Accepted Manuscript

PARENTERAL NUTRITION

Federico Bozzetti

PII: S0899-9007(19)30036-X
DOI: https://doi.org/10.1016/j.nut.2019.03.013
Reference: NUT 10484

To appear in: Nutrition

Received date: 20 March 2019

Accepted date: 20 March 2019

Please cite this article as: Federico Bozzetti , PARENTERAL NUTRITION, Nutrition (2019), doi:
https://doi.org/10.1016/j.nut.2019.03.013

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PARENTERAL NUTRITION
Federico Bozzetti*

Faculty of Medicine, Oncology, University of Milan, Res Querce Midue 20090

Segrate, Lombardia, Italy

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Tel.:+39 3297655385; Fax:+39 0226410267

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Email address: [email protected]

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Although about 50 years have elapsed since the introduction of parenteral nutrition (PN) in oncologic

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clinical practice [1-3], only in recent years has its use been encoded in international guidelines [4-6].

It is useful to distinguish two types of PN: total (TPN) or supplemental PN (SPN). They differ with regard to
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aims, nutritional regimen, and user-friendliness.

TOTAL PARENTERAL NUTRITION

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PN is defined as “total” when the intravenous administration of nutrients represents the exclusive (or the
near-exclusive) way of feeding the patients and is used when patients cannot eat by mouth, and tube
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feeding is not possible or not accepted by the patient who may refuse this approach [7]. This treatment is
quite demanding, requiring a specific technique to avoid excessive or deficient administration of nutrients
and prevent metabolic complications as well as catheter mechanical and infective problems. Long-term TPN
and especially home TPN (HPN) usually requires the presence of a dedicated service or of a nutrition
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support team [8].

TPN meets the original need to replace a gut that is either absent or not working with an artificial gut [9].
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TPN is not the primary treatment of cachexia--which is characterized both by starvation and alteration of
the metabolic pathways--since it can control only the “nutritional” component of this syndrome. From this
perspective the clinical benefit of TPN can be expected only in cancer patients for whom nutrient
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deprivation plays a major role in the outcome. However it should be also considered that no anticachectic
treatment can be expected to be beneficial if the patient is not adequately fed. Furthermore, the recent
research on the different utilization of nutritional substrates in healthy and cancer patients is showing that
it is possible to optimize the intravenous diet with a regimen that is specific for the malnourished cancer
patient, in which case the aim is to feed the patient rather than the tumour.

Given these premises it appears rational that TPN be proposed generally for hypo-aphagic outpatients
(home PN: HPN), whose life expectancy due to the tumoral spread is reasonably long and can be adversely
affected by a progressive nutritional deterioration due to unrelenting starvation. In clinical practice this
happens when the oral intake is almost totally precluded by the presence of a malignant obstruction of the
bowel, often due to a peritoneal carcinomatosis. In such cases the obstruction may also be intermittent--
immediately worsening when the patient attempts to eat something--and is associated with early satiation,
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nausea, vomiting, abdominal distension and pain. Sometimes there is a severe anorexia; however, a few
patients may refrain from eating just to avoid the onset of gastrointestinal symptoms and they can
experience some feeling of hunger. Almost all these patients are incurable even if few of them are still
receiving some type of so-called palliative chemotherapy.

Rationale for HPN in incurable cancer patients

Worldwide experience shows that HPN is used in cancer patients in very advanced stages of disease when
death from progressive starvation is expected to occur prior to the evolution of the cancer towards the
final outcome. The quality of life of the patients at their entry in a programme of HPN should be acceptable

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and concurrent symptoms rather mild or well-controlled, otherwise the indication for a program of HPN
would immediately decay.

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Cachexia is the main cause for death of cancer patients in cachexia in a percentage ranging from 5 to 23%

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[10-14]. Even if cancer cachexia cannot be equated with simple starvation, a wide body of literature has
shown that weight loss in cancer patients is proportional to the severity of anorexia or to the reduction of
nutrient intake or to persistence of negative energy balance [15-19]. On the other hand, there is now a
growing bulk of evidence showing that specific nutritional support is able to maintain/improve not only the
body weight but also the lean soft tissue.
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It is well known that the life expectancy of subjects undergoing total starvation is quite limited. The survival
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of healthy people undergoing extreme hunger strike is about 2 months [20-22] and mean survival of cancer
patients undergoing a total or almost total macronutrients deprivation (usually for malignant bowel
obstruction) is reported to be 62 days in patients undergoing surgical exploration only [23-28] and 52 days
in hospitalized patients [29-36] without nutritional support. If we consider cancer patients discharged at
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home without HPN the literature reports a mean survival of 19, 27 and 15 days [37-39], respectively.
These were the basic reasons why an International Consensus [40] more than 20 years ago suggested that
HPN in advanced hypo/aphagic cancer patients should be considered only if the expected survival due to
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the malignancy was ≥ 2 months.

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Prospective studies on survival of incurable cancer patients on HPN

Since most of the studies on HPN in (hypo)aphagic advanced cancer patients are retrospective and most of
the wider series are collected from HPN registries, it appears quite difficult to draw conclusions on the
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precise indication for such treatment (and consequently on the results) because of the heterogeneity of the
patient population. Few studies are prospective [37,41-44] and hence more reliable as concerns the
outcome data. The largest prospective series [42] on 414 patients reported a 4.7-month and a 3.0-month
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mean and median survival, respectively.

A meta-analysis by Naghibi et al. [45] reviewed extensively this topic focusing on patients with inoperable
malignant bowel obstruction and reported, from the analysis of 12 papers meeting the criteria of eligibility,
a median survival of 83 days (95% CI 67-100 days) and a mean of 116 days. Survival was 86%, 64%, 45%,
31%, 26%, and 22% at 1, 2, 3, 4, 5, and 6 months, respectively. These data show that if we accept a
threshold of 2 months as the longest potential length of survival tolerated by patients undergoing total
starvation, the treatment with HPN might prolong survival in about half of them.

More recently a Cochrane review on the same topic [46] concluded that due to the very low certainty of
evidence, it is difficult to assess whether HPN improves length of survival in people with malignant bowel
obstruction and emphasized the limitations of the existing literature. Such conclusion is unsurprising
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because the quality assessment according to the methodology of Cochrane analysis relies on parameters
(random sequence generation, allocation concealment, criteria for assigning treatments, comparability of
treatment groups, blinding of participants and personnel, etc.) which are adequate for evaluating the
effectiveness of drugs (which can be--or not be--administered) but do not fit as well for nutrients that are
deemed essential for health. This intrinsic discrepancy between a pharmacologic therapy and a nutritional
treatment had been already emphasized in the introduction to the ESPEN Guidelines on Parenteral
Nutrition [47]. On the other hand, if we consider success to be survival of aphagic cancer patients on total
starvation as longer than two months and we recalculate the survival of the five prospective series [37,41-
44], which are more reliable as regards the outcome data, we get a mean survival of exceeding four months
on a total of 593 patients.

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We followed a different approach: in a large international prospective study on incurable cancer patients
on HPN when we identified three prognostic factors for survival at the multivariable analysis, namely, the

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Glasgow Prognostic Score, the Karnofsky Performance Status, and tumour spread [42]. The prognostic
value of these variables, coupled with type of primary tumour, was subsequently validated on another

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series of patients [48] and led to the construction of a prognostic nomogram reported in Figure 1.

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This nomogram, especially if we consider its extreme values, may represent a guide for assessing the
potential benefit of HPN and gives the caregiver the possibility of negotiating with the patient the option of
a program of HPN on the basis of the expected survival.
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It is worthy of note that a sub-analysis of patients with so-called “refractory” cachexia according to an
International Consensus [17] (that is Karnofsky Performance Status index was ≤50 and life expectancy ≤ 3
months), showed a 3- and 6 month survival of 29.4% and 8.4%. These figures were 31.7% and 12.2% for
patients without vital organ involvement, 27.1% and 5.9% for those with vital organ involvement. These
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figures argue against an “en principle” denial of PN in patients with so-called refractory cachexia as stated
in the International Consensus [17].
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In these incurable patients HPN was withdrawn a few days before of death in one third of them and
reasons were tumour progression (73%), patients refusal (20%), onset of HPN/CVC complications (6%) and
family refusal (0.7%). The cause of death was vital organs failure (46.0%), progressive wasting (33.8%) and
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HPN/CVC complications (1.2%) and unknown in the remaining patients.

In the clinical practice the discrimination between good and poor candidates may not be easy and in these
cases it is worthwhile to adopt the trial-and-error method. That is, one can initiate HPN and withdraw it if
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it is found to be inappropriate or not beneficial on a subsequent reassessment. This was also the final
conclusion of the Consensus Meeting launched by the European Association for Palliative Care in 1996 [40].
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Prospective studies on quality of life in incurable cancer patients on HPN

Data on quality of life as summarized in the review by Naghibi et al [45] are scanty and difficult to interpret.
There are only 2 prospective studies: August et al. [49] reported 17 patients: in 14, both patients and their
families (82%) perceived their therapy as highly beneficial or beneficial. The Nutritional Support Team
agreed with this assessment in 11 patients but did not share this perception in three patients. These three
patients had a short duration of HPN (less than 25 days) or minimal rehabilitation.

Another study [41] investigated the quality of life in 69 incurable cancer patients through the Rotterdam
Symptom Checklist questionnaire. These variables were collected at the start of HPN and then at monthly
intervals. Median survival was four months (range 1-14) and quality of life parameters remained
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approximately stable till 2-3 months before death. A study that is often quoted, albeit retrospective [50],
used a validated instrument to measure quality of life, and reported statistically significant improvement in
gastrointestinal discomfort, nausea, vomiting, fatigue level, morale and social interactions during HPN use
as compared to pre-HPN status. It should be noted, however, that 7 out of 92 patients were in HPN because
of surgical or radiation therapy late complications.

It is clear that evidence of a benefit from such studies is very limited; however, it should be considered that
no RCT is possible in this clinical context and such matter of investigation is per se so subjective that it
appears quite difficult to find appropriate parameters of evaluation. The potential benefit reported in some
papers is in keeping with the experience of Orrevall et al. [51] in a similar patient population, where the
authors found that the quality of life could be positively affected by the sense of relief and security in both

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patients and relatives because the nutritional needs were met through HPN. There is, to our knowledge,
only one study [52] investigating the burden superimposed to the family caregivers by HPN in incurable

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cancer patients. It reported on a small series of patients for whom the basal level of strain was already high
among the relatives-caregivers and did not increase after two weeks of home care.

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Studies regarding the effect on nutritional status of HPN in incurable cancer patients

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Three studies [41, 50, 53] measured in 150 patients the nutritional status and found that it was maintained.
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Complications from HPN

Only a few studies [37,42,44,46, 54-56] reported sufficient data to allow calculation of central venous
catheter sepsis rates, which ranged from 0.40 to 2.89 per 1000 days. Thrombotic complications were
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reported by two studies [55,57] with a wide discrepancy between them: one reported a rate of 0.19 per
1000 days [57] and the other [55] 4.34 per 1000 days. Metabolic complications were reported by four
studies [42-44,56] and ranged from 0.32 to 1.37 per 1000 days.
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Controversial issues in incurable cancer patients on HPN

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Indications for HPN in incurable cancer patients represent a continuous source of debate and controversy
not only among different specialists but even among health professionals belonging to the same specialty.
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There are a few issues to consider:

a) On the one hand, there is the clear awareness of clinicians involved in clinical nutrition that current
medical care has evolved to such an extent--by transforming previously lethal diseases, like cancer,
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into chronic conditions--that malnutrition and inability to feed may finally represent in some
patients the main determinant for length of survival. On the other side, all caregivers involved in
HPN practice are perfectly aware that patients with benign intestinal failure survive “thanks” to
HPN whereas cancer patients finally die “despite” nutritional support. The consequence of this last
evidence is an undervaluation of the role of HPN in cancer patients.
b) There is some confusion in the terminology regarding HPN in advanced cancer patients since the
word “terminal” which often appears when referring to incurable patients and PN is ambiguous and
misleading. In the common language the word “terminal” is often used with reference to patients
almost-imminently dying, whereas in oncological jargon it may mean that anticancer therapy is no
longer available. The survival of these oncologic patients may range from a few days to several
months [58]. Hence there should be the implicit awareness that some of these “terminal” cancer
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patients are not “biologically” terminal, but simply incurable. To avoid any ambiguity in defining the
severity of the state of the patients with special reference to their potential candidacy for HPN, it is
wiser to use the term “incurable” for cancer patients who have exhausted all available oncological
therapies, with the awareness that a subset of them might sometimes require PN if they are
aphagic and not imminently dying.
c) A further area of controversy relies on the different conception of PN as medical therapy or just a
supportive care. Nowadays a medical therapy needs to be validated through randomised clinical
trials in order to be accepted as an evidence-based treatment and in such a trial one arm may
receive no treatment or merely the standard treatment. However, in aphagic/obstructed cancer
patients it would be impermissible to have a randomised no-treatment arm, which means
progressive undernutrition until death, as the standard treatment simply does not exist. Such

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discrepancy is not confined to the health professional [59-63] but, more importantly, involves all

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the relatives of the patients because the anorexia and hypophagia of an advanced cancer patient
represent a major concern for both the patient and their family members [64-66]. Miles [67],
emphasizing the cultural and symbolic value of nourishment, which is traditionally viewed as an

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expression of love and care for both the living and the dying, made with extreme acuity the
important distinction that while physicians tend to see “nourishment” as a medical treatment
aimed at achieving physiological objectives, families see feeding “as an act of community.” A

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specific study on the nutritional situation prior to the introduction of HPN, from the perspective of
patients with advanced cancer and their family members in order to understand factors
contributing to the decision to accept HPN was published in 2004 [66]. Patients reported wanting
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and trying to eat, but being unable to do so; family members experienced powerlessness and
frustration as they could not enable the patient to eat. This desperate and chaotic nutritional
situation in the family influenced the patient’s willingness to accept HPN. A further study of the
same authors reported that the interviewed patients with advanced cancer and their family
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members experienced physical, social, and psychological benefits from HPN treatment [51].

How to approach HPN for the incurable cancer patient candidate

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An approach that fits all possible situations of an incurable aphagic cancer patient does not exist.
The ideal condition of a patient who is perfectly aware of his/her prognosis, asks for the potential
benefits and adverse effects of HPN and then decides whether to enter or not a program of HPN, is
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really an exception. Certainly awareness of the diagnosis and of the prognosis are essential for an
informed consent to HPN, but this matter may be extremely complicated and delicate. In fact many
patients arrive to the candidacy for HPN late, being already conditioned, as regard their prognosis,
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by the information provided by the several specialists who followed them in the previous phases of
disease.
What really matters is an exhaustive predefinition of the goals of HPN and the chances of
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success. It cannot be just about avoiding overoptimistic expectations such as “my husband was
condemned to die because he could not eat…now HPN will avoid it!” Furthermore, if HPN will not
be able to attain the predefined endpoints, withdrawing it will be less traumatic for the family and
ethically acceptable for the physician.
The main expectation of a clinician who recommends HPN is to maintain the patient with a
quality of life that is probably better, because the patient receives the same treatments at home
rather than in hospital.
The phase of progressively withdrawing HPN is very delicate. It may appear that the general
status of the patient progressively deteriorates, or liver or lung (or other vital organ) function is
failing and requires continuous adjustments of the nutritional regimen, or symptoms are poorly
controlled and quality of life declines headlong. When this occurs it is important to gradually shift
from a nutrition support to a palliative hydration with isotonic electrolyte-glucose mixed solutions.
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The patient might have the impression of not being abandoned by his late caregiver but just
accompanied in the progression of his disease.

Nutritional regimen
If PN is total, that is the nutrients’ intake is negligible, it is important to meet all the nutritional
requirements.

a) Energy requirement
Although several malnourished cancer patients have a resting energy expenditure higher than
standard for gender, age and weight, the total energy expenditure may be decreased in
malnourished cancer patients because of a reduction in physical activity. Total energy expenditure

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of weight-stable leukaemic patients [68] and of weight-losing bedridden patients with

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gastrointestinal tumours [69] is around 24 and 28 kcal/kg/day, respectively. ESPEN Guidelines [6]
recommend 30 kcal/kg/day; however, the intake of ≥30 kcal/kg/day and 1.2 g/kg/d protein were
not able to attenuate weight loss in patients with head and neck cancer [70]. An adequate

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nutritional regimen should be likely combined with anabolic/anticatabolic agents to achieve a
nutritional replenishment.

b) Calorie substrates
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Fat-enriched regimens (50% of the non-protein calories) are recommended on the basis of the
following pathophysiological arguments:
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i) Literature [71-76] has shown an efficient mobilisation and oxidation of endogenous fat
in the post-absorptive state, which ranged from 0.7 to 1.9 g/kg/day (that is about 6.3 to
17 kcal/kg/day, approximately 60%-78% of the REE), in weight-stable and weight-losing
patients. A large study [77] has reported that cancer patients consistently had a non-
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protein RQ<1.
ii) Subsequent investigations showed that, after administration of LCT or mixed LCT/MCT
emulsions, the clearance of lipid was 1.4 versus 2.3 versus 3.5 or 1.2 versus 1.6 versus
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2.1 g/kg/day in healthy subjects versus weight-stable versus weight-losing cancer

patients, respectively [76].
iii) After intravenous administration of LCT or mixed LCT/MCT emulsions in weight-losing
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cancer patients, the oxidation rate was reported to be 1.3-1.6 or 0.62 g/kg/day,
respectively [76,78].
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c) Amino-acid requirement
Amino-acid requirement relies on two orders of data:
i) The negative balance between whole body protein synthesis and breakdown measured
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in the post-absorptive state was 2.3-2.7 g protein/kg/day in cancer patients versus 1.2
in normal subjects [79].
ii) A literature review [80] suggests that doses of amino acid closer to 2 g/kg/day may be
required to control muscle and whole body catabolism and stimulate the synthesis.

Hence the suggestion is to administer > 1.0 g AA/kg/day and, if possible, up to 1.5 g/kg/day or
more to support protein balance. Unfortunately many of the commercial bags have high Cal/N
ratios and hence supplying the suggested amount of amino acid carries the risk of overfeeding
the patient. As regard the quality of the amino acid it should be considered that the accelerated
rate of muscle protein breakdown that occurs in cachexia provides an abundant source of
intracellular amino acid, which in turn stimulate muscle protein synthesis. However, some are
oxidized and are not available for protein synthesis. Therefore the rate of muscle protein
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synthesis will never keep pace with the accelerated rate of breakdown in the absence of intake
of exogenous essential amino acid and branched chain amino acid [79]. In the nutritive
admixtures of HPN essential amino acid should be present in large proportion and branched
chain amino acid should account for about 50% of total amino acid.

SUPPLEMENTAL PARENTERAL NUTRITION

PN is supplemental when patients maintain a limited oral intake of nutrients. Such support may
be used also for some incurable patients, even if for a short time because of the progressive
evolution of the disease towards a more severe hypophagia. Hence most of experiences with

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supplemental SPN or HPN are in patients undergoing an oncologic therapy when there is some
worry that malnutrition and/or poor oral intake due to cancer anorexia or to the adverse effects

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of the oncologic therapy may compromise the administration of the oncologic therapy. This
approach represents something new when compared with the usual practice to reserve HPN to

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incurable patients who are expected to die mainly from starvation rather than for tumour
progression. In addition in this context, some RCT are possible because the control arm includes
patients receiving the standard supportive treatment and this appears ethically acceptable.

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Looking at the literature we can focus on RCT [82,84] or on prospective studies, which used
validated methods of measure of quality of life [85-89] (Table 1).
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Even if prospective non-RCT have clear limitations well pointed out in the recent reviews and
meta-analyses [45,46], however all these studies [85-89] reported some improvement in quality
of life evaluated through the recognized methodology (Therapy Impact Questionnaire, Fact-G,
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EORTC-QOL-C30), a finding also observed in the RCT by Obling et al [84].

As regard the nutritional status of the patients data are relatively few and controversial because
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a benefit on fat-free mass was reported by Obling et al [84] with a relatively low nutritional
regimen and not by Hyltander et al. [81] with a full regimen, whereas the positive results by
Lundholm et al. [82] may be also due to the concurrent antiinflammatory treatment and the
long duration of PN.
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An important issue is that no study investigated the relationship between response to the
oncologic therapy and change of quality of life, and, obviously, the potential regression of the
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tumour could play an important role on the quality of life of the patient. However the Cotogni
study [89] reported that a benefit is also possible, even if lower, in incurable cancer patients
with no concurrent oncologic therapy.
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Another point that warrants further investigation is the optimal nutritional regimen for patients
on supplemental HPN. In some paper the information was very scanty, but, when available it
ranged from a near-total nutrition [81-83, 85, 87] to a much lighter regimen [84].

CONCLUSION

The increased awareness of the relevance of a good nutritional status and of the nutritional
support of the cancer patient by the oncologists, coupled with availability of prepared all-in-one
admixtures has simplified the nutritional approach in the clinical practice.
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We are facing now the transition from the personalised TPN in the aphagic obstructed patient to
the simpler intravenous support of the patient with poor oral feeding. In parallel the oncologic
experience is moving from total nutritional support provided at home to very advanced,
cachectic, often incurable cancer patients by an experienced team of nutritionists, to a more
simple partial support, which appears in the range of every clinician. After half a century from
the naissance of TPN [90], finally this mode of nutritional support enters the clinical area, which
is the most affected by the incidence and severity of malnutrition.

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Figure 1. Cox modelling-based nomogram to estimate the survival probability (modified from ref 48)
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Table 1. Prospective studies on the effects of sHPN on QoL measured through validated scores in
malnourished advanced cancer patients on chemotherapy

AUTHOR N pts MODE of HPN METHODS RESULTS COMMENTS

Finocchiaro, 2002 70 27 Kcal+1.1 g AA/Kg/d TIQ at > months QoL: =48%, ↑31.5%, ↓20.5 Evaluated 27 patients
Culine, 2013 437 26 Kcal+1.g AA/Kg/d FACT-G day 1-28 ↑ physical, functional, Responsiveness to
usually overnight emotional, familial/social chemotherapy my affect
domains QoL
Seys,2014 221 overnight FACT-G day 1-28 ↑body weight and global QoL in Regimen of HPN ill-
68% and 59% of patients (and defined, no statistical
sub-score physical, functional, analysis, responsiveness to
emotional) chemotherapy may affect

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QoL
Vashi, 2014 52 Total (oral+ PN) 25-30 EORTC QLQ-C30 ↑ Global QoL index at 1-3 Small sample, loss of

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Kcal+25-30 g AA/Kg/d months patients, responsiveness
to chemotherapy may
affect QoL, assessment of
requirements unpractical

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Girke, 2016 23 ? EORTC QLQ-C30 ↑emotional/social domains, = Nutritional regimen not
day 1-28 muscle strength, physical activity, assessed, large patients
BMI, ↓phase angle drop out
Cotogni, 2017 111 21 Kcal+0.8 g AA/Kg/d EORTC QLQ-C30, ↑ Global QoL, physical-role High attrition rate to death
monthly for 1-4 emotional functioning, appetite in 49/111 completed at 4
months

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FACT: Functional Assessment of Cancer Therapy: General, QoL: quality of life , TIQ: Therapy Impact Questionnire
months
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