Intravenous nutrition in cancer patients, aimed at preventing cachexia rather than trying to treat it, may bring clinically relevant benefits
Department of Clinical
Based on most recent international guidelines, parenteral nutrition appears to have limited indications in cancer patients. Indeed, many clinical trials failed to demonstrate clinically relevant benefits for intravenous nutrition during tumour growth. However, these negative results are caused, at least in part, by the clinical setting of these studies. The clinical journey of the cancer patient is frequently characterised by the progressive onset of malnutrition, resulting in clinically significant negative outcomes.
Malnourished cancer patients develop chemotherapy- associated toxicity more frequently than those who are well nourished, resulting in a reduction of the given dose or failure to complete the planned anti-neoplastic therapy. A number of studies have demonstrated that the quality of life of malnourished cancer patients is significantly reduced. Considering this negative impact on patients’ quality of life, morbidity and mortality, cancer-associated malnutrition is becoming a clinical priority.
The pathogenesis of malnutrition in cancer is multifactorial, but it is now generally acknowledged that cancer-induced reduction of appetite and energy intake (anorexia) and profound changes in host metabolism represent the main catabolic factors. Malnutrition observed in cancer patients is different, in this regard, from malnutrition of starvation, since the metabolic derangements induced by tumour growth may prevent the efficient utilisation of nutrients by host tissues. As a consequence, normalisation of food intake in cancer patients may ameliorate body weight but may not restore body composition. Decreasing muscle mass remains largely unaffected, whereas water retention and body fat gain account for the increase of body weight observed during artificial nutrition.
During tumour growth, a chronic and low-grade inflammatory response develops, which is thought to represent the body’s attempt to counteract tumour proliferation (See Figure 1). Pro-inflammatory cytokines, in particular interleukin-1, interleukin-6 and tumour necrosis factor-alpha mediate most of the metabolic effects of the inflammatory response, acting at the brain level to suppress appetite and derange energy metabolism, and at the peripheral level to increase wasting of muscle mass and fat tissue. These molecular and biochemical events translate into the clinical syndrome of cancer cachexia, which should be considered as a specific subset of malnutrition.
The use of artificial nutrition (enteral and parenteral) has been advocated as an effective tool in malnourished cancer patients. Unfortunately, as mentioned, the results obtained in many clinical trials are disappointing, since the provision of exogenous calories and proteins via the enteral and parenteral route do not consistently yield to improved clinical outcomes.,
The possibility that exogenous calories may stimulate tumour growth has also been a concern. Better understanding of the biology of tumour cells and of the mechanisms of cancer cachexia may now help to devise more effective nutritional and metaboic strategies to replenish cancer patients.
Bridging the caloric gap
Cancer patients frequently develop anorexia and reduced food intake. In general, the gap between energy requirements and energy intake in cancer patients ranges between 200 and 400 Kcal/day. Consequently, if not corrected, cancer anorexia will progressively contribute to the development of malnutrition.
To bridge the caloric gap, the use of artificial nutrition is an intuitive approach. In particular, the use of parenteral nutrition appears best suited to overcome thereluctance of cancer patients to eat due to anorexia and to by-pass the psychological distress related to the insertion of the feeding tube. On the other hand, the issue of the possible stimulation of tumour growth remains unresolved and, until now, limited evidence exists of the benefit for parenteral nutrition in cancer patients.
Clinical trials have not demonstrated a consistent direct effect of parenteral nutrition on tumour cells’ replication rates. Bozzetti and Mori have recently reviewed this issue and retrieved 12 studies evaluating tumour growth in patients receiving nutritional support.
Although no stimulation of replication rate was observed in the control groups not receiving nutritional support, tumour growth was reported to increase following artificial nutrition in 7 studies out of 127. The contrasting results could be explained by the different nutritional regimens and by the heterogeneity of the cancer patients enrolled in these studies.
Recent evidence underlines the importance of considering the unique genetic profiles of human cancers when trying to give general recommendations regarding nutritional support. Tumour metabolism is based mainly on aerobic glycolysis (Cori cycle) as cancer cells frequently lack key enzymes for fat oxidation. Consequently, the infusion of glucose by parenteral nutrition may well stimulate tumour replication rate. However, the susceptibility of cancer cells to the negative effects of dietary, and particularly glucose restriction, is not universal. It is linked to specific mutations within the glucose metabolism pathways.
Cancer cells that form tumours that are resistant to dietary restriction, carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase pathway. A recommendation to avoid parenteral nutrition would benefit only those cancer patients whose tumours carry those specific mutations. To overcome this uncertainty, the infusion of a lipidbased parenteral nutrition (70-100% of calories provided as lipids) or the prescription of a ketogenic diet with minimal content of carbohydrates have shown interesting results.,
Recent experimental evidence demonstrates that glucose deprivation contributes to the development of mutations in cancer cells which favour their survival in hypoglycaemic environments. Therefore, withdrawal of parenteral nutrition to cancer patients should not be based on the concern of stimulating tumour growth because cancer cells are genetically
equipped to escape the negative effects of dietary restriction.
Recent guidelines for the use of parenteral nutrition in cancer patients issued by ESPEN-European Society of Clinical Nutrition and Metabolism state that parenteral nutrition should be offered to malnourished or aphagic cancer patients when:
- Spontaneous food intake or enteral nutrition are not feasible.
- Expected survival is longer than 2-3 months.
- Parenteral nutrition is expected to improve performance status and quality of life.
This restrictive approach is justified by the disappointing research results but does not acknowledge that the absence of evidence is not evidence of absence.
Inflammation-driven changes in cancer patient’s metabolism prevent full utilisation of the nutrients infused. However, by integrating parenteral nutrition with anti-inflammatory therapy, relevant clinical outcomes could be achieved. Lundholm et al demonstrated in patients with malignant disease that the combination of nutritional support, including parenteral nutrition, and cyclo-oxigenase inhibitor resulted in improved energy balance, enhanced maximum exercise capacity and increased survival. This study underlines the relevance of parenteral nutrition in covering nutritional requirements when oral intake and enteral nutrition are insufficient. It suggests that, in the future, the integration of standard parenteral nutrition with the infusion of nutraceuticals nutrients with specific anti-inflammatory properties such as the n-3 fatty acids-given on top of the estimated energy and protein needs, may maintain or restore nutritional status and yield significant clinical results. In addition, parenteral nutrition in cancer patients with mild hypophagia at the beginning of their clinical journey- rather than at the very end when severe malnutrition has already developed-may protect metabolic and physical functions.
A new approach
Better knowledge of the pathogenesis of cancer cachexia and the availability of nutrients with anti-inflammatory properties enable a new model for the use of parenteral nutrition in cancer patients to be proposed. This new approach is based on the early initiation of intravenous feeding in mildly aphagic and malnourished cancer patients when oral intake or enteral nutrition are not feasible, even in conjunction with active antineoplastic treatment. More importantly, the coverage of the energy and protein needs, achieved by parenteral nutrition, should be integrated by the provision of nutraceuticals- to favourably affect the changes of patients’ metabolism- and, therefore, restore the ability to fully utilise the infused nutrients, minimally influencing tumour replication rate.
1. Werner A. The male climacteric. JAMA 1939;112:1441-3.
1. Laviano A, Meguid MM, Inui A, Muscaritoli M, Rossi-Fanelli F. Therapy Insight: Cancer anorexia-cachexia sindrome-when all you can eat is yourself. Nat Clin Pract Oncol 2005;2:158-65.
2. Andreyev HJ, Norman AR, Oates J, Cunningham D. Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? Eur J Cancer 1998;34:503-9.
3. Marin Caro MM, Laviano A, Pichard C. Nutritional intervention and quality of life in adult oncology patients. Clin Nutr 2007;26:289-301.
4. Muscaritoli M, Bossola M, Aversa Z, Bellantone R, Rossi-Fanelli F. Prevention and treatment of cancer cachexia: new insights into an old problem. Eur J Cancer 2006;42:31-41.
5. Arends J, Bodoky G, Bozzetti F, Fearon K, Muscaritoli M, Selga G, van Bokhorst-de van der Schueren MA, von Meyenfeldt M, et al. ESPEN Guidelines on Enteral Nutrition: non-surgical oncology. Clin Nutr 2006;25: 245-59.
6. Bozzetti F, Arends J, Lundholm K, Micklewright A, Zurcher G, Muscaritoli M. ESPEN Guidelines on Parenteral Nutrition: non-surgical oncology. Clin Nutr 2009;28:445-54.
7. Bozzetti F, Mori V. Nutritional support and tumour growth in humans: a narrative review of the literature. Clin Nutr 2009;28:226-30.
8. Gatenby RA, Gillies RJ. Why do cancer have high aerobic glycolysis? Nat Rev Cancer 2004; 4:891-9
9. Kalaany NY, Sabatini DM. Tumours with PI3K activation are resistant to dietary restriction. Nature 2009;458:725-32.
10. Rossi-Fanelli F, Franchi F, Mulieri M, Cangiano C, Cascino A, Ceci F, Muscaritoli M, Seminara P, et al. Effect of energy substrate manipulation on tumour cell proliferation in parenterally fed cancer patients. Clin Nutr 1991;10:228-32.
11. Seyfried TN, Klebish M, Mukherjee P, Marsh J. Targeting energy metabolism in brain cancer with calorically restricted ketogenic diets. Epilepsia 2008;49 (suppl. 8):114-6.
12. Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Wilson JKV, et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 2009; doi: 10.1126/science.1174229 (e-pub ahead of print).
13. Lundholm K, Daneryd P, Bosaeus I, Korner U, Lindholm E. Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: effects on survival, metabolism, and function. A randomized prospective study. Cancer 2004;100:1967-77.