Current guidelines for nutrition therapy in cancer: The arrival of a long journey or the starting point?

INTRODUCTION

A 2017 estimate found that among the leading causes of death in the United States, cancer research receives ∼4000 USD per life lost.1 When the number of annual cancer deaths is considered, the economic magnitude of the efforts made to influence cancer epidemiology becomes apparent. Whether past and current funding yielded to significant clinical achievements is constantly under the scrutiny of taxpayers and cancer patients’ associations. In 2019, The Global Burden of Disease Cancer Collaboration reported that the average annual percentage change in age-standardized incidence rate for all cancers from 2007 to 2017 has increased in most countries of the world.2 In contrast, the average annual percentage change in age-standardized mortality rate slightly declined during the same period.2 A superficial analysis of these data may suggest that cancer prevention remains a significant challenge, but a relevant contribution could have been offered by the increased efficiency of diagnostic tools, whereas annual cancer deaths are still rising but at a reduced pace. Are these results economically, societally, and clinically meaningful? It is difficult to say. Particularly, when a more in-depth analysis of the changing epidemiology of cancer is considered.

MORTALITY RATE OR PATIENTS’ FUNCTIONING: WHICH TO PREFER IN PATIENTS WITH CANCER?

Mortality rate is superficially considered the key marker of success of the fight against cancer. However, quality of life remains a major outcome measure for patients with cancer and especially for those diagnosed and living with advanced disease. When considering the change in the absolute number of disability-adjusted life-years (DALYs) between 1990 and 2017 for Global Burden of Disease level 2 causes, it appears that neoplasms (ie, all cancers as defined under the International Classification of Diseases, 10th Revision) raised from the seventh position in the 2007 ranking to the second position in 2017, when only cardiovascular diseases had a greater impact from DALY.2 This evidence may suggest that fewer patients with cancer die annually but more are living with disability and, possibly, poor quality of life. This interpretation of the available data is supported by the lack of correlation in cancer clinical trials between improved survival and enhanced quality of life,3 as well as by reports showing that approved systemic oncology therapies often do not have published evidence to suggest quality of life improvement, despite its recognized importance.4 It should be noted that the gap in research on quality of life does not belong to cancer only but to many acute and chronic diseases as well.

It could be speculated that this discrepancy is the consequence of placing mortality as the main target for cancer research. When translating this research objective into clinical practice, an asymmetric approach to patients with cancer occurs. Patients with cancer, and particularly those with advanced disease, should receive two concurrent treatment modalities: disease-modifying therapies and supportive care. Disease-modifying therapies target cancer cells and aim at prolonging survival. Palliative care, also defined as supportive care, targets the needs of the patients with cancer and aims at improving their quality of life. Highlighting mortality rate as the real objective of the fight against cancer undermined the role of palliative care, which includes nutrition care among other therapies, contributing to missing the goal of a longer and better life for patients with cancer.

CURRENT GUIDELINES: EVIDENCE-BASED RECOMMENDATIONS VS PRAGMATIC APPROACH

The importance of nutrition care, as an important contributor to supportive care, is being increasingly recognized. The term malnutrition refers to a wide set of nutrition disorders, ranging from obesity to undernutrition. Although obesity in cancer is frequently reported, the term malnutrition in this manuscript will be used to describe undernutrition. Malnutrition is a frequent comorbidity in patients with cancer and negatively influences quality of life and clinical outcomes. In contrast with other comorbidities, malnutrition is, most of the times, preventable and treatable and should represent a meaningful target in the multimodal approach to patients with cancer. As a consequence of the increased relevance of nutrition care in the oncology setting, national and international guidelines have been produced and published.5 Of great relevance, guidelines issued by nutrition societies, including the American Society for Parenteral and Enteral Nutrition (ASPEN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), have been recently followed by those developed by cancer societies, including the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO).

Although the quality of the different guidelines may significantly change,5 all of them highlight two key messages: (1) malnutrition is a negative prognostic factor, and (2) all patients with cancer should be screened for malnutrition on referral. When it comes to treatment, recommendations significantly vary from guideline to guideline because of the many limitations of nutrition research, at least in the oncology setting, in which the presence of healthcare professionals with specific competencies in nutrition care is often missing or underrepresented.

When the ASCO guideline are considered,6 the only suggestion given deals with nutrition counseling, which may be offered with the goals of providing patients and caregivers with advice for the management of cachexia. No other nutrition intervention is recommended. Consistent with the approach outlined in the ASCO guideline, the vast majority of medical oncologists acknowledge the clinical relevance of malnutrition, yet nutrition therapy remains overlooked and underprescribed because of the absence of evidence and, in some cases, because of evidence of absence. The ESMO guideline appears to propose a different approach to the issue of malnutrition of patients with cancer,7 although the literature considered is the same as that in the ASCO guidelines. The ESMO Guideline Committee acknowledges the weakness of the available evidence but recommends to thoroughly investigate nutrition risk in all patients with cancer and to prioritize multimodal care for those patients with malnutrition or at risk of malnutrition. Also, the ESMO guideline identified specific nutrients possibly yielding nutrition benefits, at least in specific clinical conditions. In this regard, the ESMO guideline shares the approach already put forward by ESPEN guidelines.8 ESMO guidelines appear more pragmatic than those of ASCO: they acknowledge the clinical problem of malnutrition in cancer and the lack of solid and robust evidence of nutrition intervention effectiveness. Nevertheless, they offer a strategy, as weak as it could be, to deal with malnutrition because malnutrition and its negative consequences do not disappear from the clinical radar just because we do not have statistical evidence.

FUTURE GUIDELINES: WHERE TO GO FROM HERE?

The analysis of the changing trend of national and international guidelines on the role of nutrition care in patients with cancer allows researchers to identify the initial steps of the hopefully unstoppable shift toward patients’ care of the fight against cancer. It is now becoming clearer that the focus of basic and clinical research should be on the patients rather than the disease. Also, nonpharmacological interventions should not be judged based on outcome measures that minimally impact the needs and aspiration of patients. This critical reassessment has already started for nonpharmacological intervention in patients with chronic headache.9 In a Delphi panel of healthcare professionals and patients, it has been concluded that disability and ability to function are outcome measures superior to headache frequency.9 Also, the panel agreed that improved functioning is the preferable goal of nonpharmacological intervention rather than symptom reduction.9 Future trials of nonpharmacological treatment in patients with cancer, including those testing the relevance of nutrition intervention, should therefore include primary outcome measures better capturing the most relevant goals of patients, that is, time spent at home with the family rather than overall survival.

Reconsidering the goals of nutrition research in patients with cancer should represent a priority for the nutrition community but should not obscure the errors made in the previous years. In particular, the nutrition community should be blamed for contributing to the confusion on the nature and diagnosis of malnutrition in cancer. As stated in the ASCO guideline, “to date, the primary limitations of cancer cachexia clinical research include the use of highly varied definitions, heterogeneous end point, and a lack of integrated biomarkers.”6 The recent initiative of the Global Leadership Initiative on Malnutrition appears to be a good start to address the current limitations of nutrition research10, 11 because they are intended to be used in parallel with established concepts and nomenclature, including cachexia, sarcopenia, and frailty.

Beyond these initial steps, how do we further enhance the relevance of the guidelines for nutrition care in cancer to patients and healthcare professionals? I once overheard at an oncology meeting that “the more I study cancer, the more I am convinced that cancer is a rare disease.” Human cancers differ among them in terms of phenotype, molecular pathways, and metabolic impact. More importantly, patients with cancer are unique in their clinical features, needs, and goals and deserve a multimodal and multidisciplinary approach, as proposed years ago by the late Ken Fearon, the pioneer of the comprehensive management of patients with cancer.12 Consequently, issuing general nutrition guidelines may not capture the individual and specific needs of patients experiencing cancers of different tissues, as well as during different steps of his/her clinical journey.13 Also, solid basic and preliminary clinical data suggest that under specific clinical conditions, modulation of short-term fasting with appropriate refeeding may yield clinical benefits.14, 15 Rather than denying the issue, the nutrition community should start investigating the combination of nutrition intervention with fasting-mimicking diets and/or ketogenic diets and include such multidimensional approach in guidelines when robust evidence has accumulated, which will detail the possible benefits and limitations.

CONCLUSION

The available evidence is growing in support of the importance of nutrition intervention in the management of patients with cancer. A general understanding of the needs of patients with cancer during catabolic crisis has been achieved.15 However, and from the nutrition point of view, patients with cancer are more than catabolic crisis or body composition. Future guidelines should, therefore, address the changing needs of the patients as the result of a renaissance on new premises of nutrition research.

AUTHOR CONTRIBUTIONS

Alessandro Laviano conceived and designed the structure of the review; Alessandro Laviano was responsible for the acquisition, analysis, and interpretation of the available and relevant literature; and Alessandro Laviano drafted the manuscript. Alessandro Laviano critically revised the manuscript, agrees to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript.

CONFLICT OF INTEREST

Alessandro Laviano received honoraria for independent lectures at events organized by Abbott, Baxter, BBraun, Fresenius Kabi, Nestlé Health Science, Nutricia, and Smartfish. Alessandro Laviano is a member of the advisory board of Royal DSM NV and of Nutricia Oncology.

FINANCIAL DISCLOSURE

The content of this article was presented during the virtual course Comprehensive Nutritional Therapy, Tactical Approaches in 2021 (part 1, March 19, 2021; part 2, March 20, 2021), which was organized by the ASPEN Physician Engagement Committee and preceded the ASPEN 2021 Nutrition Science & Practice Conference. The author received a modest monetary honorarium. The conference recordings were posted to the ASPEN eLearning Center (https://aspen.digitellinc.com/aspen/store/6/index/6).

REFERENCES

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