Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.

Advanced cancer patients in a randomized clinical trial of night-simulating eyeglasses observed to have a normal 24-h circadian rhythm during chemotherapy.

Objectives: Cancer patients routinely exhibit dysfunctional circadian organization. Indeed, a dysfunctional circadian organization is a hallmark of advanced cancer. A cohort of advanced cancer patients undergoing chemotherapy was recruited to investigate whether manipulating exposure to blue light could restore or ameliorate their circadian organization. Methods: Thirty advanced metastatic cancer patients participated in a randomized crossover trial to evaluate whether blue light-blocking night-simulating eyeglasses could ameliorate a disrupted circadian organization better than sham eyeglasses. Circadian organization was evaluated by actigraphy and patients' self-reports of sleep, fatigue, and quality of life. Kruskal-Wallis tests compared patients' outcomes in circadian organization with a cohort of non-cancer, disease-free individuals with normal sleep as a negative control, and with advanced cancer patients with disrupted circadian organization as a positive control. Quality-of-life outcomes of the patients were compared with population-based controls (negative controls) and with cohorts of advanced cancer patients (positive controls). Results: Actigraphy measurements, self-reported sleep, fatigue levels, and quality-of-life outcomes of trial participants were similar to those of negative controls with a normal circadian organization, in spite of the trial patients' concurrent chemotherapy. Night-simulating glasses did not improve circadian organization. The 24-h correlation of day-to-day rhythms of rest and activity was 0.455 for the experimental eyeglasses and 0.476 for the sham eyeglasses (p = 0.258). Actigraphic and patient-reported outcomes compared favorably to outcomes of positive controls. Conclusion: The circadian organization of patients in this study unexpectedly resembled that of healthy controls and was better than comparison populations with disrupted circadian organization. The study clinic implements chronomodulated chemotherapy and a systematic, supportive integrative treatment protocol. Results suggest a need for further research on interventions for circadian rhythm. Although the study intervention did not benefit the participants, this work highlights the value of supporting circadian time structure in advanced cancer patients.

Survival impact of integrative cancer care in advanced metastatic breast cancer.

Integrative cancer treatment is of substantial interest to many cancer patients. Research is needed to evaluate the effects of integrative treatment on patient outcomes. We report survival data for a consecutive case series of advanced metastatic breast cancer patients who received a comprehensive clinical program combining conventional treatments with nutrition and supplementation, fitness and mind-spirit instruction at the Block Center for Integrative Cancer Treatment. Treatment outcomes using integrative care for this disease have not previously been documented; survival data will thus contribute to decisions concerning future research directions and design. Ninety consecutive patients with metastatic breast cancer diagnosed during 1984-1997 who received chemotherapy at the integrative cancer center were included. Prognostic factors, treatments and survival from onset of metastases were determined from analysis of scans, labs, pathology and medical records. The log-rank test and Cox proportional hazards analyses were used, and a Kaplan-Meier curve was calculated. All patients had metastatic disease at baseline, 96% were relapsed and 52% had received prior chemotherapy for metastatic disease. Median age at onset of metastasis was 46 years. Median survival was 38 months (95% CI 27,48). Published literature on populations with somewhat more favorable prognostic factors treated in conventional clinics showed median survivals of 20 to 23 months. Through the 1990s, median survival reported in metastatic breast cancer trials or observations generally ranged from 12 to 24 months. Five-year survival was 27% for Center versus 17% for comparison patients. Despite a higher proportion of younger and relapsed patients, survival of metastatic breast cancer patients at the Center was approximately double that of comparison populations and possibly even higher compared to trials published during this period. Explanations for the advantage relative to conventional treatment alone may include the nutritional, nutraceutical, exercise and psychosocial interventions, individually or in combination; self-selection of patients cannot be ruled out. Further research to evaluate the impact of integrative breast cancer treatment on survival is warranted.

Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials.

Much debate has focused on whether antioxidants interfere with the efficacy of cancer chemotherapy. The objective of this study is to systematically review the randomized, controlled clinical trial evidence evaluating the effects of concurrent use of antioxidants with chemotherapy on toxic side effects. We performed a search of literature from 1966-October 2007 using MEDLINE, Cochrane, CinAhl, AMED, AltHealthWatch and EMBASE databases. Randomized, controlled clinical trials reporting antioxidant-based mitigation of chemotherapy toxicity were included in the final tally. Searches were performed following a standardized protocol for systematic reviews. Only 33 of 965 articles considered, including 2,446 subjects, met the inclusion criteria. Antioxidants evaluated were: glutathione (11), melatonin (7), vitamin A (1), an antioxidant mixture (2), N-acetylcysteine (2), vitamin E (5), selenium (2), L-carnitine (1), Co-Q10 (1) and ellagic acid (1). The majority (24) of the 33 studies included reported evidence of decreased toxicities from the concurrent use of antioxidants with chemotherapy. Nine studies reported no difference in toxicities between the 2 groups. Only 1 study (vitamin A) reported a significant increase in toxicity in the antioxidant group. Five studies reported the antioxidant group completed more full doses of chemotherapy or had less-dose reduction than control groups. Statistical power and poor study quality were concerns with some studies. This review provides the first systematically reviewed evidence that antioxidant supplementation during chemotherapy holds potential for reducing dose-limiting toxicities. However, well-designed studies evaluating larger populations of patients given specific antioxidants defined by dose and schedule relative to chemotherapy are warranted.

Integrative Treatment for Colorectal Cancer: A Comprehensive Approach.

A comprehensive approach to integrative treatment of colorectal cancer (CRC) patients involves three spheres of intervention: lifestyle, biology, and conventional treatment. Individualization of treatment is emphasized. The lifestyle sphere includes nutritional therapies, biobehavioral strategies with circadian interventions, and physical care modalities. The biology sphere comprises six host factors in the patient's internal biochemical environment or "terrain": inflammation, glycemia, oxidative stress, immune dysregulation, coagulopathy, and stress chemistries. Laboratory testing of these factors guides integrative lifestyle and supplement recommendations. The conventional treatment sphere includes individualized lifestyle recommendations, and supplements or drugs used to enhance tolerability or effectiveness of conventional treatments. Innovative strategies are implemented, including chronomodulated chemotherapy, chemosensitivity testing, and using results of molecular genomic testing to guide nutritional infusions and supplement recommendations. In the lifestyle sphere, substantial evidence from cohort studies supports recommendations for a diet that emphasizes plant and fish proteins, healthful fats in amounts that are tailored to the clinical circumstance of the patient, and carbohydrates based on unrefined whole grains, vegetables and whole fruits. High glycemic diets and refined carbohydrates, especially sugar-sweetened beverages, should be avoided. Biobehavioral strategies include practice of the relaxation response and related approaches. In addition, specific strategies to promote robust circadian organization (CO) are used to combat quality of life concerns and worsened survival that accompany disrupted CO. Physical activity, including aerobic activity and muscle strengthening, is recommended at all disease stages. In the biology sphere, supplements and lifestyle recommendations for inflammation and glycemia are discussed. In the conventional treatment sphere, supplements and innovative and complementary therapies that may remedy treatment toxicities are reviewed. Approaching CRC treatment with a comprehensive, individualized intervention enables safe and beneficial outcomes in this patient population, which can vary widely in individual biology, treatment toxicities, and disease complications. Further research in integrative therapies for CRC patients is needed.

Impact of antioxidant supplementation on chemotherapeutic efficacy: a systematic review of the evidence from randomized controlled trials.

PURPOSE: Much debate has arisen about whether antioxidant supplementation alters the efficacy of cancer chemotherapy. Some have argued that antioxidants scavenge the reactive oxygen species integral to the activity of certain chemotherapy drugs, thereby diminishing treatment efficacy. Others suggest antioxidants may mitigate toxicity and thus allow for uninterrupted treatment schedules and a reduced need for lowering chemotherapy doses. The objective of this study is to systematically review the literature in order to compile results from randomized trials that evaluate concurrent use of antioxidants with chemotherapy. DESIGN: MEDLINE, Cochrane, CinAhl, AMED, AltHealthWatch and EMBASE databases were searched. Only randomized, controlled clinical trials that reported survival and/or tumor response were included in the final tally. The literature searches were performed in duplicate following a standardized protocol. No meta-analysis was performed due to heterogeneity of tumor types and treatment protocols used in trials that met the inclusion criteria. RESULTS: Of 845 articles considered, 19 trials met the inclusion criteria. Antioxidants evaluated were: glutathione (7), melatonin (4), vitamin A (2), an antioxidant mixture (2), vitamin C (1), N-acetylcysteine (1), vitamin E (1) and ellagic acid (1). Subjects of most studies had advanced or relapsed disease. CONCLUSION: None of the trials reported evidence of significant decreases in efficacy from antioxidant supplementation during chemotherapy. Many of the studies indicated that antioxidant supplementation resulted in either increased survival times, increased tumor responses, or both, as well as fewer toxicities than controls; however, lack of adequate statistical power was a consistent limitation. Large, well-designed studies of antioxidant supplementation concurrent with chemotherapy are warranted.

Toward a core nutraceutical program for cancer management.

As previously suggested, it may be feasible to impede tumorevoked angiogenesis with a nutraceutical program composed of glycine, fish oil, epigallocatechin-3-gallate, selenium, and silymarin, complemented by a low-fat vegan diet, exercise training, and, if feasible, a salicylate and the drug tetrathiomolybdate. It is now proposed that the scope of this program be expanded to address additional common needs of cancer patients: blocking the process of metastasis; boosting the cytotoxic capacity of innate immune defenses (natural killer [NK] cells); preventing cachexia, thromboembolism, and tumor-induced osteolysis; and maintaining optimal micronutrient status. Modified citrus pectin, a galectin-3 antagonist, has impressive antimetastatic potential. Mushroombeta-glucans and probiotic lactobacilli can amplify NK activity via stimulatory effects on macrophages. Selenium, beta-carotene, and glutamine can also increase the number and/or cytotoxic activity of NK cells. Cachectic loss of muscle mass can be opposed by fish oil, glutamine, and beta-hydroxy-beta-methylbutyrate. Fish oil, policosanol, and vitamin D may have potential for control of osteolysis. High-dose aspirin or salicylates, by preventing NF-B activation, can be expected to aid prevention of metastasis and cachexia while down-regulating osteolysis, but their impacts on innate immune defenses will not be entirely favorable. A nutritional insurance formula crafted for the special needs of cancer patients can be included in this regimen. To minimize patient inconvenience, this complex core nutraceutical program could be configured as an oil product, a powder, and a capsule product, with the nutritional insurance formula provided in tablets. It would be of interest to test this program in nude mouse xenograft models.

Preadministration of high-dose salicylates, suppressors of NF-kappaB activation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy.

NF-kappaB activity is elevated in a high proportion of cancers, particularly advanced cancers that have been treated previously. Cytotoxic treatment selects for such up-regulation inasmuch as NF-kappaB promotes transcription of a large number of proteins that inhibit both the intrinsic and extrinsic pathways of apoptosis; NF-kappaB also boosts expression of mdr1, which expels many drugs from cells. Indeed, high NF-kappaB activity appears to be largely responsible for the chemo- and radioresistance of many cancers. Thus, agents that suppress NF-kappaB activity should be useful as adjuvants to cytotoxic cancer therapy. Of the compounds that are known to be NF-kappaB antagonists, the most practical for current use may be the nonsteroidal anti-inflammatory drugs aspirin, salicylic acid, and sulindac, each of which binds to and inhibits Ikappa kinase- beta, a central mediator of NF-kappa activation; the low millimolar plasma concentrations of salicylate required for effective inhibition of this kinase in vivo can be achieved with high-dose regimens traditionally used to manage rheumatic disorders. The gastrointestinal toxicity of such regimens could be minimized by using salsalate or enteric-coated sodium salicy-late or by administering misoprostol in conjunction with aspirin therapy. Presumably, best results would be seen if these agents were administered for several days prior to a course of chemo- or radiotherapy, continuing throughout the course. This concept should first be tested in nude mice bearing xenografts of chemoresistant human tumors known to have elevated NF-kappa activity. Ultimately, more complex adjuvant regimens can be envisioned in which salicylates are used in conjunction with other NF-kappa antagonists and/or agents that target other mediators of down-regulated apoptosis in cancer, such as Stat3; coadministration of salicylate and organic selenium may have intriguing potential in this regard. These strategies may also have potential as adjuvants to metronomic chemotherapy, which seeks to suppress angio-genesis by targeting cycling endothelial cells in tumors.

The demise of the super-aspirins: an opportunity for integrative medicine?

The recent findings of significant cardiac risks with longterm use of the selective COX-2 inhibitors and naproxen leave many patients without access to drugs they may depend on for sustained management of pain. These cardiac risks can arise from disturbances in the ratio of prostacyclin and thromboxane A-2. Integrative medicine offers a variety of interventions that do not disrupt this ratio, including herbs, nutriceuticals, mind-body strategies, and physical care. Clinical studies for evaluating these interventions, and research on sustainable production of those that are natural substances, should be given greater funding priority at this time.

Multifocal angiostatic therapy: an update.

Multifocal angiostatic therapy (MAT) is a strategy that seeks to impede cancer-induced angiogenesis by addressing multiple targets that regulate the angiogenic capacity of a cancer and/or the angiogenic responsiveness of endothelial cells, using measures that are preferentially, but not exclusively, nutraceutical. A prototype of such a regimen has been proposed previously, composed of green tea polyphenols, fish oil, selenium, and high-dose glycine, complementing a low-fat vegan diet, exercise training, and the copper-sequestering drug tetrathiomolybdate (TM). A review of more recent evidence suggests additional agents that could appropriately be included in this regimen and clarifies to some extent the mechanisms of action of its constituents. Diindolylmethane, a widely available crucifera-derived nutraceutical, has inhibited cancer growth in several mouse xenograft models; this effect may be largely attributable to an angiostatic action, as concentrations as low as 5 to 10 muM inhibit proliferation, migration, and tube-forming capacity of human endothelial cells in vitro, and a parenteral dose of 5 mg/kg markedly impairs matrigel angiogenesis in mice. Silymarin/silbinin, which has slowed the growth of human xenografts in a number of studies, suppresses the proliferation, migration, and tube-forming capacity of endothelial cells and inhibits vascular endothelial growth factor (VEGF) secretion by a range of human cancer cell lines, in concentrations that should be clinically feasible. The angiostatic activity of orally administered green tea now appears likely to reflect inhibition of the kinase activity of VEGFR-2. Glycine's angiostatic activity may be attributable to a hyperpolarizing effect on endothelial cells that decreases the activity of NADPH oxidase, now known to promote tyrosine kinase signaling in endothelial cells. The ability of TM to suppress cancer cell production of a range of angiogenic factors results at least in part from a down regulation of NF-kappaB activation. Dual-purpose molecular targets, whose inhibition could be expected to decrease the aggressiveness and chemoresistance of cancer cells while simultaneously impeding angiogenesis, include NF-kappaB, cox-2, c-Src, Stat3, and hsp90; drugs that can address these targets are now in development, and salicylates are notable for the fact that they can simultaneously inhibit NF-kappaB and cox-2. The potential complementary of the components of MAT should be assessed in nude mouse xenograft models.

Commentary: the pharmacological antioxidant amifostine -- implications of recent research for integrative cancer care.

Amifostine is a pharmacological antioxidant used as a cytoprotectant in cancer chemotherapy and radiotherapy. It is thought to protect normal tissues relative to tumor tissue against oxidative damage inflicted by cancer therapies by becoming concentrated at higher levels in normal tissues. The degree to which amifostine nevertheless accumulates in tumors and protects them against cancer therapies has been debated. Guidelines have been published that direct its use in chemotherapy and radiation, taking into consideration the concerns of tumor protection. In this article, clinical studies of amifostine appearing since the publication of the most recent set of guidelines are reviewed. Randomized and nonrandomized trials of regimens involving chemo-therapeutic agents (chemotherapy, chemoradiation, conditioning regimens for bone marrow transplant) are discussed. Nineteen studies showed positive effects for amifostine reducing the level of side effects of these regimens, while 9 showed no effect and 1 had a questionable result. Clinically relevant levels of amifostine toxicity were observed in several studies, but subcutaneous administration may reduce such toxicity. Amifostine showed protection against mucositis, esophagitis, neuropathy, and other side effects, although protection against cisplatin-induced ototoxicity was not observed. No evidence of tumor protection was observed. Amifostine may enable populations unable to tolerate conventional cancer therapy to receive treatment of their cancers, even if some degree of tumor protection is eventually discovered. The authors discuss the implications of this research for patient populations seen in integrative cancer care centers and for research on phytochemical antioxidants such as vitamins and carotenoids.

Integrative therapies in cancer: modulating a broad spectrum of targets for cancer management.

Integrative medicine is an approach to health and healing that "makes use of all appropriate therapeutic approaches, health care professionals, and disciplines to achieve optimal health and healing." A comprehensive integrative medicine intervention for cancer patients typically includes nutritional counseling, biobehavioral strategies, and promotion of physical activity, as well as dietary supplements including herbs, nutraceuticals, and phytochemicals. A broad-spectrum intervention of this type may contribute uniquely to improvement in cancer outcomes through its impact on a wide variety of relevant molecular targets, including effects on multiple cancer hallmarks. Hallmarks that may be particularly affected include genetic instability, tumor-promoting inflammation, deregulated metabolism, and immune system evasion. Because of their susceptibility to manipulation by diet, exercise, and supplementation, these may be characterized as metabolic hallmarks. Research on the use of comprehensive integrative approaches can contribute to the development of systems of multitargeted treatment regimens and would help clarify the combined effect of these approaches on cancer outcomes.

A Case of Complete and Durable Molecular Remission of Chronic Lymphocytic Leukemia Following Treatment with Epigallocatechin-3-gallate, an Extract of Green Tea.

We report the case of a 48-year-old man who achieved a complete molecular remission 20 years after a diagnosis of chronic lymphocytic leukemia while using epigallicatechin-3-gallate, an extract of green tea. The patient presented at age 28 with lymphocytosis, mild anemia, mild thrombocytopenia, and massive splenomegaly, for which a splenectomy was performed. He was then followed expectantly. Over the next two decades, he suffered two symptomatic chronic lymphocytic leukemia-related events. The first occurred twelve years after diagnosis (at age 40) when the patient developed fevers, night sweats, and moderate anemia. He was diagnosed with autoimmune hemolytic anemia secondary to chronic lymphocytic leukemia. The patient declined conventional therapy in favor of a diet, exercise, and supplement regimen, and recovered from the autoimmune hemolytic anemia though the underlying chronic lymphocytic leukemia remained evident. This is the first published case report of "spontaneous" recovery from secondary autoimmune hemolytic anemia in an adult.  Over the second decade following chronic lymphocytic leukemia diagnosis, serial bone marrow biopsies demonstrated increasing lymphocytosis, with minimal peripheral lymphocytosis. However, twenty years after diagnosis, peripheral lymphocytosis accelerated, with white blood cell counts rising to 55,000/µL. Because the patient continued to refuse conventional therapy, he was treated instead with a supplement regimen that included high doses of epigallocatechin-3-gallate, a green tea extract. Peripheral lymphocytosis resolved. More remarkably, a bone marrow examination, including flow cytometry, showed no evidence of a malignant clone. Two years later (at age 51), the peripheral blood and bone marrow were without molecular evidence of chronic lymphocytic leukemia or any malignancy. The patient remains well at age 52.

Antioxidants and cancer therapy: furthering the debate.

The consideration of whether to use antioxidants concomitantly with chemotherapy and radiation therapy has evolved into a heated debate. This special theme issue brings together several contributors to this debate, whose perspectives enlarge our views of the questions at hand, pointing out several very relevant ideas. First, the early hypotheses of the role of antioxidants in carcinogenesis gave a simplified and often inaccurate picture of the physiological effects of specific antioxidants. Antioxidants can have protective effects that have nothing to do with oxidation; on the other hand, they can under some circumstances develop prooxidant properties and promote carcinogenesis. During treatment, however, their role is far from clear and may be either quite positive or potentially negative. A number of clinical studies have already demonstrated beneficial effects of antioxidants in ameliorating side effects of chemotherapy. More theoretical work on the chemistry of antioxidants and chemotherapy drugs suggests that antioxidants might improve therapeutic efficacy of antineoplastics by counteracting aldehydes that impede the passage of cells through the cell cycle. However, detailed clinical study also makes it clear that we are only at the very beginning of understanding the dynamics of antioxidants and oxidant damage in the body during conventional treatment. Nevertheless, research is under way on radioprotective and chemoprotective substances, some of them rooted in traditional medicine and others in our understanding of dietary antioxidants, that may eventually lead to antioxidant-based supplements that support tolerability and efficacy of treatment, without protecting tumors through interference from antineoplastic treatment.

Immune system effects of echinacea, ginseng, and astragalus: a review.

Traditional herbal medicine provides several remedies for strengthening the body's resistance to illness through effects on immune system components. This review article examines 3 popular herbal immune stimulants that are often of interest to cancer patients. Echinacea, a native of North America, is widely used to prevent, or provide early treatment for, colds. Preclinical studies lend biological plausibility to the idea that echinacea works through immune mechanisms. Numerous clinical trials have been carried out on echinacea preparations: it appears that the extracts shorten the duration and severity of colds and other upper respiratory infections (URIs) when given as soon as symptoms become evident. However, trials of long-term use of echinacea as a preventive have not shown positive results. Ginseng has been studied in some depth as an antifatigue agent, but studies of immune mechanisms have not proceeded so far. Preclinical evidence shows some immune-stimulating activity. There have been several clinical trials in a variety of different diseases. Astragalus is the least-studied agent. There are some preclinical trials that show intriguing immune activity. The herbs discussed appear to have satisfactory safety profiles. Cancer patients may wish to use these botanicals to inhibit tumor growth or to boost resistance to infections. However, passive immunotherapy with herbs, with no mechanism to expose tumor antigens, is unlikely to be effective in inhibiting tumor growth. Although the margin of safety for these herbs is large, more research is needed to demonstrate the clear value of using herbs to improve resistance to infections.

Vitamin C in alternative cancer treatment: historical background.

Ascorbic acid is the single-nutrient supplement most commonly used by cancer patients, although in most cases this takes place without the physician's knowledge or supervision. A comprehensive review of the literature is presented on the impact of ascorbic acid on cancer survival. Findings from 6 uncontrolled studies suggest that ascorbic acid may increase survival, whereas 2 controlled trials have yielded null results. The relative strengths and limitations of these studies are discussed. A turning point occurred with the release of the 2 controlled (null) studies, which influenced many physicians to turn away from nutrition in the care of cancer patients. Controversy about these trials still persists, however, in the alternative cancer community.