Effects on the Immune System
The use of dietary supplements that affect the immune system is also a concern for patients with cancer. Patients with malignancies often use CAM with the intention of enhancing the immune system. In a survey of 453 cancer patients with various solid and hematologic malignancies, 83% of the patients had used at least one type of CAM.[1] The majority of CAM users expected the therapy to boost their immune system (71%) and improve their quality of life (76%). Other surveys have also identified boosting the immune system as a reason for using CAM.[83,84]
It is important to remember that the immune system is involved to varying degrees in both hematologic and solid tumor malignancies. By nature of their disease, these patients are immunocompromised, albeit to different degrees. Hematologic malignancies are more profoundly immunosuppressive secondary to the clonal expansion of nonfunctional, immune, cancer cells (T or B lymphocytes). For solid tumors, it is less clear what role the immune system plays in the carcinogenic pathway. In addition, many conventional treatments are immunosuppressive, further compromising the ability of the immune system to function. Also, the immune system is a complex system with many different components. Despite great advances over the past several decades, much about the immune system remains unknown or not well understood. Therefore, extrapolating information from laboratory or animal data or theorizing what effects may occur with dietary supplements and the immune system should be done with caution. There are three general areas for discussion regarding potential benefits and risks for the immune system associated with dietary supplement use: (1) stimulation of the immune system, (2) further immunosuppression induced by dietary supplements, and (3) dietary supplementdrug interactions.
Stimulation of the immune system may be viewed as a potential benefit for many patients; however, it may be problematic for patients with certain diseases, such as leukemia. Leukemia involves uncontrolled proliferation of specific cells within the immune system (myeloid or lymphoid).[85] Theoretically, immune stimulation by dietary supplements may result in or add to the proliferation of these leukemic cells. It is currently unknown what effect immune-stimulating dietary supplements may have on proliferation and differentiation of hematopoietic cells in these patients. Caution should also be used when patients are receiving therapy with colony-stimulating factors pegfilgrastim and filgrastim, because of the presence of the granulocyte colony-stimulating-factor receptor target of pegfilgrastim and filgrastim on tumor cell lines, including some myeloid, T-lymphoid, lung, head and neck, and bladder tumor cell lines.[86,87] The prescribing information for pegfilgrastim states, "the possibility that pegfilgrastim can act as a growth factor for any tumor type cannot be excluded."[86] The sargramostim prescribing information contains similar precautions regarding tumor cell growth and the need to exercise caution, particularly in cancers with myeloid characteristics.[88] While these effects may clearly be detrimental to an untreated patient, many investigators have attempted to exploit this effect by "priming" tumor cells with a growth factor (e.g., filgrastim) and then immediately administering cytotoxic chemotherapy. The theory is that this increases cell proliferation so cell-cycle-specific chemotherapy would be more likely to kill more tumor cells. Along with the increased effect on tumor cells is a corresponding effect on normal cells, leading to increased chemotherapy-related toxicity. Clinical trials examining this practice have been inconclusive, and many clinicians have abandoned this approach because there is no clear benefit and it increases risks associated with more adverse events.[89] The use of myeloid growth factors after chemotherapy to facilitate bone marrow recovery has become common-place in some aspects of cancer treatment. Extrapolating this information to dietary supplements is difficult. Coadministration of dietary immunostimulants with chemotherapy may increase the number of tumor cells killed but may also increase adverse events related to chemotherapy. There is limited laboratory and clinical information investigating these types of interactions, and concerns exist related to the unknown level of risk.
Neutropenia and subsequent serious infections are well-recognized adverse effects of some conventional therapies. Conventional medicine in oncology relies heavily on the use of colony-stimulating factors, such as filgrastim, pegfilgrastim, and sargramostim, to help recover neutrophil counts, prevent infections, and continue to administer necessary cytotoxic therapy. As discussed previously, many patients use dietary supplements to stimulate the immune system, which may be beneficial in patients taking colony-stimulating factors. Another potential benefit that may come with immunostimulation is enhancement of the immune system to fight the cancer itself. This approach to anticancer therapy has been investigated for many years in the realm of conventional medicine with mixed success (e.g., interferon [IFN], interleukin [IL]). The tumor types that most often respond to these types of therapies include hematologic malignancies, melanomas, and renal cell carcinomas. Other solid tumors have generally not been successfully treated with conventional immunotherapies. In cancers that appear somewhat responsive to immunotherapy, concurrent administration of dietary immunostimulants may tip a very intricate balance in the immune system, leading to unpredictable outcomes. Therefore, unless a dietary supplement has sound evidence supporting its safety when coadministered with conventional immunotherapy, the combination should be avoided. However, data in humans supporting the use of dietary immunostimulants as either beneficial or detrimental are limited.
Some dietary supplements have demonstrated immunologic enhancement in vitro, in animals, and, to a limited extent, in humans ( Table 4 ). However, not all studies support this phenomenon. Data in cancer patients are more limited, though melatonin, echinacea, Panax ginseng, and coriolus mushroom (Coriolus versicolor) have been evaluated specifically in cancer patients.[90,91,93,94] Although some of these studies were positive, the following examples help illustrate the variable evidence. Panax ginseng, dong quai (Angelica sinensis), and milk thistle (Silybum marianum) have been shown to enhance lymphocyte proliferation in vitro.[92] A study in rats demonstrated that an extract of astragalus (Astragalus membranaceus) and glossy privet (Ligustrum lucidium) did not prevent cyclophosphamide-induced myelosuppression.[95] In addition, bitter melon (Momordica charantia) did not increase natural killer cells in cervical cancer patients undergoing radiotherapy compared with those who did not receive the supplement.[96] As evidenced by these studies, it is difficult to draw strong conclusions about the efficacy of dietary supplements to enhance the immune system. Also, the complex nature of the immune system makes extrapolation of these data to humans even more difficult.
As an example, we can look at the data for one of the most commonly used dietary supplements that have been studied in cancer patients. Echinacea may be the most well-known dietary supplement used as an immunostimulant. Several randomized, placebo-controlled trials have studied the immunostimulant activities of Echinacea species for the prevention or treatment of the common cold. A recent review concluded that studies of Echinacea species do not support their use for the prevention of the common cold, but some studies support their use for early treatment.[97] Conversely, studies of Echinacea species for treating cancer-related illnesses are limited. The effect of an extract of Echinacea angustifolia on cytokine production was studied using blood samples from 23 patients with solid tumor malignancies after curative surgery.[98] No significant differences in cytokine levels (IL-1, IL-2, IL-6, tumor necrosis factor [TNF] α, IFN-γ) were seen after two or four weeks of echinacea therapy. In addition, no significant differences in absolute leukocyte, lymphocyte, monocyte, or granulocyte counts were observed.
A study of 15 patients with advanced, pretreated colorectal cancer evaluated the toxicity and immunostimulating potential of low-dose cyclophosphamide (300 mg/m[2] ) and thymostimulin plus Echinacea purpurea extract.[94] Significant increases in CD3+ and CD4+ T lymphocytes and natural killer cells were observed. Significant decreases in CD8+ T lymphocytes and the CD4:CD8 ratio also occurred, while no significant changes in the number of B lymphocytes or other leukocytes occurred. This study has several factors limiting its clinical significance, including its difficulty differentiating the effects of the individual agents in this regimen, the small number of patients, and the lack of an active or historical control. Nevertheless, concerns regarding the decreased CD8+ T lymphocytes and the CD4:CD8 ratio remain.Prolonged use of echinacea has been associated with leukopenia.[99] This illustrates the complex nature of the immune system and the effects dietary supplements may have on these intricate processes. Cancer patients should use echinacea with caution and should not ingest it for extended periods of time. Use of any immunostimulant should also be evaluated in the context of the individual clinical situation, concurrent medications, and other underlying conditions. For example, a patient receiving immunosuppressive therapy for rheumatoid arthritis should avoid dietary immunostimulants. However, the risks and benefits of each therapy should be evaluated independently in the context of that patients clinical situation and goals of therapy.
An important consideration is that immunosuppression is a potential adverse effect of some dietary supplements. As previously mentioned, long-term use of echinacea may cause immunosuppression.[99] Immunocompromised states and immunosuppressant therapies have been commonly listed as supplementdisease and drugsupplement interactions, respectively, with echinacea.[100,101,102] Other problematic dietary supplements include green tea and ginger (Zingiber officinale), which have demonstrated suppression of lymphocyte proliferation in vitro via inhibition of IL-2 production.[92] Clinical outcomes related to these laboratory findings are unknown, but these changes could be harmful for patients already significantly immunosuppressed by their disease or concurrent medications.
Immunosuppressant medications are necessary to prevent graft-versus-host disease (GVHD), maintain engraftment after bone marrow transplantation, and prevent donor organ rejection in solid organ transplantation. Therefore, it is important to avoid pharmacokinetic and pharmacodynamic drug interactions that may interfere with the role of immunosuppressants. Echinacea and other dietary supplements that stimulate the immune system may antagonize the actions of immunosuppressants and could lead to rejection of the transplant or exacerbation of GVHD. While this pharmacodynamic interaction remains theoretical, it has been recognized as a potential problem in renal transplantation.[103] Based on the potential for immunostimulation and life-threatening outcomes, it has been recommended that echinacea be avoided by patients receiving antirejection medications, such as azathioprine, tacrolimus, corticosteroids, and cyclosporine.[104,105]
Drug interactions have been documented with concomitant use of St. Johns wort and both cyclosporine and tacrolimus in solid organ transplant recipients.[106,107,108,109,110,111,112] The interaction is likely the result of induction of CYP3A4 isoenzymes by St. Johns wort, leading to decreased levels of the immunosuppressive agents that are metabolized by this isoenzyme. The interaction with cyclosporine occurred between three days and several weeks of initiating concomitant therapy. Cyclosporine dosage adjustments were attempted but were often not adequate to compensate for the decrease in serum drug concentrations. Tacrolimus dosage adjustments were able to compensate for decreased tacrolimus levels in 10 renal transplant recipients.[111] These factors make management of post-transplantation regimens difficult.
Garlic (Allium sativum) may also be used as an immunostimulant and poses at least two concerns for bone marrow transplant recipients. Similar to echinacea, the stimulating effects of garlic on the immune system may reverse or antagonize the actions of the immunosuppressant agents. The second concern is the induction of CYP3A4 isoenzymes by allicin, a therapeutically active component of garlic.[104] Similar to the interaction with St. Johns wort, this interaction may lower plasma concentrations of tacrolimus, cyclosporine, or other drugs, resulting in subtherapeutic levels of the immunosuppressant. This interaction has not been documented with any of these agents, but a 50% decrease in the area under the concentrationtime curve was reported with saquinavir, another substrate of the CYP3A4 isoenzyme.[113]
Clinicians should review dietary supplements on an individual basis to assess their potential for immunosuppression or immunostimulation and the potential benefits and risks to patients. Dietary supplements such as echinacea may be beneficial for immune system support in some patients; however, these data are not strong, and the agent should not be recommended. Rather, clinicians may choose to accept their patients desire to utilize this product based on the patients individual situation. Long-term use of echinacea should be discouraged because immunosuppression may occur. Use of dietary immunostimulants should be discouraged in patients with hematologic malignancies until further safety data are available. Bone marrow transplant recipients should avoid immunostimulants, St. Johns wort, garlic supplements, and other CYP3A4 inducers. While dietary supplements for immune system support may sound promising to some cancer patients, there are several potentially serious safety issues to discuss. In addition, the data supporting their efficacy in this respect are limited.
Am J Health Syst Pharm. 2007;64(5):467-480. © 2007 American Society of Health-System Pharmacists
Cite this: Dietary Supplements in Patients With Cancer: Risks and Key Concepts, Part 2 - Medscape - Mar 01, 2007.
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