Integrative Oncology – An Overview
Ira Cantor, MD
Copyright © 2006

The last two decades of the twentieth century saw the development of the field of integrative medicine. This discipline developed out of a core of basic needs and impulses.

There was a sense, initially from patients, and eventually from practitioners, that there were important gaps in the generally recognized and practiced approach to health and illness.  These included most particularly the role of nutrition (diet and natural supplements), and the effect of the psyche on the body (mindbody medicine).

There was a dissatisfaction with the complete reliance on established scientific methods such as randomized, double blind studies.  Patients with illnesses that were inadequately addressed by conventional treatments were willing and interested in exploring treatment methods that weren’t as strongly validated, and were likely to be safe.  Many of these treatments involved natural substances, such as herbs, that had a long history of apparently safe use in traditional medical approaches from other cultures, such as those from the Far East ( traditional Chinese medicine ), East Indian ( ayurvedic ), native American, as well as European cultures which had used plant based medicines for centuries.

Patients wanted to share responsibility and decision making with their health care practitioners.  Therefore, treatment approaches that they could control and choose, such as diet, exercise, psychological methods, and the use of readily available, often non-regulated, and apparently safe substances, such as vitamins, minerals and herbs, became very attractive and widely used.

Historically, practioners of integrative medicine have tended to deal with certain types of medical situations.  These have included (a) preventive medicine, (b) illnesses with a self limiting course, such as viral and mild bacterial infections like otitis media, and (c) illnesses and symptoms where the conventional diagnostic and treatment options were very limited.  These latter illnesses are extremely prevalent, and include chronic fatigue, fibromyalgia and other chronic pain conditions, irritable bowel and other “functional” digestive illnesses, and environmental and food allergies.  Many patients with malignant illnesses, particularly in situations where conventional options are limited and potentially more toxic, also began searching for other treatment options.

There were very few “alternative” approaches that had any level of scientific validity, and treatments were either taken from traditional, historical usage, or their effects were described in quasi-scientific terms, such as their ability to “strengthen the immune system”.

However, two interrelated developments have led to the present practice of  “Integrative Oncology”, which is considerably more scientifically based, and can with justification be described as Integrative as opposed to “alternative”. The first of these developments has been the considerable scientific interest in studying natural substances, such as herbs and vitamins, as well as documenting the effects of psychological processes like meditation.  The second development has been the deepening scientific understanding of malignancies, leading to the growing understanding of processes such as signal transduction, apoptosis, angiogenesis, etc, and the subsequent development of targeted therapies. As we’ve begun to uncover the basis of essential processes like angiogenesis and apoptosis, we’ve also discovered that many natural substances have effects on these processes.  As an example, a substance such as genistein, which is an isoflavone present in soy foods, has the ability to act as a weak estrogen agonist, as well as downregulating various signal transduction pathways, such as NFkappaB, which is commonly upregulated in malignant conditions (1,2). These are obviously attributes that can be of potential importance in the treatment of malignancies. Another of many examples, is that Vitamins A and D have been shown to have the effect, by coupling to nuclear receptors which subsequently effect specific genes, of stimulating normal differentiation processes in cancer cells (3,4).

With the scientific study of these substances, and the validation of the relevant physiological effects, the important issue of level of evidence arises. There is a considerable scientific base describing the effect of many of these natural substances in various research settings, including cell cultures, in vitro, in vivo, and animal studies.  There is a small, but growing body of literature describing their effects in relevant clinical situations. Some examples of the latter are with Vitamin D, which because of it’s multiple effects (an increase in G₀/G₁ arrest, induction of apoptosis and differentiation, and modulation of expression of growth factor receptors, as well as important effects on cell differentiation ) (3), has elicited considerable attention.  The clinical use of Vitamin D brings up the concern regarding adverse reactions when high doses are used, therefore there is great interest in developing analogs which might not cause hypercalcemia, as well as in the development and study of different dosing regimens, which are being actively pursued.  Examples of clinical studies include patients with hormone resistant prostate cancer which have compared the use of docetaxol with or without weekly high doses of calcitriol (1-25 OH Vitamin D), with encouraging results and minimal toxicity. (5,6). The exploration of vitamins, herbs and related substances in these settings is growing and offers considerable promise, but is still extremely limited, especially as compared to the literature and experience available for conventional treatments.

Therefore the scientifically based use of these substances and methods is quite limited and variable, depending on which substances are being used..  The ethical judgment regarding the use of these incompletely validated methods is therefore open to debate.  There are some circumstances where the physician should clearly be very reluctant to introduce these into the treatment protocol.  These are clinical situations when the degree of success of the conventional approach is very high, and we would want to limit any intervention that might adversely impact this success.  On the other side, there are those situations, unfortunately too common, where the conventional treatment options are minimal, non existent, and potentially very toxic. The choice to consider a treatment that has some rational chance of benefit and is very likely non toxic is much more justified.  There are innumerable clinical situations that fall in between these two extremes.  In addition to the potential efficacy against the tumor itself, there are also considerations regarding ameliorating the adverse effects of many treatments. Some treatments appear clearly warranted even if minimally studied, such as the use of massage and relaxation therapy in conjunction with surgery.  Others are more controversial, such as the use of high doses of antioxidants concurrent with patients receiving chemotherapy or radiation therapy. There is a theoretical basis to suspect that antioxidants, though they might limit adverse reactions to chemotherapy or radiation therapy, might also limit their effectiveness.  Clinical studies though, are mixed in confirming these theoretical concerns (7,8,9,10).  These decisions, from an ethical perspective, require input from the practitioner and the patient.

With the above as a background, we would like to describe, in a general and somewhat generic manner, the approach of the integrative physician to integrative oncology, particularly as it’s practiced at the Jefferson Myrna Brind Center for Integrative Medicine at Thomas Jefferson University Hospital in Philadelphia. More detailed discussions on specific cancer types, as well as specific substances, follow in later chapters.

Synergism

Most malignancies appear to be very complex, with multiple biological factors supporting proliferation, local and metastatic spread.  These include processes such as growth factor stimulation, resistance to apoptosis, a local chronic inflammatory milieu, the breakdown of the local limiting extracellular tissue, a resistance to immune recognition and destruction, and enhanced angiogenesis. Conventional treatment approaches have recognized this complexity by treatments that employ multiple agents with different modes of action.  With the advent of targeted therapy, new agents are beginning to be combined with older treatment protocols.  So while the targeted therapy might address specific growth factors, or the process of angiogenesis, the older chemotherapeutic agents most often effect the cell cycle, by blocking certain key steps.  It’s recognized that if only one door is blocked, cancer cells will often escape through another exit that hasn’t been addressed.  Therefore many escape mechanisms are addressed in the treatment protocol.

The same approach is employed in integrative oncology, even more so as it is likely that single interventions are not powerful or effective by themselves, but can develop efficacy when combined with other agents, either natural or conventional. There are numerous studies supporting this synergistic effect ( 6,7,11,12 ).

The integrative approach will therefore target various relevant pathophysiological processes (such as resistance to apoptosis, chronic inflammation, angiogenesis), simultaneously.  It will also commonly use different agents to synergistically address each of these processes individually.  For instance, when addressing chronic inflammation, a protocol employing fish oils, herbs which are known to inhibit different inflammatory pathways, and antioxidants are commonly used together.

It’s of great interest that many of these natural substances ( as well as some conventional medications ), have been shown to have multiple effects.  This was noted above in describing Vitamin D, but could equally be applied to other substances.  Melatonin has significant antioxidant, cell cycle, proapoptotic, immune modulating, and signal transduction effects (13). Mushroom preparations have a wide range of overlapping capacities (14). Therefore, in using a multiagent protocol, with agents that by themselves have a wide range of effects, we are attempting to target numerous essential pathophysiological processes.

A caveat to be aware of, is that, in our present state of knowledge, we are relatively ignorant of how such agents interact when combined in this way.  The synergism hoped for, while partly studied in specific instances, has not been studied or evaluated  in the complex regimens that are commonly recommended.

Outlines of a general integrative approach

There are pathophysiological processes common to all cancers, as well as processes unique to individual cancers.  Whereas chronic inflammation, angiogenesis and resistance to apoptosis is found in most malignant situations, hormonal stimulation is more unique to breast and prostate cancer.  As is the case in conventional treatment, the integrative approach will address both the common and unique aspects.  The common pathophysiological processes that are targeted in integrative oncology protocols, which will be addressed below, include (a) chronic inflammation, (b) angiogenesis, (c) excessive toxin and free radical formation, (d) impaired differentiation, (e) impaired immune response, and (f) resistance to apoptosis.

Chronic inflammation

It is recognized that the milieu surrounding malignant cells has a chronic inflammatory character.  Measurement of various proinflammatory substances, such as COX 2 enzymes, proinflammatory prostaglandins, and signaling agents such as NFkB shows an increased concentration of these substances (15,16).  The presence of inflammation has the effect of promoting growth and spread.  Coussens has described this as follows:  “The protumor actions of inflammatory cells include releasing growth and survival factors, promoting angiogenesis and lymphangiogenesis, stimulating DNA damage, remodeling the extracellular matrix to facilitate invasion, coating tumor cells to make available receptors for disseminating cells via lymphatics and capillaries, and evading host defence mechanisms.” (16).

The approach to counter chronic inflammation includes diet, various supplements, and occasionally prescription medications.

An anti-inflammatory diet is one which emphasizes w-3 fatty acids (found especially in fish and to a lesser extent whole grains), and limits arachidonic acid containing foods (meat and dairy).  This approach leads to the formation of anti-inflammatory prostaglandins and eicosanoids.  In addition, high antioxidant and flavonoid foods (fruits and vegetables) are favored whereas toxin producing processes (processing, additives, deep frying) are discouraged.  In practical terms, this is a whole food diet, rich in varied vegetables and fruit, with an ample amount of fish (especially oily fish like salmon, herring, sardines and, to a lesser degree because of mercury toxicity concerns,  tuna), and  a lesser amount of dairy and especially red meat.

Supplements include (a) fish and flax oils (containing w-3 fatty acids), (b) anti-inflammatory herbs such as curcumin (curry) and boswellia (frankincense).  Antioxidants counter inflammation and include vitamins like C in moderate doses, as well as plants such as grapeseed (containing pycnogenol), and green tea concentrates.

Attempts to block multiple inflammatory pathways, such as those involving COX and leukotrienes is encouraged, as if only one pathway is blocked, substances will then use the alternate pathway (17).  The supplements mentioned above can have dual COX/LOX inhibitory properties, as opposed to the sole use of pure COX and LOX inhibitors such as celecoxib and zileuton.  In highly inflammatory states, these prescription medications can be considered along with the broader but less potent acting supplements, although recent information regarding the potential of negative cardiovascular consequences with COX-2 inhibitors, albeit incomplete, needs to be strongly considered.

Various lab tests, such as high sensitivity CRP and fibrinogen give general indications of the overall degree of inflammation and can help guide treatment intensity (18,19), though in practice, these are often too non specific. Other assays can inexpensively monitor free radicals such as malondialdehyde (reflecting ROS in the lipid soluble compartment). Better lab tests, which would help monitor response to these measures, have not been adequately identified to date.

Angiogenesis

It is widely recognized that angiogenesis is an important factor in almost all tumor types, including solid and probably most hematological malignancies.  Angiogenesis is a very complex process, involving the tumor cell and the microenvironment, as well as vascular endothelial cells.  It’s widely thought that a successful antiangiogenic treatment must involve many agents that target numerous factors, such as the endothelial cells directly as well as growth factors produced by the tumor and the microenvironment which stimulate the endothelial cells to form new blood vessels (20,21).  There are also suggestions that angiogenesis treatment might potentiate chemotherapy and overcome chemotherapy resistance, by improving medication delivery through normalization of the tumor vasculature (22). However, there is also that possibility that angiogenesis can diminish the efficacy of chemotherapy.  This is because angiogenesis inhibitors might slow the growth of malignant cells, which could interfere with chemotherapeutic agents that target cells which are in an active growth cycle.

In the real life clinical situation, it is somewhat artificial to characterize the pathophysiological situations of angiogenesis, inflammation and apoptosis as distinct, separate processes, as they are intimately related.  Chronic inflammation produces various growth promoting substances that stimulate angiogenesis, and blocking angiogenesis can lead to apoptosis.  Therefore the clinical approach to chronic inflammation, as discussed above, can have indirect beneficial effects in limiting angiogenesis.

The direct integrative approach to angiogenesis involves an attempt to block numerous steps in the process, both directly and indirectly.

An agent of considerable interest is ammonium tetrathiomolybdate (TM), which functions primarily as a copper chelating agent, lowering the amount of copper available. As opposed to agents such as anti-VEGF  antibodies, TM has multiple and wide ranging effects on angiogenesis. This is because copper has an important role in many processes that stimulate angiogenesis, including the production and delivery of various growth factors, including VEGF, as well as effecting signaling molecules such as NFkB (23,24).

TM has generally been used and studied in more advanced clinical situations, often in patients with metastatic disease, primarily due to cost considerations (it is only prepared, at present, by compounding pharmacies, and is generally not reimbursed by insurance companies).  There are also considerations regarding adverse drug reactions. These involve the potential for the development of cytopenias (WBC, RBC and infrequently platelets).  As copper is essential for blood vessel formation, it is also involved in blood cell formation.  Reversible cytopenias can occur if the copper is lowered too quickly or excessively.  Frequent monitoring, 2-4 weekly, of complete blood counts and ceruloplasmin levels are required. There are also necessary precautions to be taken if TM is used concurrently with chemotherapy due to a higher likelihood of cytopenias, though this can be ameliorated by the use of red and white blood cell growth factors.

Various clinical situations might benefit from the inclusion of TM in an integrative treatment protocol.  These range from patients with no measurable disease, but at increased risk for recurrence.  An example would be patients with breast or ovarian cancer with rising tumor markers such as CA 27-29 or CA 125.  Other examples include patients with a first recurrence, as well as with more advanced metastatic disease.

Studies with TM have been suggestive of benefit, particularly of stabilization of progressive situations.  The use of TM as part of an integrative protocol, where the potential for further synergism exists, has not been formally studied. As with the potential synergistic actions discussed above, we can’t completely extrapolate results where only a single agent, such as TM, is used, to situations where multiagent protocols are employed.

Various vitamins, most specifically Vitamin D, Vitamin E (notably Vitamin E succinate) (25,26,27), Vitamin B6 (28,29), and Vitamin C (30), have been demonstrated to have inhibiting effects on angiogenesis. Numerous other natural medications, such as the coriolus mushroom, which is primarily used for it’s effects on immune function, also have beneficial effects on angiogenesis (31).

The Use of Antioxidants and Detoxification

The rationale behind the use of antioxidants and detoxifying agents will be discussed in two parts.  The first section will discuss their use when the patient is not receiving chemotherapy or radiation therapy.  The second section will discuss their use when patients are receiving these therapies.

Antioxidants and detoxifying agents protect the body against the effects of free radicals and other substances which produce toxic effects, such as xenobiotics.  These therapeutic agents have other effects, however, which should be considered.  They have beneficial effects on countering inflammation and immunosuppression, deleterious processes which are very prevalent in patients with malignancies (32,33). It is well known that patients with malignancies have an increased level of inflammation and oxidative stress, as well as a deficiency of protective antioxidant and detoxifying substances such as glutathione (34,35). The presence of free radicals can also directly effect DNA and foster further mutations in malignant cells already prone to these. Other antioxidants, such as Vitamin A, have additional effects, such as promoting normal cell differentiation.

An integrative treatment program involves the use of multiple antioxidants and detoxifying agents, rather than one or two.  Various studies looking at antioxidants and cancer have examined, perhaps unfortunately, the use of only a few agents, and have shown inconclusive or even negative effects, such as with B-carotene in the CARET trial (36). It has subsequently been realized that the particular physiological conditions in this trial led to B-carotene functioning as a prooxidant, and to a depletion of protective detoxifying agents (37). Therefore, if the hypothesis in this trial was that malignancies would increase as the level of free radicals increase, it would have been a positive trial, as the particular protocol of B-carotene usage led to an increase, rather than the expected decrease, of free radicals!  This is the opposite, in one sense, of the message that most physicians have gotten from this trial, which is that the use of antioxidants, particularly B-carotene, is deleterious.  It would be inappropriate to extrapolate these negative results to a situation where multiple antioxidants and detoxifying agents were being used simultaneously, such as in a typical integrative treatment program. The goal would still seem to be developing a program where the net effect is an improved antioxidant status and improved detoxification, the opposite of what occurred in the CARET trial.

With these rationales and a certain level of uncertainty as discussed above, an integrative program involves the combined use of  micronutrient antioxidants, such as are found in high potency multivitamins, plant based antioxidants (such as pycnogenol from grape leaves), and substances such as melatonin in supraphysiological doses. Melatonin in particular has been studied in conjunction with conventional treatment protocols. Patients with a range of advanced metastatic solid tumors were treated with chemotherapy with or without melatonin, and the active treatment group was shown to have very significantly decreased toxicity, as well as improved regression and survival rates (38).

The use of antioxidants concurrent with chemotherapy or radiation therapy is a very controversial topic.  Most oncologists advise their patients not to use significant doses of antioxidants while receiving these therapies.  This is based on the understanding that certain chemotherapeutic agents, most particularly alkylating agents, tumor antibiotics, and platinum based compounds, as well as radiation therapy, have some of their cytotoxic effects through the formation of free radicals.  It is therefore theoretically, but completely rationally, felt that antioxidants can interfere with these effects.  It should be understood though, that there is basically no clinical literature, and a paucity of in vitro studies that support this position.  The literature that is available supports the opposite position, that the use of antioxidants decreases sideeffects and might actually increase the efficacy of chemotherapy and radiation therapy (39).  There is, however, one specific detoxifying agent, glutathione, and related substances such as n-acetyl cysteine and lipoic acid, which are very likely to decrease chemotherapy efficacy and promote resistance (40,41).  These agents should always be omitted when chemotherapy or radiation therapy is being used.  Of interest is that other substances, most notably Vitamin C, leads to depletion of glutathione in cancer cells (42). Numerous studies show synergistic benefit when vitamin C is combined with chemotherapy or radiation therapy (43,44).  The mechanism of depleting glutathione in malignant cells might be behind this seeming beneficial effect. When Vitamin C, bypassing the limitations of absorption through the gastrointestinal tract, is given in very high doses intravenously, contrary to lower oral doses, dramatically higher levels are able to be attained, and a prooxidant effect occurs (45).  The combination of attaining higher blood levels, which are potentially cytotoxic, (46), production of free radicals, and depletion of glutathione, suggests the potential that intravenous administration of high doses of Vitamin C has of augmenting the effects of chemotherapy and radiation therapy. 

The decision to use or omit antioxidants (which as noted above have other beneficial effects on inflammation, immune function and differentiation) when patients are receiving chemotherapy or radiation therapy is therefore a difficult, and ultimately, individual one.  Clearly, glutathione and related substances should be omitted.  From a particular theoretical point of view, we should be very cautious with other antioxidants as well.  However, the literature, which is limited, doesn’t support their omission, and in some situations suggests that they can improve the efficacy.  As with most decisions in integrative oncology, we are basing our decisions on a very limited evidence base.  In situations where conventional treatment is known to be very effective, we should clearly be very cautious in the use of antioxidants.  In situations where conventional treatment offers little benefit, the use of antioxidants as an active treatment method should be strongly considered.  In all the situations in between, the physicians and the patient will need to make their individual decisions.

Although the use of antioxidants and chemo/radiation therapy is controversial, the use of anti-inflammatory substances (as found in numerous flavonoids containing herbs) concurrent with chemo/radiation therapy is widely supported in the literature (47-54).  The use of chemotherapy evokes an increased production of the signaling molecule, NFkB, which fosters chemoresistance.  Many anti-inflammatory herbs, such as curcumin and milk thistle, block this production of NFkB, and appear to increase efficacy of numerous chemotherapeutic agents.

Differentiation Therapy

In general, cells that are less differentiated have a greater tendency to proliferation.  This is most clearly seen with embryonal, and especially stem cells.  As cells mature, they become more differentiated into specific cell types, with a consequent significant decrease in proliferative ability.  Cancer cells tend to regress to a less differentiated phenotype.  Those that are the least differentiated tend to show greater malignant properties.  This is evident in the pathological description of cancer cells, often described on a range of well differentiated to poorly differentiated or anaplastic. These processes of differentiation are largely under genetic control.

Vitamins A and D, as well as the class of hypoglycemic agents known as the glitazones effect specific nuclear receptors (RAR, RXR, VDR and PPAR), which induce differentiation.  These agents also have other beneficial effects.  Vitamin D, for instance, has the ability to (a) induce differentiation, (b) induce apoptosis, (c) induce the activity of the tumor suppressors  p21 or p27, (d) inhibit angiogenesis, and (e) inhibit cell migration (53). The use of these agents has been limited by toxicity, such as hypercalcemia with high doses of Vitamin D.  There is active research investigating different forms and dosing schedules of these agents (56,57). 

Another potential way to conserve efficacy and reduce toxicity is to use these agents together, inducing synergistic effects.  This would potentially allow lower doses to be employed.  These substances are known to work synergistically (58,59). Studies looking at single agent efficacy has shown only mild efficacy (60,61). Vitamin D as calcitriol, given in high weekly oral doses in combination with Taxotere, has shown benefit in prostate cancer patient with androgen independent tumors, compared to historical controls (62). A phase 3, placebo controlled trial has recently been reported and the use of calcitriol with Taxotere has led to improved results compared to Taxotere alone (recent presentation at ASCO by Beers). These differentiating agents have not been studied, however, when used as a potentially synergistic combination of agents, in the context of an integrated treatment protocol.

These agents have actions besides inducing differentiation.  Retinoids such as the forms found in food and supplements (retinyl esters such as retinyl palmitate), 9 and 13 cis retinoic acid, as well as pharmacological forms such as all trans retinoic acid (ATRA), exert their effect by effecting the transcription of a variety of genes critical to cellular proliferation and differentiation. These vitamins have also been shown to promote apoptosis and cell cycle arrest through degradation of stimulatory proteins.  This degradation occurs through the proteosome/ubiquitin pathway (61), known as proteosome inhibition.  PPAR agonists have also been shown to have numerous relevant clinical effects besides differentiation, including inhibition of NFkB, proapoptotic, antiproliferative, and antiangiogenetic actions.

A synergistic program of differentiating agents would vary, depending on the specific clinical situation.  Short term use would employ much higher doses than ongoing maintenance treatment.  Appropriate monitoring of levels of retinol, 25 OH and 1-25 OH Vitamin D, liver enzymes, calcium and glucose is essential.

Issues of toxicity, especially with the fat soluble vitamins A and D are important considerations.  The dosages of vitamin A are likely to be very dependent on the length of the course of treatment. Most physicians prescribe Vitamin D in doses far below the optimal range, typically in doses of  400-800i.u./day. Significant literature suggests that doses as high as 4-6000 i.u./day are very safe.  Nevertheless, high doses can potentially induce hypercalcemia. Therefore monitoring should be regularly performed.  It should be noted that most laboratories report normal ranges of Vitamin D which are probably significantly lower than the optimal levels.  One should aim for a range of  50-100 ng/ml, or 100-180 mmol/liter.  The use of PPAR agonists involves at present mainly prescription medications primarily used for diabetics, the glitazones.

In addition to the synergistic effects noted between these three groups of agents, numerous other substances, including antioxidants and anti-inflammatory agents, have been shown to increase their benefits. Therefore the use of differentiation agents should be combined with the general integrative treatment protocol outlined elsewhere.

Immune Function

“Alternative medical” approaches to malignancies have often based themselves on “stimulating the immune system”.  As with all such generic statements, the issue is much more complex, and incompletely understood.  It is widely thought that that there exists an innate immune surveillance system, whereby nascent malignant cells are recognized by the immune system, and destroyed before they have a chance to grow and become established.  It is also widely thought that the immune system, if appropriately activated and directed, can be a potent ally in the fight to eradicate already established cancers, or prevent their recurrence once a patient undergoes surgery, chemotherapy or radiation therapy. Conventional attempts to enlist the help of the immune system in the treatment of malignancies have included general stimulation such as occurs with BCG, the use of cytokines such as interferon or interleukin, usually in high doses, monoclonal antibodies such as rituximab, and vaccines. In patients with malignancies, it is recognized that certain deficiencies exist, such as defective maturation of dendritic cells, which are essential for the presentation of the tumor antigens to the immune system (62,63). It is also recognized that other factors, such as the presence of reactive oxygen species, or inflammation, can play a role in the suppression of the immune response, and help the tumor escape the effects of this response (64,65). Work in these areas is very active.

It is known that various natural substances have direct effects on immune processes.  The most well known examples are medicinal mushrooms, which are used very widely in Asia, and mistletoe preparations, which are used very widely in Europe. A preparation made from the Coriolus mushroom, called PSK (polysaccharide Krestin) has been shown to positively effect dendritic cell maturation, as well as stimulate NK and LAK function (66,67). Various potentially beneficial immune effects have also been noted with Mistletoe (67,68). These agents have also been studied in clinical settings. Coriolus preparations have been studied in numerous gastrointestinal malignancies, with statistically positive results (69,70,71). Mistletoe has likewise been studied in various clinical settings, with unclear but potentially beneficial effects (72,73).

In the context of the known immune defects in patients with malignancies, and the above information, it has become routine in most integrative treatment protocols to include an immune active agent, such as the mushroom or mistletoe preparations discussed above.  This is done, as always, in the context of the comprehensive protocol.  The inclusion of antioxidants and anti-inflammatory preparations is likely to have further potentially beneficial effects on the immune functioning.  There are certain caveats and exceptions to the inclusion of these immune active agents.  This is particularly with hematological malignancies.  These malignancies, such as lymphomas, typically involve immune active cells, such as B or T lymphocytes.  As substances like mushrooms and mistletoe have effects on a multitude of immune active cells and functions, there is the potential concern that the use of these medications could inadvertently stimulate the malignant cells.

Apoptosis

The inducement of apoptosis, or programmed cell death, stands side by side with the inhibition of increased cell proliferation, as a vital therapeutic goal in the treatment of malignancies.  Apoptosis is a common final pathway for dying cells, and therefore is effected in multiple ways. Many cancer cells, through the upregulation of the gene BCl-2, resist apoptosis.  This has numerous consequences.  The resistance to apoptosis allows damaged and mutated cells to survive, and ultimately proliferate.  It also prolongs the lifespan of cells, and makes them more likely to develop mutations.  It also helps resist the cytotoxic action of various agents, such as chemotherapy.  It can change the effect of a cytotoxic agent into one of cytostasis.   The normalization of all of the above mentioned functions, such as antiangiogenesis, decreasing inflammation and strengthening immune function, lead to apoptosis.  Most chemotherapeutic drugs induce apoptosis. There are, in addition, specific natural substances which have been noted for their ability to induce apoptosis.

Vitamin E succinate has been shown to increase the expression of Fas protein, and decrease PCNA protein on gastric carcinoma cells in a dose dependent manner (74).  The presence or absence of these proteins, respectively, is associated with the tendency to apoptosis. Another study showed its effects were related to BCl-2 (75). An in vivo study of immunocompromised mice with malignant mesothelioma being treated with Vitamin E succinate, showed a significant effect on survival (76). There is however, considerable doubt regarding the ability of Vitamin E succinate to survive the proteolytic activity in the GI tract.  The above mentioned studies were in cell culture, and consequently cannot be extrapolated to oral ingestion of this agent.

Green tea, and polyphenols found in green tea such as epigallocatechin gallate (ECGC), have also demonstrated the ability to induce apoptosis (77,78). Direct effects on BCl-2 proteins have been shown (79). There are numerous green tea concentrates available commercially which allow the administration of the equivalent amount of ECGC found in 30-45 cups of decaffeinated green tea.

Factors in different tumor types

In addition to the overall approach outlined above, various tumor types, such as hormone sensitive breast and prostate cancer, are approached through substances that address these hormone sensitivities.  The relative proliferative stimulation of estrogens can be effected through the use of indoles, such as diindole methane (80). Various brain tumors have shown sensitivity to boswellic acid, derived from frankincense (81). Different cancers, such as colon and prostate, have demonstrated an enhanced sensitivity to inflammatory factors, and therefore the anti-inflammatory aspect of the general protocol would be emphasized in these tumors.  Other tumors, such as indolent lymphomas, have a significant upregulation of BCl-2 proteins and resistance to apoptosis.  Therefore proapoptotic agents are emphasized in the overall treatment program.  As more is learned about the specific biochemical, signal transduction and molecular aspects of tumor types, and how different natural substances can effect these processes, the treatments can potentially be tailored in a more exact way.  In a similar way, as gene profiling of individual tumors progresses, this will allow tumor tailored to the individual patient.

Other therapeutic approaches

Integrative medicine employs tools besides herbs, vitamins and other substances.  Treatment methods such as therapeutic massage, acupuncture, and mindbody approaches can be very helpful.  Examples of situations where they can potentially be of benefit are as follows:

• Acupuncture for chemotherapy associated nausea, and to improve energy
• Therapeutic massage post surgical procedures, and as general stress reduction
• Mindfulness meditation and hypnosis pre and post surgery, and during chemotherapy.

A potential area of exploration would be the use of these non medicinal approaches for patients being hospitalized for surgical procedures.  The potential to decrease morbidity and shorten hospital stays could be considerable.

Summary

The integrative approach to the treatment of malignancies usually involves a multiagent protocol, attempting to address known factors that promote the growth, spread and metastasis of tumors.  Numerous agents are typically employed to address these factors, such as inflammation, angiogenesis, and apoptosis.  Inflam-mation, as an example, is often addressed through diet, high doses of w-3 fatty acids, and herbs such as curcumin and boswellia which are known to effect COX-1, COX-2 and leukotriene pathways. As in all illnesses, different phases of the illness are treated differently.  The treatment of a patient undergoing surgery can be significantly different from one in a watch and wait mode. The level of evidence supporting these treatments is relatively low compared to that available for conventional treatments, though a great deal more literature exists than is generally recognized.  The toxicity of these integrative agents is however, relatively low. 

Various controversies exist regarding the use of these incompletely studied agents.  One very important one is if antioxidants should be used concurrently with chemotherapy or radiation therapy. 

In addition to the use of natural substances, other modalities, such as acupuncture and therapeutic massage, are often suggested, and can be of significant benefit in certain clinical situations.

We feel that the basic science literature concerning these substances is substantial enough, and the presence and experience of clinicians is mature enough, to allow fruitful clinical inquiry as to their potential role in the treatment of patients with malignancies.  We feel this area holds significant promise.

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