The Impact of Parenteral Nutrition on Patient Outcomes in Palliative Oncology Patients

Critical appraisal of research paper:

FERRANDO, A., PADDON-JONES, D., HAYS, N., KORTEBEIN, P., RONSEN, O., WILLIAMS, R., MCCOMB, A., BROCK SYMONS, R., WOLFE, R. AND EVANS, W. 2010. EAA supplementation to increase nitrogen intake improves muscle function during bed rest in the elderly. Clinical Nutrition Vol. 29; pp 18-23.

PART TWO:

Literature Review :

The impact of parenteral nutrition on patient outcomes in palliative oncology patients

Matriculation Number: 16011403

Critical Appraisal

This report provides a critique of the study by Ferrando et al. (2010). It is a controlled clinical trial. The SIGN controlled trials checklist tool was used to support the critical appraisal of the articles and the questions outlined in the tool have been set out as sub-headings in the appraisal section below. Following this appraisal, consideration has been given to application of the findings into my current practice, whether the data justifies the conclusions, and limitations to the study.

1.1 The study addressed an appropriate and clearly focused question

This was achieved through the hypothesis (page 19). The effects of increasing protein intake by essential amino acid (EAA) supplementation was investigated in older individuals subjected to 10 days of best rest. Lean body mass and muscle function were assessed as primary outcome measures.

1.2 Treatment and control groups were similar at the start of the trial

Each group was not similar at the start of the trial. Although it was reported all subjects were moderately active and of a similar age, there was an uneven gender distribution in the treatment group (1 male and 9 females) and mean weights for each group were different. RMANCOVA however was performed to account for these effects. Subject’s demographics and daily nutritional intake at enrolment were not reported. Rondanelli et al. (2011) included subject’s education, demographics and dietary intake. Reporting subject characteristics may have further strengthened the study results, by enabling exploration of the impact of sedentary lifestyle and diet on reduced function and lean body mass (Rondanelli et al. 2011).  Variability in the mean weight of each group may also effect results, particularly as the percentage of muscle loss and associated functional limitations may be effected by weight (Paddon Jones 2006).

1.3 The only difference between the groups is the treatment under investigation

The only difference reported is the administration of EAA supplementation to the treatment group. It was reported the control group was studied first however it is not clear if both groups were studied in the same centre. This may increase the chance of the groups being treated unequally therefore increasing the chance of bias.  In Kim et al. (2012) study groups were assessed at the same time and this increased the validity of the findings.

1.4 All relevant outcomes measured in a standard, valid and reliable way

Outcomes were measured in a standard, valid and reliable way. The outcome measures chosen included assessing lean body mass, function and strength. Lean body mass was assessed using dual energy x-ray absorptiometry (DEXA). The use of DEXA to measure different body compartments, has been described and validated against gold standard methods in multiple clinical studies (Branski et al. 2015).

Stair ascent/decent power, floor transfer time and standing plantar flexion strength were assessment measures used to assess function and strength. Kortebein et al (2008) reported that whilst methods assessing functional outcomes can be subjective and less sensitive to identify changes in subjects following short periods of bed rest, there are many studies in elderly hospitalised patients that have demonstrated bed rest can have a clear negative effect on function status (Sager et al. 1996; Covinsky et al. 2003). Furthermore, these measures have been used by many studies to assess essential functional outcomes including muscle strength and general mobility in older adults (Steffen et al 2002 and Lusardi et al 2003). To increase reliability of the functional and strength assessments, it was reported assessors from the study carried out these exercises twice (Day 1 and 3) to minimise learning effect. Handgrip strength is one validated tool used by Baier et al. (2009) to assess strength in subjects that may have been appropriate for use to strengthen the results of this study.

1.8 What percentage of the individuals or clusters recruited into each treatment arm of the study dropped out before the study was completed?

One subject withdrew from the control group (8.3% drop out rate). In the treatment group there were two subjects who were too weak to perform post bed rest functions and one subject who was not tested in these functions (23% drop out rate). Although the demographics of subjects were not reported at baseline, this information can be useful when exploring reasons for high dropout rates. Gustavson et al. (2012) reported socio-demographic variables such as education level, unemployment and being single are typically related to increased risk of non-response and attrition in epidemiological studies. Furthermore, to reduce the drop out rates, assessors could monitor patient safety by asking subjects about unwanted side effects during the study, as was demonstrated in Rondenelli et al. (2011).

1.9 All the subjects are analysed in the groups to which they were randomly allocated

The subjects were analysed in the groups they were allocated as each group was not studied at the same time, the control group was studied first. Results reported were understandable and reported clearly and concisely. However, in the control group there are two different figures reported for the number of subjects studied. The methods section reports n = 11 (page 19) and the summary reports n = 12.  It was unclear how the number of subjects in Table 3 was obtained, as it does not appear to correlate with information provided in earlier sections. Therefore it would be helpful for more descriptive text to explain Table 3. Like Aleman-Mateo et al. 2012, to reduce bias, all subjects, including those who dropped out of the protocol should be allocated to a group, measured twice (where possible) and included in an intention-to-treat analysis.

1.10 Where the study is carried out at more than one site, results are comparable for all sites

The study does not report on any site specific data. There is uncertainty if the control group was studied in the same location as the treatment group, particularly as the control group was studied first. To reduce potential treatment bias, all groups should be studied at the same time and in the same location as was carried out in Paddon Jones et al. (2004).

2.1 How well was the study done to minimise bias

Although important aspects including validated measures to assess outcomes, a large exclusion criteria, concealment of subjects and statistical tests to account for baseline variables were considered, this paper is acceptable, however is of a low quality. Justification for this includes uncertainty on randomisation of subjects, non-blinding of assessors and finally power is not reported.

The assignment of subjects to a treatment group was not randomised, therefore increasing selection bias. Randomisation is in important aspect of reducing bias and strengthens a studies results. Studies assessing healthy elderly subjects and supplementation of EAA including Aleman-Mateo et al. (2012) and Verhoeven et al. (2008) demonstrate random allocation of subjects into treatment groups.

Furthermore, this study did not blind the assessors. This may reduce detection bias as assessors may expect certain results from treatment groups and therefore reassess results if they are uncharacteristic.

To minimise performance bias, both control and study groups should be tested concurrently. It was unclear if both groups were studied on the same site, therefore we are uncertain if the subjects were assessed by the same assessors. For example, in a study by Paddon Jones et al (2004), all groups were studied at the same time with the same assessors to minimise bias.

2.2   Is there certainty that the overall effect is due to the study intervention

The data from this study is encouraging, however there is no clear evidence of the benefits EAA supplementation has on lean muscle mass and function. This paper is limited by its relatively small sample size and duration of the intervention.  Leenders et al. (2011) and Verhoeven et al. (2009) are two studies that although also assessed physical activity, analysed an even gender distribution of subjects for 12 weeks or more, and had sample sizes of greater than 10. Ferrando et al. (2010) reports changes to lean body mass were not statistically significant with EAA supplementation. These findings correlate with Baldi et al. (2010) and Dal Negro et al. (2010) who reported non-significant results with EAA supplementation and changes in fat free muscle. Results from this study did however have an effect on strength and functional outcomes. These findings obtained support Dal Negro et al. 2010, who reported EAA supplementation improved functional outcomes. However it must be noted from Ferrando et al. (2010), confidence intervals were not reported, a power calculation was not performed and as randomisation was not implemented, intention to treat analysis was not assessed. It is for this reason we are unable to confidently observe an anticipated effect, therefore we cannot be certain supplementing a diet with EAA can be beneficial in bed rest subjects.

We should cautiously apply these results to practice. With such a large exclusion criteria including many chronic diseases, the results may not be justified to guide practice for wider patient groups.  This limits the application of the study findings to acutely unwell patients in hospital due to inflammatory and catabolic conditions, often associated with chronic and acute diseases as well as aging (Bauer et al. 2013). Wilkins et al. (2005) report that 75% of hip fracture patients will lose more muscle mass and previous level of function is never regained. Furthermore, in hospitalised chronic heart failure patients, 50–68% will experience cardiac cachexia due to disease progression and malnutrition (Azhar et al. 2006). Therefore these results may cast a level of uncertainty on applicability of these findings in my own practice in the hospital setting.

The authors do no suggest any specific further research that should be carried out as a result of this study. If similar research were to be repeated, it should consider increasing the sample size, a longer period of bed rest and implementing randomisation and blinding to both subjects and assessors.

Words: 1634

References – Critical Appraisal.

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BAIER, S., JAHANNSEN, D., ABUMRAD, N (2009). Year-long changes in protein metabolism in elderly men and women supplemented with a nutrition cocktail of beta-hydroxy-beta-methybutyrate (HMB), L-arginine, and L-lysine. Journal of parenteral and enteral nutrition. Vol.  33, pp.71-82.

BALDI, S., AQUILANI, R., PINNA, GD., POGGI, P., DE MARTINI, A. AND BRUSCHI, C. (2010). Fat-free mass change after nutritional rehabilitation in weight losing COPD: Role of insulin, C-reactive protein and tissue hypoxia. International journal of chronic obstructive pulmonary disease. Vol. 5, pp. 29-39.

BAUER, J., BIOLO, G., CEDERHOLM, T., CESARI, M., CRUZ-JENTOFT, AJ, MORLEY, JE., PHILLIPS, S., SIEBER, C., STEHLE, P., TETEA, D., VISCANATHAN, R., VOLPI, E. AND BOIRIE, Y. 2013. Evidence based recommendations for optimal dietary protein intake in older people: a position paper from the PRO-AGE study group. Journal of American Medical Directors Association. Vol. 14, pp. 542-559.

BRANSKI, LK., NORBURY, WB., HERNDON, DN., CHINKES, DL., CHCORAN, A., SURMAN, O., BENJAMIN, D. AND JESCHKE, M. (2010). Measurement of body composition: is there a gold standard. Journal of parenteral and Enteral Nutrition. Vol. 34, pp. 55-63.

BOZZETTI, F., COZZAGLIO, L., BIGANZOLI, E., CHIAVENNA, G., DE CICCO, M., DONATI, D., GILLI, G., PERCOLLA, S. AND PIRONI, L. (2002). Quality of life and length of survival in advanced cancer patients on home parenteral nutrition. Clinical Nutrition. Vol.21, pp. 281-288.

COVINSKY, KE., PALMER, RM., FORTINSKY, RH., COUNSELL, S., STEWART, AL., KRESEVIC, D., BURANT, C. AND LANDEFELD, CS. (2003). Loss of independence in activities of daily living in older adults hospitalised with medical illnesses: Increased vulnerability with age. Journal of American Geriatric Society. Vol.51, pp. 451-458

DAL NEGRO, RW., AGUILANI, R., BERTACCO, S., BOSCHI, F., MICHELETTO, C. AND TOGNELLA, S. (2010). Comprehensive effects of supplemented essential amino acids in patients with severe COPD and sarcopenia. Monaldi Achieves for Chest Disease. Vol.73, pp. 25-33.

FERRANDO, A., PADDON-JONES, D., HAYS, N., KORTEBEIN, P., RONSEN, O., WILLIAMS, R., MCCOMB, A., BROCK SYMONS, R., WOLFE, R. AND EVANS, W. 2010. EAA supplementation to increase nitrogen intake improves muscle function during bed rest in the elderly. Clinical Nutrition Vol. 29; pp 18-23.

GUSTAVSON, K., VON SOEST, T., KAREVOLD, E. AND ROYSAMB, E. (2012). Attrition and generalizability in longitudinal studies: findings from a 15 year population based study and a Monte Carlo simulation study. Biomed Central Public Health. Vol.12, pp. 918-929.

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KORTEBEIN, P., FERRANDO, A., AND LOMBEIDA. J. (2007)  Effect of 10 days of bed rest on skeletal muscle I healthy older adults. Journal of American Medical Association. Vol. 297, pp.1772-1774.

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Literature Review

The impact of parenteral nutrition on patient outcomes in palliative oncology patients

Introduction

A well known risk factor related to cancer patient’s survival is weight loss, resulting in malnutrition (Vigano et al. 2004). In palliative cancer patients, cancer cachexia and malnutrition are commonly seen (Bosaeus, I. 2008). Parenteral Nutrition (PN) provides nutrition via the vein. PN provides nutrition in patients with advanced cancers that experience gastrointestinal (GI) obstruction due to the spread of primary tumours, infiltration of the bowel by tumour and adhesions (Fan. 2007).  The aim of this literature review is to assess the impact of parenteral nutrition on quality of life (QoL) and survival in palliative oncology patients.

Method

Figure 1 represents the method used to identify literature for this search

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Figure one: flow chart representing how literature was identified.

Selecting studies within the past 20 years ensured current literature was identified. Patient outcomes encompassed quality of life and survival.

Discussion

Appendix 1 contains additional descriptive information of studies discussed.

Quality of life

Bozzetti et al. (2002) assessed the quality of life (QoL) of 69 advancer cancer patients receiving home parenteral nutrition (HPN) using the Rotterdam Symptom Checklist questionnaire. This validated tool in the Italian population assesses physical and psychological symptoms, activities of daily living and overall QoL (Paci. E; 1992). There were no clear trends identified in the four assessed areas at the same time points. There appears to be some benefit in all domains at the initial stages of commencing PN. Nutritional status was maintained from commencement HPN to death. This is in agreeance with Bozzetti et al. (2013) which reported the preservation of nutritional status from progressive deterioration is a more common outcome than restoration to normal with nutrition support. Results were difficult to interpret as there is uncertainty on how the number of subjects at each time point was identified. Although a validated tool was used to assess QoL, results must be considered cautiously as this was an observational study with a limited sample size, no control group or confidence intervals. Further, with six centres used to recruit subjects, there may be some variability in the process used to select patients for HPN, as recommendations to commence PN were done by the individual centres. This may increase selection bias.

A qualitative study analysing the impact of HPN on palliative cancer patients and their families was conducted by Orrevall et al. (2005). It found HPN had a positive effect on patients’ physical, psychological and social wellbeing, weight and energy levels. Subjects in this group were provided with PN as a supplementary source of nutrition. As a large majority of patients requiring PN have a non-functional GI tract, this study may not represent the true population of PN patients who rely on this source of nutrition (Soo and Gramlich 2008). A validated tool was not used and demographic information including socio-economic status, ethnicity and gender mix was not reported. There is no reports of inclusion and exclusion criteria. Therefore, data obtained from this study must be interpreted with caution.

A longitudinal study assessing QoL in advanced cancer patients on HPN was carried out by Cotogni et al. 2015. A validated QoL questionnaire was used and completed by patients (Apolone, G et al. 1998). There were statistically significant improvements in global QoL, physical, role and emotional functioning, appetite loss and fatigue scores over time. Following analysis of confounding factors, those receiving oncological treatments showed statistically significant results with physical, role and emotional functioning. This may reflect stronger performance status (PS) of those undergoing oncological treatment (Prigerson et al. 2015). A decline in QoL was seen at month four, which is to be expected in view of survival median reaching four months. This study is of good quality as it is prospective, validated tools were used, no participants were lost to follow up and an adequate inclusion/exclusion criteria of subjects from hospital was used.

Survival

A retrospective review by Duerkson et al. (2004) identified a survival rate longer than two months for six out of nine patients who received PN and had gastric malignancy with metastatic bowel obstruction. Nutrition status and PS were not associated with longer survival (Duerkson et al. 2014). These results do not correlate with Cozzaglio et al. (1997) who found a relationship between the Karnofsky Performance Status (KPS) and survival. This study does not have good methodological quality owing to a small sample size and no analysis adjustments made for confounding factors, which contribute to a lack of power to detect statistically significant differences.

A retrospective cohort study by Brard et al. (2006) found PN prolonged survival in terminally ill ovarian cancer patients. The median survival time from diagnosis of obstruction was 72 days for patients receiving PN and 41 days for those who did not (P = 0.01). This benefit however was no longer significant when patients underwent palliative chemotherapy. Hasenberg et al. (2010) however found PN can reduce toxicity from chemotherapy and improve body composition in advanced cancer patients receiving palliative treatment, which lengthened survival. Furthermore, PS has been reported to have an impact on survival (Theila et al. 2017). Therefore, as PS was not considered, this is a confounding factor and results must be interpreted with caution. As this is a retrospective study and information was gathered from medical records, reporting bias may present.

A median survival of three to five months was found in Soo and Gramlich (2008), Hoda et al. (2005) and Chermesh et al. (2011). It was identified that patients with a KPS of >50 had a significantly longer survival than patients with a KPS of <50 ( p= 0.01) (Soo and Gramlich. 2008). KPS is a validated tool to assess functional status of cancer patients (Mor et al. 1984). These results are keeping with data from Bozzetti et al. (2002). Medical records were reviewed due to the retrospective nature of Soo and Gramlich (2008), therefore this may introduce information bias of patient information. Even though a statement regarding KPS was reported by Soo and Gramlich, individual survival length and PS of each patient was not given limiting the applicability of the study.

A prospective study by Chermesh et al. (2011) did not report an inclusion or exclusion criteria, therefore selection bias of subjects may be present and it would be difficult to replicate the study. This limits the validity of the study.

Hoda et al. (2005), assessed the survival of 52 incurable cancer patients from a variety of tumour sites, with bowel obstruction being the most common initiation reason for PN. Predictive factors including tumour grade and prominence of cancer symptoms were not significant (Hoda et al. 2005).This does not correlate with Bozzetti et al. (2014) who reported statistically significant prognostic variables included KPS and tumour spread. This study presented a small sample size and did not report standard deviation, therefore preventing the study from having adequate power to identify association with predictive factors.

A prospective cohort study of 414 patients from 13 centres involved incurable malignant patients receiving HPN and without concurrent oncological therapy (Bozzetti et al. 2014). Median survival was three months. According to Bozzetti (2013) this is in accordance with advanced cancer patients who are treated by palliative measures. Bozzetti et al. (2014) has a good methodological quality owing to adequate sample size, statistical consideration of confounding factors, data collected from multiple centres, reporting of confidence intervals and prospective in nature.

Fan’s retrospective study over six years involved 115 patients with malignant GI obstruction from advanced cancer. Median time from initiation of PN to death was six months (Fan 2007). This study presents low power due to limited information provided by the authors as to the statistical analysis and confidence intervals used in the study. Results were not adjusted for confounding variables including complications and PS using KPS, which according to Bozzetti (2013), are factors which can influence survival. Furthermore, the retrospective nature may increase selection bias.

Bozzetti et al. (2002) assessed survival of advanced cancer patients on HPN and the median time of survival from commencement of HPN to death was four months with one third of patients surviving past seven months. This is in keeping with Van Gossum et al. 1993. Although this study appears to be of adequate methodical quality, differences between the six centres was not adequately explored.

Further discussion points relevant to all studies

This literature review did not discriminate against type of malignancy, however studies have reported the prevalence of malnutrition in GI cancer patients is approximately 80% (Xu et al. 2014). Presence of malnutrition has negative prognostic implications and weight loss is associated not only with decreased physical function and QoL but also reduced survival (Theila et al. 2017). As the type of malignancy and PS  can impact on survival, to be able to consider these clinical factors prospectively based on the literature is limited – without considering each case more comprehensively through meta-analysis. This could be a reasonable explanation for findings demonstrating a varied survival rate.

Several studies did not implement blinding, which could be argued to be unethical due to the nature of the type of study. A majority of studies matched groups for diagnosis of advanced incurable cancer and reason for initiation of PN. Many studies however failed to specify if groups were matched according nutritional status, PS or cancer cachexia. A relationship exists between weight loss and cancer stage (Burden et al. 2011). There is a correlation between PS, survival and QoL (Finkelstein et al. 1988). Cancer cachexia limits the effect of nutrition support due to metabolic alternations caused by the systemic pro-inflammatory response (Bozzetti 2013). Hence these factors are all confounding variables and should be considered to increase the applicability of study findings to practice.

The studies reviewed enrolled a population of incurable oncology patients who were established on PN. Some studies however included patients who were receiving concomitant palliative treatment or were having PN as supplemental feeding. This context must be considered when generalising study findings to clinical environments.

Implication for practice

There were several methodological flaws identified from reviewing the current literature. This emphasises the importance of critically considering the evidence behind our current guidelines and standards of practice (ESPEN 2009). We must note that many of these guidelines are based on Grade C evidence (expert opinion). Therefore, rather than instinctively following guidelines, the decision making process for initiating PN in palliative oncology patients should involve clinical judgement regarding the proposed nutritional, clinical and psychological benefits for each individual.

With a lack of robust studies in this specific area, the need for larger scale, well designed prospective trials using validated tools is evident. This highlights the need for research dietitians to support implementation of evidence based practice, based on higher grade evidence. The involvement of specialist clinical dietitians in research will further strengthen effectiveness of their practice.

Current studies focus on the initiation of PN and survival. However there is minimal robust studies which looks at PN in palliative care and QoL using validated tools. Furthermore, no recent studies estimate nutritional requirements or compare intake through PN against these. This forms an integral part of ESPEN guidelines for initiation of PN, so may be a useful addition for future studies.

Conclusion

There is some evidence to suggest PN can improve QoL and assist with survival of palliative oncology patients. These benefits however tend to be limited to patients with a KFS of >50. However, we must consider some measures of QoL can be overly subjective and consequently these findings must be generalised with caution to the individual subject.

Initiation of PN support should be a multidisciplinary team decision of which dietitian’s form an integral part (SIGN 2003). If appropriate, PN should be instigated after a nutritional assessment is carried out for all cancer patients at the time of diagnosis or as part of the anticancer treatment plan.  Nutritional status, estimated duration of PN, PN related benefits and possible complications must be taken into consideration on an individual basis. Additionally, PS and estimated prognosis will also need to be considered by a trained health professional.

Overall, the impact of PN in palliative oncology patients remains questionable largely due to lack of robust studies. Further, well designed prospective studies within this area will support high quality evidence based practice.

Word count: 2141 (including references)

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Appendix 1: Critical Appraisal of Studies using CASP