoing pelvic radiation therapy. All of the selenium studies found a significant increase in the serum selenium concentrations measured after supplements had been taken.

The safety and efficacy of intravenous administered sodium selenite in cancer patients ( n = 34, 70% of the patients had lung carcinoma) refractory to cytostatic drugs was assessed in a recent phase I trial (SECAR study). Patients received first line of chemotherapy following intravenous (i.v.) sodium selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Interestingly, many of the patients in this study responded again to their first line of chemotherapy after i.v. administration of sodium selenite. These results were in support of other findings and indicated that even if sodium selenite in itself might be clinically useful in a subset of cancer patients, its subsequent use with chemotherapy might be therapeutically valuable. Furthermore the findings from this study indicate that sodium selenite might work in three ways against cancer: the antitumor effect by itself, by reversing chemoresistance and by ameliorating toxic effects from chemotherapy. In this trial sodium selenite was safe and well-tolerated when administered up to 10.2 mg/m 2 under the current protocol [ 159 ].

Recommendation for clinical practice:

In routine clinical practice—outside of studies—the idea is to counterbalance any deficiencies, wherever possible after performing the relevant lab tests. This seems particularly important for the trace element selenium. The studies presented here indicate that the toxicity of chemo- and radiotherapy can be reduced by raising the serum selenium concentration without impacting the main anticancer effects. This is also the practical experience with sodium selenite in our group (e.g., 1 mg sodium selenite in 100 mL 0.9% NaCl as pre-medication before chemotherapy). Efforts should be made to achieve a target selenium level between 130 and 150 µg/L [ 3 , 4 , 149 ]. In oncology the selenium salt of choice is sodium selenite. Selenomethionine is incorporated non-specifically into proteins in place of methionine and, therefore, accumulate in organs and tissues.

7. l -Carnitine

7.1. l -Carnitine: Biological Functions

l -Carnitine is a naturally-occurring quaternary ammonium compound formed from the essential amino acids l -lysine and l -methionine. The human body needs an adequate supply of iron, vitamin C, pyridoxine, and niacin for its endogenous synthesis, which takes place mainly in the cytosol and in the mitochondrial matrix of liver and kidney cells. l -carnitine is critical for energy generation by mitochondrial ß-oxidation. Corresponding to its key position in fatty acid metabolism and energy balance, the largest quantities of l -carnitine are to be found in tissues that meet their energy requirement primarily though the oxidation of fatty acids (skeletal and cardiac muscle). The most important storage compartment is skeletal muscle [ 3 , 4 , 33 ].

In addition to its widespread use in competitive sports [ 160 ], l -carnitine is also being used more often in complementary oncology. The number of international publications on the subject of l -carnitine and cancer has risen enormously in recent years. Numerous preclinical studies and small-scale clinical studies (mostly not conforming to good clinical practice (GCP)) have been published. Apart from basic questions of physiology, bioavailability, and toxicity, the focus of these studies has been supportive questions such as the reduction of chemotherapy-associated neuro- or cardiotoxicity (e.g., paclitaxel and anthracyclines), as well as the reduction of fatigue in the context of anticancer pharmacotherapy (e.g., cisplatin, ifosfamide) [ 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 ].

In the studies cited, l -carnitine was used in the form of l -carnitine, acetyl- or propionyl- l -carnitine. In the USA, propionyl- l -carnitine is used particularly in cardiovascular disease. Acetyl l -carnitine has the same properties as l -carnitine but, according to the current data, seems to be more effective in the treatment of neurological disorders and neuropathies. The acetylation may increase the enteral absorption ratio for acetyl l -carnitine and make it more effective in penetrating the blood-brain barrier. The cardioprotective effect of propionyl- l -carnitine should be greater than that of l -carnitine or acetyl l -carnitine, because of the intracellular conversion to succinyl coenzyme A (CoA) and subsequent stimulation of the citric acid cycle. In Germany, it is mainly l -carnitine that is used. This is also the only compound available for infusion. We recommend patients with cancer in a poor nutritional condition and on chemotherapy regimens that can induce a carnitine deficiency to take l -carnitine tartrate as oral supplementation because of its better gastrointestinal tolerability [ 3 , 4 , 33 ].

l -Carnitine shows stabilising effects on the biomembranes of erythrocytes and cell organelles (mitochondria). A pro-apoptotic effect on colorectal cancer cells has also been described; the authors of this publication assume the underlying mechanism to be an increase in the beta-oxidation of fatty acids within cancer cells, which show disrupted energy metabolism [ 169 ]. Given that l -carnitine inhibits pro-inflammatory cytokines and skeletal muscle apoptosis, increases available energy from beta-oxidation and, in the context of chemotherapy, may exacerbate pre-existing l -carnitine deficiency [ 170 , 171 ], investigations into the efficacy of l -carnitine in preventing cachexia, anorexia, and fatigue seem to be indicated.

7.2. l -Carnitine Deficiency in Patients with Cancer

A deficiency of l -carnitine has been described in many chronic diseases and especially in cancer. Studies on the subject indicate that up to 80% of patients with advanced malignant disease have a general l -carnitine deficiency, for which the body cannot compensate, as is the case with surgical patients [ 32 , 33 ].

Many causes of l -carnitine deficiency are already known in patients with cancer: Nutritive l -carnitine deficiency with an inadequate diet (e.g., deficient in iron, vitamin C, and l -methionine). Competition with cytostatics (e.g., competition with anthracyclines for the carnitine transporter OCTN2, which is necessary for the transport of l -carnitine into the cells). Disruption of l -carnitine biosynthesis by anthracyclines. Increase in renal l -carnitine excretion by cisplatin and ifosfamide; formation of non-physiological l -carnitine esters and, hence, increased l -carnitine excretion via the kidneys.

A deficiency of the micronutrient l -carnitine may play a role in prevalent symptoms in patients with cancer such as fatigue, malnutrition, and depression [ 3 , 4 , 32 , 33 , 164 , 166 , 172 , 173 , 174 ].

7.3. l -Carnitine Depletion by Cisplatin and Ifosfamide

Cisplatin is nephrotoxic: it inhibits the renal resorption of l -carnitine and can increase l -carnitine excretion in the urine of cancer patients by a factor of 10 [ 170 ]. Ifosfamide can also cause considerable renal loss of l -carnitine. Chloracetaldehyde, the metabolite of ifosfamide, may be oxidized to chloroacetic acid, which then binds to free CoA. This in turn disrupts the CoA pool in the mitochondria and inhibits energy-supplying CoA-dependent metabolic pathways. The chloroacetyl group can be transferred from CoA to l -carnitine; in this way it can then be transported out of the mitochondria and out of the cells ( Figure 2 ). As chloroacetyl carnitine is not as well resorbed in the kidneys as free l -carnitine, the excretion of l -carnitine is increased, leading to a secondary l -carnitine deficiency [ 166 , 169 , 174 ].

The consequences of a cisplatin- or ifosfamide-induced l -carnitine deficiency can be: l -Carnitine depletion (secondary l -carnitine deficiency in the blood and tissues) with a fall in the plasma l -carnitine levels (<35 µmol/L). Impairment of carnitine-palmitoyl transferase 1 activity (an enzyme that catalyzes the carnitine-dependent transport of fatty acids into the mitochondria) and of the cellular carnitine transporter OCTN2. Disruption of mitochondrial ATP synthesis, energy deficiency. Increased mitochondrial toxicity of cisplatin and ifosfamide. Increased risk of fatigue [ 164 ] as well as of cisplatin- and ifosfamide-induced adverse neurotoxic and cardiotoxic effects.

l -Carnitine supplements may reduce the cardiotoxic effects of anthracyclines and interleukin-2 and the neurotoxic effects of taxanes or sagolipone, without affecting the cytoreductive effects of these anticancer drugs [ 32 , 33 , 164 , 175 , 176 , 177 , 178 , 179 , 180 ]. But the results of some trials are still conflicting. An older randomized trial with 30 cancer patients found out that supplementation of l -carnitine (1 g/day) may be used successfully to prevent cardiac complications during interleukin-2 (IL-2) immunotherapy in cancer patients with clinically relevant cardiac disorders. Since cardiac metabolism depends mainly on fatty acid oxidation, the stimulatory role of l -carnitine on fatty acid oxidation could explain at least in part its ability to prevent heart disturbances in response to IL-2 administration [ 181 ]. However, a randomized, placebo-controlled trial with 40 patients with non-Hodgkin lymphoma found no evidence that supplementation of l -carnitine (3 g before each chemotherapy cycle, followed by 1 g/day during the following 21 days) protects against anthracyclin-related cardiotoxicity [ 182 ]. There is also evidence from two prospective, uncontrolled studies including 52 patients with different grades of CIPN that acetyl- l -carnitine is beneficial in the treatment of paclitaxel- and cisplatinum-induced peripheral neuropathy [ 161 , 183 ]. Evidence that acetyl- l -carnitine or l -carnitine might protect from paclitaxel- and cisplatinum-induced peripheral neuropathy (CIPN) comes from two randomized controlled trials and is contradictory. The findings from the most recent trial, including 409 women receiving adjuvant taxane-containing chemotherapy, introduce a note of caution in that there are indications that acetyl- l -carnitine could even increase CIPN ( Table 4 ) [ 184 ]. However the authors of an unpublished double-blind, placebo-controlled trial with 239 cancer patients treated with taxol alone or in combination with other neurotoxic or non-neurotoxic drugs mentions in the abstract a significant action of acetyl- l -carnitine (3 g ALC/day) in improving vibratory sensation in patients with CIPN, compared with placebo was found [ 185 ].

7.4. High-Dose l -Carnitine Supplements in Patients with Cancer

A deficiency of l -carnitine has been proposed to be an underlying cause of cancer cachexia and tumor associated fatigue [ 33 , 165 , 188 ]. A few studies have shown that the adjuvant administration of l -carnitine at doses between 2 g and 6 g per day may reduce the weight loss and/or the weakness and fatigue experienced by patients with cancer, but the results of some studies are still conflicting [ 42 , 168 , 186 , 187 , 189 ]. An improvement in the physical and mental health of cancer patients after the administration of high-dose l -carnitine can be attributed not only to an improved cellular energy balance from improved mitochondrial fat burning but also to the favorable effect of l -carnitine on glucose utilization and cytokine metabolism [ 33 , 166 ]. There is evidence from four recent randomized trials, involving more than 800 participants with sufficiently robust measures of cancer-related fatigue that l -carnitine does not reduce moderate to severe cancer-related fatigue or that acetyl- l -carnitine prevents from cancer-related fatigue occurring during taxane-based chemotherapy [ 33 , 186 , 189 , 190 ]. These findings contradict those from several uncontrolled studies suggesting that l -carnitine might help against cancer-related fatigue ( Table 4 ) [ 165 , 187 , 191 ]. There is evidence that l -carnitine has beneficial effects on parameters related to cancer anorexia-cachexia syndrome (CACS) based on the results of a prospective, uncontrolled study including 12 patients with advanced cancers and on the results from one randomized controlled trial [ 33 , 191 ]. In this trial from our group (CARPAN study), which enrolled 72 patients with advanced pancreatic cancer, we found a significant positive effect on both quality of life and nutritional status with l -carnitine therapy (2 g twice daily, p.o.) compared with placebo. We screened 152 and enrolled 72 patients suffering from advanced pancreatic cancer in a prospective, multi-center, placebo-controlled, randomized and double-blind trial to receive oral l -carnitine (4 g) or placebo for 12 weeks. At entry patients reported a mean weight loss of 12 ± 2.5 (SEM) kg. During treatment body-mass-index increased by 3.4% ± 1.4% under l -carnitine and decreased (−1.5 ± 1.4%) in controls ( p < 0.05). Moreover, nutritional status (body cell mass, body fat) and quality-of-life parameters improved under l -carnitine. There was a trend towards an increased overall survival in the l -carnitine group (median 519 ± 50 days versus 399 ± 43 days, not significant) and towards a reduced hospital-stay (36 ± 4 days versus 41 ± 9 days, not significant). While these data are preliminary and need confirmation they indicate that patients with pancreatic cancer may have a clinically-relevant benefit from the inexpensive and well tolerated oral supplementation of l -carnitine [ 33 ].

Cachexic patients can also benefit from a combination of l -carnitine with omega-3 fatty acids. Omega-3 fatty acids exert anti-inflammatory effects and, therefore, recent studies investigated their role in cancer prevention, in cancer cachexia treatment and in enhancement of anti-tumour therapies. Combination of chemotherapy (e.g., gemicitabine) and omega-3 supplementation (e.g., 1–2 g eicosapentaenoic acid/ docosahexaenoic acid (EPA/DHA) daily) appears an effective strategy to enhance the clinical outcome of cancer patients in their curative and palliative clinical trajectory [ 192 , 193 , 194 ].

Recommendations for clinical practice:

There is weak evidence from some randomized controlled trials that l -carnitine has a positive influence on cancer anorexia-cachexia syndrome (CACS). Oral supplements and/or parenteral administration of l -carnitine may be of help in cancer patients in a poor nutritional condition and on chemotherapy regimens that can induce a carnitine deficiency, such as cisplatin and ifosfamide. Acetyl- l -carnitine or l -carnitine could also be of help in the prevention and treatment of chemotherapy-induced peripheral neuropathy (e.g., taxanes).

8. Vitamin C

8.1. Vitamin C Deficiency

In addition to selenium, vitamin C is the antioxidant micronutrient most frequently used in complementary oncology. Vitamin C deficiency, which may extend to overt scurvy, is found particularly in patients with advanced malignant disease. Pre-existing vitamin C deficiency may be exacerbated by anticancer treatment such as aldesleukin (recombinant interleukin 2) therapy for metastasizing renal cell carcinoma. In patients with cancer, low plasma vitamin C levels (<11 µmol/L) are associated with increased inflammatory activity (raised C-reactive protein (CRP) levels), poor nutritional condition (low albumin levels), and a shorter survival time. There is some evidence that vitamin C potentiates the actions of certain cytostatic agents and, at the same time, attenuates their adverse effects [ 34 , 195 , 196 , 197 , 198 ].

8.2. Preclinical Data: Combination with Chemotherapy and Radiotherapy

In vitro studies have shown that vitamin C increases the cytotoxic effects of cisplatin, dacarbazine, doxorubicin, paclitaxel, tamoxifen, and fluorouracil [ 199 , 200 , 201 ]. Animal studies have demonstrated that the intraperitoneal administration of vitamin C together with vitamin K potentiates the cytoreductive effects of various cytotoxic drugs [ 202 ]). In addition, combining the administration of doxorubicin with a parenteral dose of vitamin C (2 g/kg body weight, i.v. or intraperitoneal) in animals brings about a significant reduction in the adverse cardiotoxic effects of anthracycline and a significant prolongation of the survival time, while the anthracycline’s cytotoxic effects were not affected [ 203 ].

8.3. Vitamin C: Effect on Cancer Cells in Vitro

Further in vitro and animal studies have shown that the administration of high-dose vitamin C alone can kill selective cancer cells (ovarian cancer, pancreatic cancer, and glioblastoma) by inducing free radicals, without harming healthy cells [ 204 ]. As established by seminal studies, in concentrations higher than 1 mM, ascorbate can cause a build-up of hydrogen peroxide (H 2 O 2 ), which is preferentially toxic toward tumor cells. High-dose intravenous vitamin C induces the formation of H 2 O 2 radicals. Even though these radicals are neutralized in the bloodstream with the help of glutathione peroxidase, this mechanism does not work in the interstitial spaces. Cancer cells are more sensitive than healthy cells to increased concentrations of peroxide radicals [ 205 , 206 , 207 ].

It is proposed that external peroxide (H 2 O 2 ) radicals formed from pharmacologic ascorbate concentrations diffuse into cells and mediate toxicity in sensitive cells by ATP depletion via one or more pathways ( Figure 3 ). H 2 O 2 may cause DNA single-strand breaks, repaired by polyADP-ribose polymerase (PARP). Enhanced PARP activity may deplete NAD+, resulting in ATP depletion. On the other hand H 2 O 2 removal within cells may be mediated in part by glutathione (GSH) peroxidase. GSH peroxidase has an essential requirement for GSH, which, upon enzyme activity, is oxidized to GSH disulfide (GSSG). GSSG is regenerated to GSH with reducing equivalents from NADPH, which in turn is regenerated from glucose via the pentose shunt. Glucose used to reduce NADP+ to NADPH is not available for ATP generation. In cancer cells that depend on anaerobic metabolism for ATP generation (the Warburg effect), loss of glucose to the pentose shunt may result in decreased ATP, leading to cell death. Furthermore mitochondria in some cancer cells may have increased sensitivity to H 2 O 2 . Mitochondria in such cells may be less efficient at baseline in generating ATP compared with normal cells. Enhanced mitochondrial sensitivity to H 2 O 2 , with or without inefficient generation of ATP at baseline, may result in decreased ATP production. These pathways for ATP depletion induced by H 2 O 2 are independent, and more than one could be responsible for cell death in sensitive cells. Pharmacologic ascorbate concentrations should not impair normal cells because their primary ATP generation is via aerobic metabolism and because their mitochondria may not be as sensitive to H 2 O 2 as those in some cancer cells [ 204 , 207 , 208 ].

8.4. Vitamin C and Radiotherapy

According to a recent in vitro study, cells from glioblastoma multiform brain tumors seem to be considerably more sensitive to radiotherapy when high doses of vitamin C are given shortly before treatment sessions. The authors of this study showed that the combination of vitamin C (5 mmol/L) with irradiation (6 Gy) killed significantly more tumor cells by inducing double-strand DNA breaks than did either radiotherapy or vitamin C alone [ 208 , 209 ]. A similar effect was seen in leukemia cells irradiated with 2 Gy [ 210 ]. Should clinical trials confirm that high-dose vitamin C in combination with radiotherapy increases the chance of cure, it may well be worthwhile combining the two forms of treatment in radiotherapy-resistant cancers.

8.5. Vitamin C in Cancer Therapy

Effects on the efficacy of cancer therapy. As part of a prospective Chinese cohort study, 4877 women (aged 20–75 years) with invasive breast cancer were asked about their consumption of vitamin preparations and followed up for a period of about four years on average. Analysis of the data showed that taking vitamins within the first six months of diagnosis was associated with a reduction in mortality and the risk of recurrence; the effects were dependent on the choice of vitamins and the length of time for which they were taken, although the differences did not always reach significance [ 12 ]. Mortality was reduced by 44% and the risk of recurrence by 38% ( p = 0.009 and p = 0.01, respectively) in women who took vitamin C for more than three months. In women who had chemotherapy, the risk was similarly reduced, no matter whether they took the vitamins during the chemotherapy or not. In women who had radiotherapy, however, taking vitamins did not reduce either the mortality or the risk of recurrence.

In a recent epidemiological multicenter cohort study, including 15 gynecologists and general practitioners representatively distributed in Germany, data from 125 breast cancer patients in UICC stages IIa to IIIb were selected. A total of 53 of these patients were treated with i.v. vitamin C (7.5 g) additional to standard tumor therapy for at least 4 weeks (study group) and 72 without this additional therapy (control group). Main outcome measures were efficacy in regard to outcome and severity of disease- or therapy-induced complaints during adjuvant chemo- and radiotherapy and aftercare. Comparison of control and study groups revealed that i.v. vitamin C administration resulted in a significant reduction of complaints induced by the disease and chemo-/radiotherapy, in particular of nausea, loss of appetite, fatigue, depression, sleep disorders, dizziness, and hemorrhagic diathesis. After adjustment for age and baseline conditions (intensity score before adjuvant therapy, chemotherapy, radiotherapy), the overall intensity score of symptoms during adjuvant therapy and aftercare was nearly twice as high in the control group compared to the study group. No side-effects of the i.v. vitamin C administration were documented [ 211 ].

A case report from gynecologists at the University of Kansas describes a good response to cytotoxic chemotherapy (carboplatin, paclitaxel) in two women with advanced epithelial ovarian cancer who took high-dose oral antioxidants in combination with high-dose vitamin C infusion therapy (15–60 g/infusion, daily to twice a month; the combination was well-tolerated [ 55 , 212 ].

At the present time, there are no further data from controlled interventional studies concerning the effects of vitamin C on the efficacy of chemotherapy. Initial results of high-dose vitamin C infusion therapy (125 g vitamin C per infusion) in combination with gemcitabine (PACMAN study) in a small number of patients with pancreatic cancer have shown good tolerability of the cytostatic drug with the vitamin C infusion, as well as a favorable effect on disease progression [ 213 , 214 ].

In a recent case report the regression of multiple pulmonary metastases, which originated from hepatocellular carcinoma after treatment with intravenous administration of high-dose vitamin C are reported. A 74-year-old woman presented to the clinic for her cancer-related symptoms such as general weakness and anorexia. After undergoing initial transarterial chemoembolization (TACE), local recurrence with multiple pulmonary metastases was found. She refused further conventional therapy, including sorafenib tosylate (Nexavar). She did receive high doses of vitamin C (70 g), which were administered into a peripheral vein twice a week for 10 months, and multiple pulmonary metastases were observed to have completely regressed. She then underwent subsequent TACE, resulting in remission of her primary hepatocellular carcinoma [ 215 ].

Recommendation for clinical practice:

Further studies are needed on the efficacy and safety of high-dose vitamin C. The PDQ cancer information summary for health professionals can help to provide comprehensive, peer-reviewed, evidence-based information about the use of high-dose vitamin C in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH) [ 216 ]. Reported complications of intravenous ascorbate are unusual, but include rare cases of hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and oxalate nephropathy. Adverse effects may also occur in patients with iron overload and renal failure. Before a vitamin C infusion G6PD should always be assessed therefore by laboratory testing.

Oral supplements or parenteral administration of vitamin C could be considered in cancer patients with poor nutritional condition, with delayed postoperative wound healing, fatigue or cachexia. Even though the first publications are available showing that vitamin C infusions during chemotherapy have beneficial effects on the incidence of adverse reactions and the patient’s quality of life, their use must be regarded critically until such time as further interventional studies provide clear confirmation of the clinical efficacy and safety of vitamin C infusions in oncology patients. Clinicians should have an open dialogue with patients about vitamin C supplements and vitamin C treatment. The advice for a vitamin C treatment needs to be individualized and come from a credible source, and it is best communicated by the physician.

Acknowledgments

The authors of this peer-review received no funds for covering the costs to publish in open access.

Author Contributions

All authors contributed writing of this review and approved the text.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Bray F. Jemal A. Grey N. Ferlay J. Forman D. Global cancer transitions according to the Human Development Index (2008–2030): A population-based study Lancet Oncol. 2012 13 790 801 10.1016/S1470-2045(12)70211-5 22658655

2. American Cancer Society Global Cancer: Facts and Figures 3rd ed. American Cancer Society New York, NY, USA 2015

3. Holzhauer P. Gröber U. Checkliste: Komplementäre Onkologie Hippokrates Verlag Stuttgart, Germany 2010

4. Gröber U. Mücke R. Adamietz I.A. Holzhauer P. Kisters K. Büntzel J. Micke O. Komplementärer Einsatz von Antioxidanzien und Mikronährstoffen in der Onkologie—Update 2013 Der Onkol. 2013 19 136 143 10.1007/s00761-012-2385-9

5. Gröber U. Hübner J. Holzhauer P. Kleeberg U.R. Antioxidanzien und andere Mikronährstoffe in der komplementären Onkologie Der Onkol. 2010 16 73 79 10.1007/s00761-009-1753-6

6. Micke O. Bruns F. Glatzel M. Schönekaes K. Micke P. Mücke R. Predictive factors for the use of complementary and alternative medicine (CAM) in radiation oncology Eur. J. Integr. Med. 2009 1 22 30 10.1016/j.eujim.2009.02.001

7. Zirpoli G.R. Brennan P.M. Hong C.C. McCann S.E. Ciupak G. Davis W. Unger J.M. Budd G.T. Hershman D.L. Moore H.C. Supplement use during an intergroup clinical trial for breast cancer (S0221) Breast. Cancer Res. Treat. 2013 137 903 913 10.1007/s10549-012-2400-2 23306462 PMC3552360

8. D’Andrea G. Use of antioxidants during chemotherapy and radiotherapy should be avoided CA Cancer J. Clin. 2005 55 319 321 10.3322/canjclin.55.5.319 16166076

9. Block K. Koch A. Mead M. Newman R.A. Gyllenhaal C. Re: Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J. Natl. Cancer Inst. 2009 101 124 125 10.1093/jnci/djn446 19141775

10. Yasueda A. Urushima H. Ito T. Efficacy and interaction of antioxidant supplements as adjuvant therapy in cancer treatment: A systematic review Integr. Cancer Ther. 2015 15 17 39 10.1177/1534735415610427 26503419 PMC5736082

11. Block K.I. Koch A.C. Mead M.N. Tothy P.K. Newman R.A. Gyllenhaal C. Impact of antioxidant supplementation on chemotherapeutic toxicity: A systematic review of the evidence from randomized controlled trials Int. J. Cancer 2008 123 1227 1239 10.1002/ijc.23754 18623084

12. Nechuta S. Lu W. Chen Z. Zheng Y. Gu K. Cai H. Zheng W. Shu X.O. Vitamin supplement use during breast cancer treatment and survival: A prospective cohort study Cancer Epidemiol. Biomark. Prev. 2011 20 262 271 10.1158/1055-9965.EPI-10-1072 21177425 PMC3057050

13. Gröber U. Kisters K. Adamietz I.A. Vitamin D in oncology: Update 2015 Med. Monatsschr. Pharm. 2015 38 512 516 26837159

14. Fearon K.C. Voss A.C. Hustend D.S. Definition of cancer cachexia: Effect of weight loss, reduced food intake and systemic inflammation on functional status and prognosis Am. J. Clin. Nutr. 2006 83 1345 1350 16762946 10.1093/ajcn/83.6.1345

15. Tong H. Isenring E. Yates P. The prevalence of nutrition impact symptoms and their relationship to quality of life and clinical outcomes in medical oncology patients Support Care Cancer 2009 17 83 90 10.1007/s00520-008-0472-7 18551322

16. Laviano A. Meguid M.M. Nutritional issues in cancer management Nutrition 1996 12 358 371 10.1016/S0899-9007(96)80061-X 8875522

17. Bozzetti F. SCRINIO Working Group Screening the nutritional status in oncology: A preliminary report on 1000 outpatients Support Care Cancer 2009 17 279 284 10.1007/s00520-008-0476-3 18581148

18. Ströhle A. Zänker K. Hahn A. Nutrition in oncology: The case of micronutrients (review) Oncol. Rep. 2010 24 815 828 10.3892/or.2010.815 20811659

19. Zürcher G. Mangelernährung bei onkologischen Patienten Vitamine, Spurenelemente und Mineralstoffe Thieme Stuttgart, Germany 2002

20. Züricher G. Medikamentöse Strategien zur Gewichtszunahme bei kachektischen Patienten Akt Ernährungsmed. G 2002 27 398 407

21. Pirlich M. Schütz T. Norman K. Gastell S. Lübke H.J. Bischoff S.C. Bolder U. Frieling T. Güldenzoph H. Hahn K. The German hospital malnutrition study Clin. Nutr. 2006 25 563 572 10.1016/j.clnu.2006.03.005 16698132

22. Dewys W.D. Begg C. Lavin P.T. Band PR. Bennett J.M. Bertino J.R. Cohen M.H. Douglass H.O. Jr. Engstrom P.F. Ezdinli E.Z. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group Am. J. Med. 1980 69 491 497 10.1016/S0149-2918(05)80001-3 7424938

23. Barker L.A. Gout B.S. Crowe T.C. Hospital malnutrition: Prevalence, identification and impact on patients and the healthcare system Int. J. Environ. Res. Public Health 2011 8 514 527 10.3390/ijerph8020514 21556200 PMC3084475

24. Tisdale M.J. Mechanisms of cancer cachexia Physiol. Rev. 2009 89 381 410 10.1152/physrev.00016.2008 19342610

25. Seelaender M. Laviano A. Busquets S. Püschel G.P. Margaria T. Batista M.L. Jr. Inflammation in Cachexia Mediators Inflamm. 2015 10.1155/2015/536954 26523095 PMC4615207

26. Fedeles B.I. Freudenthal B.D. Yau E. Singh V. Chang S.C. Li D. Delaney J.C. Wilson S.H. Essigmann J.M. Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer Proc. Natl. Acad. Sci. USA 2015 112 E4571 E4580 10.1073/pnas.1507709112 26243878 PMC4547254

27. Russell S.T. Tisdale M.J. The role of glucocorticoids in the induction of zinc-alpha2-glycoprotein expression in adipose tissue in cancer cachexia Br. J. Cancer 2005 92 876 881 10.1038/sj.bjc.6602404 15714206 PMC2361908

28. Grant M. Kravits K. Symptoms and their impact on nutrition Semin. Oncol. Nurs. 2000 16 113 121 10.1053/on.2000.5738 10842780

29. Büntzel J. Bruns F. Glatzel M. Garayev A. Mücke R. Kisters K. Schäfer U. Schönekaes K. Micke O. Zinc concentrations in serum during head and neck cancer progression Anticancer Res. 2007 27 1941 1943 17649800

30. Churilla T.M. Brereton H.D. Klem M. Peters C.A. Vitamin D deficiency is widespread in cancer patients and correlates with advanced stage disease: A community oncology experience Nutr. Cancer 2012 64 521 525 10.1080/01635581.2012.661515 22452722

31. Crew K.D. Shane E. Cremers S. McMahon D.J. Irani D. Hershmann D.L. High prevalence of vitamin D deficiency despite supplementation in premenopausal women with breast cancer undergoing adjuvant chemotherapy J. Clin. Oncol. 2009 27 2151 2156 10.1200/JCO.2008.19.6162 19349547 PMC2674001

32. Cruciani R.A. Dvorkin E. Homel P. Culliney B. Malamud S. Shaiova L. Fleishman S. Lapin J. Klein E. Lesage P. l -Carnitine supplementation for the treatment of fatigue and depressed mood in cancer patients with carnitine deficiency: A preliminary analysis Ann. N. Y. Acad. Sci. 2004 1033 168 176 10.1196/annals.1320.016 15591014

33. Kraft M. Kraft K. Gärtner S. Mayerle J. Simon P. Weber E. Schütte K. Stieler J. Holzhauer P. Gröber U. l -Carnitine-supplementation in advanced pancreatic cancer (CARPAN)—A randomized multicentre trial Nutr. J. 2012 11 52 10.1186/1475-2891-11-52 22824168 PMC3439338

34. Mayland C.R. Bennett M.I. Allan K. Vitamin C deficiency in cancer patients Palliat. Med. 2005 19 17 20 10.1191/0269216305pm970oa 15690864

35. De Araújo L.L. Barbosa J.M. Ribeiro A.P.G. dos Santos A.C.O. Pedrosa F. Nutritional status, dietary intake and serum levels of vitamin C upon diagnosis of cancer in children and adolescents Nutr. Hosp. 2012 27 496 503 22732974 10.1590/S0212-16112012000200022

36. Babaknejad N. Sayehmiri F. Sayehmiri K. Rahimifar P. Bahrami S. Delpesheh A. Hemati F. Alizadeh S. The relationship between selenium levels and breast cancer: A systematic review and meta-analysis Biol. Trace Elem. Res. 2014 159 1 7 10.1007/s12011-014-9998-3 24859854

37. Chang D. Wang F. Zhao Y.S. Pan H.Z. Evaluation of oxidative stress in colorectal cancer patients Biomed. Environ. Sci. 2008 21 286 289 10.1016/S0895-3988(08)60043-4 18837290

38. Leung E.Y. Crozier J.E. Talwar D. O’Reilly D.S. McKee R.F. Horgan P.G. McMillan D.C. Vitamin antioxidants, lipid peroxidation, tumour stage, the systemic inflammatory response and survival in patients with colorectal cancer Int. J. Cancer 2008 123 2460 2464 10.1002/ijc.23811 18729200

39. Lin C.C. Yin M.C. B vitamins deficiency and decreased anti-oxidative state in patients with liver cancer Eur. J. Nutr. 2007 46 293 299 10.1007/s00394-007-0665-8 17571208

40. Look M.P. Musch E. Lipid peroxides in the polychemotherapy of cancer patients Chemotherapy 1994 40 8 15 10.1159/000239163 8306820

41. Mantovani G. Macciò A. Madeddu C. Mura L. Massa E. Gramignano G. Lusso M.R. Murgia V. Camboni P. Ferreli L. Reactive oxygen species, antioxidant mechanisms and serum cytokine levels in cancer patients: Impact of an antioxidant treatment J. Cell. Mol. Med. 2002 6 570 582 10.1111/j.1582-4934.2002.tb00455.x 12611641 PMC6741317

42. Macciò A. Madeddu C. Gramignano G. Mulas C. Floris C. Sanna E. Cau M.C. Panzone F. Mantovani G. A randomized phase III clinical trial of a combined treatment for cachexia in patients with gynecological cancers: Evaluating the impact on metabolic and inflammatory profiles and quality of life Gynecol. Oncol. 2012 124 417 425 10.1016/j.ygyno.2011.12.435 22198049

43. Palan P.R. Woodall A.L. Anderson P.S. Mikhail M.S. Alpha-tocopherol and alpha-tocopheryl quinone levels in cervical intraepithelial neoplasia and cervical cancer Am. J. Obstet. Gynecol. 2004 190 1407 1410 10.1016/S0002-9378(04)00152-8 15167851

44. Skrzydlewska E. Sulkowski S. Koda M. Zalewski B. Kanczuga-Koda L. Sulkowska M. Lipid peroxidation and antioxidant status in colorectal cancer World J. Gastroenterol. 2005 11 403 406 10.3748/wjg.v11.i3.403 15637754 PMC4205348

45. Tsao S.M. Yin M.C. Liu W.H. Oxidant stress and B vitamins status in patients with non-small cell lung cancer Nutr. Cancer 2007 59 8 13 10.1080/01635580701365043 17927496

46. Stefanini M. Cutaneous bleeding related to zinc deficiency in two cases of advanced cancer Cancer 1999 86 866 870 10.1002/(SICI)1097-0142(19990901)86:5<866::AID-CNCR24>3.0.CO;2-A 10463987

47. Ravasco P. Monteiro-Grillo I. Vidal P.M. Camilo M.E. Dietary counseling improves patient outcomes: A prospective, randomized, controlled trial in colorectal cancer patients undergoing radiotherapy J. Clin. Oncol. 2005 23 1431 1438 10.1200/JCO.2005.02.054 15684319

48. Dormand E.L. Banwell P.E. Goodacre T.E. Radiotherapy and wound healing Int. Wound J. 2005 2 112 127 10.1111/j.1742-4801.2005.00079.x 16722862 PMC7951225

49. Muecke R. Micke O. Schomburg L. Glatzel M. Reichl B. Kisters K. Schaefer U. Eich H.T. Fakhrian K. Adamietz I.A. German Working Group Trace Elements and Electrolytes in Oncology-AKTE. Multicenter, phase III trial comparing selenium supplementation with observation in gynecologic radiation oncology: Follow-up analysis of the survival data 6 years after cessation of randomization Integr. Cancer Ther. 2014 13 463 467 25015649 10.1177/1534735414541963

50. Jaakkola K. Lähteenmäki P. Laakso J. Harju E. Tykkä H. Mahlberg K. Treatment with antioxidant and other nutrients in combination with chemotherapy and irradiation in patients with small-cell lung cancer Anticancer Res. 1992 12 599 606 1320355

51. Jatoi A. Williams B.A. Marks R. Nichols F.C. Aubry M.C. Wampfler J. Yang P. Exploring vitamin and mineral supplementation and purported clinical effects in patients with small cell lung cancer: Results from the Mayo Clinic lung cancer cohort Nutr. Cancer 2005 51 7 12 10.1207/s15327914nc5101_2 15749624

52. Jatoi A. Williams B. Nichols F. Aubry M.C. Wampfler J. Yang P. Is voluntary vitamin and mineral supplementation associated with better outcome in non-small cell lung cancer patients? Results from the Mayo Clinic lung cancer cohort Lung Cancer 2005 49 77 84 10.1016/j.lungcan.2005.01.004 15949593

53. Simone C.B. II Simone N.L. Simone V. Simone C.B. Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, Part 2 Altern. Ther. Health Med. 2007 13 40 47 17405678

54. Sieja K. Talerczyk M. Selenium as an element in the treatment of ovarian cancer in women receiving chemotherapy Gynecol. Oncol. 2004 93 320 327 10.1016/j.ygyno.2003.12.013 15099940

55. Drisko J.A. Chapman J. Hunter V.J. The use of antioxidants with firstline chemotherapy in two cases of ovarian cancer J. Am. Coll. Nutr. 2003 22 118 123 10.1080/07315724.2003.10719284 12672707

56. Lawenda B.D. Kelly K.M. Ladas E.J. Sagar S.M. Vickers A. Blumberg J.B. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J. Natl. Cancer Inst. 2008 100 773 783 10.1093/jnci/djn148 18505970

57. Mutschler E. Geisslinger G. Kroemer H.K. Mutschler Arzneimittelwirkungen: Pharmakologie—Klinische Pharmakologie—Toxikologie. 10. Auflage Wissenschaftliche Verlagsgesellschaft Stuttgart, Germany 2013

58. Schmoll H.J. Höffken K. Possinger K. Kompendium Internistische Onkologie Standards in Therapie und Diagnostik, Teil I–III Springer Heidelberg, Germany 2005

59. Moss R.W. Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants? Integr. Cancer. Ther. 2006 5 63 82 10.1177/1534735405285882 16484715

60. Pathak A.K. Bhutani M. Guleria R. Bal S. Mohan A. Mohanti B.K. Sharma A. Pathak R. Bhardwaj N.K. Prasad K.N. Chemotherapy alone vs. chemotherapy plus high dose multiple antioxidants in patients with advanced non small cell lung cancer J. Am. Coll. Nutr. 2005 24 16 21 10.1080/07315724.2005.10719438 15670980

61. Prasad K.N. Multiple dietary antioxidants enhance the efficacy of standard and experimental cancer therapies and decrease their toxicity Integr. Cancer. Ther. 2004 3 310 322 10.1177/1534735404270936 15523102

62. Prasad K.N. Cole W.C. Antioxidants in cancer therapy J. Clin. Oncol. 2006 24 e8 e9 10.1200/JCO.2005.04.1327 16484690

63. Block K. Koch A.C. Mend M.N. Tothy P.K. Newman R.A. Gyllenhaal C. Impact of antioxidant supplementation on chemotherapeutic efficacy: A systematic review of the evidence from randomized controlled trials Cancer Treat. Rev. 2007 33 407 418 10.1016/j.ctrv.2007.01.005 17367938

64. Gröber U. Micronutrients in complementary oncology Med. Monatsschr. Pharm. 2008 31 217 223 18661912

65. Norman H.A. Butrum R.R. Feldman E. Heber D. Nixon D. Picciano M.F. Rivlin R. Simopoulos A. Wargovich M.J. The role of dietary supplements during cancer therapy J. Nutr. 2003 133 Suppl. 11 S3794 S3799 10.1093/jn/133.11.3794S 14608116

66. Rock C.L. Doyle C. Demark-Wahnefried W. Nutrition and physical activity guidelines for cancer survivors CA. Cancer J. Clin. 2012 62 243 274 10.3322/caac.21142 22539238

67. Hoffman F.L. The Mortality from Cancer throughout the World Prudential Press Newark, NJ, USA 1916

68. Peller S. Stephenson C.S. Skin irritation and Cancer in the US navy Am. J. Med. Sci. 1937 194 326 333 10.1097/00000441-193709000-00004

69. Apperly F.L. The relation of solar radiation to cancer mortality in North America Cancer Res. 1941 1 191 195 10.1158/0008-5472.CAN-15-3169 26773094

70. Garland C.F. Garland F.C. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int. J. Epidemiol. 1980 9 227 231 10.1093/ije/9.3.227 7440046

71. Garland C.F. Comstock G.W. Garland F.C. Helsing K.J. Shaw E.K. Gorham E.D. Serum 25-hydroxyvitamin D and colon cancer: Eight-year prospective study Lancet 1989 2 1176 1178 10.1016/S0140-6736(89)91789-3 2572900

72. Lefkowitz E.S. Garland C.F. Sunlight, vitamin D, and ovarian cancer mortality rates in US women Int. J. Epidemiol. 1994 23 1133 1136 10.1093/ije/23.6.1133 7721513

73. Garland F.C. Garland C.F. Gorham E.D. Young J.F. Geographic variation in breast cancer mortality in the United States: A hypothesis involving exposure to solar radiation Prev. Med. 1990 19 614 622 10.1016/0091-7435(90)90058-R 2263572

74. Mizoue T. Ecological study of solar radiation and cancer mortality in Japan Health Phys. 2004 87 532 538 10.1097/01.HP.0000137179.03423.0b 15551791

75. Hanchette C.L. Schwartz G.G. Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation Cancer 1992 70 2861 2869 10.1002/1097-0142(19921215)70:12<2861::AID-CNCR2820701224>3.0.CO;2-G 1451068

76. Grant W.B. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation Cancer 2002 94 1867 1875 10.1002/cncr.10427 11920550

77. Grant W.B. Ecological studies of the UVB-vitamin D-cancer hypothesis Anticancer Res. 2012 32 223 236 22213311

78. Grant W.B. Update on evidence that support a role of solar ultraviolet-B irradiance in reducing cancer risk Anticancer Agents Med. Chem. 2013 13 140 146 10.2174/187152013804487425 23094927

79. Boscoe F.P. Schymura M.J. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993–2002 BMC Cancer 2006 6 264 10.1186/1471-2407-6-264 17096841 PMC1665523

80. Knight J.A. Lesosky M. Barnett H. Raboud J.M. Vieth R. Vitamin D and reduced risk of breast cancer: A population-based case-control study Cancer Epidemiol. Biomark. Prev. 2007 16 422 429 10.1158/1055-9965.EPI-06-0865 17372236

81. Luscombe C.J. Fryer A.A. French M.E. Liu S. Saxby M.F. Jones P.W. Strange R.C. Exposure to ultraviolet radiation: Association with susceptibility and age at presentation with prostate cancer Lancet 2001 358 641 642 10.1016/S0140-6736(01)05788-9 11530156

82. Giovannucci E. Liu Y. Rimm E.B. Hollis B.W. Stampfer M.J. Willett W.C. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men J. Natl. Cancer Inst. 2006 98 451 459 10.1093/jnci/djj101 16595781

83. Grant W.B. Role of solar UVB irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries Dermato-Endocrinology 2012 4 203 211 10.4161/derm.20965 22928078 PMC3427201

84. Lin S.W. Wheeler D.C. Park Y. Cahoon E.K. Hollenbeck A.R. Freedman D.M. Abnet C.C. Prospective study of ultraviolet radiation exposure and risk of cancer in the United States Int. J. Cancer 2012 131 E1015 E1023 10.1002/ijc.27619 22539073 PMC3402606

85. Holick M.F. Vitamin D deficiency N. Engl. J. Med. 2007 357 266 281 10.1056/NEJMra070553 17634462

86. Gröber U. Holick M.F. Vitamin D. Die Heilkraft des Sonnenvitamins. 3. Auflage, 340 S Wissenschaftliche Verlagsgesellschaft Stuttgart, Germany 2015

87. Wacker M. Holick M.F. Vitamin D—Effects on skeletal and extraskeletal health and the need for supplementation Nutrients 2013 5 111 148 10.3390/nu5010111 23306192 PMC3571641

88. Mohr S.B. Gorham E.D. Kim J. Hofflich H. Garland C.F. Meta-analysis of vitamin D sufficiency for improving survival of patients with breast cancer Anticancer Res. 2014 34 1163 1166 24596354

89. Gröber U. Reichrath J. Holick M.F. Live longer with vitamin D? Nutrients 2015 7 1871 1880 10.3390/nu7031871 25774604 PMC4377887

90. Holick M.F. Binkley N.C. Bischoff-Ferrari H.A. Endocrine Society Evaluation, treatment, and prevention of vitamin D deficiency: An endocrine society clinical practice guideline J. Clin. Endocrinol. Metab. 2011 96 1911 1930 10.1210/jc.2011-0385 21646368

91. Abbas S. Linseisen J. Slanger T. Kropp S. Mutschelknauss E.J. Flesch-Janys D. Chang-Claude J. Serum 25-hydroxyvitamin D and risk of postmenopausal breast cancer—Results of a large casecontrol study Carcinogenesis 2008 29 93 99 10.1093/carcin/bgm240 17974532

92. Gorham E.D. Garland C.F. Garland F.C. Mohr S.B. Lipkin M. Newmark H.L. Giovannucci E. Wei M. Holick M.F. Optimal vitamin D status for colorectal cancer prevention: A quantitative meta analysis Am. J. Prev. Med. 2007 32 210 216 10.1016/j.amepre.2006.11.004 17296473

93. Drake M.T. Maurer M.J. Link B.K. Habermann T.M. Ansell S.M. Micallef I.N. Kelly J.L. Macon W.R. Nowakowski G.S. Vitamin D insufficiency and prognosis in non-Hodgkin’s lymphoma J. Clin. Oncol. 2010 28 4191 4198 10.1200/JCO.2010.28.6674 20713849 PMC2953973

94. Yin L. Grandi N. Raum E. Haug U. Meta-analysis: Longitudinal studies of serum vitamin D and colorectal cancer risk Aliment. Pharmacol. Ther. 2009 30 113 125 10.1111/j.1365-2036.2009.04022.x 19392870

95. Goodwin P.J. Ennis M. Pritchard K.I. Koo J. Hood N. Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer J. Clin. Oncol. 2009 27 3757 3763 10.1200/JCO.2008.20.0725 19451439

96. Chen G.C. Zhang Z.L. Wan Z. Wang L. Weber P. Eggersdorfer M. Qin L.Q. Zhang W. Circulating 25-hydroxyvitamin D and risk of lung cancer: A dose-response meta-analysis Cancer Causes Control 2015 26 1719 1728 10.1007/s10552-015-0665-6 26358829

97. Zhang L. Wang S. Che X. Li X. Vitamin D and lung cancer risk: A comprehensive review and meta-analysis Cell Physiol. Biochem. 2015 36 299 305 10.1159/000374072 25967968

98. Maalmi H. Ordóñez-Mena J.M. Schöttker B. Brenner H. Serum 25-hydroxyvitamin D levels and survival in colorectal and breast cancer patients: Systematic review and meta-analysis of prospective cohort studies Eur. J. Cancer 2014 50 1510 1521 10.1016/j.ejca.2014.02.006 24582912

99. Kim Y. Je Y. Vitamin D intake, blood 25(OH)D levels, and breast cancer risk or mortality: A meta-analysis Br. J. Cancer 2014 110 2772 2784 10.1038/bjc.2014.175 24714744 PMC4037823

100. Schöttker B. Jorde R. Peasey A. Thorand B. Jansen E.H. Groot L.D. Streppel M. Gardiner J. Ordóñez-Mena J.M. Perna L. Vitamin D and mortality: Meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States BMJ 2014 348 10.1136/bmj.g3656 24938302 PMC4061380

101. Printz C. High vitamin D levels increase survival rates in patients with metastatic colorectal cancer Cancer 2015 121 2105 10.1002/cncr.29513 26878558

102. Zhang K. Song L. Association between vitamin D receptor gene polymorphisms and breast cancer risk: A meta-analysis of 39 studies PLoS ONE 2014 9 163 10.1371/journal.pone.0096125 24769568 PMC4000223

103. Lappe J.M. Travers-Gustafson D. Davies K.M. Recker R.R. Heaney R.P. Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial Am. J. Clin. Nutr. 2007 85 1586 1591 17556697 10.1093/ajcn/85.6.1586

104. Bade B. Zdebik A. Wagenpfeil S. Gräber S. Geisel J. Vogt T. Reichrath J. Low serum 25-hydroxyvitamin D concentrations are associated with increased risk for melanoma and unfavourable prognosis PLoS ONE 2014 9 163 10.1371/journal.pone.0112863 25437008 PMC4249825

105. Santini D. Galluzzo S. Vincenzi B. Zoccoli A. Ferraro E. Lippi C. Altomare V. Tonini G. Bertoldo F. Longitudinal evaluation of vitamin D plasma levels during anthracycline—And docetaxel-based adjuvant chemotherapy in early-stage breast cancer patients Ann. Oncol. 2010 21 185 186 10.1093/annonc/mdp497 19892747

106. Fink M. Vitamin D deficiency is a cofactor of chemotherapy-induced mucocutaneous toxicity and dysgeusia J. Clin. Oncol. 2011 29 e81 e82 10.1200/JCO.2010.31.5317 21060025

107. Zhang B. Xie W. Krasowski M.D. PXR: A xenobiotic receptor of diverse function implicated in pharmacogenetics Pharmacogenomics 2008 9 1695 1709 10.2217/14622416.9.11.1695 19018724 PMC2593625

108. Gröber U. Kisters K. Influence of drugs on vitamin D and calcium metabolism Dermato-Endocrinology 2012 4 158 166 10.4161/derm.20731 22928072 PMC3427195

109. Khan Q.J. Reddy P.S. Kimler B.F. Sharma P. Baxa S.E. O’Dea A.P. Klemp J.R. Fabian C.J. Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer Breast Cancer Res. Treat. 2010 119 111 118 10.1007/s10549-009-0495-x 19655244 PMC4182952

110. Rastelli A.L. Taylor M.E. Gao F. Armamento-Villareal R. Jamalabadi-Majidi S. Napoli N. Ellis M.J. Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): A phase II, double-blind, placebo-controlled, randomized trial Breast Cancer Res. Treat. 2011 129 107 116 10.1007/s10549-011-1644-6 21691817

111. Carmel A.S. Shieh A. Bang H. Bockman R.S. The 25(OH)D level needed to maintain a favorable bisphosphonate response is ≥33 ng/mL Osteoporos. Int. 2012 23 2479 2487 10.1007/s00198-011-1868-7 22237813 PMC3893033

112. Berruti A. Cook R. Saad F. Buttigliero C. Lipton A. Tampellini M. Lee K.A. Coleman R.E. Smith M.R. Berruti A. Prognostic role of serum parathyroid hormone levels in advanced prostate cancer patients undergoing zoledronic acid administration Oncologist 2012 17 645 652 10.1634/theoncologist.2011-0448 22523198 PMC3360904

113. Hokugo A. Christensen R. Chung E.M. Sung E.C. Felsenfeld A.L. Sayre J.W. Garrett N. Adams J.S. Nishimura I. Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats J. Bone Miner. Res. 2010 25 1337 1349 10.1002/jbmr.23 20200938 PMC3153137

114. Favus M.J. Bisphosphonates for osteoporosis N. Engl. J. Med. 2010 363 2027 2035 10.1056/NEJMct1004903 21083387

115. Bedogni A. Saia G. Bettini G. Tronchet A. Totola A. Bedogni G. Tregnago P. Valenti M.T. Bertoldo F. Ferronato G. Osteomalacia: The missing link in the pathogenesis of bisphosphonate-related osteonecrosis of the jaws? Oncologist 2012 17 1114 1119 10.1634/theoncologist.2012-0141 22723507 PMC3425530

116. Epperla N. Pathak R. Hypocalcemia secondary to zoledronate therapy in a patient with low vitamin D level WMJ 2015 114 163 166 26436186

117. Bergman P. Sperneder S. Höijer J. Low vitamin D levels are associated with higher opioid dose in palliative cancer patients—Results from an observational study in Sweden PLoS ONE 2015 10 163 10.1371/journal.pone.0128223 26018761 PMC4446094

118. Bittenbring J.T. Neumann F. Altmann B. Achenbach M. Reichrath J. Ziepert M. Geisel J. Regitz E. Held G. Pfreundschuh M. Vitamin D deficiency impairs rituximab-mediated cellular cytotoxicity and outcome of patients with diffuse large B-cell lymphoma treated with but not without rituximab J. Clin. Oncol. 2014 32 3242 3248 10.1200/JCO.2013.53.4537 25135997

119. Baggerly C.A. Cuomo R.E. French C.B. Garland C.F. Gorham E.D. Grant W.B. Heaney R.P. Holick M.F. Hollis B.W. McDonnell S.L. Sunlight and vitamin D: Necessary for public health J. Am. Coll. Nutr. 2015 34 359 365 10.1080/07315724.2015.1039866 26098394 PMC4536937

120. Grant W. Roles of solar UVB and vitamin D in reducing cancer risk and increasing survival Anticancer Res. 2016 36 in press 26977037

121. Fearon K.C. Cancer cachexia: Developing multimodal therapy for a multidimensional problem Eur. J. Cancer 2008 44 1124 1132 10.1016/j.ejca.2008.02.033 18375115

122. Polly P. Tan T.C. The role of vitamin D in skeletal and cardiac muscle function Front. Physiol. 2014 5 145 10.3389/fphys.2014.00145 24782788 PMC3995052

123. Hopkins M.H. Owen J. Ahearn T. Fedirko V. Flanders W.D. Jones D.P. Bostick R.M. Effects of supplemental vitamin D and calcium on biomarkers of inflammation in colorectal adenoma patients: A randomized, controlled clinical trial Cancer Prev Res. (Phila.) 2011 4 1645 1654 10.1158/1940-6207.CAPR-11-0105 21724580 PMC3188339

124. Bacchetta J. Zaritsky J.J. Sea J.L. Chun R.F. Lisse T.S. Zavala K. Nayak A. Wesseling-Perry K. Westerman M. Hollis B.W. Suppression of iron-regulatory hepcidin by vitamin D J. Am. Soc. Nephrol. 2014 25 564 572 10.1681/ASN.2013040355 24204002 PMC3935584

125. Ghorbanzadeh-Moghaddam A. Gholamrezaei A. Hemati S. Vitamin D deficiency is associated with the severity of radiation-induced proctitis in cancer patients Int. J. Radiat. Oncol. Biol. Phys. 2015 92 613 618 10.1016/j.ijrobp.2015.02.011 25890844

126. Hill A.B. The environment and disease: Association or causation? Proc. R. Soc. Med. 1965 58 295 300 10.1177/0141076814562718 14283879 PMC1898525

127. Potischman N. Weed D.L. Causal criteria in nutritional epidemiology Am. J. Clin. Nutr. 1999 69 1309S 1314S 10359231 10.1093/ajcn/69.6.1309S

128. Grant W.B. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using hill's criteria for causality Dermato-Endocrinology 2009 1 17 24 10.4161/derm.1.1.7388 20046584 PMC2715209

129. Grant W.B. Long follow-up time and different sensitivities of cancer types may have obscured the effect of 25-hydroxyvitamin D on cancer incidence and mortality rates Am. J. Clin. Nutr. 2015 102 230 10.3945/ajcn.114.102129 26135035 PMC4480664

130. Bellinger F.P. Raman A.V. Reeves M.A. Berry M.J. Regulation and function of selenoproteins in human disease Biochem. J. 2009 422 11 22 10.1042/BJ20090219 19627257 PMC2912286

131. Wallenberg M. Misra S. Wasik A.M. Marzano C. Björnstedt M. Gandin V. Fernandes A.P. Selenium induces a multi-targeted cell death process in addition to ROS formation J. Cell Mol. Med. 2014 18 671 684 10.1111/jcmm.12214 24400844 PMC4000118

132. Wallenberg M. Misra S. Björnstedt M. Selenium cytotoxicity in cancer Basic Clin. Pharmacol. Toxicol. 2014 114 377 386 10.1111/bcpt.12207 24529300

133. Clark L.C. Combs G.F. Jr. Turnbull B.W. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group JAMA 1996 276 1957 1963 10.1001/jama.1996.03540240035027 8971064

134. Schrauzer G.N. White D.A. Schneider C.J. Cancer mortality correlation studies-III: Statistical associations with dietary selenium intakes Bioinorg. Chem. 1977 7 23 31 10.1016/S0006-3061(00)80126-X 856291

135. Willett W.C. Polk B.F. Morris J.S. Stampfer M.J. Pressel S. Rosner B. Taylor J.O. Schneider K. Hames C.G. Prediagnostic serum selenium and risk of cancer Lancet 1983 2 130 134 10.1016/S0140-6736(83)90116-2 6134981

136. Whanger P.D. Selenium and its relationship to cancer: An update dagger Br. J. Nutr. 2004 91 11 28 10.1079/BJN20031015 14748935

137. Lopez-Saez J.B. Senra-Varela A. Pousa-Estevez L. Selenium in breast cancer Oncology 2003 64 227 231 10.1159/000069312 12697962

138. Shamberger R.J. Willis C.E. Selenium distribution and human cancer mortality CRC Crit. Rev. Clin. Lab. Sci. 1971 2 211 221 10.3109/10408367109151308 4950948

139. Hughes D.J. Fedirko V. Jenab M. Schomburg L. Méplan C. Freisling H. Bueno-de-Mesquita H.B. Hybsier S. Becker N.P. Czuban M. Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort Int. J. Cancer 2015 136 1149 1161 10.1002/ijc.29071 25042282

140. Pourmand G. Salem S. Moradi K. Serum selenium level and prostate cancer: A case-control study Nutr. Cancer 2008 60 171 176 10.1080/01635580701627277 18444148

141. Reid M.E. Duffield-Lillico A.J. Slate E. Natarajan N. Turnbull B. Jacobs E. The nutritional prevention of cancer: 400 mcg per day selenium treatment Nutr. Cancer 2008 60 155 163 10.1080/01635580701684856 18444146

142. Facompre N. El-Bayoumy K. Potential stages for prostate cancer prevention with selenium: Implications for cancer survivors Cancer Res. 2009 69 2699 2703 10.1158/0008-5472.CAN-08-4359 19318549 PMC2909787

143. Duffield-Lillico A.J. Dalkin B.L. Reid M.E. Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: An analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial BJU Int. 2003 91 608 612 10.1046/j.1464-410X.2003.04167.x 12699469

144. Rayman M.P. Selenoproteins and human health: Insights from epidemiological data Biochim. Biophys. Acta 2009 1790 1533 1540 10.1016/j.bbagen.2009.03.014 19327385

145. Dennert G. Zwahlen M. Brinkman M. Vinceti M. Zeegers M.P. Horneber M. Selenium for preventing cancer (review) Cochrane Database Syst. Rev. 2011 11 10.1002/14651858.CD005195.pub2 PMC3692366 21563143

146. Vinceti M. Dennert G. Crespi C.M. Zwahlen M. Brinkman M. Zeegers M.P. Horneber M. D’Amico R. del Giovane C. Selenium for preventing cancer Cochrane Database Syst. Rev. 2014 3 10.1002/14651858.CD005195.pub3 PMC4441528 24683040

147. Lippmann S.M. Klein E.A. Goodman P.J. Lucia M.S. Thompson I.M. Ford L.G. Parnes H.L. Minasian L.M. Gaziano J.M. Hartline J.A. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: The selenium and vitamin E cancer prevention trial (SELECT) JAMA 2009 301 39 51 10.1001/jama.2008.864 19066370 PMC3682779

148. Bleys J. Navas-Acien A. Guallar E. Serum selenium levels and all cause, cancer, and cardiovascular mortality among US adults Arch. Intern. Med. 2008 168 404 410 10.1001/archinternmed.2007.74 18299496

149. Rayman M.P. Selenium and human health Lancet 2012 379 1256 1268 10.1016/S0140-6736(11)61452-9 22381456

150. Chiang E.C. Shen S. Kengeri S.S. Xu H. Combs G.F. Morris J.S. Bostwick D.G. Waters D.J. Defining the optimal selenium dose for prostate cancer risk reduction: Insights from the U-Shaped relationship between selenium status, DNA damage, and apoptosis Dose Response 2009 8 285 300 10.2203/dose-response.09-036.Chiang 20877485 PMC2939616

151. Kristal A.R. Darke A.K. Morris J.S. Tangen C.M. Goodman P.J. Thompson I.M. Meyskens F.L. Jr. Goodman G.E. Minasian L.M. Parnes H.L. Baseline selenium status and effects of selenium and vitamin E supplementation on prostate cancer risk J. Natl. Cancer Inst. 2014 106 10.1093/jnci/djt456 24563519 PMC3975165

152. Geybels M.S. van den Brandt P.A. Schouten L.J. van Schooten F.J. van Breda S.G. Rayman M.P. Green F.R. Verhage B.A. Selenoprotein gene variants, toenail selenium levels, and risk for advanced prostate cancer J. Natl. Cancer. Inst. 2014 106 10.1093/jnci/dju003 24563517

153. Hu Y.J. Chen Y. Zhang Y.Q. Zhou M.Z. Song X.M. Zhang B.Z. Luo L. Xu P.M. Zhao Y.N. Zhao Y.B. The protective role of selenium on the toxicity of cisplatinum-contained chemotherapy regimen in cancer patients Biol. Trace Elem. Res. 1997 56 331 341 10.1007/BF02785304 9197929

154. Asfour I.A. Shazly S.E. Fayek M.H. Effect of high-dose sodium selenite therapy on polymorphonuclear leukocyte apoptosis in non-Hodgkin’s lymphoma patients Biol. Trace Elem. Res. 2006 110 19 32 10.1385/BTER:110:1:19 16679545

155. Asfour I.A. Fayek M.H. Raouf S. The impact of high-dose sodium selenite therapy on Bcl-2 expression in adult non-Hodgkin’s lymphoma patients: Correlation with response and survival Biol. Trace Elem. Res. 2007 120 1 10 10.1007/s12011-007-0029-5 17916949

156. Büntzel J. Riesenbeck D. Glatzel M. Berndt-Skorka R. Riedel T. Mücke R. Kisters K. Schönekaes K.G. Schäfer U. Bruns F. Limited effects of selenium substitution in the prevention of radiation-associated toxicities. Results of a randomized study in head and neck cancer patients Anticancer Res. 2010 30 1829 1832 20592387

157. Mücke R. Schomburg L. Glatzel M. Multicenter, phase III trial comparing selenium supplementation with observation in gynecologic radiation oncology Int. J. Radiat. Oncol. Biol. Phys. 2010 70 825 835 10.1016/j.ijrobp.2009.08.013 20133068

158. Muecke R. Micke O. Schomburg L. Buentzel J. Glatzel M. Baaske D. Berndt-Skorka R. Prott F.J. Reichl B. Kisters K. Impact of treatment planning target volumen (PTV) size on radiation induced diarrhoea following selenium supplementation in gynecologic radiation oncology—A subgroup analysis of a multicenter, phase III trial Radiat. Oncol. 2013 8 72 10.1186/1748-717X-8-72 23531280 PMC3621795

159. Brodin O. Eksborg S. Wallenberg M. Asker-Hagelberg C. Larsen E.H. Mohlkert D. Lenneby-Helleday C. Jacobsson H. Linder S. Misra S. Pharmacokinetics and toxicity of sodium selenite in the treatment of patients with carcinoma in a phase I clinical trial: The SECAR Study Nutrients 2015 7 4978 4994 10.3390/nu7064978 26102212 PMC4488827

160. Karlic H. Lohninger A. Supplementation of l -carnitine in athletes: Does it make sense? Nutrition 2004 20 709 715 10.1016/j.nut.2004.04.003 15212755

161. Bianchi G. Vitali G. Caraceni A. Ravaglia S. Capri G. Cundari S. Zanna C. Gianni L. Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl- l -carnitine Eur. J. Cancer 2005 41 1746 1750 10.1016/j.ejca.2005.04.028 16039110

162. De Grandis D. Acetyl- l -carnitine for the treatment of chemotherapy-induced peripheral neuropathy: A short review CNS Drugs 2007 21 Suppl. 1 39 43 10.2165/00023210-200721001-00006 17696592

163. Haschke M. Vitins T. Lüde S. Urinary excretion of carnitine as a marker of proximal tubular damage associated with platin-based antineoplastic drugs Nephrol. Dial. Transplant. 2010 25 426 433 10.1093/ndt/gfp456 19736245

164. Hockenberry M.J. Hooke M.C. Gregurich M. McCarthy K. Carnitine plasma levels and fatigue in children/adolescents receiving cisplatin, ifosfamide, or doxorubicin J. Pediatr. Hematol. Oncol. 2009 31 664 669 10.1097/MPH.0b013e3181b259a7 19707160

165. Graziano F. Bisonni R. Catalano V. Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients Br. J. Cancer 2002 86 1854 1857 10.1038/sj.bjc.6600413 12085175 PMC2375434

166. Sayed-Ahmed M.M. Role of carnitine in cancer chemotherapy-induced multiple organ toxicity Saudi Pharm. J. 2010 18 195 206 10.1016/j.jsps.2010.07.008 23960728 PMC3730973

167. Al-Majed A.A. Sayed-Ahmed M.M. Al-Yahya A.A. Propionyl- l -carnitine prevents the progression of cisplatin-induced cardiomyopathy in a carnitine-depleted rat model Pharmacol. Res. 2006 53 278 286 10.1016/j.phrs.2005.12.005 16436331

168. Iwase S. Kawaguchi T. Yotsumoto D. Efficacy and safety of an amino acid jelly containing coenzyme Q10 and l -carnitine in controlling fatigue in breast cancer patients receiving chemotherapy: A multi-institutional, randomized, exploratory trial (JORTC-CAM01) Support. Care Cancer 2016 24 637 646 10.1007/s00520-015-2824-4 26105516

169. Wenzel U. Nickel A. Daniel H. Increased carnitine-dependent fatty acid uptake into mitochondria of human colon cancer cells induces apoptosis J. Nutr. 2005 135 1510 1514 15930461 10.1093/jn/135.6.1510

170. Heuberger W. Berardi S. Jacky E. Pey P. Increased urinary excretion of carnitine in patients treated with cisplatin Eur. J. Clin. Pharmacol. 1998 54 503 508 10.1007/s002280050504 9832290

171. Marthaler N.P. Visarius T. Küpfer A. Lauterburg B.H. Increased urinary losses of carnitine during ifosfamide chemotherapy Cancer Chemother. Pharmacol. 1999 44 170 172 10.1007/s002800050963 10412953

172. Armenian S.H. Gelehrter S.K. Vase T. Venkatramani R. Landier W. Wilson K.D. Herrera C. Reichman L. Menteer J.D. Carnitine and cardiac dysfunction in childhood cancer survivors treated with anthracyclines Cancer Epidemiol. Biomark. Prev. 2014 23 1109 1114 10.1158/1055-9965.EPI-13-1384 24718281 PMC4053243

173. Alshabanah O.A. Hafez M.M. Al-Harbi M.M. Hassan Z.K. Al Rejaie S.S. Asiri Y.A. Sayed-Ahmed M.M. Doxorubicin toxicity can be ameliorated during antioxidant l -carnitine supplementation Oxid. Med. Cell. Longev. 2010 3 428 433 10.4161/oxim.3.6.14416 21307642 PMC3154045

174. Dubourg L. Michoudet C. Cochat P. Baverel G. Human kidney tubules detoxify chloroacetaldehyde, a presumed nephrotoxic metabolite of ifosfamide J. Am. Soc. Nephrol. 2001 12 1615 1623 11461933 10.1681/ASN.V1281615

175. Andrieu-Abadie N. Jaffrezou J.P. Hatem S. l -Carnitine prevents doxorubicin-induced apoptosis of cardiac myocytes: Role of inhibition of ceramide generation FASEB J. 1999 13 1501 1510 10463940 10.1096/fasebj.13.12.1501

176. Chao H.H. Liu J.C. Hong H.J. l -Carnitine reduces doxorubicin-induced apoptosis through a prostacyclin-mediated pathway in neonatal rat cardiomyocytes Int. J. Cardiol. 2011 146 145 152 10.1016/j.ijcard.2009.06.010 19552975

177. Delaney C.E. Hopkins S.P. Addison C.L. Supplementation with l -carnitine does not reduce the efficacy of epirubicin treatment in breast cancer cells Cancer Lett. 2007 252 195 207 10.1016/j.canlet.2006.12.027 17275999

178. Jin H.W. Flatters S.J. Xiao W.H. Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl- l -carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells Exp. Neurol. 2008 210 229 237 10.1016/j.expneurol.2007.11.001 18078936 PMC2323600

179. Yoon H.R. Hong Y.M. Boriack R.L. Bennett M.J. Effect of l -carnitine supplementation on cardiac carnitine palmitoyltransferase activities and plasma carnitine concentrations in adriamycin-treated rats Pediatr. Res. 2003 53 788 792 10.1203/01.PDR.0000057988.62605.13 12621117

180. Campone M. Berton-Rigaud D. Joly-Lobbedez F. Baurain J.F. Rolland F. Stenzl A. Fabbro M. van Dijk M. Pinkert J. A double-blind, randomized phase II study to evaluate the safety and efficacy of acetyl- l -carnitine in the prevention of sagopilone-induced peripheral neuropathy Oncologist 2013 18 1190 1191 10.1634/theoncologist.2013-0061 24105751 PMC3825303

181. Lissoni P. Galli M.A. Tancini G. Barni S. Prevention by l -carnitine of interleukin-2 related cardiac toxicity during cancer immunotherapy Tumori 1993 79 202 204 8236505 10.1177/030089169307900309

182. Waldner R. Laschan C. Lohninger A. Gessner M. Tüchler H. Huemer M. Spiegel W. Karlic H. Effects of doxorubicin-containing chemotherapy and a combination with l -carnitine on oxidative metabolism in patients with non-Hodgkin lymphoma J. Cancer Res. Clin. Oncol. 2006 132 121 128 10.1007/s00432-005-0054-8 16283381 PMC12161048

183. Maestri A. de Pasquale Ceratti A. Cundari S. Zanna C. Cortesi E. Crinò L. A pilot study on the effect of acetyl- l -carnitine in paclitaxel- and cisplatin-induced peripheral neuropathy Tumori 2005 91 135 138 15948540 10.1177/030089160509100206

184. Hershman D.L. Unger J.M. Crew K.D. Minasian L.M. Awad D. Moinpour C.M. Hansen L. Lew D.L. Greenlee H. Randomized double-blind placebo-controlled trial of acetyl- l -carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy J. Clin. Oncol. 2013 31 2627 2633 10.1200/JCO.2012.44.8738 23733756 PMC3699727

185. Sun Y. Baorui L. Ping L. Wu C. Zheng R. Zhang X. Zhuang Z. Deng Y. Zheng L. Xu Q. A prospective study to evaluate the efficacy and safety of oral acetyl- l -carnitine (ALC) in treatment of chemotherapy-induced peripheral neuropathy (CPIN) Proceedings of the 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Chicago, IL, USA 1–5 June 2012; abstract 9017

186. Cruciani R.A. Zhang J.J. Manola J. l -Carnitine supplementation for the management of fatigue in patients with cancer: An eastern cooperative oncology group phase III, randomized, double-blind, placebo-controlled trial J. Clin. Oncol. 2012 30 3864 3869 10.1200/JCO.2011.40.2180 22987089 PMC3478577

187. Cruciani R.A. Dvorkin E. Homel P. Malamud S. Culliney B. Lapin J. Portenoy R.K. Esteban-Cruciani N. Safety, tolerability and symptom outcomes associated with l -carnitine supplementation in patients with cancer, fatigue, and carnitine deficiency: A phase I/II study J. Pain Symptom. Manag. 2006 32 551 559 10.1016/j.jpainsymman.2006.09.001 17157757

188. Stone P. Richardson A. Ream E. Smith A.G. Kerr D.J. Kearney N. Cancer-related fatigue: Inevitable, unimportant and untreatable? Results of a multi-centre patient survey. Cancer Fatigue Forum Ann. Oncol. 2000 11 971 975 10.1023/A:1008318932641 11038033

189. Madeddu C. Dessì M. Panzone F. Serpe R. Antoni G. Cau M.C. Montaldo L. Mela Q. Mura M. Astara G. Randomized phase III clinical trial of a combined treatment with carnitine + celecoxib ± megestrol acetate for patients with cancer-related anorexia/cachexia syndrome Clin. Nutr. 2012 31 176 182 10.1016/j.clnu.2011.10.005 22047681

190. Cruciani R.A. Dvorkin E. Homel P. Culliney B. Malamud S. Lapin J. l -Carnitine supplementation in patients with advanced cancer and carnitine deficiency: A double-blind, placebo-controlled study J. Pain Symptom. Manag. 2009 37 622 631 10.1016/j.jpainsymman.2008.03.021 18809275

191. Gramignano G. Lusso M.R. Madeddu C. Massa E. Serpe R. Deiana L. Efficacy of l -carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Nutrition 2006 22 136 145 10.1016/j.nut.2005.06.003 16459226

192. Laviano A. Rianda S. Molfino A. Fanelli F.R. Omega-3 fatty acids in cancer Curr. Opin. Clin. Nutr. Metab. Care 2013 16 156 161 10.1097/MCO.0b013e32835d2d99 23299701

193. Azrad M. Turgeon C. Demark-Wahnefried W. Current evidence linking polyunsaturated fatty acids with cancer risk and progression Front Oncol. 2013 3 224 10.3389/fonc.2013.00224 24027672 PMC3761560

194. Arshad A. Isherwood J. Mann C. Cooke J. Pollard C. Runau F. Morgan B. Steward W. Metcalfe M. Dennison A. Intravenous ω-3 fatty acids plus gemcitabine: Potential to improve response and quality of life in advanced pancreatic cancer JPEN J. Parenter. Enteral. Nutr. 2015 10.1177/0148607115595221 26220200

195. Gröber U. Hübner J. Holzhauer P. Vitamin C in der komplementären Onkologie Der Onkol. 2010 16 303 313 10.1007/s00761-010-1809-7

196. Günes-Bayir A. Kiziltan H.S. Palliative vitamin C application in patients with radiotherapy-resistant bone metastases: A retrospective study Nutr. Cancer 2015 67 921 925 10.1080/01635581.2015.1055366 26168394

197. Hoffer L.J. Robitaille L. Zakarian R. Melnychuk D. Kavan P. Agulnik J. Cohen V. Small D. Miller W.H. Jr. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: A phase I-II clinical trial PLoS ONE 2015 10 163 10.1371/journal.pone.0120228 25848948 PMC4388666

198. Cieslak J.A. Cullen J.J. Treatment of pancreatic cancer with pharmacological ascorbate Curr. Pharm. Biotechnol. 2015 16 759 770 10.2174/138920101609150715135921 26201606 PMC4895694

199. Kurbacher C.M. Wagner U. Kolster B. Andreotti P.E. Krebs D. Bruckner H.W. Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro Cancer Lett. 1996 103 183 189 10.1016/0304-3835(96)04212-7 8635156

200. Guerriero E. Sorice A. Capone F. Napolitano V. Colonna G. Storti G. Castello G. Costantini S. Vitamin C effect on mitoxantrone-induced cytotoxicity in human breast cancer cell lines PLoS ONE 2014 9 163 10.1371/journal.pone.0115287 25531443 PMC4274052

201. Yiang G.T. Chou P.L. Hung Y.T. Chen J.N. Chang W.J. Yu Y.L. Wei C.W. Vitamin C enhances anticancer activity in methotrexate-treated Hep3B hepatocellular carcinoma cells Oncol. Rep. 2014 32 1057 1063 10.3892/or.2014.3289 24969544 PMC4121419

202. Chen M.F. Yang C.M. Su C.M. Liao J.W. Hu M.L. Inhibitory effect of vitamin C in combination with vitamin K 3 on tumor growth and metastasis of Lewis lung carcinoma xenografted in C57BVL/6 mice Nutr. Cancer 2011 63 1036 1043 10.1080/01635581.2011.597537 21888506

203. Shimpo K. Nagatsu T. Yamada K. Sato T. Niimi H. Shamoto M. Takeuchi T. Umezawa H. Fujita K. Ascorbic acid and adriamycin toxicity Am. J. Clin. Nutr. 1991 54 Suppl. 6 1298S 1301S 1962586 10.1093/ajcn/54.6.1298s

204. Chen Q. Espey M.G. Sun A.Y. Pooput C. Kirk K.L. Krishna M.C. Khosh D.B. Drisko J. Levine M. Pharmacologic doses of ascorbate act as prooxidant and decrease growth of aggressive tumor xenografts in mice Proc. Natl. Acad. Sci. USA 2008 105 11105 11109 10.1073/pnas.0804226105 18678913 PMC2516281

205. Chen Q. Espey M.G. Sun A.Y. Lee J.H. Krishna M.C. Shacter E. Choyke P.L. Pooput C. Kirk K.L. Buettner G.R. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo Proc. Natl. Acad. Sci. USA 2007 104 8749 8754 10.1073/pnas.0702854104 17502596 PMC1885574

206. Gröber U. Vitamin C in complementary oncology—Update 2009 Med. Monatsschr. Pharm. 2009 32 263 267 19731754

207. Ohno S. Ohno Y. Suzuki N. Soma G. Inoue M. High-dose vitamin C (ascorbic acid) therapy in the treatment of patients with advanced cancer Anticancer Res. 2009 29 809 815 19414313

208. Herst P.M. Broadley K.W. Harper J.L. McConnell M.J. Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest Free Radic. Biol. Med. 2012 52 1486 1493 10.1016/j.freeradbiomed.2012.01.021 22342518

209. Shinozaki K. Hosokawa Y. Hazawa M. Kashiwakura I. Okumura K. Kaku T. Nakayama E. Ascorbic acid enhances radiation-induced apoptosis in an HL60 human leukemia cell line J. Radiat. Res. 2011 52 229 237 10.1269/jrr.10089 21343676

210. Castro M.L. McConnell M.J. Herst P.M. Radiosensitisation by pharmacological ascorbate in glioblastoma multiforme cells, human glial cells, and HUVECs depends on their antioxidant and DNA repair capabilities and is not cancer specific Free Radic. Biol. Med. 2014 74 200 209 10.1016/j.freeradbiomed.2014.06.022 24992837

211. Vollbracht C. Schneider B. Leendert V. Weiss G. Auerbach L. Beuth J. Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: Results of a retrospective, multicentre, epidemiological cohort study in Germany Vivo 2011 25 983 990 22021693

212. Drisko J.A. Chapman J. Hunter V.J. The use of antioxidant therapies during chemotherapy Gynecol Oncol. 2003 88 434 439 10.1016/S0090-8258(02)00067-7 12648599

213. Welsh J.L. Wagner B.A. van‘t Erve T.J. Zehr P.S. Berg D.J. Halfdanarson T.R. Yee N.S. Bodeker K.L. Du J. Roberts L.J. 2nd Pharmacological ascorbate with gemcitabine for the control of metastastic and node-positive pancreatic cancer (PACMAN): Results from a phase I clinical trial Cancer Chemother. Pharmacol. 2013 71 765 775 10.1007/s00280-013-2070-8 23381814 PMC3587047

214. Monti D.A. Mitchell E. Bazzan A.J. Littman S. Zabrecky G. Yeo C.J. Pillai M.V. Newberg A.B. Deshmukh S. Levine M. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer PLoS ONE 2012 7 163 10.1371/journal.pone.0029794 22272248 PMC3260161

215. Seo M.S. Kim J.K. Shim J.Y. High-dose vitamin C promotes regression of multiple pulmonary metastases originating from hepatocellular carcinoma Yonsei Med. J. 2015 56 1449 1452 10.3349/ymj.2015.56.5.1449 26256994 PMC4541681

216. PDQ Cancer Complementary and Alternative Medicine Editorial Board High-Dose Vitamin C (PDQ): Health Professional Version. PDQ Cancer Information Summaries National Cancer Institute Bethesda, MD, USA 2002–2015