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.

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.

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.

A broad-spectrum integrative design for cancer prevention and therapy: The challenge ahead.

Despite exciting advances in targeted therapies, high drug costs, marginal therapeutic benefits and notable toxicities are concerning aspects of today's cancer treatments. This special issue of Seminars in Cancer Biology proposes a broad-spectrum, integrative therapeutic model to complement targeted therapies. Based on extensive reviews of the cancer hallmarks, this model selects multiple high-priority targets for each hallmark, to be approached with combinations of low-toxicity, low-cost therapeutics, including phytochemicals, adapted to the well-known complexity and heterogeneity of malignancy. A global consortium of researchers has been assembled to advance this concept, which is especially relevant in an era of rapidly expanding capacity for genomic tumor analyses, alongside alarming growth in cancer morbidity and mortality in low- and middle-income nations.

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.

Circadian angiogenesis.

Daily rhythms of light/darkness, activity/rest and feeding/fasting are important in human physiology and their disruption (for example by frequent changes between day and night shifts) increases the risk of disease. Many of the diseases found to be associated with such disrupted circadian lifestyles, including cancer, cardiovascular diseases, metabolic disorders and neurological diseases, depend on pathological de-regulation of angiogenesis, suggesting that disrupting the circadian clock will impair the physiological regulation of angiogenesis leading to development and progression of these diseases. Today there is little known regarding circadian regulation of pathological angiogenesis but there is some evidence that supports both direct and indirect regulation of angiogenic factors by the cellular circadian clock machinery, as well as by circulating circadian factors, important for coordinating circadian rhythms in the organism. Through highlighting recent advances both in pre-clinical and clinical research on various diseases including cancer, cardiovascular disorders and obesity, we will here present an overview of the available knowledge on the importance of circadian regulation of angiogenesis and discuss how the circadian clock may provide alternative targets for pro- or anti-angiogenic therapy in the future.

Anticancer activity of fish oils against human lung cancer is associated with changes in formation of PGE2 and PGE3 and alteration of Akt phosphorylation.

The beneficial effects of omega-3 fatty acids are believed to be due in part to selective alteration of arachidonate metabolism that involves cyclooxygenase (COX) enzymes. Here we investigated the effect of eicosapentaenoic acid (EPA) on the proliferation of human non-small cell lung cancer A549 (COX-2 over-expressing) and H1299 (COX-2 null) cells as well as their xenograft models. While EPA inhibited 50% of proliferation of A549 cells at 6.05 µM, almost 80 µM of EPA was needed to reach similar levels of inhibition of H1299 cells. The formation of prostaglandin (PG)E3 in A549 cells was almost threefold higher than that of H1299 cells when these cells were treated with EPA (25 µM). Intriguingly, when COX-2 expression was reduced by siRNA or shRNA in A549 cells, the antiproliferative activity of EPA was reduced substantially compared to that of control siRNA or shRNA transfected A549 cells. In line with this, dietary menhaden oil significantly inhibited the growth of A549 tumors by reducing tumor weight by 58.8 ± 7.4%. In contrast, a similar diet did not suppress the development of H1299 xenograft. Interestingly, the ratio of PGE3 to PGE2 in A549 was about 0.16 versus only 0.06 in H1299 xenograft tissues. Furthermore, PGE2 up-regulated expression of pAkt, whereas PGE3 downregulated expression of pAkt in A549 cells. Taken together, the results of our study suggest that the ability of EPA to generate PGE3 through the COX-2 enzyme might be critical for EPA-mediated tumor growth inhibition which is at least partly due to down-regulation of Akt phosphorylation by PGE3.

Integrating dietary supplements into cancer care.

Many studies confirm that a majority of patients undergoing cancer therapy use self-selected forms of complementary therapies, mainly dietary supplements. Unfortunately, patients often do not report their use of supplements to their providers. The failure of physicians to communicate effectively with patients on this use may result in a loss of trust within the therapeutic relationship and in the selection by patients of harmful, useless, or ineffective and costly nonconventional therapies when effective integrative interventions may exist. Poor communication may also lead to diminishment of patient autonomy and self-efficacy and thereby interfere with the healing response. To be open to the patient's perspective, and sensitive to his or her need for autonomy and empowerment, physicians may need a shift in their own perspectives. Perhaps the optimal approach is to discuss both the facts and the uncertainty with the patient, in order to reach a mutually informed decision. Today's informed patients truly value physicians who appreciate them as equal participants in making their own health care choices. To reach a mutually informed decision about the use of these supplements, the Clinical Practice Committee of The Society of Integrative Oncology undertook the challenge of providing basic information to physicians who wish to discuss these issues with their patients. A list of leading supplements that have the best suggestions of benefit was constructed by leading researchers and clinicians who have experience in using these supplements. This list includes curcumin, glutamine, vitamin D, Maitake mushrooms, fish oil, green tea, milk thistle, Astragalus, melatonin, and probiotics. The list includes basic information on each supplement, such as evidence on effectiveness and clinical trials, adverse effects, and interactions with medications. The information was constructed to provide an up-to-date base of knowledge, so that physicians and other health care providers would be aware of the supplements and be able to discuss realistic expectations and potential benefits and risks.