Clinical Nutrition Highlights

Science supporting better nutrition

Nutrition and Patients

Outcomes in Oncology

Special Issue
September 2013
1

Clinical Nutrition Highlights

Science supporting better nutrition
Special Issue
September 2013

Nutrition and Patients Outcomes in Oncology

Page
Cancer Treatment and Nutrition
Zeno Stanga, MD

Approaches to Nutritional Supplementation in Patients Undergoing

Neoadjuvant Chemoradiotherapy and Surgery for the Treatment of
Esophageal and Esophagogastric Cancer
Donald E Low, MD, FACS, FRCS(C)

10

Nutrition Modulation of Chemotherapy Efficacy and Toxicity

Vickie E Baracos, PhD

15

Nutritional Interventions Improve QoL

Jens Kondrup, MD, PhD

18

Specialised Nutritional Intervention During Chemotherapy

Alessandro Laviano, MD

21

Sponsored as a service to the medical profession by the Nestl Nutrition Institute.

The opinions expressed in this publication are not necessarily those of the editor, publisher or sponsor. Any liability or obligation for loss or damage howsoever
arising is hereby disclaimed. Although great care has been taken in compiling and checking the information herein to ensure that it is accurate, the editor,
publisher and sponsor shall not be responsible for the continued currency of the information or for any errors, omissions or inaccuracies in this publication.
2013 Socit des Produits Nestl S.A. All rights reserved.
No part of this publication may be reproduced by any process in any language without the written permission of the publisher.

Cancer Treatment and Nutrition

Zeno Stanga, MD
Head of the Nutritional Support Team, Division of Endocrinology, Diabetes and
Clinical Nutrition, and Division of General Internal Medicine,
University Hospital, Bern, Switzerland

Introduction
Deterioration of nutritional state and persistent weight loss
may have deleterious consequences for cancer patients. The
prevalence of cancer-related malnutrition ranges from 3074% in in- and out-patients, and is related to an increased
risk of adverse clinical outcome1,7, poor quality of life, and
lower survival rates8-10. In addition, as many as 20% of cancer
patients die from the effects of malnutrition rather than from
the malignancy11. Nutritional state tends to decline during the
course of hospitalization and malnutrition is associated with
increased morbidity and mortality, prolonged hospital stay
and increased health care costs12-14. Furthermore, malnutrition
worsens the responsiveness and tolerance to anti-cancer
therapy15. On the other hand, early and adequate provision
of nutritional support for those identified as malnourished
has demonstrated an improved outcome16-17. It is therefore
essential that nutritional issues are addressed at the time of
diagnosis and throughout the course of anticancer treatment.
In a recent multicenter, prospective cohort study Pan et
al. showed the impact of malnutrition, nutritional risk, and
nutritional treatment on clinical outcomes18. High nutritional
risk score was significant when related to the increased rate
of adverse events. Moreover the research group demonstrated
that enteral and parenteral nutrition in hospitalized cancer
patients significantly reduces the risk of adverse events18.

Goals of nutritional support in cancer

patients
Cancer disease and nutrition are key determinants of patients
quality of life. In oncology patients the quality of life scores
are determined mainly by cancer location (30%), weight loss
(30%) and nutritional intake (20%)19. The therapeutic goals of
nutritional support in cancer patients - prior to, during, and
after anticancer treatment - are to maintain and/or improve
nutritional status, function and outcome. This is done by:

Preventing and treating cancer-related or therapy-related

malnutrition

Preventing or reversing weight loss

Enhancing compliance and minimizing nutrition-related

discomfort (adverse effects) associated with anti-tumor
therapy

Improving treatment efficacy

Improving strength and quality of life.

Impact of food on anticancer drugs (e.g.,

interactions between anticancer drugs
and nutritional supplements)
There is a paucity of clinical data in the literature regarding
this issue. Use of herbal supplements and vitamins in patients
receiving chemotherapy is common: McCune et al. reported
a frequency of 78%, with 27% of the study participants
being at risk of a detrimental chemotherapy-herbal and/or
vitamin interaction20. Food interactions with chemotherapy
are often difficult to assess, given the polypharmacy that
exists in oncology patients and the frequent inability to
distinguish which factor is responsible for a specific toxicity.
Food can interact with chemotherapy through reduction of
the bioavailability and/or by induction or inhibition of the
metabolism of the administered drug, often due to their
metabolism by the cytochrome P450 system21. The most
popular are herbal supplements and micronutrients such
as calcium, multivitamins, and antioxidants. Sudden and
unexplained changes in the clinical response of a patient to
prescribed chemotherapy could be the result of a food-drug
interaction.

Nutrition support during cancer treatment

Since malnutrition can have a major influence on general wellbeing, performance status, and even symptoms (e.g., fatigue), it
also seems reasonable that they might have a negative impact
on various oncological outcomes, such as treatment success.
Weight loss is one of the factors that defines malnutrition
in patients with cancer, and it is a major cause of morbidity
and mortality18,22. Furthermore, an impaired nutritional state
during cancer treatment has been associated with a number
of clinical consequences and a range of poor outcomes,
including more emergency room visits, increased in-hospital
complication rates, increased length of hospital stay, more
treatment interruptions, compromised treatment efficacy,
reduced quality of life, and decreased survival18,23.
The global pandemic of obesity has recently yielded to an
increase in mean body mass index of cancer patients at
presentation24. Indeed, it is now frequently reported that
a relevant proportion of cancer patients at admission is
overweight or even obese. However, those patients should
receive the same nutritional attention as their underweight
counterpart, since weight loss is a negative prognostic factor
for obese or malnourished cancer patients. It is increasingly
supported by evidence that weight loss might not be detected in
those patients, yet the cancer patients are at nutritional risk for
the presence of sarcopenic obesity (i.e., simultaneous presence
of excessive fat mass and depleted muscle mass)25.

Malnutrition in cancer patients, also known as cachexia, is

a continuum of progressive depletion of nutritional state
(loss of skeletal muscle mass) and worsening of metabolic
alterations. Its clinical manifestations range from pre-cachexia
(i.e., minimal, if any, weight loss, but presence of metabolic
alterations) to refractory cachexia (i.e., severe weight loss
and wasting, characterized by a negative protein and energy
balance driven by a variable combination of reduced food
intake and abnormal metabolism)26. Therefore, in cancer
patients some suggest that actual body weight is not a
sufficient criterion to diagnose malnutrition or the nutritional
risk, but validated nutritional screening tools should be used,
or weight loss history collected (weight loss >5%, or weight
loss >2% in individuals already showing depletion according to
current body mass index <20 kg/m2), or, preferably, changes in
muscle mass assessed26.
Various authors have focused on nutritional risk as a cause
of delay and even failure in the scheduled administration of
anticancer treatment27. Malnutrition may also be responsible
for increased toxicity of anticancer drugs, and for several
complications following the treatment. It may cause changes
in drug absorption, metabolism, and ultimately elimination, as
already reported for some drugs in the literature. Therefore,
maintaining adequate energy intake during therapy is
mandatory, and requires considerable commitment and
motivation on the part of most patients. Nutritional support
should be based on nutritional state, general conditions,
patient tolerance, tumor site, stage of disease, treatment, and
related side effects27.
Nutritional counseling and psycho-oncologic support may be
needed to help and encourage patients to comply with their
nutritional support requirements. According to a recent study
by Ravasco et al. early individualized nutritional counseling
and education during radiotherapy is valuable and is effective
at improving long-term prognosis in cancer patients28.
An impaired nutritional state, identified with a nutritional
screening tool, will consequently lead to a nutritional care
program. For this purpose, a simple, reliable, easily applied
and reproducible scoring system, such as the Nutritional Risk
Screening 2002 (NRS 2002) tool developed in collaboration
with the ESPEN working group, could be used. The NRS 2002
is a reliable, applicable and reproducible tool to easily identify
hospitalized patients at nutritional risk29. Management by
dieticians is available in most cancer centers and hospitals.
Oral nutrition is always the first method of choice. Individualized
approaches are important in order to set realistic and achievable
goals30. Substrate requirements depend on the pathological
condition of the patient, with energy intake varying between 25
to 40 kcal/kg body weight/day, depending on physical activity. To
minimize weight loss and facilitate repair and regeneration of
damaged tissues, dieticians will formulate various suggestions for
consideration by treating physicians, such as a high-energy and
high-protein diet providing adequate macro- and micronutrients,
allowing specific deficiencies to be replaced. If oral intake drops
below 20% to 40% of daily energy requirements, the measures
should include a patient-adapted intervention plan, starting with
easy but essential measures such as the creation of a daily meal
schedule (quantity, quality and presentation of menu), introduction
of small and frequent snacks between meals, and addition of oral
sip drinks and supplements. Favorite foods should be offered
to tempt the appetite. The modification of food texture may be
required to facilitate chewing and swallowing. Dry mouth and
changes in taste perception may increase the effort required for
optimal intake. The goal of oral intake is to achieve more than 75%
of the daily energy requirements. If this objective cannot be met,
other types of nutritional support, such as enteral or parenteral
nutrition, have to be evaluated31-33.

In the presence of inflammation, dietary supplementation

of omega-3 fatty acids may provide beneficial effects by
modulating several aspects of the inflammatory response.
During chemotherapy, omega-3 fatty acids may contribute to a
reduced inflammatory response, but whether cancer treatment
toxicity can be prevented remains to be assessed34,35. Recent
small studies demonstrated that omega-3 fatty acids increase
response rate to chemotherapy36.
In cachectic cancer patients, low serum carnitine levels have
been reported, and this change has been suggested to play an
important contributory role in the development of cachexia.
Based on these data, carnitine supplementation has been
tested in preliminary studies concerning human cachexia,
resulting in improved fatigue and quality of life37-40.
In recent decades progress has led to reduced morbidity
and mortality after cancer surgery. However, even with such
efforts, perioperative complications are frequent in oncology
patients, and therefore adequate nutritional support needs to
be introduced to minimize the risk of potential complications
in the preoperative phase. There is substantial evidence that
a deteriorated preoperative nutritional state adversely affects
outcome in terms of increased complications and reduced
quality of life, which again have cost implications for the
health care system41. An impaired nutritional state before
major surgery is related to increased incidence of nosocomial
infections, longer length of stay (i.e., intensive care unit),
frequently re-admission to hospital and higher mortality42.
Malnutrition may also influences multiple organ dysfunction,
functional recovery, wound healing and the incidence of
postoperative surgical wound infections. The stress of
surgery or trauma additionally increases protein and energy
requirements by creating a hypermetabolic, catabolic state.
As a result, identifying and treating malnutrition in cancer
patients prior to the operation is critical to achieve favorable
patient outcomes. Preoperative nutritional support of the
patient gained increased attention due to several landmark
randomized controlled studies by Braga et al. showing that
severe morbidity could be reduced by approximately 50% in
patients undergoing major surgery for upper gastrointestinal
cancer43. With special regard to patients with obvious severe
nutritional risk, those undergoing major cancer surgery of
the neck (laryngectomy, pharyngectomy) and of the abdomen
(oesophagectomy, gastrectomy, and pancreatoduodenectomy)
benefit from the use of immune modulating formulae, namely
enriched with arginine, omega-3 fatty acids, ribonucleotides,
with or without glutamine44,45. Four recent meta-analysis
showed that preoperative immunonutrition improves outcome
in major abdominal surgery, even in patients not at nutritional
risk46-49.

Monitoring
nutritional
treatment

of nutritional state and

support
during
cancer

First-line monitoring strategies should include a routine, accurate,

practical and non-time-consuming nutritional screening (i.e. NRS
2002), which should be performed at diagnosis, before and during
anti-cancer treatment. It is mandatory to identify patients at
nutritional risk who can profit from adequate and rapid nutritional
support. Patients at nutritional risk should be assessed with a
carefully performed medical history, a clinical examination, and
collection of selected laboratory data.
Although screening and monitoring of the nutritional status can
often be performed with simple tools, the following personalized
parameters should be taken into account:

Primary tumor site affected and presence of metastases.

Pre-existing medical conditions.

Type and frequency of treatments and potential side effects,

such as nausea, vomiting, lack of appetite, mucositis,
disturbances of taste and smell, dryness of the mouth,
swallowing difficulties, constipation and/or diarrhea.

The effect of malignancy on the ingestion, digestion, and

absorption of nutrients.

Current food intake and appetite quality. To demonstrate a

reduced intake of normal food, a simple 24-48-hour recall
is usually sufficient. Calculation of the actual energy and
protein intake.

Both physical functioning and components of the psychosocial

effect should be assessed. Therefore, performance state (i.e.,
patient-reported physical functioning according to European
Organization for Research and Treatment of Cancer, EORTC)
and quality of life (i.e., quality of life questionnaire QLQ-C30)
should be measured with a standardized tool and the followup evaluation is important50.

Height, weight, and weight loss.

Dehydration or edema (hydration state).

Muscle mass: Fearon et al. stated in a consensus paper

that the assessment of the muscle mass can be performed
by anthropometry (mid-arm muscle area), bioimpedance
analysis (BIA), cross-sectional imaging (CT or magnetic
resonance imaging) or dual energy x-ray imaging (DXA). In
the daily practice the use of simple and low-cost evaluation
tools as anthropometry or BIA should be preferred26.

Muscle strength: As muscle function reacts early to

nutritional deprivation, hand-grip strength has become a
popular, useful and non-invasive indicator of nutritional
state, and is can be employed as outcome variable.

Laboratory tests such as serum albumin can be used as a

pretreatment prognostic factor in cancer patients, with low
levels being associated with poor outcome. Testing for serum
concentration of c-reactive protein at baseline may identify a
subset of patients for whom a decline in nutritional state is
linked to the presence of an active inflammatory response,
a recognized precursor of cachexia. The interpretation of
laboratory results must be done carefully, as cancer and/or
its treatment often results in pathological values independent
of nutritional state.

Calculation of the daily energy, protein and micronutrient

requirements, with a drwan up nutritional support concept
(action plan).

Use/indications of enteral nutrition (EN)

and parenteral nutrition (PN) during
cancer treatment
Before the decision is made to use artificial nutrition, the
caregiver must be completely informed about the patients overall
circumstances (disease development, general and performance
state, social situation, etc.). The functioning and capacity of
the gastrointestinal tract, the underlying disease, and patient
tolerance must be assessed in order to determine the appropriate
method of administration.
Enteral nutrition (EN)
EN is used to provide nutritional support when oral consumption
is inadequate but gastrointestinal function is normal. Enteral
nutrition preserves intestinal function and promotes efficient
31,32

nutrient use.The insertion of an enteral access is an interdisciplinary

decision. The primary medical team, the patient, and the patients
family must be involved in the evaluation process. A decision as
to whether enteral tube access is appropriate will be made after
taking into consideration the underlying disease, clinical situation,
prognosis, ethical issues, and the patients wishes. Patients with
swallowing difficulties or mucositis can usually use nasogastric
(duration up to 3 weeks) or gastrostomy (>3 weeks) tubes to
overcome nutritional obstacles. Feeding tubes are beneficial
in facilitating adequate nutrition and hydration during cancer
treatment. The percutaneous endoscopic gastrostomy (PEG) has
rapidly become a standard procedure for nutritional purposes - for
example, in patients with severe mucositis, to prevent weight loss
and interruption of radiation therapy51. Percutaneous tubes are
preferred over nasogastric tubes in patients with head and neck
cancer. Prophylactic PEG placement at treatment initiation, prior to
development of mucositis and weight loss, is now recommended
more frequently. Although PEG insertion is considered relatively
safe and has low rate of significant associated complications, it
is not a completely benign non-invasive procedure. Frequent
complications associated with PEG are local site infections, tube
blockage, and migration or dislodgement. Serious complications,
such as peritonitis, fistula development, or abscess, are relatively
rare. The major complications of enteral tube feeding are
diarrhea and abdominal cramps secondary to the high osmotic
load. Tube feeding may be contraindicated in situations of severe
gastrointestinal dysfunction or bleeding, intractable vomiting, or
diarrhea.
EN can be administered in a continuous (over 20-22 hours/day),
in a cyclic mode (over 8-12 hours, often overnight) or in combined
modus intermittend/bolus (3-4 times per day over a 30-60 minute
period). Use of and indications for EN in cancer patients are listed
in Table 1.
Parenteral nutrition (PN)31,33
For selected patients, parenteral delivery of nutrition through a
central venous catheter will represent the only practicable way
to guarantee receipt of the scheduled daily energy requirements
(short-term PN: 2-3 weeks). Long-term (home) PN (duration >3
weeks) should be applied through a tunneled central venous
catheter (e.g., Hickman device) or implanted port systems
(e.g., Port-a-Cath), and may be recommended, for instance, in
hypophagic/(sub)obstructed (e.g., peritoneal carcinomatosis)
patients if there is an acceptable performance state and if
they are expected to die from malnutrition prior to the tumor
dissemination52. A careful and in-depth risk-benefit analysis
should be performed to justify use of PN in cancer patients,
because of a high potential for life-threatening complications,
such as catheter-related and metabolic problems.
Analogue to EN, PN can be administered in a continuous (over
20-22 hours/day) or in a cyclic mode (over 8-12 hours, often
overnight). In patients with transient and partial gastrointestinal
failure, peripheral PN can be administered as a complement to
enteral or oral nutrition. Use of and indications for PN in cancer
patients are listed in Table 2.

Conclusions
During cancer treatment it is critical that body weight loss is
prevented or at least minimized in order to reduce morbidity
and to enhance effectiveness; by the timely use of the tools
available (i.e., nutritional counseling, oral nutritional supplements,
complementary EN and/or PN) will help achieve this.

References
1.
2.
3.

4.

5.

6.

7.

8.

9.

10.
11.
12.
13.
14.

15.

16.
17.
18.

19.
20.
21.

22.

23.

24.
25.

26.
27.
28.

29.

30.

Fearon K, Barber M, Moses AG. The cancer cachexia syndrome. Surg Oncol Clin
North Am 2001;10:109-26.
Pirlich M, Schutz T, Norman K, et al. The German hospital malnutrition study. Clin
Nutr 2006;25:563-72.
Sorensen J, Kondrup J, Prokopowicz J, et al. EuroOOPS: an international, multicentre
study to implement nutritional risk screening and evaluate clinical outcome. Clin
Nutr 2008;27:340-9.
Bozzetti F, Mariani L, Lo Vullo S, et al. The nutritional risk in oncology: a study of
1,453 cancer outpatients. Support Care Cancer 2012 Aug;20:1919-28. doi: 10.1007/
s00520-012-1387-x.
Ravasco P, Monteiro-Grillo I, Marques Vidal PM, Camilo ME. Impact of Nutrition on
outcome: A prospective randomized controlled trial in patients with head and neck
cancer undergoing radiotherapy. Head Neck 2005;27:659-68.
Bauer J, Capra S, Ferguson M. Use oft he scored Patient-Generated Subjective
Global Assessment (PG-SGA) as a nutrition assessment tool in patients with cancer.
Eur J Clin Nutr 2001;56:779-85.
Isenring E, Cross G, Kellett E, et al. Nutritional status and information needs of
medical oncology patients receiving treatment at an Australian public hospital. Nutr
Cancer 2010;62:220-8.
Nozoe T, Kimura Y, Ishida M, et al. Correlation of pre-operative nutritional condition
with post-operative complications in surgical treatment for oesophageal carcinoma.
Eur J Surg Oncol 2002;28:396-400.
Gupta D, Lammersfeld CA, Vashi PG, et al. Prognostic significance of subjective
global assessment (SGA) in advanced colorectal cancer. Eur J Clin Nutr 2005;59:3540.
Gupta D, Lis CG, Granick J, et al. Malnutrition was associated with poor quality of
life in colorectal cancer: a retrospective analysis. J Clin Epidemiol 2006;59:704-9.
Ottery FD. Cancer cachexia: prevention early diagnosis und management. Cancer
Pract 1994;2:123.
McWhirter JP, Pennington CR. Incidence and recognition of malnutrition in hospital.
BMJ 1994;308:945-8.
Gallagher-Allred CR, Voss AC, Finn SC, McCamish MA. Malnutrition and clinical
outcome: the case for medical nutrition therapy. J Am Diet Assoc 1996;96:361-6.
Correia MI, Waitzberg DL. The impact of malnutrition on morbidity, mortality, length
of hospital stay and costs evaluated through a multivariate model analysis. Clin
Nutr 2003;22:235-9.
Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to
chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med
1980;69:491-7.
Huhmann MB, Cunningham RS. Importance of nutritional screening in treatment of
cancer-related weight loss. Lancet Oncol 2005;6:334-43.
Unsal D, Mentes B, Akmansu M, et al. Evaluation of nutritional status in cancer
patients receiving radiotherapy: a prospective study. Am J Clin Oncol 2006;29:183-8.
Pan H, Cai S, Ji J, et al. The Impact of Nutritional Status, Nutritional Risk, and
Nutritional Treatment on Clinical Outcome of 2248 Hospitalized Cancer Patients: A
Multi-Center, Prospective Cohort Study in Chinese Teaching Hospitals. Nutr Cancer
2013;65:62-70. doi: 10.1080/01635581.2013.741752.
Ravasco P, Monteiro-Grillo I, Vidal PM, Camilo ME. Cancer: disease and nutrition are
key determinants of patients quality of life. Support Care Cancer 2004;12:246-52.
McCune JS, Hatfield AJ, Blackburn AA, et al. Potential of chemotherapy-herb
interactions in adult cancer patients. Support Care Cancer 2004;12:454-62.
Yap KY, See CS, Chan A. Clinically-relevant chemotherapy interactions with
complementary and alternative medicines in patients with cancer. Recent Pat Food
Nutr Agric 2010;2:12-55.
Hill A, Kiss N, Hodgson B, et al. Associations between nutritional status, weight loss,
radiotherapy treatment toxicity and treatment outcomes in gastrointestinal cancer
patients. Clin Nutr 2011;30:92-8.
Platek ME, Myrick E, McCloskey SA, et al. Pretreatment weight status and weight
loss among head and neck cancer patients receiving definitive concurrent
chemoradiation therapy: implications for nutrition integrated treatment pathways.
Support Care Cancer 2013 Jun 7. [Epub ahead of print]
Boeing H. Obesity and cancer The update 2013. Best Pract Res Clin Endocrinol
Metab 2013;27:219-27. doi: 10.1016/j.beem.2013.04.005. Epub 2013 May 15.
Prado CMM, Lieffers JR, McCargar LJ, et al. Prevalence and clinical implications
of sarcopenic obesity in patients with solid tumours of the respiratory and
gastrointestinal tracts: a population-based study. Lancet Oncol 2008;9:629-35.
Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia:
an international consensus. Lancet Oncol 2011;12:489-95.
Beretta M, Micheli M, Di Francia R, et al. Nutrition in oncologic patients during
antiblastic treatment. Front Biosci 2013;18:120-32.
Ravasco P, Monteiro-Grillo I, Camilo M. Individualized nutrition intervention is of
major benefit to colorectal cancer patients: long-term follow-up of a randomized
controlled trial of nutritional therapy. Am J Clin Nutr 2012;96:1346-53.
Kondrup J, Rasmussen HH, Hamberg O, Stanga Z. Nutritional risk screening (NRS
2002): a new method based on an analysis of controlled clinical trials. Clin Nutr
2003;22:321-36.
Isenring EA, Bauer JD, Capra S. Nutrition support using the American Dietetic

31.

32.
33.
34.

35.
36.

37.

38.

39.

40.
41.

42.

43.
44.
45.
46.
47.
48.
49.

50.

51.

52.

Association Medical Nutrition Therapy protocol for radiation oncology patients

improves dietary intake compared with standard practice. J Am Diet Assoc
2007;107:404-12.
Bozzetti F. Nutritional support of the oncology patient. Crit Rev Oncol Hematol 2013
Jun 6. doi:pii: S1040-8428(13)00066-8. 10.1016/j.critrevonc.2013.03.006. [Epub
ahead of print].
Arends J, Bodoky G, Bozzetti F, et al. ESPEN Guidelines on Enteral Nutrition: Nonsurgical oncology. Clin Nutr 2006;25:245-59.
Bozzetti F, Arends J, Lundholm K, et al. ESPEN Guidelines on Parenteral Nutrition:
Non-surgical oncology. Clin Nutr 2009;28:445-54.
Murphy RA, Mourtzakis M, Chu QS, et al. Nutritional intervention with fish oil provides
a benefit over standard of care for weight and skeletal muscle mass in patients with
non-small cell lung cancer receiving chemotherapy. Cancer 2011;117:1775-82.
Laviano A, Rianda S, Molfino A, Rossi Fanelli F. Omega-3 fatty acids in cancer. Curr
Opin Clin Nutr Metab Care 2013;16:156-61. doi: 10.1097/MCO.0b013e32835d2d99.
Merendino N, Costantini L, Manzi L, et al. Dietary -3 Polyunsaturated Fatty Acid DHA:
A Potential Adjuvant in the Treatment of Cancer. Biomed Res Int 2013;2013:310186.
doi: 10.1155/2013/310186. Epub 2013 May 23.
Kraft M, Kraft K, Grtner S, et al. L-Carnitine-supplementation in advanced
pancreatic cancer (CARPAN) a randomized multicentre trial. Nutr J 2012 Jul
23;11:52. doi: 10.1186/1475-2891-11-52.
Busquets S, Serpe R, Toledo M, et al. L-Carnitine: an adequate supplement for a
multi-targeted anti-wasting therapy in cancer. Clin Nutr 2012;31:889-95. doi:
10.1016/j.clnu.2012.03.005. Epub 2012 May 19.
Macci A, Madeddu C, Gramignano G, et al. A randomized phase III clinical trial of
combined treatment for cachexia in patients with gynecological cancers: evaluating
the impact on metabolic and inflammatory profiles and quality of life. Gynecol Oncol
2012;124:417-25. doi: 10.1016/j.ygyno.2011.12.435. Epub 2011 Dec 20.
Silvrio R, Laviano A, Rossi Fanelli F, Seelaender M. L-carnitine and cancer cachexia:
Clinical and experimental aspects. J Cachexia Sarcopenia Muscle 2011;2:37-44.
Garth AK, Newsome CM, Simmance N, Crowe TC. Nutritional status, nutrition
practices and post-operative complications in patients with gastrointestinal cancer.
J Hum Nutr Diet 2010;23:393-401.
Schwegler I, von Holzen A, Gutzwiller JP, et al. Nutritional risk is a clinical predictor
of postoperative mortality and morbidity in surgery for colorectal patients. Br J Surg
2010;97:92-7.
Braga M, Gianotti L, Nespoli L, et al. Nutritional approach in malnourished surgical
patients: a prospective randomized study. Arch Surg 2002;137:174-80.
Weinmann A, Braga M, Harsanyi L, et al. ESPEN Guidelines on Enteral Nutrition:
Surgery including Organ Transplantation. Clin Nutr 2006;25:224-44.
Braga M. Perioperative immunonutrition and gut function. Curr Opin Clin Nutr Metab
Care 2012:15:485-8.
Cerantola Y, Hubner M, Grass F, et al. Immunonutrition in gastrointestinal surgery.
Br J Surg 2011;98:37-48.
Marik PE, Zaloga GP. Immunonutrition in high-risk surgical patients: a systematic
review and analysis of the literature. JPEN 2010;34:378-86.
Drover JW, Dhaliwal R, Weitzel L, et al. Perioperative use of arginine-supplemented
diets: a systematic review of the evidence. J Am Coll Surg 2011;212:385-99.
Marimuthu K, Varadhan KK, Ljungqvist O, Lobo DN. A meta-analysis of the impact
of enteral immune modulating nutrition cocktails on postoperative outcomes after
major abdominal and head and neck surgery. Ann Surg 2012;255:1060-8.
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organisation for
Research and Treatment of cancer QLQ-C30a quality-of-life instrument for use in
international clinical trials in oncology. J Natl Cancer Inst 1993;85:365-76.
Beer KT, Krause KB, Zuercher T, Stanga Z. Early percutaneous endoscopic
gastrostomy insertion maintains nutritional state in patients with aerodigestive
tract cancer. Nutr Cancer 2005;52:29-34.
Richter F, Denecke A, Klapdor S, Klapdor R. Parenteral nutrition support for patients
with pancreatic cancer-improvement of the nutritional status and the therapeutic
outcome. Anticancer Res 2012;32:2111-8.

Table 1: Use of/indications for enteral nutrition (EN) in cancer patients according to the
guidelines of the European Society of Clinical Nutrition and Metabolism
Use/indications
Nutritional state
In general, start (complementary) EN if malnutrition already exists or if it is anticipated
that the patient will be unable to eat for >7 days.
Start EN if inadequate food intake (<60% of estimated energy expenditure for >10
days) is anticipated.
In patients losing weight due to insufficient nutritional intake, EN should be provided to
improve or maintain nutritional state.
Use tube feeding if an obstructing head and neck or esophageal cancer interferes with
swallowing or if severe local mucositis is expected.
In general use standard formulae.
Prefer the enteral route whenever feasible.
EN should be preferred in cancer patients because it is more cost-effective than PN
and results in fewer complications.
Regarding omega-3 fatty acids, the evidence is controversial and at present it is not
possible to make any concrete conclusion with regard to improved nutritional state
and physical function.
During radio-chemotherapy
Use dietary advice and oral nutritional supplements to increase dietary intake and to
prevent therapy-associated weight loss and interruption of radiation therapy.
During radio- or radiochemotherapy EN can be delivered via either transnasal or
percutaneous routes.
Because of radiation-induced oral and esophageal mucositis, a PEG may be preferred.
Routine EN is not indicated during radiation therapy.
Routine EN during chemotherapy has no effect on tumor response to chemotherapy
or on chemotherapy-associated undesirable effects, and therefore is not considered
useful.
Hematopoietic stem cell transplantation
The routine use of EN during stem cell transplantation is not recommended.
If oral intake is decreased, PN may be preferred to EN in certain situations (i.e.,
increased risk of hemorrhage and infections associated with enteral tube placement in
immuno-compromised and thrombocytopenic patients).
Enteral administration of glutamine or eicosapentanoic acid is not recommended due
to inconclusive data.
Peri-operative care
Administer preoperative EN preferably before admission to the hospital.
Use preoperative EN preferably with immune modulating substrates for 5-7 days in all
patients undergoing major abdominal surgery independent of their nutritional state.
Incurable patients
Provide EN in order to minimize weight loss as long as the patient consents and the
dying phase has not started.
When the end of life is very near, most patients require only minimal amounts of food
and water to reduce hunger and thirst.
PEG can also be considered in order to produce decompression of the upper
gastrointestinal tract, typically in the situation of (malignant) bowel obstruction.
Tumor growth
There are no reliable data that show any effect of EN on tumor growth.

Grade of
recommendation*
C
C
B
C
C
A
A
C

A
C
C
C
C

C
C

C
A

C
B
C

*Grades of recommendation:
A:
Meta-analysis of randomized controlled trials, at least one randomized controlled trial
B:
At least one well-designed controlled trial without randomization or one other type of well-designed, quasi-

experimental study or well-designed non-experimental descriptive studies such as comparative studies, correlation

studies, case-control studies
C:
Expert opinions and/or clinical experience of respected authorities

Table 2: Use of/indications for parenteral nutrition (PN) in cancer patients according to
the guidelines of the European Society of Clinical Nutrition and Metabolism
Use/indications
Nutritional state
The majority of patients requiring PN for only a short period of time do not need a
special formulation.
A higher percentage of the lipid component (e.g., 50% of non-protein energy) may be
beneficial for those patients with frank cachexia needing prolonged PN.
PN is ineffective and probably harmful in non-aphagic patients in whom there is no
gastrointestinal reason for intestinal failure.
Nutritional provision
Cyclic administration is recommended in patients with home PN.
The use of infusion pumps is recommended, but is not practiced in all European
countries.
Supplemental PN is recommended in patients if inadequate oral/enteral intake (<60%
of estimated daily energy requirements) is anticipated for more than 10 days.
PN is not recommended in patients with adequate oral/enteral intake.
During chemo-radiotherapy
Short-term PN is recommended in patients with acute gastrointestinal complications
(gastrointestinal toxicity) from chemotherapy and/or radiotherapy, because it is
usually better tolerated and more efficient in preventing nutritional deterioration.
Long-term PN is often indicated in patients with sub-acute/chronic radiation
enteropathy.
PN is recommended in patients with severe mucositis or severe radiation enteritis.
The routine use of PN during chemotherapy, radiotherapy or combined therapy is not
recommended.
Peri-operative care
If patients are malnourished or facing a period >1 week of starvation and enteral
nutrition support is not feasible, PN is recommended.
Peri-operative PN is recommended in malnourished candidates for artificial nutrition
when enteral nutrition is not possible.
Peri-operative PN should not be used in well-nourished patients.
Incurable patients
In incurable patients with intestinal failure, long-term PN should be offered if (a)
enteral nutrition is insufficient, (b) expected survival due to tumor progression is
longer than 2-3 months, (c) it is expected that PN can stabilize or improve performance
state and quality of life, and (d) the patient desires this type of nutritional support.
Hematopoietic stem cell transplantation
In hematopoietic stem cell transplantation, PN should be reserved for those patients
with severe mucositis, ileus, or intractable vomiting.
No clear recommendation can be made as to the time of introduction of PN in those
patients. Its withdrawal should be considered when patients are able to tolerate
approximately 50% of their requirements enterally.
Hematopoietic stem cell transplantation patients may benefit from glutaminesupplemented PN.
Tumor growth
Although PN provides nutrients to the tumor, there is no evidence that this has
detrimental effects on outcome. This fact should not have an influence on the decision
to feed the oncologic patient when PN is clinically indicated.

Grade of
recommendation*
C
C
A

B
B
C
A
C

C
C
A

C
A
A
C

B
C

Approaches to Nutritional Supplementation in

Patients Undergoing Neoadjuvant Chemoradiotherapy
and Surgery for the Treatment of Esophageal and
Esophagogastric Cancer
Donald E Low, MD, FACS, FRCS(C)
Department of Thoracic Surgery and Thoracic Oncology
at Virginia Mason Medical Center, Seattle, Washington, USA
Background
Historical outcomes with respect to the surgical management of
patients presenting with esophageal cancer show documented
differences between high- and low-volume centers1.
Esophagectomy also remains an outlier compared to other
major cancer surgical procedures with a mortality rate in all
Medicare patients in the United States, approaching 10% as
recently as 20082.
The application of Enhanced Recovery Protocols programs3
and standardized clinical pathways4 has led to significant
improvement in outcomes in high-volume centers. Nutritional
assessment and support are typically part of the standard
assessment in most Enhanced Recovery Protocols programs
and clinical pathways. Nutritional assessment is also now
recommended as an routine component of care in current NCCN
guidelines,5 and is increasingly targeted as a quality indicator in
the overall management of esophageal cancer6.
Previous assessments have demonstrated that malnutrition
is a clearly-defined negative prognostic factor in patients
undergoing definitive chemoradiotherapy for esophageal
cancer7. It is currently estimated that up to 80% of patients
presenting with esophageal cancer will be malnourished at
the time of diagnosis8. The reasons for malnutrition at the
time of presentation are easy to understand considering the
frequency with which patients presenting with esophageal
cancer demonstrate dysphagia, odynophagia, altered tastes,
regurgitation, anorexia and altered gastric motility. The
addition of neoadjuvant therapy can increase the potential
for malnutrition due to the increased incidence of anorexia,
nausea, vomiting, diarrhea, and especially with the utilization of
radiotherapy, mucositis and xerostomia which can significantly
increase problems with dysphagia and odynophagia.
Nutritional support has documented benefits regarding
decreasing morbidity and mortality, associated with tri-modality
therapy (chemoradiation followed by surgical resection)
while also decreasing the incidence of hospitalizations during
neoadjuvant therapy and length of stay associated with surgical
resection. Early initiation of nutritional support can decrease
complications associated with the treatment of esophageal
cancer7. Selected nutritional support can also help maintain
quality of life in patients with esophageal cancer and, especially
in the era in which multi-modality therapy is becoming more
common, it increases the potential that patients will receive and
tolerate their entire recommended therapy. Table 1 summarizes
the issues affected by malnutrition and improved with nutritional
support in patients undergoing treatment for cancer.

10

Rationale for Neoadjuvant

Chemoradiotherapy Followed by Surgery
in the Treatment of Esophageal Cancer
Neoadjuvant chemoradiotherapy is currently recommended
under NCCN guidelines for the treatment of locoregional
(T2-3 N1-3 MX) esophageal cancer5. Multiple studies
have demonstrated that the utilization of neoadjuvant
chemoradiotherapy is not associated with significant increases
in morbidity and mortality and leads to improvements in R0
resection rates9,10. A recent randomized controlled clinical trial
comparing chemoradiotherapy followed by surgery versus
surgery alone (CROSS trial), reinforced these previous issues
but also demonstrated improvements in two-year survivorship
of 15% and three years survivorship of 11% in the tri-modality
treatment group.
Although the opinion regarding the best treatment approach
in patients with locoregional esophageal cancer remains
controversial. The international trend in the treatment of
esophageal cancer is increasingly toward the application of trimodality therapy11.
A systematic review of the benefits and risks of neoadjuvant
chemoradiotherapy was recently completed and, in spite
of documented advantages, nutritional support was
provided in only 6-35% of patients receiving neoadjuvant
chemoradiotherapy12. Previous general assessments have
clearly demonstrated that nutritional status deteriorates in
a significant proportion of patients with the application of
radiotherapy13 and chemotherapy14. Nutritional supplementation
can not only increase the likelihood of patients tolerating all of
their proposed treatment, but there is also strong evidence to
document that it can decrease grade III or IV toxicities associated
with neoadjuvant therapy15 which has been directly related to
perioperative mortality16.

Nutritional Assessment
There are currently multiple recognized standardized
assessment tools available for grading nutritional status
(Table 2). The application of these assessment tools is variable,
but several randomized controlled trials have documented
the positive effect of enteric supplementation on mortality,
complication rates, length of stay, reoperations and early
return of gut function in major gastrointestinal cancer
surgery17. The assessment of nutritional status has been
made increasingly complex with the recognition that BMI
(body mass index) is demonstrating a progressive increase
over time within Western society but particularly in patients

presenting with esophageal adenocarcinoma. Although

obesity as an individual factor does not seem to increase the
risk of complications associated with surgery,18 these patients
can present overweight, but also malnourished. As shown in
Table 3, irrespective of presenting weight or BMI, significant
malnutrition should be suspected when a change in weight or
BMI of greater than 10% is documented. However, a BMI of <18.5
has been associated with a five-fold increase in perioperative
mortality18. Increasingly, carcinogenesis is specifically being
associated with visceral obesity and metabolic syndrome19.This
association is particularly well-documented in esophageal and
esophagogastric adenocarcinoma20.
More high-volume centers are now routinely recommending
embedding nutritional assessment into routine clinical
practice.21 At our institution, nutritional assessment is now
a component of discussion and review in every esophageal
cancer patient at the time of presentation at multidisciplinary
tumor board. The information in Table 3 is available for review
at every tumor board and, if the patient is found to have three of
these factors positive, then they are considered for nutritional
supplementation as outlined in our institutional nutritional
treatment algorithm (Figure 1).

Methodologies for Providing Nutritional

Supplementation during Neoadjuvant
Chemoradiotherapy
1. Oral Supplementation
There are a wide variety of oral nutritional supplements
available in liquid form which can aid in maintaining or restoring
nutritional status during neoadjuvant therapy. Dieticiandelivered intensive nutritional support can help preserve
pre-operative weight and decrease complications associated
with esophagectomy3. Peri-operative immunonutrition diets,
especially those containing glutamine, arginine, and omega-3
fatty acids have been demonstrated to decrease operative
morbidity and length of hospital stay. Diets containing glutamine
have especially been shown beneficial in preserving small bowel
function and maintaining T-cell responsiveness associated with
major surgery. Recent meta-analyses demonstrate the potential
benefits of enteral pre-operative immunonutrition for 5-7 days
in both well-nourished and malnourished patients22,23.
Oral nutritional supplementation and dietary supervision is
clearly an important issue in patients undergoing treatment for
esophageal cancer. However, a component of patients will have
severe esophageal obstruction associated with significant preexistent weight loss which has the potential to be exacerbated
by the esophagitis and loss of appetite often associated with
chemoradiotherapy.
The role and efficacy of immunonutrition in patients undergoing
neoadjuvant chemoradiation and surgery for esophageal
cancer is not well-defined24,25. There is a current international
multicenter Phase III randomized controlled trial (NCT
01423799) assessing immunologically active components in
nutritional support on tolerance to neoadjuvant therapy and
overall outcomes including quality of life of trimodality therapy
for esophageal cancer.
2. Parenteral Nutrition
Current recommendations of the American Society for
Parenteral and Enteral Nutrition is to utilize enteral nutrition
whenever feasible due to the recognized benefits of maintaining
normal gastrointestinal function and flora as well as mucosal
barrier, providing a more physiologic approach to nutrition,

improved support of the immune response and overall decreased

costs26. Previous studies comparing parenteral nutrition to
standard supplementation of oral diet has not demonstrated
defined advantages to parenteral nutrition27. A randomized
controlled trial comparing enteral and parenteral nutrition in
patients receiving neoadjuvant therapy for esophageal cancer
demonstrated that enteral nutrition was superior at limiting
chemotherapy-related toxicity15. There is also the issues
surrounding the maintenance of central venous catheters
and the potential for increase catheter-related complications
including infections and thrombosis28 which supports the
desirability of utilizing enteral nutritional approaches whenever
feasible.
3. Nasoenteric Feeding Tubes
These catheters can routinely be placed in either radiology or
with endoscopic guidance and can be positioned in the stomach
or upper small bowel. Except for premature removal, they
have a very low complication rate and, provide the most overall
cost-effective approach to enteric nutritional supplementation.
Understandably, these tubes are considered unacceptable
to the vast majority of patients on the basis of both personal
comfort and social acceptability. They should be reserved for
situations in which nutritional supplementation is planned for a
short period, likely not exceeding 7-14 days.
4. Surgical, Endoscopic
Gastrostomy Tubes

and

Radiographically

Placed

Gastrostomy tubes have historically provided an excellent

option for enteric nutritional supplementation in cancer patients.
Gastrostomy tubes can typically be placed as an outpatient
procedure, and can be used for either gastric feeding which can
be provided as bolus feeds or it can be converted to jejunal feeding
if gastric function is impaired. Certain high-volume centers have
demonstrated that radiologically placed gastrostomy tubes
can be utilized feasibly and safely prior or during neoadjuvant
chemoradiotherapy in patients with esophageal cancer29. There
remains controversy regarding gastrostomy tubes in other
centers because the stomach is the most commonly utilized
conduit for reconstruction after esophageal resection, and there
remains the hypothetical risk of interrupting a crucial blood
supply to the stomach during the insertion of a gastrostomy
tube inserted either with endoscopic or radiologic guidance.
There are also reports indicating the potential for malignant
cell seeding with percutaneous endoscopic gastrostomies in
patients with oral pharyngeal and esophageal cancers30. With
appropriate planning, gastrostomy tubes will remain an option
for a nutritional augmentation in esophageal cancer patients. It
has been our practice, however, to utilize jejunostomy tubes as
we routinely advocate continued jejunostomy tube nutritional
augmentation after surgical resection and therefore, patients
who require nutritional supplementation during neoadjuvant
therapy can use the same enteric approach throughout their
entire therapy.
5. Surgical, Endoscopic
Jejunostomy Tubes

and

Radiographically

Placed

Jejunostomy tubes can be utilized throughout the entire course

of therapy in patients undergoing tri-modality therapy for
esophageal cancer. There is also little potential that they will
impact conduit selection at the time of esophageal resection.
Jejunostomy tubes, however, are more inconvenient to the
patient in that bolus feeding is typically not feasible, and
feedings must be provided through a pump, although nutritional
supplementation can usually be given within 12 hours, much of
which can be concentrated at night so the patient is free during
the daytime hours.

11

When a patient is recommended for nutritional supplementation

at our tumor board according to the treatment algorithm (Figure
1), it has been our practice to insert the jejunostomy surgically
in conjunction with the insertion of the Port-A-Cath to facilitate
chemotherapy or in conjunction with a diagnostic laparoscopy
in patients who require this additional staging procedure due
to extensive gastric involvement. This approach improves
both costs and efficiency of initiating therapy. We initially
inserted these catheters laparoscopically but now use a 2 cm
supraumbilical incision to simplify the operation and reduce
costs. Table 4 shows the incidence of nutritional supplementation
prior to chemoradiotherapy in 245 consecutive resections at
our institution between 2005 and 2011. Of the 50 jejunostomy
tubes that were inserted, 44 (88%) were placed in conjunction
with an additional surgical procedure. We typically use a large
14 French jejunostomy tube (Kimberly-Clark Worldwide Sales,
LLC, Roswell, Georgia, USA) which decreases potential for tube
blockage and allows the jejunostomy tube to be used not only
for nutrition but also for crushed medications. See Figure 3.
We advocate the surgical approach to jejunostomy insertion as
studies demonstrating the safety of endoscopic percutaneous
jejunostomy have demonstrated a 10% incidence of major
adverse events or death31. Percutaneous radiologic-directed
jejunostomy tubes demonstrate even higher levels of risk for
major adverse events and therefore are not to be recommended.
6. Insertion of Temporary Self-Expanding Plastic and Metal
Stents
Many of the issues directly contributing to malnutrition in
patients presenting with esophageal cancer have to do with
esophageal obstruction and dysphagia. Previous reports
have presented the concept of inserting a metal or plastic
stent which can immediately relieve dysphagia and provide
improved opportunities for maintaining oral nutrition32. There
are now a wide variety of stents available which can be placed
endoscopically as an outpatient (Figure 3) and can produce
immediate improvement in dysphagia scores and patients
ability to support their nutrition with an oral diet. There are now
a series of papers highlighting that this approach can be done
safely33-37. The majority of these studies utilize an expanding
plastic stent and the biggest drawback to this approach is the
incidence of stent migration that is reported between 18%
and 46%. Stent placement is not appropriate in all patients,
especially those with severe loss of appetite, nausea and
abnormal gastric motility.
A retrospective review comparing self-expanding plastic
stent versus surgical jejunostomy demonstrate equal levels
of technical success, complications and improvement in
peri-treatment albumin levels and all stents were removed
uneventfully prior to surgery38.
The most significant unresolved controversy regarding the
application of these stents is whether they should remain in place
during the entire course of neoadjuvant chemoradiotherapy or
be removed electively three to four weeks after the initiation of
chemoradiotherapy. A study examining this issue demonstrated
that dysphagia scores improved equally in patients who had
their stents remain in place or where electively removed
at four weeks. However, reinterventions and stent-related
complications were seen to be less in the patients that
underwent elective stent removal39. Although biodegradable
stents are conceptually an interesting option, the evolution of
these devices is not at a point where they should be considered
for current application40.
It is our current practice to consider temporary stent placement
(see Figure 4) in conjunction with staging with endoscopic

12

ultrasound when it is recommended at our multidisciplinary

tumor board (Figure 1). We are currently recommending
elective removal of the stent three weeks after insertion
and after initiation of neoadjuvant chemoradiotherapy when
improvements in swallowing typically continue due to the
chemoradiation effect and pressure necrosis associated with
the stent.

Conclusions
Neoadjuvant chemoradiotherapy followed by surgery is
becoming the most common multi-modality approach for
patients presenting with locoregional cancer. A significant
component of these patients will present with malnutrition
which can be exacerbated by the initiation of chemoradiotherapy.
This scenario not only leads to poor overall outcomes but also
impacts the patients ability to receive their entire course
of planned therapy and increases costs. Having a specific
orchestrated institutional plan embedded in a standardized
clinical pathway or Enhanced Recovery Protocols program to
assess and support nutrition in these patients will certainly be a
recognized quality parameter in the future.

References
1.

2.
3.

4.

5.

6.

7.

8.
9.

10.

11.

12.

13.

14.

15.

16.
17.
18.

19.
20.
21.
22.

Markar SR, Karthikesalingam A, Thrumurthy S, Low DE. Volume-outcome

relationship in surgery for esophageal malignancy: systematic review and metaanalysis 2000-2011. J Gastrointest Surg 2012; 16(5):1055-1063.
Finks JF, Osborne NH, Birkmeyer JD. Trends in hospital volume and operative
mortality for high-risk surgery. N Engl J Med 2011; 364(22):2128-2137.
Fearon KC, Ljungqvist O, Von Meyenfeldt M, et al. Enhanced recovery after surgery:
a consensus review of clinical care for patients undergoing colonic resection. Clin
Nutr 2005; 24(3):466-477.
Low DE, Kunz S, Schembre D, et al. Esophagectomy--its not just about mortality
anymore: standardized perioperative clinical pathways improve outcomes in
patients with esophageal cancer. J Gastrointest Surg 2007; 11(11):1395-1402.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines
in Esophageal and Esophagogastric Junction Cancers Version 2.2011. National
Comprehensive Cancer Network. http://www.nccn.org/professionals/physician_
gls/pdf/esophageal.pdf. 2013.
Courrech Staal EF, Wouters MW, Boot H, Tollenaar RA, van Sandick JW. Quality-ofcare indicators for oesophageal cancer surgery: A review. Eur J Surg Oncol 2010;
36(11):1035-1043.
Bollschweiler E, Herbold T, Plum P, Holscher AH. Prognostic relevance of nutritional
status in patients with advanced esophageal cancer. Expert Rev Anticancer Ther
2013; 13(3):275-278.
Larrea J, Vega S, Martinez T, Torrent JM, Vega V, Nunez V. [The nutritional status and
immunological situation of cancer patients]. Nutr Hosp 1992; 7(3):178-184.
Markar S, Rosales J, Song G, Low DE. The Impact of Neoadjuvant Chemoradiotherapy
on Tumor Pathology, Perioperative Outcomes and Survival in Stage II and III
Esophageal Cancer. Ann Surg Oncol (in press) 2013.
Mariette C, Piessen G, Lamblin A, Mirabel X, Adenis A, Triboulet JP. Impact of
preoperative radiochemotherapy on postoperative course and survival in patients
with locally advanced squamous cell oesophageal carcinoma. Br J Surg 2006;
93(9):1077-1083.
Makowiec F, Baier P, Kulemann B, et al. Improved long-term survival after
esophagectomy for esophageal cancer: influence of epidemiologic shift and
neoadjuvant therapy. J Gastrointest Surg 2013; 17(7):1193-1201.
Courrech Staal EF, Aleman BM, Boot H, van Velthuysen ML, van Tinteren H,
van Sandick JW. Systematic review of the benefits and risks of neoadjuvant
chemoradiation for oesophageal cancer. Br J Surg 2010; 97(10):1482-1496.
Hill A, Kiss N, Hodgson B, Crowe TC, Walsh AD. Associations between nutritional
status, weight loss, radiotherapy treatment toxicity and treatment outcomes in
gastrointestinal cancer patients. Clin Nutr 2011; 30(1):92-98.
Ross PJ, Ashley S, Norton A, et al. Do patients with weight loss have a worse
outcome when undergoing chemotherapy for lung cancers? Br J Cancer 2004;
90(10):1905-1911.
Miyata H, Yano M, Yasuda T, et al. Randomized study of clinical effect of enteral
nutrition support during neoadjuvant chemotherapy on chemotherapy-related
toxicity in patients with esophageal cancer. Clin Nutr 2012; 31(3):330-336.
Robb WB, Messager M, Goere D, et al. Predictive Factors of Postoperative Mortality
After Junctional and Gastric Adenocarcinoma Resection. JAMA Surg 2013:1-8.
Stratton RJ, Elia M. Who benefits from nutritional support: what is the evidence? Eur
J Gastroenterol Hepatol 2007; 19(5):353-358.
Mullen JT, Davenport DL, Hutter MM, et al. Impact of body mass index on
perioperative outcomes in patients undergoing major intra-abdominal cancer
surgery. Ann Surg Oncol 2008; 15(8):2164-2172.
Doyle SL, Donohoe CL, Lysaght J, Reynolds JV. Visceral obesity, metabolic syndrome,
insulin resistance and cancer. Proc Nutr Soc 2012; 71(1):181-189.
Beddy P, Howard J, McMahon C, et al. Association of visceral adiposity with
oesophageal and junctional adenocarcinomas. Br J Surg 2010; 97(7):1028-1034.
Stratton RJ, Elia M. Encouraging appropriate, evidence-based use of oral nutritional
supplements. Proc Nutr Soc 2010; 69(4):477-487.
Cerantola Y, Hubner M, Grass F, Demartines N, Schafer M. Immunonutrition in

23.

24.

25.

26.

27.

28.

29.

30.

31.

gastrointestinal surgery. Br J Surg 2011; 98(1):37-48.

Marimuthu K, Varadhan KK, Ljungqvist O, Lobo DN. A meta-analysis of the effect of
combinations of immune modulating nutrients on outcome in patients undergoing
major open gastrointestinal surgery. Ann Surg 2012; 255(6):1060-1068.
Lobo DN, Williams RN, Welch NT, et al. Early postoperative jejunostomy feeding with
an immune modulating diet in patients undergoing resectional surgery for upper
gastrointestinal cancer: a prospective, randomized, controlled, double-blind study.
Clin Nutr 2006; 25(5):716-726.
Klek S, Sierzega M, Szybinski P, et al. The immunomodulating enteral nutrition in
malnourished surgical patients - a prospective, randomized, double-blind clinical
trial. Clin Nutr 2011; 30(3):282-288.
Gottschlich M. A.S.P.E.N. Nutrition Support Core Curriculum: A Case-Based
Approach - The Adult Patient: American Society for Parenteral and Enteral Nutrit;
2007.
Sikora SS, Ribeiro U, Kane JM, III, Landreneau RJ, Lembersky B, Posner MC. Role of
nutrition support during induction chemoradiation therapy in esophageal cancer.
JPEN J Parenter Enteral Nutr 1998; 22(1):18-21.
Bozzetti F, Mariani L, Bertinet DB, et al. Central venous catheter complications in
447 patients on home parenteral nutrition: an analysis of over 100.000 catheter
days. Clin Nutr 2002; 21(6):475-485.
Tessier W, Piessen G, Briez N, Boschetto A, Sergent G, Mariette C. Percutaneous
radiological gastrostomy in esophageal cancer patients: a feasible and safe access
for nutritional support during multimodal therapy. Surg Endosc 2013; 27(2):633641.
Ellrichmann M, Sergeev P, Bethge J, et al. Prospective evaluation of malignant
cell seeding after percutaneous endoscopic gastrostomy in patients with
oropharyngeal/esophageal cancers. Endoscopy 2013; 45(7):526-531.
Maple JT, Petersen BT, Baron TH, Gostout CJ, Wong Kee Song LM, Buttar NS. Direct
percutaneous endoscopic jejunostomy: outcomes in 307 consecutive attempts. Am

Table 1. Effect of nutrition on outcomes of medical and

surgical treatment of cancer

32.
33.

34.

35.

36.

37.

38.

39.

40.

J Gastroenterol 2005; 100(12):2681-2688.

Vleggaar FP. Stent placement in esophageal cancer as a bridge to surgery.
Gastrointest Endosc 2009; 70(4):620-622.
Lopes TL, Eloubeidi MA. A pilot study of fully covered self-expandable metal
stents prior to neoadjuvant therapy for locally advanced esophageal cancer. Dis
Esophagus 2010; 23(4):309-315.
Langer FB, Schoppmann SF, Prager G, et al. Temporary placement of selfexpanding oesophageal stents as bridging for neo-adjuvant therapy. Ann Surg
Oncol 2010; 17(2):470-475.
Brown RE, Abbas AE, Ellis S, et al. A prospective phase II evaluation of esophageal
stenting for neoadjuvant therapy for esophageal cancer: optimal performance and
surgical safety. J Am Coll Surg 2011; 212(4):582-588.
Adler DG, Fang J, Wong R, Wills J, Hilden K. Placement of Polyflex stents in patients
with locally advanced esophageal cancer is safe and improves dysphagia during
neoadjuvant therapy. Gastrointest Endosc 2009; 70(4):614-619.
Bower M, Jones W, Vessels B, Scoggins C, Martin R. Nutritional support with
endoluminal stenting during neoadjuvant therapy for esophageal malignancy. Ann
Surg Oncol 2009; 16(11):3161-3168.
Siddiqui AA, Glynn C, Loren D, Kowalski T. Self-expanding plastic esophageal stents
versus jejunostomy tubes for the maintenance of nutrition during neoadjuvant
chemoradiation therapy in patients with esophageal cancer: a retrospective study.
Dis Esophagus 2009; 22(3):216-222.
Shin JH, Song HY, Kim JH, et al. Comparison of temporary and permanent stent
placement with concurrent radiation therapy in patients with esophageal
carcinoma. J Vasc Interv Radiol 2005; 16(1):67-74.
Krokidis M, Burke C, Spiliopoulos S, et al. The use of biodegradable stents
in malignant oesophageal strictures for the treatment of Dysphagia before
neoadjuvant treatment or radical radiotherapy: a feasibility study. Cardiovasc
Intervent Radiol 2013; 36(4):1047-1054.

Table 3. Factors available for review at multidisciplinary

tumor board. Finding three factors positive leads to
recommendations for nutritional support.

Nutritional status in cancer patients has been correlated

with:

Presentation assessment

Surgical resectability rates

Chemotherapy response rates
Length of hospital stay
Complication rates
Survival

Wt Loss >10% in 3 Mo.

BMI <18.5 Kg/m2
Dysphagia to all solid food
Zubrod score 3
Albumin <3.25 g/dl

Nutritional support in association with cancer therapy can:

Improve tolerance to therapy

Decrease number of hospitalizations
Improved quality of life
Reduction in operative morbidity and mortality
Increased likelihood of receiving entire recommended
treatment

Table 2. Nutrition Screening Tools

Table 4. Nutritional support utilized in 245 patients prior to

neoadjuvant chemoradiotherapy 2005-2011
PEG

Jejunostomy

50
44

Removable Stent

(placed by referring institution)

(placed in conjunction with
additional procedure)

12

Malnutrition Universal Screening Tool (MUST)

Mini Nutritional Assessment (MNA)
Nutritional Risk Index (NRI)
Nutritional Risk Screening (NRS)

13

Figure 1. VMMC Institutional Nutritional Algorithm Associated with Neoadjuvant Chemoradiation for Esophageal Cancer

3UHVHQWDWLRQ$VVHVVPHQW

:W/RVV!LQ0R
%0,.JP
'\VSKDJLDWRDOOVROLGV
=XEURGVFRUHRU
$OEXPLQJGO

6WDJLQJ$VVHVVPHQW

&73(73K\VLRORJLF$VVHVVPHQW
(*'86 ORQJHVRSKDJHDOVWULFWXUH
&RQVLGHU6(06

7XPRU%RDUG

6WDJH,,Dr,,E,,,5HVHFWDEOH6WDJH,9
5HFRPPHQGDWLRQIRUQHRDGMXYDQWFKHPRUDGLDWLRQ

1XWULWLRQDO&RQFHUQV

6(06

5RXWLQH&;5
:HHNV

(OHFWLYH6WHQW5HPRYDO
:HHNV

1XWULWLRQDOO\6WDEOH

)HHGLQJ-HMXQRVWRP\
)*
3ODFHGLQFRQMXQFWLRQZLWK
 3RUW3ODFHPHQW
 'LDJQRVWLFODSDURVFRS\DQGZDVKLQJV

&\FOHWR1RFWXUQDO)HHGV

Figure 2. Examples of SEPS (self-expanding plastic stents) and SEMS (self-expanding metal stents)

Figure 3. Demonstrates the 14 Fr jejunostomy tube and the incision

used for insertion

14

Figure 4. Deployment of temporary expandable

metal stent in patient with near complete
obstruction due to distal esophageal adenocarcinoma

Nutrition Modulation of
Chemotherapy Efficacy and Toxicity
Vickie E Baracos, PhD
Professor and Alberta Cancer Foundation Chair in Palliative Medicine
Department of Oncology and Division of Human Nutrition, University of Alberta,
Edmonton, Canada

Introduction
The premise of nutritional oncology is to deploy nutritional
assessment and nutrition therapy to optimize cancer therapy
in both the short term and longer-term. Cancer treatment
with chemotherapy is always a delicate balance between the
efficacy and toxicity of the treatment. The objective of both the
oncologist and of the nutritionist is to increase the therapeutic
index of treatment [i.e. increase the efficacy and /or reduce the
toxicity].

Cancer chemotherapy is a balancing act

between efficacy and toxicity
The term therapeutic index which refers to the amount of a
therapeutic agent (drug) that causes the therapeutic effect
(anti-cancer), to the amount that causes toxicity (Figure 1).

Figure 1. Nutritional modulation of therapeutic index

A higher therapeutic index is preferable to a lower one: a patient
would have to take a much higher dose of such a drug to reach
the toxic threshold than the dose taken to elicit the therapeutic
effect. Anti-cancer drugs generally have a low therapeutic
index (i.e. having little difference between toxic and therapeutic
doses). Since doses are standardized for a population of
patients, for some individuals there is potential for significant
overdose with toxicity which may be life threatening or even
fatal, as well as for substantial under-dosing with risks of
cancer progression or recurrence. It is accepted that there will
be a trade-off between efficacy and toxicity in cancer therapy.
The recommended chemotherapy dose in Phase II studies of

a single new drug or drug combination is determined by a

dose-finding study. The upper limit of the recommended dose
is the dose at which <33% of patients experience dose-limiting
toxicity (DLT) 1. These doses become the standard of care if
a treatment is found to be effective in subsequent phase III
studies2.
Several strategies are adopted by medical oncologists to
manage toxicity of cancer therapy. Scaling drug doses is used
to reduce variation in drug exposure, efficacy and toxicity.
Cytotoxic chemotherapy is generally scaled to an individuals
height and weight, most often using the anthropometric scaler
body surface area (BSA) which is calculated by equations such
as Mostellers formula (BSA (m) = ([Height(cm) x Weight(kg) ]/
3600 )). For drugs that have a renal pathway of elimination,
dosing is adjusted to estimated glomerular filtration rates in
addition to height and weight. Rarely, dosage may be adjusted
according to measurements of the actual blood levels achieved
in the person taking it. In addition to dose scaling, stringent
criteria for eligibility are applied to individual patients based on
their performance status (PS), renal, hepatic and hematological
functions and co-morbidities.
Despite the precautions described above, significant numbers
of patients are made seriously ill by chemotherapy3. Some
patients with apparently good PS experience treatment toxicity
that is severe, life threatening and even fatal3-5. Adverse events
in cancer treatment are precisely defined. The standard scale
is the National Cancer Institute Common Terminology Criteria
for Adverse Events version 4.06 [4]. Grade 1 or 2 adverse events
are considered mild and tolerable, Grade 3 is considered
serious, Grade 4 life-threatening and Grade 5 toxicity is fatal.
Adverse events occur in every tumor group. For example,
Schiller et al. 7 summarized a series of trials on 1207 patients
with advanced nonsmall-cell lung cancer (NSCLC) treated
with cisplatin- and carboplatin-based therapies. Despite
restricting treatment to patients with PS 0, 1 or 2 and adequate
hematologic, hepatic and renal function, 4-6% of patients had
fatal toxicity of infectious, cardiac or renal origin and 68% had
Grade 4 toxicity.
Severe toxicity in treatment is managed by reducing or delaying
the next dose, or stopping treatment, thus limiting benefits of
a complete course of anti-cancer therapy. Patients may even
stop treatment even though it is controlling their cancer, if
toxicities are intolerable8. Stopping cancer treatment early is an
obvious detriment to the patient in terms of controlling cancer
progression, and it is also to patient physical and emotional
well-being. The serious nature of treatment toxicity raises the
question of our ability to accurately predict treatment toxicity
and appropriately manage susceptible individuals3.

15

Nutrition risk = Toxicity Risk

Cancer treatment toxicity in some individuals is unusually
severe. Some aspects of nutritional status including weight
loss and depletion of the lean body mass [skeletal muscle] are
predictive of such high risk toxicity. Screening/assessment of
nutritional risk is used by the nutrition support team to plan
individual nutrition counseling and therapy, but also yields
valuable information concerning patients fitness to tolerate
chemotherapy. The prognostic effect of weight loss prior to
chemotherapy was shown 30 y ago using data from 3,047
patients enrolled in 12 chemotherapy protocols of the Eastern
Cooperative Oncology Group9. Weight loss has repeatedly been
shown to be a significant independent predictor of severe
toxicity and of cessation of treatment10-12.
The term sarcopenia was coined to denote a reduced quantity
of skeletal muscle. The generally accepted definition of
sarcopenia is an absolute muscle mass >2 standard deviations
below that typical of healthy adults. Sarcopenia is not restricted
to people who appear thin or wasted. Aging is often paralleled
by decreased muscle and increased fat, which may culminate
in sarcopenic obesity. Starting in 2008, computed tomography
imaging has been adopted to detect this underlying muscle
wasting in patients with cancer13-15. Patients with sarcopenia
behave as if overdosed and had toxicity of sufficient magnitude
to require dose reductions, treatment delays or definitive
termination of treatment. This was consistent across a range of
drugs (5-fluorouracil (5FU), capecitabine, sorafenib, sunitinib),
a chemotherapy regimen (adjuvant FEC: 5FU, epirubicin;
cyclophosphamide) and in patients with cancers of the colon,
breast and kidney 16-21. Sarcopenia may reflect a generalized
inability to respond appropriately to stress.
Mechanisms underlying drug toxicity in patients with
sarcopenia are not well understood. One measure of drug
exposure [area under the concentration time curve, in patients
with hepatocellular carcinoma treated with sorafenib, was
nearly double in patients with sarcopenia compared to that of
patients without this feature (102.4 vs. 53.7 ng/mL.h)]21. This
is suggestive of overexposure in patients with sarcopenia,
however additional pharmacokinetic data are needed. Cancer
is clearly more advanced in patients with sarcopenia, and it
has been shown in large population based cohorts13,14 that their
survival times are shorter than in non-sarcopenic individuals
of the same age, sex, stage and PS.
While none of the currently employed scaling systems for
chemotherapy drug dosing formally incorporate elements of
nutritional assessment such as weight loss or sarcopenia,
the presence of these factors, either individually or together,
may provide key independent indicators of the likelihood of
developing DLT. For example, the simultaneous presence of
low BMI and sarcopenia associated with >70% incidence of
DLT in patients with renal cell carcinoma16,19. The sensitivity
and specificity of these measures for predicting DLT requires
testing in large data sets including nutritional parameters and
detailed toxicity data. Robust predictors would be of immediate
value for choosing patients for reduced dosages in standard
therapy. The relevance of early identification of patients with
sarcopenia, is that they are at risk for a rapid decline, with a
high risk for toxicity leading to exacerbation of malnutrition
and wasting, with further depletion of the leab tissue mass
(Figure 2) and further enhanced risk of toxicity in subsequent
chemotherapy cycles.

16

Figure 2. Vicious circle of malnutrition and chemotherapy toxicity

Nutritional modulation of the therapeutic

index of cancer therapy
The outcome of chemotherapy depends on complex interplays
between tumor, host, and the anticancer drug. Diet may be used
to modulate changes that favor increased anti-cancer efficacy
and/or lesser injury to normal tissues. Diverse dietary elements
(amino acids, fatty acids, oligosaccharides, minerals, vitamins,
antioxidants) have been suggested to modulate gastrointestinal
toxicities of chemotherapy22. Their proposed actions include
interfering with mechanisms of drug toxicity (modulating
pharmacokinetics, altering key mechanisms of injury) and
mitigating injury to non-tumor tissues (modulating immune
responses, cytokine/hormone network, cellular protective and
repair machinery, and signaling events involved in regulating cell
cycle, cell proliferation or cell death). Most of the evidence for
these effects come from experimental studies and suggest that
specific nutrients can alter both the efficacy and the toxicity of
anticancer therapy. While it is not the intention here to treat this
topic systematically, an example may be made of the omega-3
polyunsaturated fatty acids (PUFA) for which there is an emerging
body of clinical evidence.
In animals omega-3 PUFA decrease tumor cell proliferation,
enhance tumor cell apoptosis, promote cell differentiation,
limit tumor angiogenesis, and modulates tumor-extracellular
matrix interaction. Dietary omega-3 PUFA can enhance toxicity
of drugs to tumor cells and offer protection to nontumor
tissues23-25. Eicosapentaenoic acid, docosahexanoic acid (DHA)
and fish oil enhance anti-cancer activity of anthracyclines,
cisplatin, alkylating agents, vincristine, taxanes, CPT-11, and
5-FU24-27 omega-3 PUFA supplementation appears to attenuate
the toxicity of cyclophosphamide, arabinosylcytosine, doxorubicin,
and CPT-1124-32 including gut weight, histo-pathology, intestinal
epithelial apoptosis, and inflammatory mediator production33-35.
Preliminary clinical findings suggest that dietary supplementation
with omega-3 PUFA may enhance tumor response to
chemotherapy. In metastatic breast cancer patients supplemented
with DHA, individuals who showed robust incorporation of this
fatty acid into plasma phospholipids showed increased time to
progression and overall survival compared with those patients
who showed weak or total incorporation36. Those results have led
to a large randomized phase 3 placebo-controlled study [DHALYA
trial, NCT01548534 ]37, which is ongoing. Patients with advanced
NSCLC supplemented with 2 g / day of omega-3 PUFA (as fish oil),
was associated with a higher rate [80%] of objective response of
tumor to cisplatin-based chemotherapy, compared with patients
receiving standard of care [20%]38.

Conclusions and future developments

Further studies are required to accurately define how nutritional
assessment can contribute to the early identification of patients
at risk for severe treatment toxicity. Further understanding of the
interaction between nutritional status and drug pharmacokinetics
could lead to more appropriate dosing scales for malnourished
individuals. The positive interaction between omega-3 PUFA
and chemotherapy to enhance treatment efficacy suggested by
preliminary results, is worthy of further investigation.

References
1.
2.
3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

Schilsky RL, Milano GA, Ratain MJ. Principles of Antineoplastic Drug

Development and Pharmacology.Dekker Pub 1996. 399-433.
Schilsky RL, Milano GA, Ratain MJ. Principles of Antineoplastic Drug
Development and Pharmacology.Dekker Pub 1996. 399-433.
Cleeland CS, Allen JD, Roberts SA, Brell JM, Giralt SA, Khakoo AY, et al. Reducing
the toxicity of cancer therapy: recognizing needs, taking action. Nature Reviews
Clinical Oncology. 2012;9:471-8.
Krzyzanowska MK, Treacy J, Maloney B, Lavino A, Jacobson JO. Development
of a patient registry to evaluate hospital admissions related to chemotherapy
toxicity in a community cancer center. Journal of oncology practice / American
Society of Clinical Oncology. 2005;1:15-9.
Makrilia N, Syrigou E, Kaklamanos I, Manolopoulos L, Saif MW. Hypersensitivity
reactions associated with platinum antineoplastic agents: a systematic review.
Metal-based drugs. 2010;2010
Liu YJ, Zhu GP, Guan XY. Comparison of the NCI-CTCAE version 4.0 and version
3.0 in assessing chemoradiation-induced oral mucositis for locally advanced
nasopharyngeal carcinoma. Oral oncology. 2012;48:554-9
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al.
Comparison of four chemotherapy regimens for advanced non-small-cell lung
cancer. The New England journal of medicine. 2002;346:92-8
Becker A, van Wijk A, Smit EF, Postmus PE. Side-effects of long-term
administration of erlotinib in patients with non-small cell lung cancer. Journal
of thoracic oncology : official publication of the International Association for the
Study of Lung Cancer. 2010;5:1477-80
Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, Cohen MH,
Douglass HO Jr, Engstrom PF, Ezdinli EZ, Horton J, Johnson GJ, Moertel CG,
Oken MM, Perlia C, Rosenbaum C, Silverstein MN, Skeel RT, Sponzo RW, Tormey
DC.Prognostic effect of weight loss prior to chemotherapy in cancer patients.
Eastern Cooperative Oncology Group. Am J Med. 1980 Oct;69(4):491-7.
Ross PJ, Ashley S, Norton A, Priest K, Waters JS, Eisen T, Smith IE, OBrien
ME. Do patients with weight loss have a worse outcome when undergoing
chemotherapy for lung cancers? Br J Cancer. 2004;90(10):1905-11.
Socinski MA, Zhang C, Herndon JE 2nd, Dillman RO, Clamon G, Vokes E, Akerley
W, Crawford J, Perry MC, Seagren SL, Green MR. Combined modality trials of the
Cancer and Leukemia Group B in stage III non-small-cell lung cancer: analysis
of factors influencing survival and toxicity. Ann Oncol. 2004;15(7):1033-41.
Moore KN, Frank SG, Alward EK, Landrum LM, Myers TK, Walker JL, Gold MA,
McMeekin DS, Vesely SK, Mannel RS. Adjuvant chemotherapy for the oldest
old ovarian cancer patients: can we anticipate toxicity-related treatment
failure in a vulnerable population? Cancer. 2009;115(7):1472-80.
Prado CM, Lieffers JR, McCargar LJ, Reiman T, Sawyer MB, Martin L, et al.
Prevalence and clinical implications of sarcopenic obesity in patients with solid
tumours of the respiratory and gastrointestinal tracts: a population-based
study. The Lancet Oncology. 2008;9:629-35
Martin L, Birdsell L, McDonald N, Reiman T, Clandinin MT, McCarger L, Murphy R,
Ghosh S, Sawyer MB, Baracos VE. Cancer Cachexia in the age of obesity: skeletal
muscle depletion is a powerful prognostic factor, independent of body mass
index. J Clin Oncol. 2013;31(12):1539-47
Baracos V, Kazemi-Bajestani SM. Clinical outcomes related to muscle mass in
humans with cancer and catabolic illnesses. Int J Biochem Cell Biol. 2013 Jun
29. doi:pii: S1357-2725(13)00200-8. 10.1016/j.biocel.2013.06.016. [Epub ahead
of print] PubMed PMID: 23819995.
Huillard O, Mir O, Peyromaure M, Tlemsani C, Giroux J, Boudou-Rouquette P,
Ropert S, Delongchamps NB, Zerbib M, Goldwasser F. Sarcopenia and body
mass index predict sunitinib-induced early dose-limiting toxicities in renal
cancer patients. Br J Cancer. 2013;108(5):1034-41
Prado CM, Baracos VE, McCargar LJ, Mourtzakis M, Mulder KE, Reiman T, et
al. Body composition as an independent determinant of 5-fluorouracil-based
chemotherapy toxicity. Clin Cancer Res. 2007;13(11):3264-8.
Prado CM, Baracos VE, McCargar LJ, Reiman T, Mourtzakis M, Tonkin K, et
al. Sarcopenia as a determinant of chemotherapy toxicity and time to tumor
progression in metastatic breast cancer patients receiving capecitabine
treatment. Clin Cancer Res. 2009;15(8):2920-6.

19.

20.

21.

22.

23.

24.
25.

26.

27.

28.

29.

30.
31.

32.

33.

34.

35.

36.

37.
38.

Antoun S, Birdsell L, Sawyer M, Escudier B, Baracos VE. Low body mass index
and sarcopenia predict dose-limiting toxicity of sorafenib in patients with renal
cell carcinoma. Ann Oncol. 2010 21(8):1594-8.
Prado CM, Lima IS, Baracos VE, Bies RR, McCargar LJ, Reiman T, Mackey JR,
Kuzma M, Damaraju VL, Sawyer MB. An exploratory study of body composition
as a determinant of epirubicin pharmacokinetics and toxicity. Cancer Chemother
Pharmacol. 2011;67(1):93-101
Mir O, Coriat R, Blanchet B, Durand JP, Boudou-Rouquette P, Michels J, et al.
Sarcopenia predicts early dose-limiting toxicities and pharmacokinetics of
sorafenib in patients with hepatocellular carcinoma. PloS one. 2012;7:e37563
Xue H, Sawyer MB, Wischmeyer PE, Baracos VE. Nutrition modulation of
gastrointestinal toxicity related to cancer chemotherapy: from preclinical
findings to clinical strategy. JPEN J Parenter Enteral Nutr. 2011;35(1):74-90.
Timmer-BosschaH, HospersGA, MeijerC,et al .Influence of docosahexaenoic
acid on cisplatin resistance in a human small cell lung carcinoma cell line.J Natl
Cancer Inst.1989;81:1069-1075.
Hardman WE, Moyer MP, Cameron IL . Dietary fish oil sensitizes A549 lung
xenografts to doxorubicin chemotherapy.Cancer Lett.2000;151:145-151.
Xue H, LRoy S, Sawyer MB, Field CJ, Dieleman LA, Baracos VE. Single and
combined supplementation of glutamine and -3 polyunsaturated fatty acids
on host tolerance and tumour response to 7-ethyl-10-[4-(1-piperidino)-1piperidino]carbonyloxy-camptothecin (CPT-11)/5-fluorouracil chemotherapy in
rats bearing Ward colon tumour.Br J Nutr.2009;102:1-9
Shao Y, Pardini L, Pardini RS . Dietary menhaden oil enhances
mitomycin C antitumor activity toward human mammary carcinoma MX1.Lipids.1995;30:1035-1045
MenendezJA,LupuR,ColomerR .Exogenous supplementation with omega-3
polyunsaturated fatty acid docosahexaenoic acid (DHA; 22:6 omega-3)
synergistically enhances taxane cytotoxicity and downregulates Her-2/neu
(c-erbB-2) oncogene expression in human breast cancer cells. Eur J Cancer
Prev.2005;14:263-270.
Hardman WE, Avula CP, Fernandes G, Cameron IL. Three percent dietary fish
oil concentrate increased efficacy of doxorubicin against MDA-MB 231 breast
cancer xenografts.Clin Cancer Res.2001;7:2041-2049.
Y, Pardini L, Pardini RS. Intervention of transplantable human mammary
carcinoma MX-1 chemotherapy with dietary menhaden oil in athymic mice:
increased therapeutic effects and decreased toxicity of cyclophosphamide.Nutr
Cancer.1997;28:63-73.
Wynter MP, Russell ST, Tisdale MJ . Effect of omega-3 fatty acids on the
antitumour effects of cytotoxic drugs.In Vivo.2004;18:543-547.
ChaMC, MecklingKA,StewartC .Dietary docosahexaenoic acid levels influence
the outcome of arabinosylcytosine chemotherapy in L1210 leukemic mice.Nutr
Cancer.2002;44:176-181.
BaracosV,MazurakV,MaD .omega-3 polyunsaturated fatty acids throughout
the cancer trajectory: influence on disease incidence, progression, response to
therapy and cancer-associated cachexia.Nutr Res Rev.2004;17:1-17.
HardmanWE,MoyerMP,CameronIL .Consumption of an omega-3 fatty acids
product, INCELL AAFA, reduced side-effects of CPT-11 (irinotecan) in mice.Br J
Cancer.2002;86:983-988.
Atkinson TG, Murray L, Berry DM, Ruthig DJ, Meckling-Gill KA. DHA feeding
provides host protection and prevents fibrosarcoma-induced hyperlipidemia
while maintaining the tumor response to araC in Fischer 344 rats. Nutr
Cancer.1997;28:225-235.
HardmanWE,MoyerMP,CameronIL.Fish oil supplementation enhanced CPT-11
(irinotecan) efficacy against MCF7 breast carcinoma xenografts and ameliorated
intestinal side-effects.Br J Cancer.1999;81:440-448.
Bougnoux P, Hajjaji N, Ferrasson MN, Giraudeau B, Couet C, Le Floch O. Improving
outcome of chemotherapy of metastatic breast cancer by docosahexaenoic
acid: a phase II trial. Br J Cancer. 2009;101(12):1978-85.
http://clinicaltrials.gov/ct2/show/NCT01548534?term=DHALYA&rank=1
Murphy RA, Mourtzakis M, Chu QS, Baracos VE, Reiman T, Mazurak VC.
Supplementation with fish oil increases first-line chemotherapy efficacy in
patients with advanced nonsmall cell lung cancer. Cancer. 2011;117(16):3774-80

17

Nutritional Interventions
Improve QoL
Jens Kondrup, MD, PhD
Clinical Nutrition Unit, Rigshospitalet,
University Hospital, Copenhagen, Denmark

Introduction
The effect of nutrition support in controlled trials commonly
include objective variables such as clinical outcomes, e.g.
infections, complications in general, LOS or survival1,2. Nutritional
outcome variables and clinical outcome variables show a low
rate of concordance in controlled trials3 and therefore most
investigators do not consider nutritional outcome variables,
such as changes in body weight, to be valid outcome variables.
However, controlled trials of clinical outcome variables
commonly require the recruitment of several hundred patients
to reach an adequate power of the study and are therefore very
costly. Physiological functions, such as muscle function and
cognitive function, may be considered valid interim outcome
variables, as they probably require fewer participants and may
be useful for smaller trials in which a new idea is tested before
undertaking a large clinical outcome study. In addition, effects of
nutrition support on physiological functions may be considered
pathophysiologically to be a prerequisite for effects on clinical
outcome4, since improvement of some cellular function must
be responsible for the improved clinical outcome. In addition,
muscle function and cognitive function may be related to the
major components of Quality of Life (QoL) measures: physical
function and mental function. In recent years, Quality of Life
scores have gained increasing interest as an outcome variable
in clinical trials, also in trials of nutrition support5-21. This
interest has arisen from the concept that medical treatment
should not only delay mortality and decrease morbidity, but
also improve the quality of the prolonged span of life. This is
in accordance with the WHO definition of health: Health is a
state of complete physical, mental, and social well-being, and
not merely the absence of disease or infirmity.

the measurement is undertaken (e.g. clinical trial, routine

physician visit). The appropriate selection will depend on
many factors and circumstances. It is clear from this review,
and other papers, that the scientific community has not yet
produced a generic health related QoL measure which is valid
under all conditions.
When considering using a measure of QoL in a nutrition support
study, it may be a useful to look at the methods that until now
have been tested in randomized controlled trials (RCTs) of
nutrition support.
Ollenschlager et al.5 failed to show an improvement in
subjective well-being in a small study of intensified oral
nutrition patients undertaking chemotherapy.

Rogers et al.6 failed to show an effect on Sickness Impact

Profile in a small study of nutritional supplements among
COPD patients.

Ovesen et al.7 failed to show improvement in Quality of Life

Index in a study of oral supplements among 105 patients
undergoing chemotherapy.

Saudny-Unterberger et al.8 showed a trend (P <0.066)

towards improvement in a general well-being score in a
small study of oral supplements among COPD patients.

Rabeneck et al.9 failed to show improvements in a custom

made QoL measure in a study of oral supplements among
118 HIV infected patients.

Beattie et al.10 showed an improvement in QoL (SF-36) in a

study of 10 weeks oral supplements, initiated among 101
gastrointestinal surgery patients.

Van Bokhorst-de van der Schueren et al.11 showed an

improvement in both a disease-specific QoL measure
(European Organization for Research and Treatment of
Cancer [EORTC-QLQ-C30]) and a generic QoL questionnaire
(Dartmouth Primary Care Cooperative Information Project
[COOP-WONCA]) in a small study of oral supplements
among head and neck cancer patients undergoing surgery.

Johansen et al.12 failed to show improvement in QoL (SF36) in a study of nurse-and-dietitian driven nutritional
therapy among 212 patients recruited from a multitude of
hospital departments.

Ravasco et al.13,14 showed an improvement in QoL (EORTCQLQ-C30) in a study of 4 weeks nutritional counselling
or oral supplements among 75 head and neck cancer
patients and 111 colorectal cancer patients undergoing
radiotherapy.

Rufenacht et al.15 showed an improvement in QoL

(Functional Assessment Anorexia-Cancer Therapy
[FAACT]) in a small study of dietitian-driven nutritional

Further, cost considerations have gained higher priority in recent

years and therefore also the concept of cost-effectiveness. One
example of cost-effectiveness is the cost of improving QoL for a
certain period: the cost-utility analysis of Quality Adjusted Life
Years (QUALYs).

Measuring Quality of Life

A large number of QoL measures have been developed. Some of
these are for specific groups of patients and others are meant
to be generic measures which can be used across all health
conditions. A review of the latter category22 noted that SF-36
is the most commonly used measure, but also that there are
no uniformly worst or best performing instruments. The
decision to use one instrument over another, will be driven by
the purpose of the measurement and depend on a variety of
factors including the characteristics of the population (e.g. age,
health status, language/culture) and the environment in which

18

therapy among patients in a department of internal

medicine.

Norman et al.16,17 showed an improvement in QoL (SF-36

and SF-6D) in a 3 months study of oral supplements,
initiated among hospitalized non-cancer gastroenterology
patients.

Starke et al.18 showed an improvement in QoL (SF-36) in a

study of nutritionist-driven nutritional therapy among 132
patients in a department of gastroenterology.

Rondanelli et al.19 showed an improvement in QoL (SF36) in a small study of 8 weeks supplementation with
oral essential amino acids among institutionalized elderly
patients.

Neelemaat et al.20 failed to show improvement in QoL,

expressed as QUALY derived from Euroqol-5D (EQ-5D)
in a study of 3 months nutritional support, including oral
supplements, initated among 210 hospitalized elderly
patients.

Baldwin21 showed an improvement in QoL (EORTC) in a

meta analysis of 5 studies of oral supplements among
cancer patients.

It appears from this list of randomized trials that several QoL

measures are responsive to nutritional support. In studies
of patients for whom specialized QoL measures, such as
EORTC, have not been validated (i.e. has not been shown to be
responsive to nutrition support), it seems that SF-36 is the most
commonly responsive QoL measure, being responsive in 4 out
of 5 RCTs in which it has been applied. Of course, the success or
failure of a QoL measure in an RCT is not only depending on the
measure chosen, but also on the design of the study, such as
the indication for nutrition supprt in the patients recruited and
the actual difference in energy and protein intakes in control
versus intervention patients, but these other aspects will not
be discussed here.

Utility versus Quality of Life

As initially discussed by Brazier et al.23, the 36 items of SF-36
can each be answered at several levels, which can generate
many millions of health states (if an average of 5 levels per
item: 5^36 = about 14 x 1024 possible combinations of health
states). For a comparison of two treatments, such as nutrition
support versus spontaneous intake, the outcome on some
items may be better for one treatment but worse on other
items and it will be dfficult to decide which health state is
actually the best outcome for the patient.
The solution was first to re-arrange SF-36 to fewer items and
for each item to have a limited number of possible answers,
and to arrange these answers on an ordinal scale24. The result
was a scale with only 249 possible health states. Secondly,
these possible health states were presented to 611 healthy
individuals who were each asked to rank and value a set of only
6 of these 249 health states. After mathematical modelling, all
249 health states were expressed on an ordinal scale from 0
to 1 in which 0 is close to being dead while 1 is the optimal
state of health. In fact, this scale from 0 to 1 represents the
states of health ranked according to the preferences of the
healthy individuals. Therefore, a significant improvement
on this scale, as a result of treatment, can be interpreted as
a superor outcome according to the preference of healthy
individuals. One advantage of this SF-6D measure is that it can
be derived from available SF-36 data. SF-6D, and other similar
measures, are called preference based QoL measures. Ideally,
these preferences should be worked out in patients, but that
has until now not been done.

Utility is originally a commercial concept dealing with how

much extra the consumer is willing to pay for an added value
of a product, or for a fulfillment of a desire, e.g. for attending a
cultural event. In healthcare, it is the extra cost that the payer
(society or insurance company) is willing to pay for a patients
preferred improvement in QoL for a certain period, expressed
per year (Quality Adjusted Life Year [QUALY]). In the UK, it
appears that at a cost of about 40,000 per QUALY, about one
half of new treatment modalities are accepted and that new
medical technologies with costs of 20,000 - 30,000/QALY are
typically accepted25.
A very illustrative example of a cost-utility analysis of a
nutrition support RCT is given by Norman et al.17. In this study,
patients were randomized at discharge to a control group or
a nutrition support group who received oral supplements for
3 months. Preference based QoL (= utility) was measured by
SF-6D at entry and after 3 months. The control group reported
an increase in utility of 0.07 (from 0.62) and the intervention
group an increase of 0.13 (from 0.59). The difference between
the groups was statistically significant. QUALY was calculated
from the time-dependent Area-under-the-curve (0.62 in
the control group and 0.66 in the intervention group). The
difference in QUALY was 0.045 and the difference in cost of
supplements was 540. Therefore, the cost/utility (extra
cost per added QUALY) was 12,099 which is well below the
threshold mentioned above for the UK.

SF-6D versus EQ-5D

EQ-5D, originally from 199026, is the traditional measure of
utility. It has been adopted in a large number of countries in
Europe, US, Africa and Asia27. A number of studies have shown
that SF-6D and EQ-5D do not measure the same. A recent
study among free living individuals, of whom a large number
suffered from chronic disease conditions, showed SF-6D to
be less sensitive towards these conditions compared to EQ5D28, perhaps because the scale of EQ-5D goes below zero
(health state worse than death). Another observational study
comparing SF-6D and EQ-5D in patients with ankylosing
spondylitis similarly showed that SF-6D discriminates
less between patients with better and worse health states
than EQ-5D29. They also reported that the ability to detect a
treatment difference in a specific RCT was similar for the two
measures. They further noted that SF-6D and EQ-5D correlate
equally well with external measures of health, but agree only
moderately among each other. They concluded that it is difficult
to recommend one of the instruments over the other.
In this authors opinion it is difficult to strongly recommend
which of the two utility measures should be used in a new RCT
on nutrition support. However, despite only 2 RCTs available,
it is worthwhile to consider that SF-6D has been shown to be
responsive to nutrition support17, in contrast to EQ-5D20. This
favoritism of SF-6D also relates to the stronger case for SF-36
in the RCTs mentioned above.

Quality of Life and physiological functions

SF-36 records subjective parameters and it would be useful to
validate objective measures that agree with these subjective
parameters. Norman et al.16 reported from their RCT that the
change in hand-grip strength correlated with the change in
two physical items of SF-36 (physical functioning and physical
role). Jakobsen et al.30 confirmed in an observational study
that handgrip strength was closely related to some SF36 physical and mental function items and suggested that
handgrip strength is a valid measurement of mobility (timed

19

up-and-go) and QoL in patients. The same group31 investigated

whether the mental functioning component of SF-36 could
be assessed by using Addenbrookes Cognitive Examination
(ACE) and Continuous Reaction time (CRT). Indeed, the CRT was
related to ACE, supporting that CRT is a measure of cognitive
function. However, neither CRT nor ACE was related to the
mental component of SF-36. It was realized afterwards that
the mental component of SF-36 is actually a reflection of mood
and social drive, rather than cognitive function. Therefore,
an objective easy bed-side correlate of the mental function
component of SF-36 is still lacking.

Conclusion
To summarize, QoL measures seem to be sensitive to nutritional
support. QoL may be regarded as a relevant outcome measure,
not only in patients where hard end points such as death
or complications are not sensitive to nutrition support but
also in its own right. Measurement of QoL allows cost utility
calculations which are meant to reflect the preferences of
the patients, and the cost of such preferences. The subjective
nature of QoL measures should be supported with validated
objective measures.

References
1.

2.

3.
4.

5.

6.

7.

8.

9.

10.

11.

12.
13.

14.

15.

16.

17.

18.

19.

20

Kondrup J, Rasmussen HH, Hamberg O et al. Nutritional risk screening (NRS

2002): a new method based on an analysis of controlled clinical trials. Clin Nutr
2003;22:321-36.
Stratton RJ, Green CJ, Elia M. Combined Analysis of the Effects of Oral Nutritional
Supplements and Enteral Tube Feeding. In: Disease-related Malnutrition: an
evidence-based approach to treatment. Wallingford: CABI Publishing; 2003. p. 276287.
Koretz RL. Death, morbidity and economics are the only end points for trials. Proc
Nutr Soc 2005;64:277-84.
Genton L, van Gemert W, Pichard C et al. Physiological functions should be
considered as true end points of nutritional intervention studies. Proc Nutr Soc
2005;64:285-96.
Ollenschlger G, Thomas W, Konkol K et al. Nutritional behaviour and quality of
life during oncological polychemotherapy: results of a prospective study on the
efficacy of oral nutrition therapy in patients with acute leukaemia. Eur J Clin Invest
1992;22:546-53.
Rogers RM, Donahoe M, Costantino J. Physiologic effects of oral supplemental
feeding in malnourished patients with chronic obstructive pulmonary disease. A
randomized control study. Am Rev Respir Dis 1992;146:1511-7.
Ovesen L, Allingstrup L, Hannibal J et al. Effect of dietary counseling on food intake,
body weight, response rate, survival, and quality of life in cancer patients undergoing
chemotherapy: a prospective, randomized study. J Clin Oncol 1993;11:2043-9.
Saudny-Unterberger H, Martin JG, Gray-Donald K. Impact of nutritional support on
functional status during an acute exacerbation of chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 1997;156:794-9.
Rabeneck L, Palmer A, Knowles JB et al. A randomized controlled trial evaluating
nutrition counseling with or without oral supplementation in malnourished HIVinfected patients. J Am Diet Assoc 1998;98:434-8.
Beattie AH, Prach AT, Baxter JP et al. A randomised controlled trial evaluating the
use of enteral nutritional supplements postoperatively in malnourished surgical
patients. Gut 2000;46:813-8.
van Bokhorst-de van der Schueren MAE, Langendoen SI, Vondeling H et al.
Perioperative enteral nutrition and quality of life of severely malnourished head
and neck cancer patients: a randomized clinical trial. Clin Nutr 2000;19:437-44.
Johansen N, Kondrup J, Plum LM et al. Effect of nutritional support on clinical
outcome in patients at nutritional risk. Clin Nutr 2004;23:539-550.
Ravasco P, Monteiro-Grillo I, Marques Vidal P et al. Impact of nutrition on outcome:
a prospective randomized controlled trial in patients with head and neck cancer
undergoing radiotherapy. Head Neck 2005;27:659-68.
Ravasco P, Monteiro-Grillo I, Vidal PM et al. Dietary counseling improves patient
outcomes: a prospective, randomized, controlled trial in colorectal cancer patients
undergoing radiotherapy. J Clin Oncol 2005;23:1431-8.
Rufenacht U, Ruhlin M, Wegmann M et al. Nutritional counseling improves quality
of life and nutrient intake in hospitalized undernourished patients. Nutrition
2010;26:53-60.
Norman K, Kirchner H, Freudenreich M et al. Three month intervention with
protein and energy rich supplements improve muscle function and quality of life in
malnourished patients with non-neoplastic gastrointestinal disease--a randomized
controlled trial. Clin Nutr 2008;27:48-56.
Norman K, Pirlich M, Smoliner C et al. Cost-effectiveness of a 3-month intervention
with oral nutritional supplements in disease-related malnutrition: a randomised
controlled pilot study. Eur J Clin Nutr 2011;65:735-42.
Starke J, Schneider H, Alteheld B et al. Short-term individual nutritional care as
part of routine clinical setting improves outcome and quality of life in malnourished
medical patients. Clin Nutr 2011;30:194-201.
Rondanelli M, Opizzi A, Antoniello N et al. Effect of essential amino acid

20.

21.

22.
23.
24.
25.

26.
27.
28.

29.

30.

31.

supplementation on quality of life, Amino acid profile and strength in institutionalized

elderly patients. Clin Nutr 2011;30:571-577.
Neelemaat F, Bosmans JE, Thijs A et al. Oral nutritional support in malnourished
elderly decreases functional limitations with no extra costs. Clin Nutr 2012;31:183190.
Baldwin C, Spiro A, Ahern R et al. Oral nutritional interventions in malnourished
patients with cancer: a systematic review and meta-analysis. J Natl Cancer Inst
2012;104:371-85.
Coons SJ, Rao S, Keininger DL et al. A comparative review of generic quality-of-life
instruments. Pharmacoeconomics 2000;17:13-35.
Brazier J, Usherwood T, Harper R et al. Deriving a preference-based single index
from the UK SF-36 Health Survey. J Clin Epidemiol 1998;51:1115-28.
Brazier J, Roberts J, Deverill M. The estimation of a preference-based measure of
health from the SF-36. J Health Econ 2002;21:271-92.
Devlin N, Parkin D. Does NICE have a cost-effectiveness threshold and what other
factors influence its decisions? A binary choice analysis. Health Econ 2004;13:43752.
EuroQol--a new facility for the measurement of health-related quality of life. The
EuroQol Group. Health Policy 1990;16:199-208.
Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states:
development and testing of the D1 valuation model. Med Care 2005;43:203-20.
Cunillera O, Tresserras R, Rajmil L et al. Discriminative capacity of the EQ-5D, SF-6D,
and SF-12 as measures of health status in population health survey. Qual Life Res
2010;19:853-64.
Boonen A, van der Heijde D, Landewe R et al. How do the EQ-5D, SF-6D and wellbeing rating scale compare in patients with ankylosing spondylitis. Ann Rheum Dis
2007.
Jakobsen LH, Rask IK, Kondrup J. Validation of handgrip strength and endurance as
a measure of physical function and quality of life in healthy subjects and patients.
Nutr 2010;26:542-50.
Jakobsen LH, Sorensen JM, Rask IK et al. Validation of reaction time as a measure
of cognitive function and quality of life in healthy subjects and patients. Nutr
2011;27:561-70.

Specialised Nutritional Intervention

During Chemotherapy
Alessandro Laviano, MD
Department of Clinical Medicine,
Sapienza University, Rome, Italy

Introduction
Despite decades of scientific effort, which has required
significant public and private resources, cancer remains a
leading cause of morbidity and mortality worldwide. Although
the incidence of many human cancers has progressively
declined over recent years, and the relative risk of cancer death
one year after diagnosis has also improved1, these results
appear to be largely due to the worldwide implementation
of prevention programs and early screening procedures,
which allow for timely eradicative therapies. In patients with
advanced cancer, overall and progression-free survival are
still limited, since the response rate to chemo- and radiotherapy is frequently below 50%. As an example, only around
30% of patients with metastatic lung cancer benefit from
first-line chemotherapy2. Consequently, there is an emerging
awareness among oncologists that the current pharmacologic
approach to cancer patients should be substantially revised,
since it impairs patients quality of life and frequently fails
to extend survival3. It is acknowledged that the development
of more intelligent drugs targeting specific molecular
pathways may significantly improve the outcome of advanced
cancer patients during the next decade. However, we are now
observing a progressive shift in the focus of researchers and
clinical oncologists from exclusively targeting cancer cells to a
more comprehensive approach to the disease, which not only
includes supportive therapies for the human body itself, but
also the metabolic modulation of tumor microenvironment.
One of the major limitations of current pharmacologic anticancer therapies is the high level of toxicity, which frequently
leads to dose limitation and interruption of the treatment
schedule4. Therefore, the development of new strategies
which limit toxicity, and would allow for a complete delivery
of antineoplastic therapies and also improve the patients
quality of life is required. It is unlikely however that such goals
could be soon achieved by new drugs, since the time needed
to devise and test a new pharmacological agent may extend
over a decade. In addition, there is growing evidence of medical
excess in wealthier countries, with increasing associated
harms and costs5. Of more clinical relevance would be the
implementation of strategies already widely available, and in
this light, nutrition could be of significant help6.

Pharmanutrition and tumour growth

Cancer treatment toxicity levels are a result of both the
pharmacological properties and the delivered dose of any
given drug. Preventable and non-preventable factors also
play a significant role, with individual genetic background
repeatedly demonstrating the predicted toxicity of radio-

and chemotherapy7,8. However, cancer-induced malnutrition,

i.e., cachexia, is closely related with the development of
complications of antineoplastic regimens. In particular,
sarcopenia, which is the hallmark of cancer cachexia9, predicts
dose-limiting toxicity10, post-operative complications11 and
survival12 of patients with tumors of different origins and
receiving different antineoplastic therapies. Therefore,
prevention or restoration of muscle mass in cancer patients
may result in better tolerance and improved compliance to
antineoplastic regimens.

There is accumulating evidence that nutritional support
improves cancer patients outcome by preserving/restoring
nutritional status. It could also be suggested that nutrition
may directly influence tumor growth. On our planet, many
examples exist showing that animals use food to prevent and
treat diseases 13, an ability which has been lost by mankind.

The key role of inflammation in cancer initiation and progression
has been first hypothesized by Virchow14. Since then, much
evidence has accumulated, demonstrating that cancer cells
require an inflammatory microenvironment to proliferate and
disseminate15. In this light, the role of stromal cells and the
tumour microenvironment in general in modulating tumour
sensitivity is increasingly becoming a key consideration for
the development of active anticancer therapeutics16. The
mechanisms by which chronic inflammation favors tumor
growth are being elucidated. Recent observations point to the
cross-communication between cancer cells and non-malignant
stromal cells as a key factor rendering tumor cells resistant
to certain drugs16, but also enhancing the responsiveness
of tumor cells to other agents (microenvironment-induced
synthetic lethality). However, a key role is also played
by the inflammation-induced reduction of host immune
surveillance17. In line with this reasoning, we demonstrated in
an experimental model of cancer cahexia that a strong decline
in contact hypersensitivity, a parameter for cell-mediated
immunity, occurs early in tumor-bearing mice, even before
cachexia occurs, reflecting an impaired immune function prior
to weight loss18.

In human cancer, it is well established that malignancy and
aggressiveness of human cancers is related to the degree
of stroma infiltration by inflammatory cells16. Consequently,
neutralizing the tumor inflammatory microenvironment,
or boosting host immune surveillance, may represent an
effective strategy to enhance the response rate of cancer
patients to chemo- and radiotherapy17. Arginine is an amino
acid which has been extensively demonstrated to increase
immune response, and therefore its use could be beneficial in

21

cancer patients. Indeed, Buijs et al. showed that patients with

head and neck cancer receiving an arginine-enriched enteral
formula in the perioperative period have a longer survival than
those receiving a standard formula19.

Tumour-induced inflammatory response can be blunted by
diet modification, and in particular by increasing the intake
of omega-3 polyunsaturated fatty acids (PUFAs), namely
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
After being incorporated in the lipid layers of cell membranes,
omega-3 PUFAs are metabolized by cyclooxygenase and
lipoxygenase yielding to the production of thromboxanes and
prostaglandins, whose pro-inflammatory activity is less potent
than that mediated by thromboxanes and prostaglandins
deriving from omega-6 PUFAs, namely arachidonic acid. In fact,
cancer patients supplemented with omega-3 PUFAs showed
reduced levels of arachidonic acid-derived prostanglandin
E2 when compared to patients receiving a standard, non
omega-3 PUFAs enriched supplement20. Consequently, this
may suggest that integration of standard chemotherapy with
specialized nutrition therapy including omega-3 PUFAs may
result in an increased response rate21. Preliminary reports are
encouraging with Murphy et al. reporting that omega-3 PUFA
supplementation to advanced lung cancer patients receiving
first-line chemotherapy almost doubles the response rate2.
Similar results were obtained by Bougnoux et al. in advanced
breast cancer patients, although clinical benefits were observed
only in those patients who were high incorporators of DHA into
plasma membranes21. More recently, Arshad et al. showed that
in pancreatic cancer patients treated with gemcitabine and
intravenous omega-3 PUFAs, the circulating levels of cytokines
and growth factors reduce with treatment over time, this effect
being potentially associated with an improved outcome22.
Similarly, restoration of mannose-binding lectin component
activity by gemcitabine and omega-3 PUFAs is associated with
improved outcome in the same clinical setting23.

Conclusion
Nutritional modulation of tumor microenvironment is a current
and available opportunity to improve the response rate to
chemo- and radiotherapy. Nutrition support with specialized
nutrients may reduce inflammatory infiltration of tumor
mass and restore innate immunity, leading to enhanced
tumor rejection. More studies are needed to assess the
impact on clinical outcomes of the integration of specialized
nutrition support within standard anti-cancer treatments. If
the preliminary results now available in the literature can be
strengthened by larger and mechanistic studies, specialized
nutrition support may be used to prime host and cancer cells
metabolisms, making the former more resistant and the
latter more sensitive to the cytotoxic effects of chemo- and
radiotherapy24.

References
1.
2.

3.
4.
5.
6.
7.

8.

22

Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the
United States: 2010-2020. J Natl Cancer Inst 2011; 103:117-128
Murphy RA, Mourtzakis M, Chu QS, et al. Supplementation with fish oil increases
first-line chemotherapy efficacy in patients with advanced nonsmall cell lung
cancer. Cancer 2011; 117:3774-3780
Cancer drugs: remedy required. Nat Med 2011; 17:231
Cleeland CS, Allen JD, Roberts RA, et al. Reducing the toxicity of cancer therapy:
recognizing needs, taking action. Nat Rev Clin Oncol 2012; 9:471-478
Godlee F. Too much medicine. BMJ 2013; 346:f1328
Laviano A, Molfino A, Rossi Fanelli F. Cancer-treatment toxicity: can nutrition help?
Nat Rev Clin Oncol 2012; 9:c1
Hildebrandt MAT, Komaki R, Liao Z, et al. Genetic variants in inflammation-related
genes are associated with radiation-induced toxicity following treatment for nonsmall cell lung cancer. PLoS ONE 2010; 5(8):e12402
Duldulao MP, Lee W, Nelson RA, et al. Gene polymorphisms predict toxicity to
neoadjuvant therapy in patients with rectal cancer. Cancer 2013; 119:1106-1112

9.
10.

11.

12.

13.
14.
15.

16.

17.
18.

19.

20.

21.

22.

23.

24.

Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia:
an international consensus. Lancet Oncol 2011; 12:489-495
Mir O, Coriat R, Blanchet B, et al. Sarcopenia predicts early dose-limiting toxicities
and pharmacokinetics of sorafenib in patients with hepatocellular carcinoma. PLoS
ONE 2012; 7(5):e37563
Lieffers JR, Bathe OF, Fassbender K, et al. Sarcopenia is associated with
postoperative infection and delayed recovery from colorectal cancer resection
surgery. Br J Cancer 2012; 107:931-936
Prado CMM, Lieffers JR, McCargar LJ, et al. Prevalence and clinical implications
of sarcopenic obesity in patients with solid tumours of the respiratory and
gastrointestinal tracts: a population-based study. Lancet Oncol 2008; 9:629-635
de Roode JC, Lefevre T, Hunter MD. Self-medication in animals. Science 2013;
340:150-151
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;
357:539-545
DeNardo DG, Coussens LM. Balancing immune response: crosstalk between
adaptive innate immune cells during breast cancer progression. Breast Cancer Res
2007; 9:212
McMillin DW, Negri JM, Mitsiades CS. The role of tumor-stromal interactions in
modifying drug response: challenges and opportunities. Nat Rev Drug Discov 2013;
12:217-228
Coussens LM, Zitvogel L, Palucka AK. Neutralizing tumor-promoting chronic
inflammation: a magic bullet? Science 2013; 339:286-291
Faber J, Vos AP, Kegler D, Argiles J, Laviano A, Garssen J, van Helvoort A. Impaired
immune function: an early marker for cancer cachexia. Oncol Rep 2009; 22:14031406
Buijs N, van Bokhorst de van der Schueren MAE, Langius JAE, Leemans CR, Kuik DJ,
Vermeulen MAR, van Leeuwen PAM. Perioperative arginine-supplemented nutrition
in malnourished patients with head and neck cancer improves long-term survival.
Am J Clin Nutr 2010; 92:1151-1156
Faber J, Berkhout M, Fiedler U, et al. Rapid EPA and DHA incorporation and reduced
PGE2 levels after one week intervention with a medical food incancer patients
receiving radiotherapy, a randomized trial. Clin Nutr 2013; 32:348-355
Bougnoux P, Hajjaji N, Ferrasson MN, et al. Improving outcome of chemotherapy
of metastaticbreast cancerby docosahexaenoic acid: a phase II trial. Br J Cancer
2009; 101:1978-1985
Arshad A, Chung WY, Steward W, et al. Reduction in circulating pro-angiogenic
and pro-inflammatory factors is related to improved outcomes in patients with
advanced pancreatic cancer treated with gemcitabine and intravenous omega-3
fish oil. HPB (Oxford) 2013; 15:428-432
Arshad A, Chung W, Isherwood J, et al. Restoration of Mannose-Binding Lectin
Complement Activity Is Associated With Improved Outcome in Patients With
Advanced PancreaticCancerTreated With Gemcitabine and Intravenous -3 Fish
Oil. JPEN J Parenter Enteral Nutr 2013; [Epub ahead of print]
Laviano A, Rossi Fanelli F. Toxicity in chemotherapy when less is more. N Engl J
Med 2012; 366:2319-2320

23

Special Issue
September 2013
24