Systemic inflammation and cancer-related frailty: shifting the paradigm toward precision survivorship medicine
Antonio Di Meglio, Inês Vaz-Luís
Abstract
Over the past few decades, multiple studies have tried to stratify cancer survivors according to their individual risk of treatment-related toxicities, particularly of persistent ‘sequelae’ and deterioration of health-related quality of life.1Hertz D.L. Lustberg M.B. Sonis S. Evolution of predictive risk factor analysis for chemotherapy-related toxicity.Support Care Cancer. 2023; 31: 601Crossref Scopus (0) Google Scholar Nevertheless, a substantial part of the contributors to this inter-individual variability remains elusive. Seemingly similar patients may follow very different long-term patterns in terms of subjective toxicity to the same—or closely related—classes of drugs or treatment protocols.2Di Meglio A. Havas J. Gbenou A.S. et al.Dynamics of long-term patient-reported quality of life and health behaviors after adjuvant breast cancer chemotherapy.J Clin Oncol. 2022; 40: 3190-3204Crossref PubMed Scopus (15) Google Scholar, 3Vaz-Luis I. Di Meglio A. Havas J. et al.Long-term longitudinal patterns of patient-reported fatigue after breast cancer: a group-based trajectory analysis.J Clin Oncol. 2022; 40: 2148-2162Crossref Scopus (14) Google Scholar, 4Charles C. Bardet A. Larive A. et al.Characterization of depressive symptoms trajectories after breast cancer diagnosis in women in France.JAMA Netw Open. 2022; 5: E225118Crossref Scopus (8) Google Scholar This observation has catalyzed a need to improve the ability to accurately define predictors of cancer-related frailty at the individual level, and to personalize care pathways accordingly, from the moment a diagnosis of cancer is made. Such model of care would allow the implementation of early, tailored management interventions as well as of preventive and proactive supportive care strategies that could reduce morbidity and optimize the utilization of health care resources. Particularly, the identification of clinically actionable biomarkers for persistent cancer-related symptom burden is crucial to intercept optimized patient stratification with delivery of adapted interventions, and thus to successfully move forward the field of ‘precision survivorship medicine’.5Hertz D.L. McShane L.M. Hayes D.F. Defining clinical utility of germline indicators of toxicity risk: a perspective.J Clin Oncol. 2022; 40: 1721-1731Crossref Scopus (6) Google Scholar,6Hayes D.F. Defining clinical utility of tumor biomarker tests: a clinician’s viewpoint.J Clin Oncol. 2021; 39: 238-248Crossref PubMed Scopus (36) Google Scholar Refined knowledge of physiological and cancer biology has allowed to unravel several mechanistic pathways that underlie the enhanced frailty of certain individuals along their survivorship trajectory,7Carroll J.E. Bower J.E. Ganz P.A. Cancer-related accelerated ageing and biobehavioural modifiers: a framework for research and clinical care.Nat Rev Clin Oncol. 2022; 19: 173-187Crossref Scopus (20) Google Scholar and to identify some of its multiple risk factors, thus leveraging the holistic connection between biology, psychology, behaviors, and other socio-environmental mediators.8Sleight A.G. Crowder S.L. Skarbinski J. et al.A new approach to understanding cancer-related fatigue: leveraging the 3P model to facilitate risk prediction and clinical care.Cancers (Basel). 2022; 14: 1982Crossref PubMed Scopus (0) Google Scholar Among the biological risk factors that have been consistently proposed as linked to increased individual susceptibility to long-lasting treatment-related toxicities, particular empirical attention has been given to cancer-induced systemic inflammation, and, to a larger extent, to related mechanisms of accelerated aging, cellular damage, and stress.7Carroll J.E. Bower J.E. Ganz P.A. Cancer-related accelerated ageing and biobehavioural modifiers: a framework for research and clinical care.Nat Rev Clin Oncol. 2022; 19: 173-187Crossref Scopus (20) Google Scholar The accumulating evidence that such mechanisms may act as physiopathological contributors to heterogeneity among cancer survivors set out the rationale to study their key pathway components and delve deeper into their molecular underpinnings, in order to discover potential biomarkers that may drive personalized clinical care. Basic research focused on neural-immune signaling has suggested that stimulation of the central nervous system through the release of a pool of circulating cytokines and activation of the proinflammatory axis may herald the appearance of multiple physical, emotional, and cognitive manifestations, and, more broadly, of a number of inflammation-related ‘sickness behaviors’.9Bower J.E. The role of neuro-immune interactions in cancer-related fatigue: biobehavioral risk factors and mechanisms.Cancer. 2019; 125: 353-364Crossref PubMed Scopus (104) Google Scholar, 10Dantzer R. O’Connor J.C. Freund G.G. et al.From inflammation to sickness and depression: when the immune system subjugates the brain.Nat Rev Neurosci. 2008; 9: 46-56Crossref PubMed Scopus (5179) Google Scholar, 11Collado-Hidalgo A. Bower J.E. Ganz P.A. et al.Inflammatory biomarkers for persistent fatigue in breast cancer survivors.Clin Cancer Res. 2006; 12: 2759-2766Crossref PubMed Scopus (320) Google Scholar, 12Bower J.E. Cancer-related fatigue--mechanisms, risk factors, and treatments.Nat Rev Clin Oncol. 2014; 11: 597-609Crossref PubMed Scopus (900) Google Scholar Several studies, mostly focused on survivors of breast cancer, have described a wide range of symptoms that may stem from a common inflammatory substrate. For example, cancer-related fatigue, cognitive decline, sleep disturbance, emotional distress, and chronic pain are part of a constellation of usually concurrent and persistent ‘behavioral’ symptoms that are highly prevalent and distressful for cancer survivors, and for which a mutual etiology has been proposed, although a lot of its granularity still needs to be elucidated.10Dantzer R. O’Connor J.C. Freund G.G. et al.From inflammation to sickness and depression: when the immune system subjugates the brain.Nat Rev Neurosci. 2008; 9: 46-56Crossref PubMed Scopus (5179) Google Scholar,13Palesh O.G. Roscoe J.A. Mustian K.M. et al.Prevalence, demographics, and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center-Community Clinical Oncology Program.J Clin Oncol. 2010; 28: 292-298Crossref PubMed Scopus (374) Google Scholar, 14Lee B.N. Dantzer R. Langley K.E. et al.A cytokine-based neuroimmunologic mechanism of cancer-related symptoms.Neuroimmunomodulation. 2004; 11: 279-292Crossref PubMed Scopus (235) Google Scholar, 15Miller A.H. Ancoli-Israel S. Bower J.E. et al.Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer.J Clin Oncol. 2008; 26: 971Crossref PubMed Scopus (459) Google Scholar Along the same lines, data are available showing that the administration or induction of proinflammatory cytokines leads to increased symptomatology also in healthy humans16Reichenberg A. Yirmiya R. Schuld A. et al.Cytokine-associated emotional and cognitive disturbances in humans.Arch Gen Psychiatry. 2001; 58: 445-452Crossref PubMed Google Scholar, 17Späth-Schwalbe E. Hansen K. Schmidt F. et al.Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men.J Clin Endocrinol Metab. 1998; 83: 1573-1579Crossref PubMed Scopus (362) Google Scholar, 18Eisenberger N.I. Inagaki T.K. Mashal N.M. et al.Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood.Brain Behav Immun. 2010; 24: 558-563Crossref PubMed Scopus (298) Google Scholar and that elevated inflammation is detected in non-cancer populations with emotional distress syndromes.19Howren M.B. Lamkin D.M. Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis.Psychosom Med. 2009; 71: 171-186Crossref PubMed Scopus (2210) Google Scholar,20Irwin M. Effects of sleep and sleep loss on immunity and cytokines.Brain Behav Immun. 2002; 16: 503-512Crossref PubMed Scopus (293) Google Scholar However, cancer-related inflammation seems to be linked with more prolonged and more severe symptoms among cancer patients compared to individuals without a history of cancer, suggesting a precipitating role for treatments (particularly chemo-, radiation-, hormone-, or immunotherapy and targeted agents), potentially triggering a hyperactivated cross-signaling and feedforwarding enhanced inflammatory cascades.12Bower J.E. Cancer-related fatigue--mechanisms, risk factors, and treatments.Nat Rev Clin Oncol. 2014; 11: 597-609Crossref PubMed Scopus (900) Google Scholar Mounting evidence has also pointed at cancer-related inflammation as an accelerator of physiological aging through sustained cellular damage and stress.7Carroll J.E. Bower J.E. Ganz P.A. Cancer-related accelerated ageing and biobehavioural modifiers: a framework for research and clinical care.Nat Rev Clin Oncol. 2022; 19: 173-187Crossref Scopus (20) Google Scholar While the accumulation of common impairments interfering with day-to-day function, such as cognitive deficit, increasing fatigue, and reduced physical performance, is typical of normative aging, leading to a physiological state of frailty in the elderly individual irrespective of a history of cancer, many cancer survivors report physical and cognitive decline that have an earlier onset and greater likelihood of becoming chronic, with substantial detriment on quality of life.21Guida J.L. Ahles T.A. Belsky D. et al.Measuring aging and identifying aging phenotypes in cancer survivors.J Natl Cancer Inst. 2019; 111: 1245-1254Crossref PubMed Scopus (0) Google Scholar, 22Searle S.D. Mitnitski A. Gahbauer E.A. et al.A standard procedure for creating a frailty index.BMC Geriatr. 2008; 8: 1-10Crossref PubMed Scopus (2046) Google Scholar, 23Fried L.P. Tangen C.M. Walston J. et al.Frailty in older adults: evidence for a phenotype.J Gerontol A Biol Sci Med Sci. 2001; 56: M146-M156Crossref PubMed Google Scholar, 24Henderson T.O. Ness K.K. Cohen H.J. Accelerated aging among cancer survivors: from pediatrics to geriatrics.Am Soc Clin Oncol Educ Book. 2014; : e423-e430Crossref PubMed Scopus (103) Google Scholar Pre-existing, predisposing factors including age at cancer diagnosis, comorbid conditions, and baseline psychosocial traits, coupled with precipitating, treatment-related factors, and with other perpetuating conditions, such as unhealthy lifestyles, may favor the accumulation of cells enriched with an inflammation- and stress mediators-biased ‘secretome’.12Bower J.E. Cancer-related fatigue--mechanisms, risk factors, and treatments.Nat Rev Clin Oncol. 2014; 11: 597-609Crossref PubMed Scopus (900) Google Scholar,15Miller A.H. Ancoli-Israel S. Bower J.E. et al.Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer.J Clin Oncol. 2008; 26: 971Crossref PubMed Scopus (459) Google Scholar,25Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors.Cell. 2005; 120: 513-522Abstract Full Text Full Text PDF PubMed Scopus (1874) Google Scholar,26Van Waart H. Stuiver M.M. Van Harten W.H. et al.Effect of low-intensity physical activity and moderate- to high-intensity physical exercise during adjuvant chemotherapy on physical fitness, fatigue, and chemotherapy completion rates: results of the PACES randomized clinical trial.J Clin Oncol. 2015; 33: 1918-1927Crossref PubMed Scopus (406) Google Scholar Refined biological knowledge has to the role of of systemic Several J.E. Ganz P.A. et and fatigue among patients with breast cancer.J Clin Oncol. 31: PubMed Scopus Google Scholar, A. Bower J.E. Ganz P.A. et and fatigue in breast cancer survivors: Behav Immun. 2008; PubMed Scopus Google Scholar, A. M. A. M. biological and mechanisms of cancer-related Res. 2010; 19: PubMed Scopus (0) Google Scholar, S. S. et of the role of circulating inflammatory biomarkers and long-term cancer related fatigue in breast cancer 2021; 56: Full Text Full Text PDF PubMed Scopus (0) Google Scholar, S. M. et al.Inflammatory stem cells, and symptoms in breast cancer patients adjuvant Cancer Scholar, M. I. R. et physical fatigue and depression in breast cancer survivors: of and PubMed Scopus (0) Google Scholar, S. D. et al.Inflammation exercise effects on fatigue in patients with breast Sci 2021; PubMed Scopus Google Scholar, A. et al.A of in breast cancer survivors Res. 2021; PubMed Scopus (0) Google Scholar, et al.Cytokine-associated fatigue and for breast cancer.J 2019; Full Text Full Text PDF Scopus (6) Google Scholar, et of and cancer-related fatigue in breast cancer a Med. 2019; PubMed Scopus (0) Google Scholar, D. stress psychological and immune of women with breast cancer: a randomized with Behav Immun. 2019; PubMed Scopus Google Scholar, et al.A randomized effects of stress for breast cancer survivors on and 2019; PubMed Scopus (0) Google Scholar, et of in with cancer-related fatigue and chemotherapy-related cognitive in breast cancer a Cancer PubMed Scopus (0) Google Scholar, Schmidt et of physical exercise on of inflammation in breast cancer patients during adjuvant Cancer Scopus Google Scholar, A.S. et inflammation and fatigue and physical in older breast cancer PubMed Scopus Google Scholar, M. et of personalized exercise during on the of physical activity fatigue, and biomarkers in patients with breast Cancer PubMed Scopus Google Scholar, C. A.H. J. et symptoms and inflammation are risk factors of fatigue in breast cancer Med. PubMed Scopus Google Scholar, H. et in immune and between and breast cancer survivors: a 2014; 8: PubMed Scopus Google Scholar, M.M. D. et fatigue of depression in breast cancer patients to Behav Immun. PubMed Scopus Google Scholar, M. et and sleep quality are with in inflammatory in breast cancer patients Behav Immun. 26: PubMed Scopus Google Scholar, J.E. Ganz P.A. et al.Inflammation and behavioral symptoms after breast cancer fatigue, and sleep a common Clin Oncol. PubMed Scopus Google Scholar, J.E. Ganz P.A. et al.Inflammatory biomarkers and fatigue during for breast and Cancer Res. 2009; PubMed Scopus Google Scholar, D.M. of cancer-related fatigue in women with breast cancer and after adjuvant 2008; 31: PubMed Scopus Google Scholar, J.E. Ganz P.A. et al.Inflammatory to psychological stress in breast cancer survivors: to Behav Immun. PubMed Scopus Google Scholar, J.E. et between fatigue and quality of life and inflammation during chemotherapy in breast 2005; PubMed Scopus Google Scholar, H. et and during of patients with breast Oncol Biol 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, S. R. et factors exercise effects on fatigue in breast cancer Sci 2014; PubMed Scopus Google Scholar particularly and tumor to have in and systemic effects leading to a wide of in cancer survivors, such as on and A. Bower J.E. Ganz P.A. et al.Inflammatory biomarkers for persistent fatigue in breast cancer survivors.Clin Cancer Res. 2006; 12: 2759-2766Crossref PubMed Scopus (320) Google H. et in immune and between and breast cancer survivors: a 2014; 8: PubMed Scopus Google Scholar, M.M. D. et fatigue of depression in breast cancer patients to Behav Immun. PubMed Scopus Google Scholar, M. et and sleep quality are with in inflammatory in breast cancer patients Behav Immun. 26: PubMed Scopus Google S. R. et factors exercise effects on fatigue in breast cancer Sci 2014; PubMed Scopus Google Scholar, J.E. Ganz P.A. et al.Acute and chronic effects of adjuvant on inflammatory in breast cancer Cancer 2022; Scholar, et al.A study of proinflammatory cytokines and fatigue in women with breast cancer during 40: PubMed Scopus (0) Google Scholar, and pathway analysis of for with cancer-related fatigue in breast cancer patients after 2014; PubMed Scopus (0) Google Scholar The proinflammatory activity of has been linked with susceptibility to cancer-related symptoms the from long-term A. Bower J.E. Ganz P.A. et al.Inflammatory biomarkers for persistent fatigue in breast cancer survivors.Clin Cancer Res. 2006; 12: 2759-2766Crossref PubMed Scopus (320) Google J.E. Ganz P.A. et and proinflammatory activity in breast cancer Med. 2002; PubMed Google J.E. A. D. et a biobehavioral model of fatigue adjuvant in women with breast 2019; 125: PubMed Scopus Google Scholar of activation also a role in the proinflammatory and to cancer-related Among C-reactive is an in to proinflammatory cytokines during inflammatory or and is also a of immune and D. J. E. et inflammation in the etiology of the life Med. 2019; PubMed Scopus (0) Google Scholar, J.E. et C-reactive and patient-reported cognitive in older breast cancer survivors: the and with cancer Clin Oncol. 2023; Scopus Google Scholar, J.E. et protein, and risk of Med 2001; PubMed Google Scholar of also have clinical as suggested some studies that have elevated of with cognitive among elderly cancer J.E. et C-reactive and patient-reported cognitive in older breast cancer survivors: the and with cancer Clin Oncol. 2023; Scopus Google Scholar the identification of associations between and a range of treatment-related has on the of identifying germline or indicators of individual susceptibility to cancer-related frailty and improve the predictive ability of on clinical D.L. McShane L.M. Hayes D.F. Defining clinical utility of germline indicators of toxicity risk: a perspective.J Clin Oncol. 2022; 40: 1721-1731Crossref Scopus (6) Google Scholar For in the of cancer-related inflammation, germline that the of in the of in stress or proinflammatory cytokines have been with several treatment-related toxicities, particularly with M.B. Lamkin D.M. Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis.Psychosom Med. 2009; 71: 171-186Crossref PubMed Scopus (2210) Google J.E. Ganz P.A. et and fatigue among patients with breast cancer.J Clin Oncol. 31: PubMed Scopus Google A. Bower J.E. Ganz P.A. et and fatigue in breast cancer survivors: Behav Immun. 2008; PubMed Scopus Google C. M. K. et evidence of an between a and fatigue and sleep in patients and their 2010; 40: Full Text Full Text PDF PubMed Scopus (0) Google Scholar, J. et predictors of fatigue in cancer patients with Behav Immun. 26: PubMed Scopus Google Scholar, A. et between and a symptom of fatigue, sleep disturbance, and depression in patients to breast cancer 2015; PubMed Scopus Google Scholar, et in the interleukin-6 and and depression and fatigue and Psychiatry. 2009; 14: PubMed Scopus Google Scholar, D.L. A.H. et interleukin-6 in cancer patients with depression: Psychiatry. 2001; PubMed Scopus Google Scholar, et and functions of and in healthy and depressed elderly Psychiatry. Full Text Full Text PDF PubMed Scopus (36) Google Scholar some of in with cellular to have been suggested to be in increased to other common toxicities, such as to of cancer 2022; Full Text Full Text PDF PubMed Scopus (8) Google A. et and a Clin Oncol. PubMed Scopus (0) Google Scholar or M. et of are with Cancer. Scopus Google Scholar is to the between systemic inflammation and cancer-related frailty to clinical and reduce cancer-related symptom of the inflammatory are in the and may patient stratification in that on clinical risk Meglio A. Havas J. D. et and of a predictive model of severe fatigue after breast cancer a personalized framework in survivorship Clin Oncol. 2022; 40: Scopus Google Scholar may also allow for of systemic inflammation as a potential at the clinical appearance of inflammation-related M. D. S. S. A for of and as potential for inflammatory 26: PubMed Scopus Google K.E. N.I. E. A for 2022; Scopus Google Scholar For example, although the inflammation is suggested that trajectories could be a of chronic inflammatory and may be for and management of and inflammation-related C. et trajectories and the risk of cancer a Cancer. 2022; Scopus Google S. S. C-reactive as a biomarker for depressive Sci. 2022; Scopus Google Scholar the mechanisms the between inflammation and cancer-related frailty also the for the of strategies that inflammation to knowledge of key of cancer-related inflammation and of their at the and systemic level, potential and have also been this a and has been described between inflammation and some behavioral For example, individuals with and of physical and are usually have increased of systemic inflammatory J.E. Cancer-related fatigue--mechanisms, risk factors, and treatments.Nat Rev Clin Oncol. 2014; 11: 597-609Crossref PubMed Scopus (900) Google of the on Rev Med. 2015; PubMed Scopus Google Scholar a between loss of and of systemic inflammation such as has been described in some tumor J.A. et of systemic inflammation and with in cancer: results from the Oncol. Google Scholar, et al.Effect of on toxicity and in patients with cancer adjuvant Care Cancer. 2015; PubMed Google Scholar, R. M.B. et as an of toxicity and in patients with cancer with Med. 5: PubMed Scopus Google Scholar This observation to the that inflammation and is enhanced at of cancer-related J.A. et of systemic inflammation and with in cancer: results from the Oncol. Google Scholar evidence that interventions that act on behavioral of physical and and psychosocial and sleep inflammation, and be to a of and thus life and health among cancer J.E. Bower J.E. Ganz P.A. Cancer-related accelerated ageing and biobehavioural modifiers: a framework for research and clinical care.Nat Rev Clin Oncol. 2022; 19: 173-187Crossref Scopus (20) Google J.E. et inflammatory signaling in breast cancer survivors: a randomized 2014; PubMed Scopus Google Scholar, R. C. et behavioral for life and inflammatory risk: a randomized 2014; PubMed Scopus Google Scholar, J.E. and of inflammatory a Behav Immun. PubMed Scopus Google Scholar, C. S. et and of behavioral for cancer-related effects on and during a Cancer. Scopus Google Scholar, C. J. et of sleep with physical and in older with Care Cancer. PubMed Scopus Google Scholar, T.A. Effects of loss and on circulating biomarkers in breast cancer survivors in a loss in the Scopus Google Scholar, D. et effects of a loss on and in breast cancer survivors: the Cancer Res. 26: PubMed Scopus Google Scholar, of loss with or without exercise on inflammatory and in the a randomized PubMed Scopus (0) Google Scholar, et of on factors and biomarkers in a loss in women baseline Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. Effects of exercise on and inflammatory in breast cancer survivors: a and 26: PubMed Scopus (0) Google Scholar many of behavioral interventions be and M. F. et and of in cancer survivorship an of Oncol. 2021; Full Text Full Text PDF PubMed Scopus Google Scholar A framework showing the among systemic inflammation, cancer-related frailty and its risk factors, and interventions is in order to be and survivorship research focused on and variability in cancer-related frailty a a deeper understanding of biological This would facilitate the of cancer-related frailty through and of and implementation of targeted interventions, and with their care. is to in the studies and data in this research toxicity and have of larger clinical However, the of prediction and clinical studies that of the toxicity such as with data patient-reported M. E. F. et role of patient-reported in the of cancer clinical Clinical Oncol. 2022; 33: Full Text Full Text PDF PubMed Google standard clinical data linked with are for a of multiple biological including for systemic inflammation, as well as of aging and be longitudinal and long-term for after completion of also be available for the of survivorship research has been on of survivors of very common such as breast cancer, to this knowledge and research to other cancer including prevalent are a the of of systemic inflammation, may identify contributors that act as precipitating, or perpetuating factors of cancer-related of biomarker including studies to identify germline predictors of cancer treatment-related few clinically mostly focused on and the of studies to long-term that may quality of life for after treatment D.L. McShane L.M. Hayes D.F. Defining clinical utility of germline indicators of toxicity risk: a perspective.J Clin Oncol. 2022; 40: 1721-1731Crossref Scopus (6) Google Scholar The study of of including and the may this R. for clinical and 2014; PubMed Scopus Google Scholar, S. The role of in identification of biomarkers of toxicity 2002; PubMed Scopus Google Scholar, D. of and toxicity of cancer chemotherapy and 2023; Full Text Full Text PDF PubMed Scopus Google Scholar, of and for 2021; PubMed Scopus (0) Google Scholar However, data the to mechanistic knowledge and some clinically research such in the cancer survivorship is still and are in and and for and of still need to be including data from health of and of data through and K. M. A. et in are and to move Rev 2021; PubMed Scopus Google Scholar, M. K.M. H. et to deterioration of cancer and in an diagnosis of Oncol. 2019; Full Text Full Text PDF PubMed Scopus (0) Google Scholar, M. et to patient chemotherapy in Clin Cancer Scopus Google Scholar, Scholar data research M. S. et in the of the data treatment Open. 2023; Full Text Full Text PDF Scopus Google Scholar is an that systemic inflammation, and a role in long-term treatment a of cancer-related is to move focused research that the of biological to optimized survivorship through identification of survivors at risk of cancer-related individual and personalized management interventions and including on behavioral strategies and health and of targeted that inflammatory and other biological Di Meglio research from a in from the of Clinical Oncology and for Clinical Cancer The also research from the Cancer and from the to Di and from the the and the or research Care the