Accepted Manuscript Feeding a cancer patient: much more than supportive care Alessandro Laviano, M.D., Luca Di Lazzaro, M.D., Maria Isabel T.D. Correia, M.D., Ph.D. PII:
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Please cite this article as: Laviano A, Di Lazzaro L, Correia MITD, Feeding a cancer patient: much more than supportive care, Nutrition (2017), doi: 10.1016/j.nut.2017.02.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
EDITORS’ PICK Feeding a cancer patient: much more than supportive care. Alessandro Laviano1, M.D., Luca Di Lazzaro1, M.D., Maria Isabel T.D. Correia2, M.D., Ph.D. Department of Clinical Medicine, Sapienza University, Rome, Italy, and, 2Department of Surgery,
Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
According to the World Health Organization (WHO), 8.8 million people worldwide died
of cancer in 2015, which is nearly 1 in 6 of global deaths (1). Also, the estimated total annual economic cost of cancer in 2010 is 1.16 trillion $ (1). On the other hand, the overall US cancer death rate between 2005 and 2014 declined by approximately 1.5% annually (2). From
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1991 to 2014, the overall cancer death rate dropped 25%, translating to approximately 2,143,200 fewer cancer deaths in the US alone (2). However, a closer look at the US statistics shows that 5-year survival rate of cancer patients diagnosed with advanced disease remains poor (2). This suggests that the progressive reduction of death rate, at least in high-income countries, may be also secondary to the implementation of early screening programs, as recommended by WHO (1), allowing for eradicative surgery.
Tumor immune evasion is an important contributor to the failure of many anti-cancer therapies (3). Similarly, malnutrition and cachexia have been repeatedly demonstrated to be associated with reduced efficacy of chemo- and radiotherapy and increased mortality (4). The current understanding of the role of nutritional status in influencing cancer patients’ clinical
outcome links nutritional decline to increased anti-cancer therapy-associated toxicity, which in turn reduces dose and duration of therapy. However, large observational studies suggest a
direct and independent influence of anorexia and reduced food intake on clinical outcome (5, 6). Nevertheless, the mechanisms linking anorexia and reduced survival have been only partially explained.
Recently, Flint et al. elucidated this relationship in established cancer cachexia models
(7). They showed that tumor-derived IL-6 inhibits hepatic ketogenesis through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. Ketone bodies are the main energy source during caloric deficit. Thus, when anorexia develops, the lack of an appropriate ketogenic response triggers a hormonal stress response, giving rise to circulating glucorticoids suppressing multiple intratumoral immune pathways and abolishing the response of
experimental cancers to immunotherapy. Whether this molecular link applies also to human cancers remains to be demonstrated. Also, Flint et al. could not assess whether food intake is superior to specialized nutritional support in attenuating the stress response (7). However,
progression tumor→anorexia→stress response→immune evasion.
experimental and clinical evidence appear to confirm the clinical relevance of the detrimental
Prior studies have demonstrated that glucocorticoids can suppress tumor progression and metastasis, although it should be acknowledged that other investigations reported that glucocorticoids inhibit chemotherapy-induced cell apoptosis (8). This controversial phenomenon
may result from different cancer subtypes, differential glucocorticoid receptor levels, and the dosage of glucocorticoids given (8). In a subgroup analysis of the Study of Chemoradiotherapy in OesoPhageal Cancer with or without Erbitux (SCOPE1), Cox et al. showed that survival was
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significantly improved in cancer patients at nutritional risk and receiving early nutrition support (9). It is important to note that cetuximab (i.e., the generic name of Erbitux®) is a monoclonal antibody binding the receptor of Epidermal Growth Factor expressed on the cancer cell’s surface and triggering the appropriate immune response. Feeding may facilitate anti-tumor immune response and enhance the efficacy of therapies by also modulating intestinal microbiota and thus facilitating the action of CD8+ cytotoxic T cells and CD4+ T-helper (Th1) cells via
mechanisms commonly involving their production of interferon-γ and cytotoxins (10). Windows of opportunity open in the clinical journey of cancer patients and should be exploited to improve short- and long-term clinical outcomes. In this light, the use of specific nutrients in the perioperative period may increase the survival rate of cancer patients (11). Finally, the Tight
Caloric Control pilot study revealed that filling the gap between actual and required energy intake by using artificial nutrition is associated with better nutritional status and improved
clinical outcome, although the study was not designed to assess impact on morbidity and mortality (12).
Although it is acknowledged that more studies are needed to assess the relevance of the
link cancer anorexia→immune evasion in human cancer, it appears safe and probably effective to adequately feed a cancer patient at nutritional risk during his/her clinical journey. There is also an ethical reason for delivering appropriate nutrition to cancer patients. Most people diagnosed with cancer live in low- and middle-income countries, where two thirds of cancer deaths occur (13). In 2015, approximately 35% of low-income countries reported that oncology services were generally available in the public sector, compared to more than 95% of high-
income countries (13). Cancer therapies are generally expensive and not affordable to the majority of patients with cancer in many countries worldwide. In this scenario, considering the metabolic effects of nutrients and their possible effects on anti-tumor immunity, it seems unacceptable that cancer patients are also denied a cheap and affordable support like food and
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therapeutic strategies. Semin Cancer Biol 2015; 35 (suppl.): S185–98
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